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  • CLASSES

    Antidepressant Augmentation Agents
    Multi-Acting Receptor-Targeted Antipsychotics (MARTA)

    BOXED WARNING

    CNS depression, coadministration with other CNS depressants, coma, driving or operating machinery, ethanol ingestion, post-injection delirium/sedation syndrome

    The sedative effects of olanzapine may be most evident during the initial days of treatment. Because olanzapine has the potential to impair cognitive and motor skills, patients should be advised to use caution when driving or operating machinery or performing other tasks that require mental alertness until they know how the drug affects them. Somnolence could lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with conditions, diseases, or concurrent medication use that could exacerbate somnolence. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Given the primary CNS effects of olanzapine, caution should be used during coadministration with other CNS depressants and alcohol. Ethanol ingestion may further impair cognitive and motor skills and patients should be advised to avoid use of alcoholic beverages. The extended-release intramuscular injection formulation (Zyprexa Relprevv) carries a specific boxed warning related to post-injection delirium/sedation syndrome (PDSS), which is the result of the drug entering the bloodstream too quickly and the development of sedation, delirium, and/or coma from significantly elevated olanzapine plasma concentrations. Patients must remain under continuous observation by a healthcare professional at the healthcare facility for at least 3 hours following the injection to help detect PDSS. After this time, the patient must be accompanied to their destination upon leaving the facility. For the remainder of the day of each injection, the patient should not drive or operate heavy machinery. Patients and/or their caregivers should be made aware of the symptoms associated with PDSS and what to do if symptoms occur. Following the 3-hour observation period, the confirm that the patient is alert, oriented, and free of any signs or symptoms of PDSS before release from the facility. Suspected PDSS cases require close medical supervision in a medical facility capable of resuscitation.

    Dementia, geriatric, stroke

    Geriatric patients may be more susceptible than younger adults to anticholinergic activity, orthostatic hypotension, movement disorders, and CNS depression with olanzapine. Geriatric patients may also be at increased risk for developing QT prolongation. Initiate olanzapine at a low dose, with longer intervals between dosage increases. Antipsychotics are not approved for the treatment of dementia-related psychosis in geriatric patients and use of olanzapine in this population should be avoided if possible due to an increase in morbidity and mortality in geriatric patients with dementia receiving atypical antipsychotics. Deaths have typically resulted from heart failure, sudden death, or infections (primarily pneumonia). An increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatal events, has also been reported. The Beers Criteria consider antipsychotics to be potentially inappropriate medications (PIMs) in elderly patients except for treating schizophrenia, bipolar disorder, and nausea/vomiting during chemotherapy. The Beers panel recommends avoiding antipsychotics in geriatric patients with delirium, dementia, or Parkinson's disease. Non-pharmacological strategies are first-line options for treating delirium- or dementia-related behavioral problems unless they have failed or are not possible and the patient is a substantial threat to self or others. If antipsychotic use is necessary for geriatrics with a history of falls or fractures, consider reducing the use of other CNS depressants and implement other fall risk strategies. Due to the potential for antipsychotic-induced hyponatremia and SIADH, sodium levels should be closely monitored when olanzapine is initiated and after dose changes. According to the federal Omnibus Budget Reconciliation Act (OBRA) regulations in residents of long-term care facilities, antipsychotic therapy should only be initiated in a patient with behavioral or psychological symptoms of dementia (BPSD) when the patient is a danger to self or others or has symptoms due to mania or psychosis. For acute conditions persisting beyond 7 days, appropriate non-pharmacologic interventions must be attempted, unless clinically contraindicated and documented. OBRA provides general dosing guidance for antipsychotic treatment of BPSD. Antipsychotics are subject to periodic review for effectiveness, medical necessity, gradual dose reduction, or rationale for continued use. Refer to the OBRA guidelines for complete information.

    DEA CLASS

    Rx

    DESCRIPTION

    Atypical antipsychotic; similar in structure to clozapine, but reduced incidence of EPS, hyperprolactinemia, neutropenia
    Use for the treatment of schizophrenia and for manic or mixed episodes of bipolar I disorder (as monotherapy or in combination with lithium or valproate) in both adults and adolescents; also used for maintenance treatment
    Is an effective adjunct to fluoxetine for treatment-refractory depression or for depressive episodes of bipolar I disorder in adults
    IM injection solution formulation (Zyprexa IntraMuscular) treats acute agitation associated with schizophrenia and bipolar disorder
    Extended-release IM depot formulation (Zyprexa Relprevv) is for maintenance treatment of schizophrenia in adults

    COMMON BRAND NAMES

    Zyprexa, Zyprexa Intramuscular, Zyprexa Relprevv, Zyprexa Zydis

    HOW SUPPLIED

    Olanzapine/Zyprexa Oral Tab: 2.5mg, 5mg, 7.5mg, 10mg, 15mg, 20mg
    Olanzapine/Zyprexa Zydis Oral Tab Orally Dis: 5mg, 10mg, 15mg, 20mg
    Olanzapine/Zyprexa/Zyprexa Intramuscular Intramuscular Inj Pwd F/Sol: 10mg
    Zyprexa Relprevv Intramuscular Inj Pwd F/Susp: 210mg, 300mg, 405mg

    DOSAGE & INDICATIONS

    For the treatment of schizophrenia.
    Oral dosage
    Adults

    ADULTS NOT AT RISK FOR HYPOTENSION: 5 to 10 mg PO once daily initially, with a target dose of 10 mg/day PO within several days. Further dosage adjustments of 5 mg/day, if indicated, should occur at weekly intervals. Doses greater than 10 mg/day should be initiated only after clinical assessment. In clinical trials, doses greater than 10 mg/day PO were not more efficacious. Max: 20 mg/day. DEBILITATED ADULTS, THOSE AT RISK FOR HYPOTENSION, THOSE WITH FACTORS FOR SLOWED DRUG METABOLISM (e.g., females, non-smokers), OR PHARMACODYNAMICALLY SENSITIVE TO OLANZAPINE: Initially, 5 mg PO once daily; dose escalation should be performed cautiously.. Maintenance therapy may reduce relapse risk. Periodically reevaluate need for therapy; maintain at the lowest effective dosage.

    Geriatric Adults

    Initially, 5 mg PO once daily. Geriatric patients may be predisposed to hypotensive reactions, have risk factors for slower metabolism of olanzapine (age-related decline in hepatic or renal function), or may be more sensitive to the drug. Dose titration should be performed cautiously. In clinical trials, doses greater than 10 mg/day PO were not more efficacious. Max: 20 mg/day PO.

    Adolescents

    2.5 or 5 mg PO once daily initially, with a target dose of 10 mg PO once daily. Dosage adjustments should be made in increments/decrements of 2.5 or 5 mg. During clinical trials, efficacy was established within a range of 2.5 to 20 mg/day, with a mean dose of 11.1 mg/day. Max: 20 mg/day PO. Continuation of therapy generally occurs in treatment responders. Use lowest dose necessary to maintain an adequate response. Periodically reevaluate the need for continued treatment.

    Children† 6 to 12 years

    2.5 mg PO once daily is the initial recommended dose. Make adjustments of 2.5 mg/day, if indicated, at 4 to 7 day intervals. Effective dose range: 2.5 to 10 mg/day. Max: 20 mg/day PO. Atypical antipsychotics are not intended for use in pediatric patients who exhibit symptoms secondary to environmental factors and/or other primary psychiatric disorders. The decision to prescribe atypical antipsychotic medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms; symptoms can be variable. Use lowest dose necessary to maintain an adequate response in treatment responders. Periodically reevaluate the need for continued treatment.

    Intramuscular dosage (i.e., extended-release injectable suspension, Zyprexa Relprevv)
    Adults

    ADULTS NOT AT RISK FOR HYPOTENSION: Efficacy has been established within the range of 150 to 300 mg deep IM every 2 weeks or 405 mg IM administered every 4 weeks. Establish tolerability with the oral formulation prior to treatment. The recommended starting dose during the first 8 weeks is based upon a corresponding oral olanzapine dose as follows: target oral dose of 10 mg/day PO = 210 mg IM every 2 weeks or 405 mg IM every 4 weeks; target oral dose of 15 or 20 mg/day PO = 300 mg IM every 2 weeks. The recommended maintenance dose after 8 weeks of treatment is as follows: target oral dose of 10 mg/day PO = 150 mg IM every 2 weeks or 300 mg IM every 4 weeks; target oral dose of 15 mg/day PO = 210 mg IM every 2 weeks or 405 mg IM every 4 weeks; and target oral dose of 20 mg/day PO = 300 mg IM every 2 weeks. Extended-release IM doses greater than 405 mg every 4 weeks or 300 mg every 2 weeks have not been formally evaluated. DEBILITATED ADULTS, THOSE AT RISK FOR HYPOTENSION, THOSE WITH FACTORS FOR SLOWED DRUG METABOLISM (e.g., females, non-smokers), OR THOSE PHARMACODYNAMICALLY SENSITIVE TO OLANZAPINE: 150 mg deep IM every 4 weeks initially; use caution with dose escalations. MONITORING: Zyprexa Relprevv must be administered in a registered healthcare facility with ready access to emergency response services. Monitor all patients after each injection at the facility for at least 3 hours. Confirm that someone will accompany patient after the 3-hour observation period.

    Geriatric Adults

    150 mg deep IM every 4 weeks initially. Geriatric patients may be predisposed to hypotensive reactions, have risk factors for slower metabolism of olanzapine (age-related decline in hepatic or renal function), or may be more sensitive to the drug. Use caution with dose escalation. MONITORING: Zyprexa Relprevv must be administered in a registered healthcare facility with ready access to emergency response services. Monitor all patients after each injection at the facility for at least 3 hours. Confirm that someone will accompany patient after the 3-hour observation period.

    For use in combination with fluoxetine for treatment-resistant depression.
    Oral dosage
    Adults

    ADULTS NOT AT RISK FOR HYPOTENSION: Initially, olanzapine 5 mg PO and fluoxetine 20 mg PO once daily in the evening. Dosage adjustments should be based upon efficacy and tolerability of individual components within the range of olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg. DEBILITATED ADULTS, THOSE AT RISK FOR HYPOTENSION, THOSE WITH SLOWED DRUG METABOLISM (e.g., females, non-smokers), OR THOSE PHARMACODYNAMICALLY SENSITIVE TO OLANZAPINE: Initially, olanzapine 2.5 to 5 mg with fluoxetine 20 mg PO once daily in the evening. Subsequent dosage titrations should be done with caution and close monitoring. Usual effective adult dose range: olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg per day. Antidepressant efficacy was established within a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg. Max: 18 mg of olanzapine and 75 mg of fluoxetine per day.The need for continued treatment should be evaluated periodically. Approximate corresponding doses for the individual components of olanzapine and fluoxetine (Zyprexa plus fluoxetine) compared to the fixed dose combination product (Symbyax) are as follows: Symbyax 3 mg/25 mg = Zyprexa 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/25 mg = Zyprexa 5 mg/fluoxetine 20 mg; Symbyax 12 mg/25 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/50 mg = olanzapine 5 mg/fluoxetine 40 mg + 10 mg; and Symbyax 12 mg/50 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 40 mg + 10 mg. NOTE: Olanzapine is not FDA approved as monotherapy for treatment-resistant depression (major depressive disorder in patients who have not responded to 2 antidepressants of adequate dose and duration in the current episode).

    Geriatric Adults

    Initially, olanzapine 2.5 to 5 mg with fluoxetine 20 mg PO once daily in the evening. Subsequent dosage titrations should be done with caution and close monitoring. Effective adult dose range: olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg per day. Max: 18 mg of olanzapine and 75 mg of fluoxetine per day. The need for continued treatment should be evaluated periodically. Approximate corresponding doses for the individual components of olanzapine and fluoxetine (Zyprexa plus fluoxetine) compared to the fixed dose combination product (Symbyax) are as follows: Symbyax 3 mg/25 mg = Zyprexa 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/25 mg = Zyprexa 5 mg/fluoxetine 20 mg; Symbyax 12 mg/25 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/50 mg = olanzapine 5 mg/fluoxetine 40 mg + 10 mg; and Symbyax 12 mg/50 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 40 mg + 10 mg. Safety and efficacy in geriatric patients older than 65 years have not been established.

    For the treatment of bipolar disorder (bipolar I disorder), including mania or mixed episodes.
    Oral dosage
    Adults

    ACUTE TREATMENT OF MANIC OR MIXED EPISODES (MONOTHERAPY): Initially, 10 to 15 mg PO once daily is recommended. May titrate in increments/decrements of 5 mg, at no less than 24 hour intervals. ADJUNCT THERAPY TO LITHIUM OR VALPROATE FOR THE ACUTE TREATMENT OF MANIC OR MIXED EPISODES: Initially, 10 mg PO once daily. Effective antimanic dose range: 5 to 20 mg/day PO in combination with lithium or valproate. MAINTENANCE TREATMENT AS MONOTHERAPY: Efficacy has been established in a dose range of 5 to 20 mg/day. Periodically reassess the need for continued therapy. MAX (ALL USES): 20 mg/day PO. Debilitated or geriatric patients may require lower total daily dosages. In all cases, the lowest effective dosage should be determined.
    CLINICAL STUDIES: Two double-blind, randomized, placebo-controlled studies evaluated the efficacy of monotherapy with olanzapine in patients (n = roughly 140 per study) meeting the DSM-IV diagnostic criteria for bipolar I disorder (manic or mixed, with or without psychotic features). Concurrent medication with lorazepam was allowed for severely agitated patients in the 3-week treatment period followed by open label extension up to 1 year. Response was defined as a 50% or more decrease in total score on the Young Mania Rating Scale (Y-MRS). Olanzapine-treated patients had a statistically significantly greater improvement in mania than those receiving placebo in the first study (48.6% vs. 24.2%), and the second study (64.8% vs. 42.9%). A 47-week comparative trial of olanzapine monotherapy (5 to 20 mg/day) vs. divalproex (500 to 2500 mg/day) for acute bipolar mania demonstrated that symptomatic remission occurred sooner (14 days vs. 62 days) and overall mania improvement was greater for olanzapine than for divalproex, but rates of bipolar relapse did not differ. There were no significant differences between olanzapine and divalproex in the rates of symptomatic mania remission over the 47 weeks (56.8% and 45.5%) and subsequent relapse into mania or depressive episode (42.3% and 56.5%). Two 6-week, placebo-controlled, randomized trials (n = 344) were performed to evaluate the efficacy of olanzapine as adjunct therapy in inadequately controlled patients (Young Mania Rating Scale; Y-MRS total score of 16 or higher) already receiving lithium (with a therapeutic range of 0.6 to 1.2 mEq/L) or valproate (with a therapeutic range of 50 to 125 mcg/mL). Combination therapy was superior (68% response) to lithium or valproate monotherapy (45% response) in reducing the Y-MRS total score in both mixed bipolar and manic cohorts. In an 18-month study, olanzapine 5 to 20 mg/day plus conventional mood stabilizer was superior to placebo plus mood stabilizer in length of time to symptomatic (but not syndromic) relapse into mania or a depressive episode (median time to symptomatic relapse: 163 days olanzapine group vs. 42 days placebo). Olanzapine has been shown effective at a mean dose of 8.1 mg/day as long-term (up to 43 weeks) adjunctive therapy for treatment-resistant bipolar I or II disorder. There was a significant reduction of Clinical Global Impressions (CGI) scores after the introduction of olanzapine, either in manic, depressive, or global symptoms. The most frequent adverse events were somnolence (17%) and weight gain (13%).

    Adolescents

    ACUTE TREATMENT OF MANIC OR MIXED EPISODES (MONOTHERAPY): Initially, 2.5 or 5 mg PO once daily, with a target dose of 10 mg/day. Titrate in increments/decrements of 2.5 or 5 mg, at no less than 24 hour intervals. Effective dose range: 2.5 to 20 mg/day; the mean dose was 8.9 mg/day PO during clinical trials. Olanzapine is not FDA-approved in adolescents as adjunct treatment to lithium or valproate. Initiate only after a thorough diagnostic evaluation and careful consideration of the potential long-term risks; as compared with adults, adolescents had an increased potential for weight gain and hyperlipidemia. MAINTENANCE (MONOTHERAPY): Responding adolescents should generally continue treatment, at the lowest dose needed to maintain remission. Periodically reassess the need for continued treatment. MAX (ALL USES): 20 mg/day PO.

    For the treatment of acute agitation associated with schizophrenia or bipolar mania.
    Intramuscular dosage (i.e., immediate-release injectable solution; i.e., Zyprexa Intramuscular)
    Adults

    ADULTS NOT AT RISK FOR HYPOTENSION: 10 mg IM as a single dose is the recommended initial dose. A lower dose of 5 to 7.5 mg IM may be given if clinical factors warrant. A dose of 5 mg IM should be considered for geriatric patients. DEBILITATED ADULTS, THOSE AT RISK FOR HYPOTENSION, THOSE WITH FACTORS FOR SLOWED DRUG METABOLISM (e.g., females, non-smokers), OR THOSE PHARMACODYNAMICALLY SENSITIVE TO OLANZAPINE: A dose of 2.5 mg IM should be considered. POST-DOSE: Patients should remain recumbent if drowsy or dizzy after injection until examination has indicated that they are not experiencing postural hypotension and/or bradycardia. A significant improvement in acute agitated behavior is usually seen within 15 to 30 minutes. REPEAT DOSING: If clinically warranted, subsequent doses up to 10 mg may be given. However, the efficacy of repeat doses has not been evaluated. LIMITS: The safety of total daily doses greater than 30 mg IM or doses of 10 mg IM given more frequently than 2 hours after the initial dose and 4 hours after the second dose has not been evaluated in clinical trials. Patients requiring subsequent IM injections should be assessed for orthostatic hypotension prior to any subsequent doses. Switch to oral therapy (5 to 20 mg/day PO) as soon as clinically feasible if continued treatment is needed. Newer antipsychotics which have shown efficacy in treating acute agitation secondary to psychiatric disorders are preferential in emergency use to conventional antipsychotics.

    Children† and Adolescents† 12 years and older

    Not FDA approved, safety and efficacy have not been established in controlled clinical trials. Data are limited; controlled studies are needed. Off-label use has been reported as effective but is reserved for when non-pharmacologic treatment fails or oral treatment is refused. SUGGESTED INITIAL DOSING: 10 mg IM for adolescents as a single dose; a lower dose of 5 to 7.5 mg IM may be given if clinical factors warrant. Give 5 mg IM for children 12 years and younger as a single dose. Limited experience with children under 12 years. POST-DOSE: Patients should remain recumbent if drowsy or dizzy after injection until examination has indicated that they are not experiencing postural hypotension and/or bradycardia. Sedation is a common side effect. LIMITS: Repeat dosing generally not recommended; if needed, do not give a second dose more frequently than 2 hours after the initial dose or 4 hours after the second dose. MAX: 30 mg/day IM in adolescents. Convert to oral therapy as soon as possible if long term treatment is indicated.

    For the adjunct treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in combination with fluoxetine.
    Oral dosage
    Adults

    ADULTS NOT AT RISK FOR HYPOTENSION: Initially, olanzapine 5 mg PO and fluoxetine 20 mg PO once daily in the evening. DEBILITATED ADULTS, THOSE AT RISK FOR HYPOTENSION, THOSE WITH SLOWED DRUG METABOLISM (e.g., females, non-smokers), OR THOSE PHARMACODYNAMICALLY SENSITIVE TO OLANZAPINE: Initially, olanzapine 2.5 to 5 mg and fluoxetine 20 mg, with cautious dosage titration thereafter. Dosage adjustments should be based upon efficacy and tolerability. Usual effective adult dose range: olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg per day. Max: 18 mg of olanzapine and 75 mg of fluoxetine per day. The need for continued treatment should be evaluated periodically. Approximate corresponding doses for the individual components of olanzapine and fluoxetine (Zyprexa plus fluoxetine) compared to the fixed dose combination fluoxetine; olanzapine product (Symbyax) are as follows: Symbyax 3 mg/25 mg = Zyprexa 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/25 mg = Zyprexa 5 mg/fluoxetine 20 mg; Symbyax 12 mg/25 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/50 mg = olanzapine 5 mg/fluoxetine 40 mg + 10 mg; and Symbyax 12 mg/50 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 40 mg + 10 mg. The dosage must be individualized according to the severity of symptoms exhibited. In all cases, the lowest effective dosage should be determined for each patient. Olanzapine is not FDA approved for the monotherapy treatment of depressive episodes associated with Bipolar I Disorder.

    Geriatric Adults

    Initially, olanzapine 2.5 to 5 mg PO with fluoxetine 20 mg PO once daily in the evening. Dosage adjustments may be necessary in patients who exhibit a combination of factors that may slow metabolism. Titrate dose with caution and close monitoring. Usual effective adult dose range: olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg per day. Max: 18 mg of olanzapine and 75 mg/day of fluoxetine per day. The need for continued treatment should be evaluated periodically.  Safety and efficacy in geriatric patients older than 65 years have not been established. Approximate corresponding doses for the individual components of olanzapine and fluoxetine (Zyprexa plus fluoxetine) compared to the fixed dose combination product (Symbyax) are as follows: Symbyax 3 mg/25 mg = Zyprexa 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/25 mg = Zyprexa 5 mg/fluoxetine 20 mg; Symbyax 12 mg/25 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/50 mg = olanzapine 5 mg/fluoxetine 40 mg + 10 mg; and Symbyax 12 mg/50 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 40 mg + 10 mg.NOTE: Olanzapine is not FDA approved for the monotherapy treatment of depressive episodes associated with Bipolar I Disorder.

    Children and Adolescents 10 years and older

    Initially, 2.5 mg/day PO of olanzapine in combination with 20 mg/day PO of fluoxetine administered once daily in the evening. Thereafter, dose adjustments can be made according to efficacy and tolerability. Max: 12 mg/day PO of olanzapine with 50 mg/day PO of fluoxetine per day. Periodically reevaluate to assess the need for continued therapy. Approximate corresponding doses for the individual components of olanzapine and fluoxetine (Zyprexa plus Prozac) compared to the fixed dose combination fluoxetine; olanzapine product (Symbyax) are as follows: Symbyax 3 mg/25 mg = Zyprexa 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/25 mg = Zyprexa 5 mg/fluoxetine 20 mg; Symbyax 12 mg/25 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/50 mg = olanzapine 5 mg/fluoxetine 40 mg + 10 mg; and Symbyax 12 mg/50 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 40 mg + 10 mg. Olanzapine is not FDA approved for the monotherapy treatment of depressive episodes associated with Bipolar I Disorder.

    For the treatment of severe behavioral or psychological symptoms of dementia† (BPSD)†.
    Oral dosage
    Geriatric Adults

    Initially, 2.5 to 5 mg PO once daily. Further dosage adjustments of no more than 2.5 to 5 mg/day, if indicated, should occur at weekly intervals. Antipsychotics are not FDA-approved for the treatment of behavioral problems associated with dementia and the labeling of all antipsychotics contains a boxed warning noting an increased risk of death in geriatric patients being treated for behavioral problems associated with dementia. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antipsychotics in long-term care facility (LTCF) residents with behavioral or psychological symptoms of dementia (BPSD). OBRA Max: 5 mg/day PO in residents meeting the OBRA criteria for treatment, except when documentation is provided showing that higher doses are necessary to maintain or improve the resident's functional status. In addition, the facility must attempt a gradual dose reduction (GDR) in 2 separate quarters, at least 1 month apart, within the first year of admission to the facility or after the facility has initiated an antipsychotic, unless clinically contraindicated. After the first year, a GDR must be attempted annually unless clinically contraindicated. The GDR may be considered clinically contraindicated if the target symptoms returned or worsened after the most recent GDR attempt within the facility and the physician has documented justification for why attempting additional dose reductions at that time would likely impair the resident's function or increase distressed behavior.

    Intramuscular dosage (injection solution, e.g., Zyprexa IntraMuscular)
    Geriatric Adults

    Single and multiple doses of 2.5 to 5 mg IM have been studied. In one controlled trial, patients meeting the criteria for possible or probable Alzheimer's disease, vascular dementia, or a combination of both (n = 272) were randomized to receive up to 3 IM injections of olanzapine, lorazepam, or placebo within 24 hours. Significantly more patients who received olanzapine 5 mg did not require a second injection for the control of agitation (63.6%) compared to 41.8% of patients receiving placebo. The number of patients requiring only 1 injection of olanzapine 2.5 mg was not significantly greater than placebo. Significantly more patients in the placebo group (46.3%) required a third injection than in either of the olanzapine treatment groups. When required, the second injection was administered at least 2 hours after the first injection and the third injection was administered at least 1 hour after the second injection. Max: 12.5 mg/24 hours. Antipsychotics are not FDA-approved for the treatment of behavioral problems associated with dementia and the labeling of all antipsychotics contains a boxed warning noting an increased risk of death in geriatric patients being treated for behavioral problems associated with dementia. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antipsychotics in long-term care facility residents; documentation of medical necessity is required according to OBRA guidelines.

    For chemotherapy-induced nausea/vomiting prophylaxis† in patients treated with high-emetic-risk antineoplastic agents.
    Oral dosage
    Adults

    The American Society of Clinical Oncology (ASCO) clinical practice guidelines recommend olanzapine 10 mg/day PO on days 1 through 4. Give as part of a 4-drug prophylactic regimen also consisting of a neurokinin 1 (NK1) receptor antagonist, a serotonin (5-HT3) receptor antagonist, and dexamethasone in patients receiving high-emetic-risk chemotherapy. Such regimens should be used with initial chemotherapy treatment, rather than first assessing the emetic response of the patient with less effective treatment; per ASCO, this recommendation is strong with a high quality of evidence and with benefits outweighing harms. In patients who experience breakthrough nausea/vomiting with chemotherapy despite optimal prophylaxis, and who did not receive olanzapine prophylactically, offer olanzapine in addition to continuing the standard antiemetic regimen. Per ASCO, this recommendation is moderate with an intermediate quality of evidence and with benefits outweighing harms. In one placebo-controlled trial in adults, the percentage of patients who reported no nausea was significantly higher in patients receiving an anti-emetic regimen containing olanzapine than a regimen without olanzapine from 0 to 24 hours (74% vs. 45%), 24 to 120 hours (42% vs. 25%), and 0 to 120 hours (37% vs. 22%) after chemotherapy. Olanzapine also improved complete response during each time interval but increased sedation on day 2. A meta-analysis of olanzapine used in various regimens and settings also suggested that olanzapine reduces chemotherapy-induced nausea and vomiting.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    20 mg/day PO; 30 mg/day immediate-release IM; 300 mg every 2 weeks or 405 mg every 4 weeks extended-release IM.

    Geriatric

    20 mg/day PO; 30 mg/day immediate-release IM; 300 mg every 2 weeks or 405 mg every 4 weeks extended-release IM.

    Adolescents

    12 mg/day PO in combination with fluoxetine for bipolar depression; 20 mg/day PO for bipolar I disorder or schizophrenia. Safety and efficacy have not been established for other indications or injectable formulations; however, 10 to 30 mg/day PO or IM (immediate-release), depending on previous antipsychotic exposure, has been used off-label for acute agitation.

    Children

    10 to 12 years: 12 mg/day PO in combination with fluoxetine for bipolar depression. Safety and efficacy have not been established for other indications or injectable formulations; however, 20 mg/day PO has been used for schizophrenia and 10 to 30 mg/day PO or IM (immediate-release), depending on previous antipsychotic exposure, has been used off-label for acute agitation.
    6 to 9 years: Safety and efficacy have not been established; however, 20 mg/day PO has been used for schizophrenia and 10 to 30 mg/day PO or IM (immediate-release), depending on previous antipsychotic exposure, has been used off-label for acute agitation.
    1 to 5 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dosage may need modification depending on the indication for use, clinical response, and degree of hepatic impairment. Lower initial starting doses, e.g., 2.5 to 5 mg PO initially, with careful titration, have been recommended according to the labeling for adjunctive use of olanzapine in treatment-resistant depression or bipolar depression. Quantitative recommendations are not available for other indications; use caution with careful titration.

    Renal Impairment

    No dosage adjustments are required; olanzapine is not removed by hemodialysis.

    ADMINISTRATION

    Oral Administration

    May be administered without regard to meals.

    Oral Solid Formulations

    Orally disintegrating tablets: Leave the disintegrating tablet in the foil package until ready to administer. Do not push the tablet through the blister pack. Peel open the package with dry hands and place the tablet on the patient's tongue. The tablet will dissolve rapidly and be swallowed in the saliva. The tablet may be administered with fluid if needed, but it is not necessary to do so.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intramuscular Administration

    Immediate-release intramuscular injection (Zyprexa IntraMuscular)
    Do not administer intravenously or intra-arterially.
    Dissolve the contents of the vial using 2.1 mL of Sterile Water for Injection to provide a solution containing approximately 5 mg/ml; refer to manufacturer table for injection volumes and corresponding doses.
    Dissolve contents of vial completely; resulting solution should be clear and yellow.
    Inject deeply into the gluteal muscle to minimize tissue irritation. Do not inject more than 5 mL into any one site.
    Use solution within 1 hour; discard any unused portion.
    Immediately after use, dispose of syringe in approved sharps box.
     
    Extended-release intramuscular injection (Zyprexa Relprevv)
    Zyprexa Relprevv is available only through a restricted distribution program where the prescriber, healthcare facility, patient, and pharmacy must all be enrolled in the Zyprexa Relprevv Patient Care Program. To enroll, call 1-877-772-9390.
    For deep intramuscular gluteal injection only. Do not administer intravenously or subcutaneously.
    Use only the diluent provided in the Zyprexa Relprevv convenience kit for preparation of the suspension.
    The vial is for single-use only.
    Administer every 2 to 4 weeks by deep intramuscular gluteal injection using the 19-gauge, 1.5-inch needle contained in the convenience kit. For obese patients, a 2-inch, 19-gauge or larger needle may be used.
    See manufacturer insert entitled "Instructions to Reconstitute and Administer Zyprexa Relprevv" for information regarding the safe and effective use of the Hypodermic Needle-Pro syringe and needle.
    Zyprexa Relprevv must be administered in a registered healthcare facility with ready access to emergency response services.
    After each injection, a healthcare professional must continuously observe the patient at the healthcare facility for at least 3 hours for symptoms of Post-Injection Delirium/Sedation Syndrome (see Contraindications).
    Before administration of the injection, confirm that there will be someone to accompany the patient to their destination after the 3 hour observation period. If this cannot be confirmed, do not give the injection.
    Following the 3 hour observation period, the healthcare professional must confirm that the patient is alert, oriented, and free of any signs or symptoms of Post-Injection Delirium/Sedation Syndrome before releasing the patient.
     
    Reconstitution of Zyprexa Relprevv
    It is advisable to wear gloves during reconstitution of the suspension to avoid irritation to the skin. Rinse skin with water if contact with preparation occurs.
    The diluent is a clear, colorless to slightly yellow solution in a glass vial; it should be noted that there is more diluent in the vial than is needed to reconstitute.
    210 mg vial: Use the 210 mg vial for a dose of 150 mg or 210 mg; reconstitute with 1.3 mL of the provided diluent.
    300 mg vial: Use the 300 mg vial for a dose of 300 mg; reconstitute with 1.8 mL of the provided diluent.
    405 mg vial: Use the 405 mg vial for a dose of 405 mg; reconstitute with 2.3 mL of the provided diluent.
    Loosen powder in the vial by lightly tapping the vial; withdraw appropriate diluent volume into the syringe using the Hypodermic Needle-Pro syringe/needle; inject diluent into the vial; pull back slightly on the syringe plunger to withdraw air to equalize the pressure in the vial; remove needle from the vial, holding the vial upright to prevent loss of material; engage needle safety device; pad a hard surface and tap the vial firmly on the surface until no powder is visible.
    Visually check reconstituted vial for clumps. Un-suspended powder appears as yellow, dry clumps on the vial surface.
    Shake reconstituted vial vigorously until the suspension appears smooth and consistent in color or texture. If foam forms, let vial stand until foam dissipates.
    The suspended product will be yellow and opaque.
    If the product is not used promptly after reconstitution, shake the vial vigorously to re-suspend at the time of injection; reconstituted suspension remains stable for up to 24 hours in the vial.
     
    Intramuscular injection (Zyprexa Relprevv)
    After reconstitution of the product, attach a new safety needle to the syringe; slowly withdraw the desired amount into the syringe.
    To help prevent clogging, a 19-gauge or larger needle must be used.
    Select and prepare a site for injection in the gluteal area.
    The injection should be administered at a steady, continuous pressure.
    Do not massage the injection site.
    After the injection, engage the needle safety device and remove needle from syringe. Properly dispose of vials, needles, and syringes.

    STORAGE

    Zyprexa:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Zyprexa Intramuscular:
    - Discard reconstituted product if not used within 1 hour
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store reconstituted product for up to 1 hour at 68 to 77 degrees F
    Zyprexa Relprevv:
    - Do not freeze
    - Store at room temperature not exceeding 86 degrees F
    Zyprexa Zydis:
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Serious rash

    Olanzapine is contraindicated in patients with a previous hypersensitivity to olanzapine or any other component of the commercial product. Olanzapine has been associated with a risk of serious hypersensitivity reactions or anaphylaxis, including serious rash. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported; DRESS is a rare but potentially fatal syndrome typically characterized by a rash that can worsen or spread over time. DRESS can include pyrexia or elevated body temperature, lymphadenopathy, and facial swelling. Eosinophilia can cause inflammation and swelling, and organ involvement (e.g., liver, kidneys, lungs, heart, and pancreas) can lead to organ injury, and death in some cases. DRESS has a mortality rate of up to 10%. Olanzapine should be discontinued immediately if DRESS is suspected. There is no specific treatment for DRESS; management includes discontinuation of the offending agent as soon as possible and supportive care. Patients should be advised to promptly report symptoms of rash, swollen lymph nodes, and/or pyrexia or elevated body temperature.

    Agranulocytosis, hematological disease, leukopenia, neutropenia

    Olanzapine should be used with caution in patients with hematological disease. Hematologic effects including leukopenia, neutropenia, and agranulocytosis have been associated with use of antipsychotics. A history of drug-induced leukopenia or neutropenia or pre-existing low white blood cell (WBC) count may increase the likelihood of these events. Monitor a complete blood count (CBC) frequently during the first few months of therapy in patients with a history of low WBC or drug-induced leukopenia/neutropenia. Consider discontinuing olanzapine at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (ANC less than 1,000/mm3) should discontinue the drug and have their WBC followed until recovery.

    CNS depression, coadministration with other CNS depressants, coma, driving or operating machinery, ethanol ingestion, post-injection delirium/sedation syndrome

    The sedative effects of olanzapine may be most evident during the initial days of treatment. Because olanzapine has the potential to impair cognitive and motor skills, patients should be advised to use caution when driving or operating machinery or performing other tasks that require mental alertness until they know how the drug affects them. Somnolence could lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with conditions, diseases, or concurrent medication use that could exacerbate somnolence. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Given the primary CNS effects of olanzapine, caution should be used during coadministration with other CNS depressants and alcohol. Ethanol ingestion may further impair cognitive and motor skills and patients should be advised to avoid use of alcoholic beverages. The extended-release intramuscular injection formulation (Zyprexa Relprevv) carries a specific boxed warning related to post-injection delirium/sedation syndrome (PDSS), which is the result of the drug entering the bloodstream too quickly and the development of sedation, delirium, and/or coma from significantly elevated olanzapine plasma concentrations. Patients must remain under continuous observation by a healthcare professional at the healthcare facility for at least 3 hours following the injection to help detect PDSS. After this time, the patient must be accompanied to their destination upon leaving the facility. For the remainder of the day of each injection, the patient should not drive or operate heavy machinery. Patients and/or their caregivers should be made aware of the symptoms associated with PDSS and what to do if symptoms occur. Following the 3-hour observation period, the confirm that the patient is alert, oriented, and free of any signs or symptoms of PDSS before release from the facility. Suspected PDSS cases require close medical supervision in a medical facility capable of resuscitation.

    Children, suicidal ideation

    The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I disorder, and close supervision of high-risk patients should accompany drug therapy. Olanzapine should be prescribed in the smallest quantity consistent with good management in order to reduce the risk of overdose. When olanzapine is prescribed in conjunction with fluoxetine for the treatment of depression, further considerations relative to antidepressant use are needed. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in children, adolescent, and young adult patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. The need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. The safety and efficacy of olanzapine injection suspension (i.e., Zyprexa Relprevv) have not been established in children or adolescents. Orally administered olanzapine is FDA approved for use in adolescents 13 years and older for the treatment of schizophrenia, the acute treatment of manic or mixed episodes associated with bipolar I disorder, and the maintenance treatment of bipolar I disorder; when oral olanzapine is used in conjunction with fluoxetine for depression, the boxed warnings regarding suicidal ideation for children and adolescents apply.

    Seizure disorder, seizures

    Olanzapine should be used cautiously in those patients with a history of seizure disorder or with conditions that may increase the risk of seizures. Like other antipsychotic drugs, olanzapine may lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients.

    Tardive dyskinesia

    Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotics. Regular evaluation for movement disorders is recommended (e.g., AIMS, DISCUS). Factors associated with a greater susceptibility to tardive dyskinesia include an age above 55 years, female gender, white or African ethnicity, presence of a mood disorder, intellectual disability, CNS injury, prior or current akathisia, significant parkinsonism, or acute dystonic reaction. The rate of tardive dyskinesia in adults treated with a first generation antipsychotic appears to be at least 3 times that observed with second generation antipsychotics. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotics administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief periods at low doses or may arise after drug discontinuation. Antipsychotics may suppress the signs and symptoms of tardive dyskinesia and thereby mask the underlying process; however, the syndrome may also remit partially or completely if the antipsychotic is withdrawn. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. If signs and symptoms of tardive dyskinesia appear, olanzapine discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.

    Apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, cerebrovascular disease, females, fever, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypotension, hypothyroidism, hypovolemia, long QT syndrome, myocardial infarction, orthostatic hypotension, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, systemic lupus erythematosus (SLE)

    Use oral and intramuscular olanzapine cautiously in patients with cardiac disease. Olanzapine may potentiate hypotension. Orthostatic hypotension, syncope, and cardiac events may be associated with aggressive dose titration. If olanzapine is prescribed, use a low initial dose followed by gradual dosage titration. Patients should remain recumbent if drowsy or dizzy after olanzapine injection solution or extended-release injection suspension til examination has indicated that they are not experiencing postural hypotension, bradycardia, and/or hypoventilation. Orthostatic hypotension could lead to falls with the potential for fractures and other injuries. Complete a fall risk assessment upon antipsychotic initiation in patients with conditions, diseases, or taking concurrent medications that could exacerbate orthostasis and recurrently during long-term therapy in at-risk patients. Due to the potential orthostatic effects of olanzapine, caution is recommended in patients with cerebrovascular disease and those with risk factors for hypotension, such as hypovolemia or the use of antihypertensive agents. Similar to other antipsychotic agents, cases of ECG changes and serious cardiac or respiratory events have been reported with olanzapine therapy, but these events are infrequent. Limited data, including some case reports, suggest that olanzapine might be associated with a significant QT prolongation in rare instances. Torsade de pointes (TdP), a life-threatening arrhythmia, has not been reported with olanzapine. Use olanzapine with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, cerebrovascular disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, older adults 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, abnormally low body temperature, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

    Hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, obesity

    Monitor patient weight prior to and during olanzapine therapy. Patients should also undergo fasting lipid profile testing at the beginning of treatment and periodically during treatment. Atypical antipsychotics have been associated with metabolic changes including dyslipidemia and weight gain. Use olanzapine with caution in patients with pre-existing obesity, hypercholesterolemia, hyperlipidemia, or hypertriglyceridemia. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risks.

    Diabetes mellitus, hyperglycemia

    Patients starting treatment with olanzapine should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Atypical antipsychotics have been associated with metabolic changes including hyperglycemia and diabetes mellitus. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risks. Assess the benefits of prescribing olanzapine versus the risks in patients with pre-existing diabetes mellitus or hyperglycemia. Monitor patients for hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness while receiving olanzapine.

    Anticholinergic medications, closed-angle glaucoma, constipation, GI obstruction, ileus, prostatic hypertrophy, urinary retention

    Olanzapine exhibits anticholinergic effects and should be used with caution in those with a current diagnosis or history of conditions that may be aggravated by anticholinergic activity, such as closed-angle glaucoma, paralytic ileus, urinary retention, or clinically significant prostatic hypertrophy. The effects of olanzapine may be additive with other anticholinergic medications. Postmarketing reports have indicated that the risk for severe anticholinergic-related adverse reactions, including fatalities, was increased during coadministration of olanzapine with anticholinergic medications. Some of these events were severe gastrointestinal adverse reactions related to hypomotility, constipation, and intestinal GI obstruction.

    Dysphagia

    Olanzapine should be used cautiously in patients with dysphagia. Esophageal dysmotility and aspiration have been associated with antipsychotic use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s disease. Olanzapine is not approved for the treatment of patients with Alzheimer’s disease.

    Neurological disease, Parkinson's disease

    Antipsychotics can cause motor and sensory instability, which may lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with diseases (e.g., neurological disease), conditions, or concurrent medication use that could exacerbate motor and sensory instability. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Olanzapine and other atypical antipsychotics should be used with caution in the patient with Parkinson's disease because of possible aggravation of EPS due to dopamine-receptor blockade.

    Ambient temperature increase, dehydration, hyperthermia, strenuous exercise

    Antipsychotics have been reported to disrupt the body's ability to reduce core body temperature presumably through effects in the hypothalamus, and they predispose patients to hyperthermia. Patients receiving olanzapine should be advised of conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, ambient temperature increase, dehydration).

    Breast cancer, hyperprolactinemia

    As with other drugs that antagonize dopamine D2 receptors, olanzapine elevates prolactin levels, and the elevation persists during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported; fertility may also be affected. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients. Some human breast cancer may be prolactin-dependent and therefore most antipsychotics should be used cautiously in those who have a history of breast cancer.

    Hepatic disease

    Due to the fixed-dose and long-acting nature of the depot injection, a decision to use the extended-release intramuscular injection in patients with pre-existing hepatic disease or impairment should be carefully considered, and only after tolerability has been established via oral dosing titration. No dosage adjustment is usually needed for patients with hepatic disease receiving oral olanzapine therapy; a lower starting dose is recommended for these patients when used in combination with fluoxetine for the treatment of depression, with careful titration.

    Dementia, geriatric, stroke

    Geriatric patients may be more susceptible than younger adults to anticholinergic activity, orthostatic hypotension, movement disorders, and CNS depression with olanzapine. Geriatric patients may also be at increased risk for developing QT prolongation. Initiate olanzapine at a low dose, with longer intervals between dosage increases. Antipsychotics are not approved for the treatment of dementia-related psychosis in geriatric patients and use of olanzapine in this population should be avoided if possible due to an increase in morbidity and mortality in geriatric patients with dementia receiving atypical antipsychotics. Deaths have typically resulted from heart failure, sudden death, or infections (primarily pneumonia). An increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatal events, has also been reported. The Beers Criteria consider antipsychotics to be potentially inappropriate medications (PIMs) in elderly patients except for treating schizophrenia, bipolar disorder, and nausea/vomiting during chemotherapy. The Beers panel recommends avoiding antipsychotics in geriatric patients with delirium, dementia, or Parkinson's disease. Non-pharmacological strategies are first-line options for treating delirium- or dementia-related behavioral problems unless they have failed or are not possible and the patient is a substantial threat to self or others. If antipsychotic use is necessary for geriatrics with a history of falls or fractures, consider reducing the use of other CNS depressants and implement other fall risk strategies. Due to the potential for antipsychotic-induced hyponatremia and SIADH, sodium levels should be closely monitored when olanzapine is initiated and after dose changes. According to the federal Omnibus Budget Reconciliation Act (OBRA) regulations in residents of long-term care facilities, antipsychotic therapy should only be initiated in a patient with behavioral or psychological symptoms of dementia (BPSD) when the patient is a danger to self or others or has symptoms due to mania or psychosis. For acute conditions persisting beyond 7 days, appropriate non-pharmacologic interventions must be attempted, unless clinically contraindicated and documented. OBRA provides general dosing guidance for antipsychotic treatment of BPSD. Antipsychotics are subject to periodic review for effectiveness, medical necessity, gradual dose reduction, or rationale for continued use. Refer to the OBRA guidelines for complete information.

    Neonates, pregnancy, pregnancy testing

    Evidence is insufficient to establish the safe use of olanzapine in humans during pregnancy. Because olanzapine is known to cross the placenta in animals, the drug is recommended for use during pregnancy only when the benefits outweigh the risks. Animal studies have not shown evidence of teratogenicity or mutagenicity. However, decreased viability or decreased birth weights have been observed in animals. Animal studies are not always predictive of human response. Neonates exposed to antipsychotics during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity and have ranged from self-limited to those requiring intensive care unit support and prolonged hospitalization. Neonates exhibiting signs or symptoms of extrapyramidal effects or withdrawal should be carefully monitored. The knowledge about long-term neurobehavioral effects in offspring is limited for all antipsychotic agents and requires further investigation. There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. According to the American Psychiatric Association treatment guidelines for schizophrenia, consider pregnancy testing in women of childbearing potential prior to initiation of an antipsychotic. It is not known if antipsychotics, through their effect on prolactin, would affect labor or delivery. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to olanzapine; information about the registry can be obtained at womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry or by calling 1-866-961-2388.

    Infertility, reproductive risk

    Olanzapine may pose a reproductive risk by increasing serum prolactin concentrations, which may lead to reversible infertility in females of reproductive potential.

    Breast-feeding

    Olanzapine is present in human milk. There are reports of excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) in babies exposed to olanzapine through breast milk. There is no information on the effects of olanzapine on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for olanzapine and any potential adverse effects on the breastfed child from the drug or from the mother's underlying condition. Any infant exposed to olanzapine should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements). In a study in lactating women, the mean infant dose at steady-state was estimated to be 1.8% of the maternal olanzapine dose. Due to individual variability in response to antipsychotics, it may be prudent to continue the existing olanzapine regimen if ongoing treatment is deemed necessary during breast-feeding. However, quetiapine may be considered as an alternate atypical agent. Regardless of the antipsychotic used, the nursing infant should be closely monitored for excessive drowsiness, lethargy, and developmental delays. Combination treatment with antipsychotics may increase the risk of these adverse events.

    Tobacco smoking

    Tobacco smoking patients receiving olanzapine can have about a 40% higher clearance rate of the drug than nonsmokers, due to induction of hepatic microsomal enzymes by the hydrocarbons in tobacco. No specific dosage recommendations are recommended for smokers. The combined effects of age, smoking, and gender could lead to substantial pharmacokinetic differences in populations and certain individuals may require dose adjustments in treatment. Sudden smoking cessation may result in a reduced clearance of olanzapine, despite the initiation of nicotine replacement. Monitor patients carefully when changes in smoking status occur.

    Phenylketonuria

    Olanzapine orally disintegrating tablets (ODT) contain aspartame, and the amounts of phenylalanine ingested should be considered in patients with phenylketonuria. The regular olanzapine tablets do not contain phenylalanine.

    Abrupt discontinuation

    When discontinuing treatment with antipsychotic or antidepressant treatment, the clinician should recognize that abrupt discontinuation of immediate-release dose forms in some patients can cause adverse symptoms. While immediate discontinuation of an antipsychotic treatment may be acceptable for some patients, more gradual discontinuation may be most appropriate for others. With extended-release injections, rate-limited elimination of olanzapine occurs following any given dose.

    Intravenous administration, subcutaneous administration

    Intramuscular olanzapine is for intramuscular administration only. Do not give via intravenous administration or via subcutaneous administration.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 2.0-2.0
    suicidal ideation / Delayed / 0.1-1.0
    stroke / Early / 0.1-1.0
    seizures / Delayed / 0.1-0.9
    coma / Early / 0-0.1
    ileus / Delayed / 0-0.1
    GI obstruction / Delayed / 0-0.1
    pulmonary edema / Early / 0-0.1
    torticollis / Delayed / Incidence not known
    tardive dyskinesia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    neuroleptic malignant syndrome / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    diabetic ketoacidosis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    water intoxication / Delayed / Incidence not known

    Moderate

    hypertriglyceridemia / Delayed / 9.2-70.7
    hypercholesterolemia / Delayed / 2.8-57.6
    hyperprolactinemia / Delayed / 30.0-47.0
    elevated hepatic enzymes / Delayed / 1.0-28.0
    akathisia / Delayed / 3.0-27.0
    hyperglycemia / Delayed / 0.9-26.0
    depression / Delayed / 18.0-18.0
    pseudoparkinsonism / Delayed / 0-14.0
    constipation / Delayed / 4.0-11.0
    peripheral edema / Delayed / 3.0-6.0
    amnesia / Delayed / 5.0-5.0
    confusion / Early / 4.0-4.0
    euphoria / Early / 3.0-3.0
    hallucinations / Early / 0-3.0
    hypertonia / Delayed / 3.0-3.0
    hypertension / Early / 0-3.0
    sinus tachycardia / Rapid / 3.0-3.0
    chest pain (unspecified) / Early / 3.0-3.0
    dyspnea / Early / 3.0-3.0
    amblyopia / Delayed / 3.0-3.0
    dysarthria / Delayed / 0.1-2.0
    hypotension / Rapid / 2.0-2.0
    QT prolongation / Rapid / 0-2.0
    neutropenia / Delayed / 2.0-2.0
    ejaculation dysfunction / Delayed / 2.0-2.0
    impotence (erectile dysfunction) / Delayed / 0.1-2.0
    vaginitis / Delayed / 2.0-2.0
    urinary incontinence / Early / 2.0-2.0
    post-injection delirium/sedation syndrome / Rapid / 0.1-2.0
    edema / Delayed / 0.1-2.0
    ataxia / Delayed / 0.1-1.0
    dystonic reaction / Delayed / 1.0-1.0
    dyskinesia / Delayed / 1.0-1.0
    peripheral vasodilation / Rapid / 0.1-1.0
    hyperbilirubinemia / Delayed / 0.1-1.0
    thrombocytopenia / Delayed / 0.1-1.0
    leukopenia / Delayed / 0.1-1.0
    urinary retention / Early / 0.1-1.0
    galactorrhea / Delayed / 0.2-0.7
    osteoporosis / Delayed / 0-0.1
    orthostatic hypotension / Delayed / 1.0
    dysphemia / Delayed / Incidence not known
    choreoathetosis / Delayed / Incidence not known
    myoclonia / Delayed / Incidence not known
    dysphagia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    priapism / Early / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    hyperlipidemia / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    hyponatremia / Delayed / Incidence not known
    hyperthermia / Delayed / Incidence not known

    Mild

    drowsiness / Early / 6.0-48.0
    weight gain / Delayed / 5.0-31.0
    appetite stimulation / Delayed / 1.0-29.0
    xerostomia / Early / 2.0-22.0
    dizziness / Early / 1.0-18.0
    asthenia / Delayed / 2.0-18.0
    headache / Early / 8.0-17.0
    fatigue / Early / 2.0-14.0
    insomnia / Early / 12.0-12.0
    dyspepsia / Early / 3.0-11.0
    polydipsia / Early / 6.0-10.0
    diarrhea / Early / 2.0-7.0
    rhinitis / Early / 7.0-7.0
    nasal congestion / Early / 1.0-7.0
    tremor / Early / 1.0-6.0
    vomiting / Early / 0.1-6.0
    abdominal pain / Early / 3.0-6.0
    fever / Early / 0-6.0
    pharyngitis / Delayed / 1.0-6.0
    paresthesias / Delayed / 5.0-5.0
    nausea / Early / 0.1-5.0
    ecchymosis / Delayed / 5.0-5.0
    arthralgia / Delayed / 2.0-5.0
    back pain / Delayed / 3.0-5.0
    dental pain / Delayed / 3.0-4.0
    vaginal discharge / Delayed / 2.0-4.0
    musculoskeletal pain / Early / 2.0-4.0
    infection / Delayed / 0-4.0
    dental caries / Delayed / 0-4.0
    otalgia / Early / 1.0-4.0
    injection site reaction / Rapid / 1.0-3.6
    restlessness / Early / 1.0-3.0
    muscle cramps / Delayed / 1.0-3.0
    hyperhidrosis / Delayed / 3.0-3.0
    epistaxis / Delayed / 0.1-3.0
    sinusitis / Delayed / 3.0-3.0
    flatulence / Early / 1.0-2.0
    menstrual irregularity / Delayed / 0.1-2.0
    libido decrease / Delayed / 0.1-2.0
    amenorrhea / Delayed / 0.1-2.0
    orgasm dysfunction / Delayed / 0.7-2.0
    acne vulgaris / Delayed / 0-2.0
    xerosis / Delayed / 2.0-2.0
    sneezing / Early / 0-2.0
    syncope / Early / 0.1-1.0
    menorrhagia / Delayed / 0.1-1.0
    mastalgia / Delayed / 0.1-1.0
    oligomenorrhea / Delayed / 0.1-1.0
    urinary urgency / Early / 0.1-1.0
    polyuria / Early / 0.1-1.0
    increased urinary frequency / Early / 0.1-1.0
    photosensitivity / Delayed / 0.1-1.0
    xerophthalmia / Early / 0.1-1.0
    chills / Rapid / 0.1-1.0
    breast discharge / Delayed / 0.2-0.7
    breast enlargement / Delayed / 0.2-0.7
    gynecomastia / Delayed / 0.2-0.7
    alopecia / Delayed / 0.1-0.1
    mydriasis / Early / 0-0.1
    hypersalivation / Early / Incidence not known
    restless legs syndrome (RLS) / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    hypothermia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Major) Since abarelix can cause QT prolongation, abarelix should be avoided in combination with other drugs that are associated with QT prolongation, such as olanzapine. Drugs that cause hyperprolactinemia, such as olanzapine, may antagonize some of the actions of gonadotropin-releasing hormone medications.
    Acarbose: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Acebutolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Acetaminophen; Chlorpheniramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Acetaminophen; Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Drugs that can cause CNS depression, including dichloralphenazone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness if used concomitantly with atypical antipsychotics.
    Acetaminophen; Diphenhydramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Acetaminophen; Oxycodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Acetaminophen; Pentazocine: (Moderate) Coadministration of pentazocine with atypical antipsychotics may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation. Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity.
    Acetaminophen; Propoxyphene: (Moderate) Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression, including opiate agonists.
    Aclidinium; Formoterol: (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Albendazole: (Moderate) Albendazole induces CYP1A, and although not studied, may induce the metabolism of olanzapine. Patients receiving these combinations should be closely monitored when albendazole is prescribed, as albendazole may increase the clearance of olanzapine. The patient's clinical status should be monitored carefully when albendazole is prescribed and on discontinuation of albendazole therapy.
    Albiglutide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Aldesleukin, IL-2: (Moderate) Both aldesleukin, IL 2 and olanzapine can cause significant CNS depression. Use with caution and monitor patients for additive CNS depression.
    Alfentanil: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Alfuzosin: (Moderate) Caution is advised when administering olanzapine with alfuzosin as concurrent use may increase the risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Alfuzosin may also prolong the QT interval in a dose-dependent manner.
    Aliskiren; Valsartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Alogliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Alogliptin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Alogliptin; Pioglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Alosetron: (Moderate) Constipation is the most frequently reported adverse effect with alosetron. Alosetron, if used with drugs that have anticholinergic effects such as olanzapine, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus. Although specific recommendations are not available from the manufacturer, it would be prudent to avoid these drugs in patients taking alosetron.
    Alpha-glucosidase Inhibitors: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Alprazolam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
    Amantadine: (Moderate) Amantadine may exhibit anticholinergic activity. Medications with significant anticholinergic activity, such as olanzapine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, neurologic function, and temperature regulation.
    Ambenonium Chloride: (Moderate) The therapeutic benefits of ambenonium may be diminished when co-administered with the antimuscarinics. Drugs known to exhibit anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity include olanzapine. When concurrent use cannot be avoided, monitor the patient for reduced ambenonium efficacy.
    Amifampridine: (Major) Carefully consider the need for concomitant treatment with atypical antipsychotics and amifampridine, as coadministration may increase the risk of seizures. If coadministration occurs, closely monitor patients for seizure activity. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Atypical antipsychotics may increase the risk of seizures.
    Amiloride: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Amiodarone: (Major) The concomitant use of amiodarone and other drugs known to prolong the QT interval, such as olanzapine, should only be done after careful assessment of risks versus benefits. If possible, avoid coadministration of amiodarone and olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with olanzapine. Amisulpride causes dose- and concentration- dependent QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Amlodipine; Benazepril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Amlodipine; Olmesartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Amlodipine; Valsartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Amobarbital: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Amoxapine: (Moderate) Use caution during coadministration of amoxapine and olanzapine. Amoxapine exhibits some antipsychotic activity and may increase the risk of tardive dyskinesia or neuroleptic malignant syndrome (NMS) when antipsychotics are given concurrently. CNS effects, orthostatic hypotension, anticholinergic effects, and lowering of seizure threshold are potential problems with the combined use of amoxapine and olanzapine.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
    Anagrelide: (Major) Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Monitor patients for cardiovascular effects during concurrent use. In addition, anagrelide has been shown to inhibit CYP1A2. Olanzapine is a CYP1A2 substrate. In theory, coadministration could lead to increases in the serum concentration of olanzapine and thus, adverse effects.
    Angiotensin II receptor antagonists: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Angiotensin-converting enzyme inhibitors: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Anticholinergics: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Apomorphine: (Moderate) Coadministration of apomorphine and olanzapine may increase the risk for QT prolongation or sedation. Apomorphine and olanzapine may decrease the effectiveness of each other due to opposing effects on dopamine. Additive CNS effects are also possible. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. In general, atypical antipsychotics are less likely to interfere with Parkinson's disease treatments than traditional antipsychotics. Monitor for movement disorders, unusual changes in moods or behavior, sedation, fast, irregular heartbeat, and diminished effectiveness of either agent during coadministration.
    Arformoterol: (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Aripiprazole: (Moderate) Coadministration may result in additive effects on the QT interval. Both aripiprazole and olanzapine have been associated with QT prolongation. In addition, the risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, tardive dyskinesia, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary.
    Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with arsenic trioxide include olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
    Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor and olanzapine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased olanzapine concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval such as olanzapine should be avoided. Consider ECG monitoring if olanzapine must be used with or after artemether; lumefantrine treatment.
    Articaine; Epinephrine: (Moderate) Olanzapine may induce significant alpha-adrenergic blockade in overdose, leading to profound hypotension. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity since the beta-stimulation may worsen hypotension in the setting of olanzapine overdose.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer, asenapine should be avoided in combination with other agents also known to have this effect (e.g., olanzapine). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. In addition, co-administration of olanzapine with asenapine may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties, like olanzapine and orphenadrine, are used concomitantly. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Atazanavir: (Moderate) Caution is warranted when atazanavir is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of uridine glucoronyltransferase (UGT). Atazanavir is an inhibitor of UGT1A1.
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when atazanavir is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of uridine glucoronyltransferase (UGT). Atazanavir is an inhibitor of UGT1A1. (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6.
    Atenolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Atenolol; Chlorthalidone: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Atomoxetine: (Moderate) Caution is advised when administering olanzapine with atomoxetine as concurrent use may increase the risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
    Atropine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Atropine; Difenoxin: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Drugs that decrease GI motility, such as olanzapine, may produce additive effects with antidiarrheals, such as diphenoxylate/difenoxin, if used concomitantly.
    Atropine; Edrophonium: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Azilsartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Azilsartan; Chlorthalidone: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Azithromycin: (Major) Avoid coadministration of azithromycin with olanzapine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Barbiturates: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with olanzapine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Belladonna; Opium: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Benazepril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Bendroflumethiazide; Nadolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with olanzapine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking olanzapine, reduce initial dosage and titrate to clinical response. If olanzapine is initiated a patient taking an opioid agonist, use a lower initial dose of olanzapine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Benztropine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Bepridil: (Contraindicated) Bepridil administration has Class I antiarrhythmic properties and is associated with a well-established risk of QT prolongation and torsades de pointes. Bepridil is contraindicated for use with drugs that prolong the QT interval, including olanzapine.
    Beta-adrenergic blockers: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Betaxolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Bethanechol: (Moderate) Drugs that possess antimuscarinic properties, such as olanzapine, are pharmacologic opposites of bethanechol (a direct agonist at muscarinic cholinergic receptors). These agents should not be used with bethanechol except when the specific intent is to counteract excessive actions of one or the other.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Bismuth Subsalicylate: (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. The concomitant administration of olanzapine may produce additive effects.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. The concomitant administration of olanzapine may produce additive effects. (Moderate) Concomitant use of metronidazole and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Bisoprolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Brexpiprazole: (Major) Caution is advisable during concurrent use of brexpiprazole with other antipsychotics such as olanzapine. The risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary.
    Brimonidine; Timolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Bromocriptine: (Moderate) The effectiveness of bromocriptine may be reduced by most of the atypical antipsychotics, via their action as dopamine antagonists. Monitor the patient for reduced response to bromocriptine. The atypical antipsychotics elevate prolactin to various degrees. Atypical antipsychotics may also aggravate diabetes mellitus and cause metabolic changes including hyperglycemia; use caution if bromocriptine is taken for diabetes. If bromocriptine is taken for diabetes, monitor for worsening glycemic control.
    Brompheniramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Brompheniramine; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Brompheniramine; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Budesonide; Formoterol: (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Buprenorphine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of olanzapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Olanzapine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of olanzapine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of olanzapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Olanzapine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of olanzapine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Bupropion; Naltrexone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Buspirone: (Moderate) The combination of buspirone and CNS depressants like the antipsychotics can increase the risk for drowsiness, sedation, and dizziness.
    Butabarbital: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Butalbital; Acetaminophen: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Butorphanol: (Moderate) Other drugs that can cause CNS depression, such as butorphanol, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Cabergoline: (Moderate) Cabergoline should not be coadministered with olanzapine due to mutually antagonistic effects on dopaminergic function. The dopamine antagonist action of olanzapine may diminish the prolactin-lowering ability of cabergoline while the dopamine agonist effects of cabergoline may exacerbate a psychotic disorder, reducing the effectiveness of antipsychotics such as olanzapine.
    Cabotegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Calcium-channel blockers: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Canagliflozin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Canagliflozin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Candesartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and olanzapine. Concurrent use may result in additive CNS depression.
    Captopril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Carbamazepine: (Moderate) Monitor for reduced olanzapine efficacy; dosage adjustments might be necessary in some patients for whom carbamazepine treatment is medically necessary. Carbamazepine (200 mg BID) increases olanzapine clearance by approximately 50% via potent induction of CYP1A2. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance. In addition, additive CNS effects (e.g., sedation) may occur, and antipsychotic therapy may also reduce the seizure threshold in some patients.
    Carbetapentane; Chlorpheniramine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbidopa; Levodopa: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
    Carbidopa; Levodopa; Entacapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease. (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
    Carbinoxamine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Carbinoxamine; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Carbinoxamine; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Cariprazine: (Moderate) The risk of adverse effects may be increased during concurrent use of cariprazine with other antipsychotics, such as olanzapine. Similar to other antipsychotics, cariprazine administration has been associated with drowsiness, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. The incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, but the risk appears to be increased.
    Carteolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Carvedilol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and olanzapine. Concurrent use may result in additive CNS depression.
    Central-acting adrenergic agents: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Ceritinib: (Major) Avoid coadministration of ceritinib with olanzapine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with atypical antipsychotics should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with atypical antipsychotics should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Cetrorelix: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
    Charcoal: (Major) Concomitant administration of olanzapine and activated charcoal is not recommended and is not expected to occur under normal clinical use. The Cmax and AUC of olanzapine were reduced by 60% when co-administered with activated charcoal. Co-administration with activated charcoal may be appropriate in an olanzapine overdose situation, especially since peak olanzapine levels do not occur until 6 hours after an oral ingestion. However, patients should avoid dietary supplements containing activated charcoal.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Chlorcyclizine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Chlordiazepoxide: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination, including excess sedation and/or cardiopulmonary depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and severity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Chlordiazepoxide; Amitriptyline: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination, including excess sedation and/or cardiopulmonary depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and severity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Chlordiazepoxide; Clidinium: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination, including excess sedation and/or cardiopulmonary depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and severity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Chloroquine: (Major) Avoid coadministration of chloroquine with olanzapine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Chlorpheniramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Chlorpheniramine; Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Chlorpheniramine; Dextromethorphan: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Chlorpheniramine; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Chlorpromazine: (Major) Concurrent use of olanzapine and chlorpromazine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Chlorzoxazone: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants, such as olanzapine. Dosage adjustments of one or both medications may be necessary.
    Cimetidine: (Minor) Inhibitors of CYP1A2, such as cimetidine, could potentially decrease the elimination of olanzapine.
    Ciprofloxacin: (Major) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP) including ciprofloxacin. Additionally, ciprofloxacin inhibits the activity of CYP1A2. Inhibitors of CYP1A2 could potentially reduce the elimination of olanzapine. However, since multiple enzyme pathways metabolize olanzapine, inhibition of only one isoenzyme may not appreciably decrease olanzapine clearance. One case study reported elevated olanzapine plasma concentrations during ciprofloxacin coadministration, possibly due to CYP1A2 inhibition of olanzapine metabolism. Ciprofloxacin inhibits the activity of CYP1A2. Inhibitors of CYP1A2 could potentially reduce the elimination of olanzapine. However, since multiple enzyme pathways metabolize olanzapine, inhibition of only one isoenzyme may not appreciably decrease olanzapine clearance. One case study reported elevated olanzapine plasma concentrations during ciprofloxacin coadministration, possibly due to CYP1A2 inhibition of olanzapine metabolism.
    Cisapride: (Contraindicated) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Because of the potential for torsade de pointes (TdP), use of cisapride with olanzapine is contraindicated.
    Citalopram: (Major) Concurrent use of olanzapine and citalopram should be avoided if possible. Citalopram causes dose-dependent QT interval prolongation and olanzapine is associated with a risk for QT prolongation and torsade de pointes (TdP). According to the manufacturer of citalopram, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. However, if concurrent therapy is considered essential, ECG monitoring is recommended.
    Clarithromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
    Clemastine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Clobazam: (Moderate) Benzodiazepines such as clobazam should be combined cautiously with antipsychotics because of the potential for additive CNS depressant effects, and reduced effectiveness of clobazam as an anticonvulsant due to the possible lowering of the seizure threshold by antipsychotics.
    Clofazimine: (Major) Monitor ECGs for QT prolongation when clofazimine is administered with olanzapine. QT prolongation and torsade de pointes have been reported in patients receiving clofazimine in combination with QT prolonging medications. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Clonazepam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
    Clorazepate: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
    Clozapine: (Major) Concurrent use of olanzapine and clozapine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Some case reports describe the re-induction of bone-marrow suppression by olanzapine when the patient is known to have a history of clozapine-induced blood dyscrasias. When olanzapine therapy follows clozapine therapy in such patients, monitoring of complete blood counts is recommended.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6.
    Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Codeine; Guaifenesin: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
    Codeine; Promethazine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
    COMT inhibitors: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
    Crizotinib: (Major) Avoid coadministration of crizotinib with olanzapine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Cyclobenzaprine: (Moderate) When cyclobenzaprine and olanzapine are used concurrently, an increase in anticholinergic side effects may occur. Cyclobenzaprine possesses antimuscarinic properties, which can cause dry mouth, urinary difficulties and slowing of gastrointestinal motility. If used with other drugs with antimuscarinic properties, such as olanzapine, anticholinergic side effects can be additive. Particular attention should be paid to GI problems because of the possible development of paralytic ileus.
    Cyproheptadine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Dantrolene: (Moderate) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as antipsychotics, can increase CNS depression.
    Dapagliflozin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Dapagliflozin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Dapagliflozin; Saxagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Darifenacin: (Moderate) Olanzapine exhibits anticholinergic effects that may be enhanced when combined with other drugs with anticholinergic activity like darifenacin. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Ritonavir may reduce olanzapine serum concentrations by approximately 50%; how this affects olanzapine efficacy, however, is not known. Ritonavir appears to induce olanzapine's metabolism by either CYP1A2 or glucuronide conjugation. If ritonavir and olanzapine are used concurrently, monitor for reduced olanzapine effect and adjust olanzapine dose as needed.
    Dasatinib: (Moderate) Due to a possible risk for QT prolongation and torsade de pointes (TdP), dasatinib and olanzapine should be used together cautiously. In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Degarelix: (Major) Avoid coadministration of degarelix with olanzapine due to the risk of reduced efficacy of degarelix; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; degarelix is a GnRH analog. Additionally, androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Deutetrabenazine: (Moderate) Caution is advised when administering olanzapine with deutetrabenazine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. Monitor for signs and symptoms of neuroleptic malignant syndrome (NMS), restlessness, and agitation. If NMS is diagnosed, immediately discontinue deutetrabenazine, and provide intensive symptomatic treatment and medical monitoring. Recurrence of NMS has been reported with resumption of drug therapy. If akathisia or parkinsonism develops during treatment, the deutetrabenazine dose should be reduced; discontinuation may be required. Deutetrabenazine is a reversible, dopamine depleting drug and olanzapine is a dopamine antagonist. The risk for parkinsonism, NMS, or akathisia may be increased with concomitant administration. Monitor for excessive sedation and somnolence during coadministration of olanzapine and deutetrabenazine. Concurrent use may result in additive CNS depression.
    Dexchlorpheniramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Dextromethorphan; Quinidine: (Major) Quinidine and dextromethorphan; quinidine cause dose-dependent QT prolongation. These drugs should be avoided in patients receiving drugs that may prolong the QT interval and are metabolized by CYP2D6, such as olanzapine. The manufacturer recommends an ECG in patients taking these drugs together.
    Diazepam: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
    Dicyclomine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Dimenhydrinate: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Diphenhydramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Diphenhydramine; Ibuprofen: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Diphenhydramine; Naproxen: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Diphenhydramine; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Diphenoxylate; Atropine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Drugs that decrease GI motility, such as olanzapine, may produce additive effects with antidiarrheals, such as diphenoxylate/difenoxin, if used concomitantly.
    Disopyramide: (Major) Olanzapine should be used cautiously and with close monitoring with disopyramide. Disopyramide administration is associated with QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP). Additive anticholinergic effects are also possible; both drugs exhibit significant anticholinergic activity.
    Dofetilide: (Major) Coadministration of dofetilide and olanzapine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Dolasetron: (Moderate) Administer dolasetron with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Donepezil: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than olanzapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Olanzapine exhibits moderate anticholinergic activity, and is more likely than most other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Donepezil; Memantine: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than olanzapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Olanzapine exhibits moderate anticholinergic activity, and is more likely than most other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Dorzolamide; Timolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Doxazosin: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Doxylamine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Doxylamine; Pyridoxine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Dronabinol: (Moderate) Drugs that can cause CNS depression such as dronabinol, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Dronedarone: (Contraindicated) Concomitant use of dronedarone and olanzapine is contraindicated. Dronedarone is an inhibitor of CYP2D6. Olanzapine is a substrate for CYP2D6. Coadministration of dronedarone and olanzapine may result in elevated plasma concentrations of olanzapine. In addition, olanzapine has been established to have a possible risk of QT prolongation and Torsade de Pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
    Dulaglutide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Duloxetine: (Moderate) Duloxetine is an inhibitor of CYP1A2 and CYP2D6 and should be used cautiously with atypical antipsychotics metabolized by CYP1A2 and CYP2D6 such as olanzapine. Plasma concentrations of atypical antipsychotics primarily metabolized via CYP1A2, such as olanzapine, may increase substantially during concurrent use. Decreased metabolism of olanzapine may lead to clinically important adverse reactions, such as orthostatic hypotension, sedation, or extrapyramidal symptoms. In addition, olanzapine is associated with a possible risk of QT prolongation and should be used cautiously with CYP1A2 and CYP2D6 inhibitors such as duloxetine.
    Efavirenz: (Moderate) Consider alternatives to efavirenz when coadministering with efavirenz as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Consider alternatives to efavirenz when coadministering with efavirenz as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with efavirenz as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Eliglustat: (Major) Coadminister olanzapine and eliglustat cautiously and with close monitoring; there may be an increased risk of QT prolongation and/or olanzapine-associated adverse effects. If coadministration is necessary, olanzapine dosage reduction may be considered but is not routinely recommended. Eliglustat is CYP2D6 inhibitor that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Olanzapine is a minor substrate of CYP2D6 in vivo. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Coadministration of olanzapine and eliglustat may result in additive effects on the QT interval and, potentially, increased plasma concentrations of olanzapine, further increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6.
    Empagliflozin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Empagliflozin; Linagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Empagliflozin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Enalapril, Enalaprilat: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Enalapril; Felodipine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Encorafenib: (Major) Avoid coadministration of encorafenib and olanzapine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Entacapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
    Entrectinib: (Major) Avoid coadministration of entrectinib with olanzapine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Epinephrine: (Moderate) Olanzapine may induce significant alpha-adrenergic blockade in overdose, leading to profound hypotension. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity since the beta-stimulation may worsen hypotension in the setting of olanzapine overdose.
    Eplerenone: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Epoprostenol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Eprosartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Eribulin: (Major) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with olanzapine include eribulin. ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Ertugliflozin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Ertugliflozin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Ertugliflozin; Sitagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Erythromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with olanzapine. Erythromycin is associated with prolongation of the QT interval and TdP. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Erythromycin; Sulfisoxazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with olanzapine. Erythromycin is associated with prolongation of the QT interval and TdP. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Escitalopram: (Moderate) Use escitalopram with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Escitalopram has been associated with a risk of QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Esketamine: (Major) Closely monitor patients receiving esketamine and olanzapine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
    Esmolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Estazolam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
    Eszopiclone: (Moderate) A reduction in the dose of eszopiclone should be considered during co-administration of other CNS depressants, such as antipsychotics, to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving. Antipsychotics with a higher incidence of sedation, such as olanzapine, clozapine, quetiapine, lurasidone, chlorpromazine, and thioridazine, are more likely to interact with eszopiclone. In one evaluation, concurrent use of eszopiclone and olanzapine reduced psychomotor function as measured by the Digit Symbol Substitution Test (DSST).
    Ethanol: (Moderate) Alcohol may potentiate the CNS effects of the atypical antipsychotics, which have the potential to cause increased sedation or to impair judgment, thinking, or motor skills. Patients should be appropriately cautioned; some manufacturers recommend alcohol avoidance during treatment.
    Ethotoin: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added.
    Exenatide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Ezogabine: (Moderate) Caution is advised when administering olanzapine with ezogabine as concurrent use may increase the risk of QT prolongation. Ezogabine has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Fenfluramine: (Moderate) Use fenfluramine and olanzapine with caution due to an increased risk of serotonin syndrome and additive CNS depression. Monitor for excessive sedation, somnolence, and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as olanzapine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of olanzapine during coadministration with fenofibric acid.
    Fentanyl: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Fesoterodine: (Moderate) Coadministration of fesoterodine and other drugs with moderate to significant anticholinergic effects such as olanzapine may increase the frequency and/or severity of anticholinergic effects such as blurred vision, constipation, xerostomia, and urinary retention. Additive effects may be seen on GI smooth muscle, bladder function, the CNS, the eye, and temperature regulation.
    Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with olanzapine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Flavoxate: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Flecainide: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering olanzapine with flecainide. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Flecainide, a Class IC antiarrhythmic, is also associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Moderate) Use fluconazole with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Fluoxetine: (Moderate) Caution is advised when administering olanzapine with fluoxetine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Fluphenazine: (Moderate) Concurrent use of olanzapine and fluphenazine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, co-administration of olanzapine with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Flurazepam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
    Fluticasone; Salmeterol: (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Vilanterol: (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated olanzapine concentrations during concurrent use of fluvoxamine and olanzapine. Caution is advisable. The manufacturer of olanzapine suggests that lower doses of olanzapine be considered in patients receiving fluvoxamine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a potent inhibitor of CYP1A2, which may result in decreased clearance of CYP1A2 substrates including olanzapine. Decreased metabolism of olanzapine may lead to excessive sedation, extrapyramidal symptoms, orthostatic hypotension, or QT prolongation. Fluvoxamine increases the mean olanzapine peak concentration by 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively.
    Food: (Major) It is recommended that patients avoid the use of marijuana, by any route, if they are treated for a psychiatric history, including psychosis and bipolar disorder, as the cannabinoids (the psychoactive ingredients, such as THC) in marijuana can produce psychotoxic effects and may exacerbate psychiatric disorders. A high frequency of use and use of products with high-potency of THC are potential risk factors for psychiatric effects. Additive CNS effects, such as sedation or CNS depression are also possible. Clinical studies suggest that cannabis use may reduce the efficacy of some antipsychotic drugs. In addition, several cannabinoids in marijuana appear to influence the activity of CYP enzymes and P-glycoprotein, which may alter the concentrations of antipsychotics and influence either safety or efficacy.
    Formoterol: (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Formoterol; Mometasone: (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as olanzapine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosinopril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Fosphenytoin: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added.
    Fostemsavir: (Moderate) Caution is advised when administering olanzapine with fostemsavir due to the potential for QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
    Gabapentin: (Major) Initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of gabapentin and olanzapine. Concomitant use of gabapentin with olanzapine may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
    Galantamine: (Moderate) Atypical antipsychotics with significant anticholinergic effects, such olanzapine, are more likely than other atypical antipsychotics to diminish the therapeutic action of galantamine in treating dementia. Use of an alternative antipsychotic should be considered. Galantamine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine. Consider the use of an antipsychotic with less prominent anticholinergic effects. Monitor for decreased clinical efficacy of galantamine if olanzapine must be used concurrently.
    Ganirelix: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
    Gemifloxacin: (Moderate) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering olanzapine with gemifloxacin. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and olanzapine together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Gilteritinib: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and olanzapine is necessary. Gilteritinib has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Glasdegib: (Major) Avoid coadministration of glasdegib with olanzapine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Glimepiride; Rosiglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Glipizide; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Glyburide; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Glycopyrrolate; Formoterol: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Goserelin: (Major) Avoid coadministration of goserelin with olanzapine due to the risk of reduced efficacy of goserelin; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; goserelin is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
    Granisetron: (Moderate) Use granisetron with caution in combination with olanzapine due to increased risk for QT prolongation and torsade de pointes (TdP). Granisetron has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Halofantrine: (Contraindicated) Olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Avoid administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointe including halofantrine.
    Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with olanzapine. Halogenated anesthetics can prolong the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP).
    Haloperidol: (Moderate) Caution is advised when administering olanzapine with haloperidol as concurrent use may increase the risk of QT prolongation; additive antipsychotic-related adverse effects (e.g., drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures) may also occur. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. The likelihood of additive pharmacodynamic interactions varies based upon the individual properties of the coadministered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Histrelin: (Major) Avoid coadministration of histrelin with olanzapine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Homatropine; Hydrocodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Hydantoins: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Hydrocodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
    Hydromorphone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Hydroxychloroquine: (Major) Avoid coadministration of olanzapine and hydroxychloroquine due to an increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine prolongs the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Hydroxyzine: (Moderate) Caution is recommended if hydroxyzine is administered with olanzapine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). In addition, because hydroxyzine causes pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including olanzapine. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Hyoscyamine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Ibuprofen; Oxycodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Ibutilide: (Major) Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval, such as olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
    Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. In addition, coadministration may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Iloprost: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Incretin Mimetics: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Indacaterol: (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indacaterol; Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with olanzapine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Insulin Degludec; Liraglutide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Insulin Glargine; Lixisenatide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Insulins: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Irbesartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Isocarboxazid: (Moderate) Due to the potential for additive sedative and cardiovascular effects (e.g., hypotension), MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor for reduced olanzapine efficacy if rifampin coadministration is medically necessary; in some patients, dosage adjustments may be needed. Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and potent inducers of this enzyme increase olanzapine clearance. While rifampin is a CYP3A inducer, it is likely its induction of CYP1A2 is responsible for the increased olanzapine clearance, and roughly 48% decrease in olanzapine AUC (exposure) seen when rifampin is used with olanzapine.
    Isoniazid, INH; Rifampin: (Moderate) Monitor for reduced olanzapine efficacy if rifampin coadministration is medically necessary; in some patients, dosage adjustments may be needed. Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and potent inducers of this enzyme increase olanzapine clearance. While rifampin is a CYP3A inducer, it is likely its induction of CYP1A2 is responsible for the increased olanzapine clearance, and roughly 48% decrease in olanzapine AUC (exposure) seen when rifampin is used with olanzapine.
    Itraconazole: (Moderate) Use itraconazole with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with olanzapine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Ketoconazole: (Moderate) Use ketoconazole with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Labetalol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
    Lapatinib: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with olanzapine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Lasmiditan: (Moderate) Monitor for excessive sedation, somnolence, and serotonin syndrome during coadministration of lasmiditan and olanzapine. Inform patients taking this combination of the risks and symptoms of excessive CNS depression and serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Lefamulin: (Major) Avoid coadministration of lefamulin with olanzapine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and atypical antipsyhotics. Dosage adjustments of lemborexant and the atypical antipsychotic may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with olanzapine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Leuprolide: (Major) Avoid coadministration of leuprolide with olanzapine due to the risk of reduced efficacy of leuprolide; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Major) Avoid coadministration of leuprolide with olanzapine due to the risk of reduced efficacy of leuprolide; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Levobetaxolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Levobunolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with atypical antipsychotics should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Levodopa: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
    Levofloxacin: (Moderate) Caution is advised when administering olanzapine with levofloxacin. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Levofloxacin has been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Levomethadyl: (Contraindicated) Olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Avoid administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointe including levomethadyl.
    Levorphanol: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial dose of levorphanol by approximately 50% or more. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Linagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Linagliptin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Liraglutide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Lisinopril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Lithium: (Moderate) Olanzapine and lithium are associated with QT prolongation. Coadministration may increase the risk of QT prolongation; therefore, olanzapine and lithium should be coadministered with caution and close monitoring. Some atypical antipsychotics, including olanzapine, are indicated as adjunctive therapy to mood stabilizers such as lithium. However, it is advisable to monitor patients for neurotoxicity during co-administration. Neuroleptic malignant syndrome (NMS) has been observed occasionally during concurrent use of lithium and either atypical or conventional antipsychotics. Additive extrapyramidal effects have also been noted. Early case reports described an encephalopathic syndrome consisting of delirium, tremulousness, dyskinesia, seizures, leukocytosis, weakness, hyperpyrexia, confusion, extrapyramidal symptoms, elevations in laboratory values (e.g., liver function tests, blood urea nitrogen, fasting blood sugar) and, in some cases, irreversible brain damage, during use of lithium and conventional antipsychotics, particularly haloperidol. Subsequent rare reports of NMS or NMS-like reactions have been described during co-administration of lithium and atypical antipsychotics (e.g., risperidone, olanzapine, clozapine). Following resolution of NMS, there are isolated instances of re-emergence of symptoms following re-initiation of lithium as monotherapy. Lithium may be a risk factor for antipsychotic-induced NMS; however, this hypothesis has not been confirmed. In many reported cases, confounding factors have been present (e.g., previous history of NMS, high dose therapy). The ability of antipsychotics alone to precipitate NMS and the rarity of the condition further complicate assessment of lithium as a risk factor. Olanzapine does not influence the pharmacokinetics of lithium.
    Lixisenatide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Lofexidine: (Moderate) Monitor ECG if lofexidine is coadministered with olanzapine due to the potential for additive QT prolongation. Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Long-acting beta-agonists: (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Loop diuretics: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Loperamide: (Moderate) Coadministration of loperamide with olanzapine may increase the risk for QT prolongation and torsade de pointes (TdP). Olanzapine has been associated with prolongation of the QT interval, and high doses of loperamide have resulted in serious cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest). In addition, both drug may decrease gastrointestinal (GI) motility; concurrent use could produce additive GI effects and induce toxic megacolon. If these drugs are given together, monitor for prolongation of the QT interval and for signs of impaired intestinal motility.
    Loperamide; Simethicone: (Moderate) Coadministration of loperamide with olanzapine may increase the risk for QT prolongation and torsade de pointes (TdP). Olanzapine has been associated with prolongation of the QT interval, and high doses of loperamide have resulted in serious cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest). In addition, both drug may decrease gastrointestinal (GI) motility; concurrent use could produce additive GI effects and induce toxic megacolon. If these drugs are given together, monitor for prolongation of the QT interval and for signs of impaired intestinal motility.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with olanzapine due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Moderate) Ritonavir may reduce olanzapine serum concentrations by approximately 50%; how this affects olanzapine efficacy, however, is not known. Ritonavir appears to induce olanzapine's metabolism by either CYP1A2 or glucuronide conjugation. If ritonavir and olanzapine are used concurrently, monitor for reduced olanzapine effect and adjust olanzapine dose as needed.
    Lorazepam: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
    Losartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Loxapine: (Moderate) Caution is advisable during concurrent use of antipsychotics, including loxapine and olanzapine. Coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, and seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Lumateperone: (Moderate) Coadministration of antipsychotics, such as lumateperone and olanzapine, may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from antipsychotic combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
    Lurasidone: (Major) Similar to other antipsychotics, lurasidone administration has been associated with drowsiness, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. The risk of these adverse effects may be increased during concurrent use of lurasidone with other antipsychotics. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as olanzapine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Maprotiline: (Major) Coadministration may result in additive effects on the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. In addition, additive anticholinergic effects may be seen with coadministration. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Mecamylamine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Meclizine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Mefloquine: (Moderate) Mefloquine should be used with caution in patients receiving olanzapine as concurrent use may increase the risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. There is also evidence that the use of halofantrine after mefloquine causes significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
    Meglitinides: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Mepenzolate: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Meperidine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Meperidine; Promethazine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
    Mephobarbital: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Meprobamate: (Moderate) The CNS-depressant effects of meprobamate can be potentiated with concomitant administration of other drugs known to cause CNS depression including antipsychotics.
    Mesoridazine: (Contraindicated) Mesoridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Mesoridazine is generally considered contraindicated for use with olanzapine which when combined with mesoridazine may prolong the QT interval, cause orthostatic hypotension and/or torsade de pointes.
    Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Metformin; Repaglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Metformin; Rosiglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Metformin; Saxagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Metformin; Sitagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval, such as olanzapine, should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). In addition, concomitant use of methadone with another CNS depressant, such as olanzapine, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Methohexital: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Methscopolamine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Metoclopramide: (Contraindicated) Avoid metoclopramide in patients receiving atypical antipsychotics. There is a potential for additive effects, including increased frequency and severity of tardive dyskinesia (TD), other extrapyramidal symptoms (EPS), and neuroleptic malignant syndrome (NMS). Some manufacturer labels for metoclopramide contraindicate the use of these drugs together, while others state avoidance is necessary. If these agents must be used together, monitor closely for movement disorders and additive CNS effects. There also may be additive sedation. Discontinue these medications at the first signs of dyskinesia.
    Metoprolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Metronidazole: (Moderate) Concomitant use of metronidazole and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Mexiletine: (Minor) Olanzapine is partially metabolized by CYP1A2. Mexiletine may inhibit CYP1A2 and may decrease the metabolism of olanzapine resulting in potential drug accumulation. Coadministration of olanzapine with mexiletine has not been studied.
    Midazolam: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
    Midostaurin: (Major) The concomitant use of midostaurin and olanzapine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. There have been case reports of significant QT prolongation occurring with olanzapine therapy.
    Mifepristone: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering olanzapine with mifepristone. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Mifepristone has also been associated with dose-dependent prolongation of the QT interval. There is no experience with high exposure or concomitant use with other QT prolonging drugs. To minimize the risk of QT prolongation, the lowest effective dose should always be used.
    Miglitol: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as olanzapine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Mirtazapine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and TdP. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Mobocertinib: (Major) Concomitant use of mobocertinib and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Moexipril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Molindone: (Major) Close monitoring is advisable during concurrent use of molindone with other antipsychotics. Because molindone shares certain pharmacological properties with other antipsychotics, additive cardiac effects (e.g., hypotension), CNS effects (e.g., drowsiness), anticholinergic effects (e.g., constipation, xerostomia), extrapyramidal effects, neuroleptic malignant syndrome, or seizures may occur. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Monoamine oxidase inhibitors: (Moderate) Due to the potential for additive sedative and cardiovascular effects (e.g., hypotension), MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.
    Morphine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. For extended-release morphine tablets (MS Contin and Morphabond), start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at one-third to one-half the recommended starting dosage. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Morphine; Naltrexone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. For extended-release morphine tablets (MS Contin and Morphabond), start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at one-third to one-half the recommended starting dosage. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Moxifloxacin: (Major) Concurrent use of olanzapine and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
    Nabilone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Nadolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Nafarelin: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Nalbuphine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and nalbuphine. Concurrent use may result in additive CNS depression.
    Nateglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Nebivolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Nebivolol; Valsartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Non-Ionic Contrast Media: (Major) Atypical antipsychotics may lower the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Norfloxacin: (Moderate) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering olanzapine with norfloxacin. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Quinolones have also been associated with QT prolongation and TdP. For norfloxacin specifically, extremely rare cases of TdP were reported during post-marketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as olanzapine. Decreased metabolism of olanzapine may lead to clinically important adverse reactions such as extrapyramidal symptoms, sedation, or orthostatic hypotension. In addition, olanzapine is associated with a possible risk for QT prolongation and TdP. Therapeutic monitoring is recommended with coadministration.
    Octreotide: (Moderate) Use octreotide with caution in combination with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Moderate) Caution is advised when administering olanzapine with ofloxacin as concurrent use may increase the risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine; Fluoxetine: (Moderate) Caution is advised when administering olanzapine with fluoxetine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Oliceridine: (Major) Concomitant use of oliceridine with olanzapine may cause excessive sedation and somnolence. Limit the use of oliceridine with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Olmesartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olodaterol: (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Ritonavir may reduce olanzapine serum concentrations by approximately 50%; how this affects olanzapine efficacy, however, is not known. Ritonavir appears to induce olanzapine's metabolism by either CYP1A2 or glucuronide conjugation. If ritonavir and olanzapine are used concurrently, monitor for reduced olanzapine effect and adjust olanzapine dose as needed.
    Ondansetron: (Major) Monitor ECG for evidence of QT prolongation if coadministration of ondansetron and olanzapine is necessary. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Opicapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
    Oritavancin: (Moderate) Olanzapine is metabolized by CYP2D6; oritavancin is a weak CYP2D6 inducer. Plasma concentrations and efficacy of olanzapine may be reduced if these drugs are administered concurrently.
    Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties, like olanzapine and orphenadrine, are used concomitantly. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur.
    Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with olanzapine. Osilodrostat is associated with dose-dependent QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Osimertinib: (Major) Avoid coadministration of olanzapine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of olanzapine with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Oxazepam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
    Oxybutynin: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Oxycodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Oxymorphone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial oxymorphone dosage by one-third to one-half. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Ozanimod: (Major) In general, do not initiate ozanimod in patients taking olanzapine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). Additionally, there is a potential for hypertensive crisis or serotonin syndrome. If treatment initiation is considered, seek advice from a cardiologist and monitor for hypertension and serotonergic effects. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis or serotonergic effects. Olanzapine has also been associated with serotonin syndrome reports postmarketing, but the mechanism is not clear. Ozanimod may also result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Olanzapine has been associated with a significant prolongation of the QTc interval.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as olanzapine. In addition, coadministration of antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. If coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
    Panobinostat: (Major) The co-administration of panobinostat with olanzapine is not recommended; QT prolongation has been reported with both drugs. Additionally, levels of olanzapine may be increased. If concomitant use of olanzapine and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of olanzapine toxicity including QT prolongation and cardiac arrhythmias. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Olanzapine is a CYP2D6 substrate, and panobinostat is a CYP2D6 inhibitor. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
    Paroxetine: (Major) Concurrent use of paroxetine and olanzapine may result in additive anticholinergic effects, such as urinary retention, constipation, blurred vision, and xerostomia. In addition, paroxetine is a potent inhibitor of CYP2D6, which is a minor isoenzyme pathway for the metabolism of olanzapine. Adverse effects of olanzapine that may become evident include fatigue, dizziness, weight gain, prolactin elevation, orthostatic hypotension, sedation, or extrapyramidal symptoms. In addition, olanzapine is associated with a possible risk of QT prolongation and should be used cautiously with strong CYP2D6 inhibitors such as paroxetine.
    Pasireotide: (Moderate) Use caution when using pasireotide in combination with olanzapine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib has been reported to prolong the QT interval. If pazopanib and the other drug must be continued, closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and TdP that should be avoided with pazopanib include olanzapine.
    Peginterferon Alfa-2b: (Minor) Monitor for adverse effects associated with increased exposure to olanzapine, such as extrapyramidal symptoms, sedation, and orthostatic hypotension, if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP1A2 inhibitor, while olanzapine is a CYP1A2 substrate.
    Penbutolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Pentamidine: (Major) Pentamidine has been associated with QT prolongation. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with pentamidine include olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
    Pentazocine: (Moderate) Coadministration of pentazocine with atypical antipsychotics may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation. Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity.
    Pentazocine; Naloxone: (Moderate) Coadministration of pentazocine with atypical antipsychotics may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation. Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity.
    Pentobarbital: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as olanzapine.
    Pergolide: (Moderate) Due to mutually opposing effects on dopamine, atypical antipsychotics and pergolide may interfere with the effectiveness of each other. Additive CNS depressant effects are also possible. In general, atypical antipsychotics are less likely to interfere with pergolide than traditional antipsychotics. Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of either agent during coadministration.
    Perindopril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Perindopril; Amlodipine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Perphenazine: (Moderate) Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation, such as olanzapine. Coadministration may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Perphenazine; Amitriptyline: (Moderate) Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation, such as olanzapine. Coadministration may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Phenelzine: (Moderate) Due to the potential for additive sedative and cardiovascular effects (e.g., hypotension), MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.
    Phenobarbital: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Phenoxybenzamine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Phenytoin: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Coadministration may increase the risk for QT prolongation.
    Pimozide: (Contraindicated) Olanzapine has a risk of QT prolongation and is contraindicated with pimozide. Concurrent use of pimozide with atypical agents may increase the risk of adverse effects such as drowsiness, sedation, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Pindolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Pioglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Pioglitazone; Glimepiride: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Pioglitazone; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Pitolisant: (Major) Avoid coadministration of pitolisant with olanzapine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Ponesimod: (Major) In general, do not initiate ponesimod in patients taking olanzapine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Limited date, including some case reports suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Posaconazole: (Moderate) Use posaconazole with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Potassium-sparing diuretics: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Pramipexole: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or pramipexole during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and pramipexole may interfere with the effectiveness of each other. Additive CNS depressant effects are also possible. In general, atypical antipsychotics are less likely to interfere with pramipexole than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
    Pramlintide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Pregabalin: (Moderate) Initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of pregabalin and olanzapine. Concomitant use of pregabalin with olanzapine may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
    Prilocaine; Epinephrine: (Moderate) Olanzapine may induce significant alpha-adrenergic blockade in overdose, leading to profound hypotension. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity since the beta-stimulation may worsen hypotension in the setting of olanzapine overdose.
    Primaquine: (Moderate) Exercise caution when administering primaquine in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Primaquine is associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Primidone: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Procainamide: (Major) Olanzapine should be used cautiously and with close monitoring with procainamide. Procainamide administration is associated with QT prolongation and torsades de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP).
    Prochlorperazine: (Moderate) Both prochlorperazine and olanzapine are associated with a possible risk for QT prolongation; this risk may be increased during concurrent use. Coadministration of antipsychotics may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Promethazine: (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
    Promethazine; Dextromethorphan: (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
    Promethazine; Phenylephrine: (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
    Propafenone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with olanzapine. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Propantheline: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Propoxyphene: (Moderate) Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression, including opiate agonists.
    Propranolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Pseudoephedrine; Triprolidine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Quazepam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
    Quetiapine: (Major) Concurrent use of quetiapine and olanzapine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that both olanzapine and quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. In addition, co-administration of quetiapine with olanzapine may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Quinapril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Quinidine: (Major) Quinidine and dextromethorphan; quinidine cause dose-dependent QT prolongation. These drugs should be avoided in patients receiving drugs that may prolong the QT interval and are metabolized by CYP2D6, such as olanzapine. The manufacturer recommends an ECG in patients taking these drugs together.
    Quinine: (Major) Concurrent use of quinine and olanzapine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Quinine has been associated with prolongation of the QT interval and rare cases of TdP. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, concentrations of olanzapine may be increased with concomitant use of quinine. Olanzapine is a CYP2D6 substrate and quinine is a CYP2D6 inhibitor.
    Ramelteon: (Moderate) Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression including ramelteon.
    Ramipril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Ranolazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during ranolazine treatment. Drugs that are CYP2D6 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include olanzapine.
    Rasagiline: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or rasagiline during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and rasagiline may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with rasagiline than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
    Relugolix: (Moderate) Caution is advised when administering olanzapine with relugolix. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
    Relugolix; Estradiol; Norethindrone acetate: (Moderate) Caution is advised when administering olanzapine with relugolix. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
    Remifentanil: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Repaglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Reserpine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Ribociclib: (Major) Avoid coadministration of ribociclib with olanzapine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with olanzapine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Concomitant use may increase the risk for QT prolongation.
    Rifampin: (Moderate) Monitor for reduced olanzapine efficacy if rifampin coadministration is medically necessary; in some patients, dosage adjustments may be needed. Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and potent inducers of this enzyme increase olanzapine clearance. While rifampin is a CYP3A inducer, it is likely its induction of CYP1A2 is responsible for the increased olanzapine clearance, and roughly 48% decrease in olanzapine AUC (exposure) seen when rifampin is used with olanzapine.
    Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Risperidone: (Moderate) Use risperidone and olanzapine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). In addition, coadministration may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Ritonavir: (Moderate) Ritonavir may reduce olanzapine serum concentrations by approximately 50%; how this affects olanzapine efficacy, however, is not known. Ritonavir appears to induce olanzapine's metabolism by either CYP1A2 or glucuronide conjugation. If ritonavir and olanzapine are used concurrently, monitor for reduced olanzapine effect and adjust olanzapine dose as needed.
    Rivastigmine: (Moderate) Olanzapine exhibits moderate anticholinergic activity, and is more likely than most other atypical antipsychotics to diminish the therapeutic action of rivastigmine. Consider the use of an antipsychotic with less prominent anticholinergic effects. Rivastigmine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine.
    Rolapitant: (Major) Monitor for olanzapine-related adverse effects, including QT prolongation, if coadministered with rolapitant. Increased exposure to olanzapine may occur. Olanzapine is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Romidepsin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with olanzapine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Ropinirole: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or ropinirole during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and ropinirole may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with ropinirole than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
    Rosiglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Rotigotine: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, excess sedation, and diminished effectiveness of the atypical antipsychotic or rotigotine during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and rotigotine may interfere with the effectiveness of each other. Additive CNS depressant effects are also possible. In general, atypical antipsychotics are less likely to interfere with rotigotine than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
    Sacubitril; Valsartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Safinamide: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or safinamide during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and safinamide may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with safinamide than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
    Salmeterol: (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Saquinavir: (Major) Concurrent use of olanzapine and saquinavir should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Saxagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Scopolamine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Secobarbital: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Selegiline: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or selegiline during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and selegiline may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with selegiline than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
    Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with olanzapine is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Semaglutide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Sertraline: (Moderate) Use caution and monitor patients for QT prolongation when administering olanzapine with sertraline. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Sertraline's FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval; however, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    SGLT2 Inhibitors: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Short-acting beta-agonists: (Minor) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Sibutramine: (Major) Caution and close monitoring should be observed when administering sibutramine with drugs that are dopamine antagonists such as the atypical antipsychotics. Monitor for CNS depression, changes in mood or behavior, and for other drug-related adverse reactions. Sibutramine has not been systematically evaluated in combination with antipsychotic medications. Sibutramine is a serotonin reuptake inhibitor that also inhibits norepinephrine and dopamine reuptake. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Simeprevir: (Minor) Simeprevir is an inhibitor of CYP1A2, which may result in decreased clearance of olanzapine. Decreased metabolism of olanzapine may lead to clinically important adverse reactions such as extrapyramidal symptoms, sedation, or orthostatic hypotension. In addition, olanzapine is associated with a possible risk for QT prolongation and TdP and should be used cautiously with CYP1A2 inhibitors.
    Simvastatin; Sitagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving olanzapine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Sitagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Moderate) Use caution when prescribing sodium picosulfate; magnesium oxide; anhydrous citric acid in patients taking concomitant medications that are known to induce Antidiuretic Hormone Secretion (SIADH), such as antipsychotics, as these drugs may increase the risk of water retention and/or electrolyte imbalance.
    Solifenacin: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering solifenacin with olanzapine. Solifenacin has been associated dose-dependent prolongation of the QT interval. TdP has been reported with post-marketing use, although causality was not determined. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Sorafenib: (Major) Avoid coadministration of sorafenib with olanzapine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Sotalol: (Major) Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. Drugs with a possible risk for QT prolongation and TdP, such as olanzapine, should be used cautiously with sotalol. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
    Spironolactone: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    St. John's Wort, Hypericum perforatum: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system and could decrease the efficacy of some medications metabolized by these enzymes including olanzapine.
    Sufentanil: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Sulfonylureas: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Sunitinib: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Sunitinib can prolong the QT interval.
    Suvorexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of suvorexant and atypical antipsyhotics. Dosage adjustments of suvorexant and the atypical antipsychotic may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if suvorexant is taken with other CNS depressants.
    Tacrine: (Moderate) Olanzapine is a primary substrate of CYP1A2, and its metabolism could be reduced by CYP1A2 inhibitors such as tacrine. In addition, olanzapine exhibits moderate anticholinergic activity, and may diminish the therapeutic action of tacrine. Tacrine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine.
    Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with olanzapine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Tamoxifen: (Moderate) Caution is advised with the concomitant use of tamoxifen and olanzapine due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Tapentadol: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Telavancin: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telavancin with olanzapine. Telavancin has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine also may be associated with a significant prolongation of the QTc interval in rare instances.
    Telithromycin: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telithromycin with olanzapine. Telithromycin is associated with QT prolongation and TdP. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
    Telmisartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Telmisartan; Amlodipine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Temazepam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
    Terazosin: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Tetrabenazine: (Major) Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc such as olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. In addition, concurrent use of olanzapine and tetrabenazine should generally be avoided since the risk of adverse effects such as drowsiness, sedation, dizziness, orthostatic hypotension, neuroleptic malignant syndrome, or extrapyramidal symptoms may be increased.
    Thiabendazole: (Major) Thiabendazole is a potent inhibitor of CYP1A2 hepatic enzymes. Decreased metabolism of olanzapine via CYP1A2 may lead to clinically important adverse reactions such as extrapyramidal symptoms, sedation, or orthostatic hypotension. In addition, olanzapine is associated with a possible risk for QT prolongation and TdP and should be used cautiously with potent CYP1A2 inhibitors. The manufacturer of olanzapine suggests lower doses of olanzapine should be considered in patients receiving potent CYP1A2 inhibitors. This interaction should also be considered with coadministration of fixed-dose combination products, such as fluoxetine; olanzapine, with thiabendazole.
    Thiazide diuretics: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Thiethylperazine: (Major) Concurrent use of olanzapine with other antipsychotics, like phenothiazines is not recommended. If used concomitantly with olanzapine, other antipsychotics may increase the risk of adverse effects such as drowsiness, sedation, dizziness, orthostatic hypotension, or anticholinergic effects. Extrapyramidal side effects may also be potentiated. Additive anticholinergic effects may also be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity like olanzapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Thiopental: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and torsade de pointes and is contraindicated with other drugs that prolong the QTc interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. In addition, coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Thiothixene: (Major) Caution is advisable during concurrent use of thiothixene and other antipsychotics. Thiothixene use may be associated with adverse events such as drowsiness, dizziness, hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of thiothixene and other antipsychotics. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Timolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Tiotropium; Olodaterol: (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Tobacco: (Moderate) Tobacco smoking causes a substantial reduction in plasma concentrations of olanzapine. Although tobacco smokers might require higher doses of olanzapine, dosage modifications are not routinely recommended due to the wide therapeutic index of olanzapine.
    Tolcapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
    Tolterodine: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with olanzapine. Tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, olanzapine exhibits anticholinergic effects that may be clinically significant; additive anticholinergic effects may be seen when drugs with antimuscarinic properties like tolterodine are used concomitantly. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the interacting agent.
    Toremifene: (Major) Avoid coadministration of olanzapine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Tramadol: (Moderate) If concomitant use of tramadol and olanzapine is warranted, monitor patients for seizures, excessive sedation and/or somnolence, and the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concomitant use of tramadol and olanzapine may increase seizure risk and cause additive CNS depression. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Tramadol; Acetaminophen: (Moderate) If concomitant use of tramadol and olanzapine is warranted, monitor patients for seizures, excessive sedation and/or somnolence, and the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concomitant use of tramadol and olanzapine may increase seizure risk and cause additive CNS depression. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Trandolapril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Trandolapril; Verapamil: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Tranylcypromine: (Moderate) Due to the potential for additive sedative and cardiovascular effects (e.g., hypotension), MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.
    Trazodone: (Major) Avoid coadministration of trazodone and olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Trazodone can also cause CNS depression and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Treprostinil: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Triamterene: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Triazolam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
    Triclabendazole: (Moderate) Monitor ECGs in patients receiving triclabendazole with olanzapine. Transient prolongation of the mean QTc interval was noted on the ECG recordings in dogs administered triclabendazole. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Tricyclic antidepressants: (Moderate) Olanzapine or tricyclic antidepressants, at elevated serum concentrations, may prolong the QTc interval. In addition, anticholinergic effects and sedation may be seen when tricyclic antidepressants are used with olanzapine.
    Trifluoperazine: (Moderate) Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation. Trifluoperazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation, such as olanzapine. Coadministration may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Trihexyphenidyl: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
    Triprolidine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Triptorelin: (Major) Avoid coadministration of triptorelin with olanzapine due to the risk of reduced efficacy of triptorelin; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; triptorelin is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval.
    Trospium: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like trospium and olanzapine are used concomitantly. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function and temperature regulation. While CNS-related side effects such as drowsiness and blurred vision are not typically noted with trospium, they may occur in some patients.
    Umeclidinium; Vilanterol: (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation. Drugs with a possible risk for QT prolongation include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Valsartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Vandetanib: (Major) Avoid coadministration of vandetanib with olanzapine due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Vardenafil: (Moderate) Caution is advised when administering olanzapine with vardenafil as concurrent use may increase the risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in the QTc interval.
    Vasodilators: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as olanzapine, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, olanzapine is a substrate of CYP1A2 and 2D6, while vemurafenib is an inhibitor of both of these enzymes. Therefore, concentrations of olanzapine could be increased with concomitant use. Monitor the patient for increase side effects.
    Venlafaxine: (Moderate) Venlafaxine is associated with a possible risk of QT prolongation. Atypical antipsychotics associated with a risk for QT prolongation and TdP that should be used cautiously with venlafaxine include olanzapine. In addition, venlafaxine is a weak inhibitor of CYP2D6. Atypical antipsychotics with partial metabolism via CYP2D6 include olanzapine. Monitor patients for potential adverse effects if these drugs are co-prescribed.
    Viloxazine: (Moderate) Monitor for olanzapine-related adverse effects, including sedation, anticholinergic effects, hypotension, and QT prolongation, if concomitant use of viloxazine is necessary. A dose reduction of olanzapine may be necessary. Concomitant use may increase olanzapine exposure. Direct glucuronidation and CYP metabolism via CYP2D6 and CYP1A2 are the primary metabolic pathways for olanzapine. Viloxazine is a strong CYP1A2 inhibitor and weak CYP2D6.
    Voclosporin: (Moderate) Concomitant use of voclosporin and olanzapine may increase the risk of QT prolongation. Consider interventions to minimize the risk of progression to torsades de pointes (TdP), such as ECG monitoring and correcting electrolyte abnormalities, particularly in patients with additional risk factors for TdP. Voclosporin has been associated with QT prolongation at supratherapeutic doses. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Voriconazole: (Moderate) Caution is advised when administering voriconazole with olanzapine as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Vorinostat: (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP). Vorinostat therapy is associated with a risk of QT prolongation and should be used cautiously with olanzapine.
    Zaleplon: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Ziconotide: (Moderate) Olanzapine is a CNS depressant medication that may increase drowsiness, dizziness, and confusion that are associated with ziconotide. If altered consciousness occurs, consider treatment discontinuation.
    Ziprasidone: (Major) Concomitant use of ziprasidone and olanzapine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. In addition, coadministration of atypical antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    Zolpidem: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Zonisamide: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.

    PREGNANCY AND LACTATION

    Pregnancy

    Olanzapine is present in human milk. There are reports of excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) in babies exposed to olanzapine through breast milk. There is no information on the effects of olanzapine on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for olanzapine and any potential adverse effects on the breastfed child from the drug or from the mother's underlying condition. Any infant exposed to olanzapine should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements). In a study in lactating women, the mean infant dose at steady-state was estimated to be 1.8% of the maternal olanzapine dose. Due to individual variability in response to antipsychotics, it may be prudent to continue the existing olanzapine regimen if ongoing treatment is deemed necessary during breast-feeding. However, quetiapine may be considered as an alternate atypical agent. Regardless of the antipsychotic used, the nursing infant should be closely monitored for excessive drowsiness, lethargy, and developmental delays. Combination treatment with antipsychotics may increase the risk of these adverse events.

    MECHANISM OF ACTION

    The exact mechanism of action of olanzapine in treating schizophrenia has not been determined. However, it is thought that atypical antipsychotics such as olanzapine reduce the positive and negative symptoms of schizophrenia through modulation of central dopaminergic and serotonergic activity. Available data suggest that the efficacy of olanzapine in treating schizophrenia is primarily attributable to a combination of dopamine and serotonin 5-HT2A antagonism. The mechanism of action in bipolar disorder is unknown.
     
    Dopamine and serotonin mediate various effects in different portions of the brain. According to one hypothesis, a dopamine excess in the mesolimbic tract is thought to be responsible for the positive symptoms of schizophrenia. In the mesocortical tract, a reduction in dopamine activity may be responsible for the negative symptoms of schizophrenia. Reduced dopamine activity in the nigrostriatal tract may be related to decreased metabolic activity in the basal ganglia. Central serotonin hyperactivity may be associated with dopamine hypoactivity in the nigrostriatal and mesocortical tracts. Antipsychotics with a high affinity for serotonin receptors are thought to be more effective for treating the negative symptoms of schizophrenia than those with dopaminergic modulation as a primary mechanism. The tuberoinfundibular tract controls neuroendocrine and hypothalamic function (e.g., prolactin release). Antipsychotic-mediated dopamine receptor blockade in the tuberoinfundibular tract increases prolactin release, which can lead to adverse effects such as amenorrhea, gynecomastia, galactorrhea, decreased libido, and impotence.[43222] [42605]
     
    Olanzapine has a high in vitro binding affinity at receptor sites including alpha-1, histamine H-1, dopamine D1 through D4, and serotonin 5-HT2A, 5-HT2C, and 5-HT6. Olanzapine moderately binds to muscarinic M1 through M5 and serotonin 5-HT3 receptors. Antagonism at muscarinic receptors, H-1 receptors, and alpha-1 receptors correlates with various side effects of olanzapine, including anticholinergic effects, somnolence, and orthostatic hypotension, respectively. The 5-HT2C receptor is involved in the regulation of food intake, which may explain the larger increase in weight associated with olanzapine compared to many other atypical antipsychotics. Olanzapine binds weakly to GABA-A, benzodiazepine, and beta-adrenergic receptors.

    PHARMACOKINETICS

    Olanzapine is administered orally or intramuscularly by immediate-release or extended-release injection. Protein binding is about 93%, primarily to albumin and alpha-1-acid glycoprotein. Olanzapine is primarily metabolized by glucuronidation and CYP450 oxidation via CYP1A2 and CYP2D6. Oxidation via CYP2D6 seems to be a minor metabolic pathway in vivo; the clearance of olanzapine is not decreased in adults with a deficiency of this enzyme. The flavin-containing mono-oxygenase system also appears to be involved in olanzapine oxidation. The major circulating metabolites are the 10-N-glucuronide and 4-N-desmethyl olanzapine; neither metabolite has any pharmacological activity. The elimination half-life averages 30 hours for immediate-release dosage forms of olanzapine with a range of 21 to 54 hours. Excretion is 30% fecal and 57% renal.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP1A2, CYP2D6, UGT
    Olanzapine is a major substrate for CYP1A2 and a minor substrate for CYP2D6. Concurrent use with a CYP1A2 inhibitor or inducer (e.g., smoking) can result in clinically significant interactions. Inducers of glucuronyl transferase (UGT) can increase olanzapine clearance. In vitro data suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A.[28785]

    Oral Route

    After oral administration, olanzapine is well absorbed. Food does not affect oral absorption. There is extensive first-pass metabolism, with about 40% of the dose being metabolized before reaching the systemic circulation. The onset of action is 20 to 30 minutes; action peaks at 6 hours and persists for 24 hours. Steady-state concentrations are reached in approximately 1 week of continuous dosing. Pharmacokinetic studies showed that olanzapine tablets and olanzapine orally disintegrating tablets (i.e., Zyprexa Zydis) are bioequivalent. Based on a pharmacokinetic study in healthy volunteers, a 5 mg IM dose produces, on average, a maximum plasma concentration roughly 5 times higher than the maximum plasma concentration produced by a 5 mg oral dose. The area under the curve achieved after an IM dose is similar to that achieved after oral administration of the same dose. Metabolic profiles after IM administration are qualitatively similar to metabolic profiles after oral administration. About 57% and 30% of an orally administered dose is recovered in the urine and feces, respectively. [64934]

    Intramuscular Route

    Immediate-release injection (Zyprexa IntraMuscular)
    Intramuscular (IM) administration results in rapid absorption with peak plasma concentrations occurring within 15 to 45 minutes. Based on a pharmacokinetic study in healthy volunteers, a 5 mg IM dose produces, on average, a maximum plasma concentration roughly 5 times higher than the maximum plasma concentration produced by a 5 mg oral dose. The AUC achieved after an IM dose is similar to that achieved after oral administration of the same dose. In clinical trials, IM olanzapine was superior to placebo at 2 hours post-injection for the treatment of agitation in patients with schizophrenia or bipolar disorder. Metabolic profiles after IM administration are qualitatively similar to metabolic profiles after oral administration.
     
    Extended-release injection (Zyprexa Relprevv)
    Slow dissolution from the injection site results in prolonged systemic olanzapine plasma concentrations for weeks to months. A 2- to 4-week injection within the therapeutic dose range provides similar plasma concentrations to those achieved by therapeutic daily doses of oral olanzapine. The effective half-life is about 30 days compared to a half-life of 30 hours for the oral formulation. Peak plasma concentrations are attained within the first week and are at trough levels just prior to the next injection. The peak-to-trough fluctuation is comparable to that of once-daily oral dosing. A Zyprexa Relprevv dose of 300 mg IM every 2 weeks corresponds to about 20 mg/day of the oral formulation and a Zyprexa Relprevv dose of 150 mg IM every 2 weeks corresponds to about 10 mg/day of the oral formulation. When switching from the oral formulation to the extended-release injection, approximately 3 months of dosing is needed to re-establish steady-state conditions. Although plasma concentrations from the injectable formulation may initially be lower than the oral formulation, olanzapine concentrations remained within a therapeutic range, and supplementation with oral olanzapine was generally not needed during clinical trials.