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    Multi-Acting Receptor-Targeted Antipsychotics (MARTA)

    BOXED WARNING

    Agranulocytosis, bone marrow suppression, chemotherapy, fever, infection, leukemia, leukopenia, neutropenia

    Clozapine is available only through a restricted program called the Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program. All prescribers of clozapine, prescriber designees, and dispensing pharmacies must be certified in the Clozapine REMS program. Because clozapine can cause severe neutropenia (agranulocytosis), which can lead to infection and death, there is a minimum baseline neutrophil count required to initiate therapy and all patients receiving clozapine must be enrolled by the prescriber or the prescriber's designee in the clozapine REMS program. More information, including enrollment and certification requirements for providers and pharmacies, is available at: https://www.clozapinerems.com.[63913] To improve and standardize understanding, severe neutropenia replaces the previous terms severe leukopenia, severe granulocytopenia, or agranulocytosis in the clozapine product labels. The ANC is the only test result accepted in the Clozapine REMS Program to monitor for neutropenia. The mechanism by which clozapine causes neutropenia is not known, and it is not dose-dependent. Clozapine dose cannot be used as a reliable indicator for severe neutropenia risk. The risk of neutropenia generally appears greatest during the first 18 weeks and then declines, but may occur at any time. Conditions that may be associated with an increased risk for neutropenia include, but are not limited to, bone marrow suppression, leukopenia, and leukemia. A complete blood count (CBC), including the ANC value, should be obtained before initiating treatment with clozapine to ensure a normal baseline neutrophil count (ANC) of at least 1,500/microL for the general population (i.e., non-Benign Ethnic Neutropenia patients). Patients with documented Benign Ethnic Neutropenia (BEN) must have at least 2 baseline ANC levels of 1,000/microL or more before treatment can be initiated. Weekly ANC monitoring is required for all patients during the first 6 months of treatment, with modifications made to the ANC monitoring requirements after that for each individual based on clinical status, BEN status, and previous laboratory results, as outlined in the Clozapine REMS program. Treatment exclusions occur when the absolute neutrophil count (ANC) falls below the required minimum ANC as outlined in the monitoring requirements. In general, patients who develop severe neutropenia (ANC less than 500/microL) with clozapine should not be re-challenged, unless the prescriber determines that the benefit outweighs the risks. The prescriber must take into account the recommended ANC thresholds, the patient's medical/psychiatric history, the severity of the neutropenic episode, and should discuss the benefits and risks of clozapine re-challenge with the patient or his/her caregiver. Patients should report the appearance of fever, sore throat, lethargy, weakness, or other signs of bone marrow suppression or infection to their health care provider immediately. Risk factors for developing severe neutropenia from clozapine therapy, other than initial bone marrow suppression, are not known. Patients with a Jewish background, those undergoing the first 4 to 10 weeks of drug therapy, female sex, older patients, cachectic patients, or those with serious underlying medical illness may theoretically be at greater risk for severe neutropenia, but definitive data are not available. It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., chemotherapy) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased ANC monitoring and consult the treating hematologist/oncologist.[28262] [31301] [53094]

    Seizure disorder, seizures

    Clozapine should be used cautiously in patients with a history of seizure disorder or those with risk factors that may predispose them to seizures (e.g., head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse). Clozapine lowers the seizure threshold in a dose-dependent manner, particularly at doses greater than 600 mg/day. Dosage increases in patients with a pre-existing seizure disorder should be cautious. Clozapine may induce EEG changes, myoclonic jerks or generalized seizures. Because of the substantial risk of seizure associated with clozapine use, patients should be cautioned about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving, operating complex machinery, swimming, climbing). Clozapine may potentially decrease the effectiveness of anticonvulsants in the treatment of seizure disorders. Additionally, anticonvulsants that are inducers of CYP3A4 or CYP1A2 may reduce the efficacy of clozapine, which is a substrate of CYP3A4 and CYP1A2. If seizures occur, the clozapine dosage should be reduced or discontinued, and, if necessary, anticonvulsant treatment initiated.[28262] [31301] [53094]

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, cardiomyopathy, cerebrovascular disease, coronary artery disease, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, hypotension, hypovolemia, long QT syndrome, malnutrition, myocardial infarction, myocarditis, orthostatic hypotension, QT prolongation, syncope, tachycardia, thyroid disease, torsade de pointes, ventricular arrhythmias

    Similar to other antipsychotic agents, ECG repolarization changes and serious cardiac events have been reported with clozapine therapy. Treatment with clozapine has been associated with QT prolongation, ventricular arrhythmias, torsade de pointes (TdP), cardiac arrest, and sudden death. Use clozapine with caution in patients with a history of QT prolongation (including congenital long QT syndrome) or other cardiac disease or conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation. Electrolyte imbalances should be corrected prior to initiating treatment with clozapine. Baseline assessments of serum potassium and magnesium levels should be performed, as well as periodic evaluation during treatment, in patients at risk for electrolyte imbalances. Given the potential for QT prolongation, clozapine should be used cautiously with other drugs that cause QT prolongation. Prescribers should evaluate symptoms of dizziness, syncope, or palpitations. The drug should be discontinued if the QT interval measurement exceeds 500 msec. Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred during clozapine treatment and can be fatal. These symptoms are consistent with neurally mediated reflex bradycardia. The risk is highest during the initial titration period, and particularly with rapid titration. Therefore, the manufacturer's dosing titration guidelines must be followed. Orthostatic hypotension 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 orthostasis. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Clozapine should be used cautiously in patients with cardiac disease (e.g., history of myocardial infarction or ischemia, heart failure, conduction abnormalities), cerebrovascular disease, or other conditions that would predispose patients to hypotension (e.g., concurrent use of antihypertensives, dehydrated state, or hypovolemia). Cardiomyopathy or myocarditis, sometimes fatal, have occurred during clozapine use. Discontinue clozapine and obtain a cardiac evaluation if either of these reactions is suspected. Myocarditis most frequently presents within the first 2 months of treatment and cardiomyopathy symptoms usually occur after 8 weeks of treatment. Cardiomyopathy or myocarditis should be considered in patients receiving clozapine who present with unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, other signs or symptoms of heart failure, or ECG findings such as ST-T wave abnormalities or cardiac arrhythmias. It is not known whether eosinophilia is a reliable predictor of myocarditis. In patients who are diagnosed with cardiomyopathy while taking clozapine, mitral valve incompetence has been reported. These cases reported either mild or moderate mitral regurgitation on two-dimensional echocardiography. In patients with suspected cardiomyopathy, consider a 2D-echo Doppler exam to identify mitral valve incompetence. Tachycardia may occur secondary to hypotension, but has also been noted as a presenting sign in patients with myocarditis. Therefore, tachycardia during the first month of therapy warrants close monitoring for other signs of myocarditis. In general, patients with clozapine-related myocarditis or cardiomyopathy should not be re-challenged with clozapine. However, if the benefit of treatment with clozapine is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, rechallenge with clozapine may be considered in consultation with a cardiologist, after a complete cardiac evaluation, and with close monitoring.

    Dementia, geriatric, stroke

    Geriatric patients, especially those with compromised cardiac functioning, may be more susceptible to the cardiovascular effects of clozapine, including orthostatic hypotension and tachycardia. Geriatric patients may also be more likely to experience tardive dyskinesia, severe neutropenia (agranulocytosis) or anticholinergic effects (e.g., urinary retention or constipation) due to clozapine. Lower initial doses and gradual titration of clozapine should be considered in the elderly, along with close monitoring. Atypical antipsychotics are not approved for the treatment of dementia-related psychosis in geriatric patients. All atypical antipsychotic labels include a boxed warning regarding increased morbidity and mortality (1.6 to 1.7 times vs. placebo) reported in geriatric patients with dementia receiving atypical antipsychotics. Deaths typically occurred due to 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. According to the Beers Criteria, antipsychotics are considered potentially inappropriate medications (PIMs) in elderly patients, and use should be avoided except for treating schizophrenia or bipolar disorder, and for short-term use as antiemetics during chemotherapy. Avoid use of clozapine in geriatric patients with the following conditions due to the potential for symptom exacerbation or adverse effects: lower urinary tract symptoms/benign prostatic hyperplasia in men (decreased urinary flow, urinary retention), delirium (possible new-onset or worsening delirium), dementia (adverse CNS effects), and Parkinson's disease (symptom exacerbation). There is an increased risk of stroke and a greater rate of cognitive decline and mortality in persons with dementia receiving antipsychotics. The Beers expert panel recommends avoiding antipsychotics to treat delirium- or dementia-related behavioral problems unless non-pharmacological options have failed or are not possible and the patient is a substantial threat to self or others. Avoid antipsychotics in elderly patients with a history of falls or fractures unless safer alternatives are not available since antipsychotics can cause ataxia, impaired psychomotor function, syncope, and new falls. If use is necessary, consider reducing the use of other CNS-active medications and implement other strategies to reduce fall risk. Because antipsychotics can cause or exacerbate hyponatremia and SIADH, particularly in the elderly, sodium levels should be closely monitored when starting or changing dosages of antipsychotics in older adults. While it is recommended that most dopamine-receptor antagonists be avoided in patients with Parkinson's disease due to the potential to worsen parkinsonian symptoms, clozapine appears less likely to precipitate a worsening of symptoms than other antipsychotics and is excluded from the recommendation. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). An antipsychotic should generally be used only for the conditions listed in the guidelines (e.g., schizophrenia, mood disorder, Tourette's disorder) and meet the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for use. The LTCF must identify and address all possible causes of behavioral or psychological symptoms of dementia (BPSD) before considering an antipsychotic, as there is an increased risk of morbidity and mortality in elderly patients treated with antipsychotics for dementia-related psychosis. To initiate antipsychotic therapy, the patient must either be a danger to self or others or have symptoms due to mania or psychosis, and the plan of care should document attempted behavioral interventions (except in an emergency). Limit emergency treatment to 7 days or less and evaluate/document within 7 days the contributors/causes to the symptoms. For acute conditions persisting beyond 7 days, appropriate non-pharmacologic interventions must be attempted, unless clinically contraindicated and documented. Treatment of non-acute, chronic, or prolonged BPSD must meet all of the OBRA criteria for BPSD treatment and ensure that the behavioral symptoms are not due to a treatable medical condition or correctable environmental or psychological stressors alone and the facility must provide documented evidence of persistence. The LTCF must evaluate the appropriateness of antipsychotic treatment during or within 2 weeks of admission for a newly admitted resident. OBRA provides general dosing guidance for antipsychotic treatment of BPSD. In all cases, the lowest possible dose and the shortest duration should be prescribed and the facility should monitor for ongoing effectiveness and potential adverse effects. Antipsychotics are subject to periodic review for effectiveness, medical necessity/rationale for use, and the potential for gradual dose reduction (GDR) or discontinuation. Refer to the OBRA guidelines for complete information.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral dibenzodiazepine-type atypical antipsychotic; relatively low potential for extrapyramidal symptoms
    Reserved for adults with refractory schizophrenia and for reducing the risk of suicidal behavior in schizophrenia or schizoaffective disorder
    Clozapine REMS Program ensures proper monitoring, especially for severe neutropenia; boxed warning for increased mortality risk in elderly patients with dementia-related psychosis

    COMMON BRAND NAMES

    Clozaril, Fazaclo, Versacloz

    HOW SUPPLIED

    Clozapine/Clozaril Oral Tab: 25mg, 50mg, 100mg, 200mg
    Clozapine/Fazaclo Oral Tab Orally Dis: 12.5mg, 25mg, 100mg, 150mg, 200mg
    Versacloz Oral Susp: 1mL, 50mg

    DOSAGE & INDICATIONS

    For the treatment of refractory schizophrenia that has failed to respond adequately to appropriate courses of standard antipsychotic agents; also to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder.
    Oral dosage
    Adults

    Patients must be enrolled in the clozapine REMS program by the prescriber.[63913] Initially, 12.5 mg PO once or twice daily on the first day. After day 1, the dose may be titrated by 25 to 50 mg every day over 2 weeks, if well tolerated, to a dose of 300 to 450 mg/day, in divided doses. Subsequently titrate no more than once or twice weekly, in increments of no more than 100 mg, to efficacy and tolerability. Debilitated or older adults, including those who are malnourished or with cardiac disease, should be carefully monitored. To minimize the risk of orthostatic hypotension, bradycardia, and syncope, use the recommended starting dose, a gradual titration schedule, and divided dosages. Due to the potentially serious side effects, avoid the extended use of clozapine in patients failing to show an acceptable level of clinical response. Max: 900 mg/day PO. Doses more than 600 mg/day and rapid dose escalation may increase the risk of seizures or other side effects. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided, or dosage adjustments may be necessary; review drug interactions. It may be necessary to reduce the dose in poor metabolizers of CYP2D6 (CYP2D6 PMs). DISCONTINUATION: Use gradual reduction over 1 to 2 weeks unless clinical circumstances (e.g., neutropenia) require abrupt discontinuation. If abruptly discontinued, monitor for recurrence of psychosis or cholinergic rebound (e.g., headache, nausea, vomiting, diarrhea). RE-INITIATION OF HELD TREATMENT: If 2 days or more have elapsed since the last dose, re-initiate with 12.5 mg once or twice daily and follow the usual titration schedule. Some symptoms respond rapidly to antipsychotic treatment; chronic schizophrenia usually improves slowly over many weeks and may continue to improve for months. Early discontinuation of therapy may increase the risk of relapse in some patients.[28262] [31301] [53094] [63395]

    For the treatment of bipolar disorder†.
    Oral dosage
    Adults

    Limited data are available describing the use of clozapine in the initial management of acute bipolar disorder; data are from studies in non-elderly adults. In one review, the mean dose of clozapine after titration at follow-up was 325.6 +/- 161.9 mg/day in 21 patients with bipolar disorder. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. It may be necessary to reduce the dose in poor metabolizers of CYP2D6 (CYP2D6 PMs). Clozapine has been evaluated as treatment in refractory bipolar I disorder. A small, 3-week, open label trial (n = 27) compared the effectiveness of clozapine (mean dose 166 mg/day) to chlorpromazine (mean dose 310 mg/day); both agents were in combination with lithium for treatment of refractory bipolar mania. At 2 weeks, reduction YMRS scores (Young Mania Rating Scale) were significantly lower in the clozapine group, indicating a more rapid response to clozapine, but at 3 weeks no difference was noted in YMRS. As add-on treatment in a 12-month study, clozapine was effective for mood stabilization at a mean doses of 156 +/- 77 mg/day. Overall, depressive symptoms were not improved. Clozapine has been shown to be effective in a 12-month study as maintenance therapy for patients refractory to combined conventional mood stabilizers (e.g., lithium, divalproex, carbamazepine). Thirty-nine patients were randomly assigned to adjunctive clozapine (mean dose 234 mg/day PO; range 50 to 403 mg/day PO) or treatment as usual. No significant effect was noted on depression scores.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    900 mg/day PO.

    Geriatric

    900 mg/day PO.

    Adolescents

    Safety and efficacy have not been established; however, doses up to 300 mg/day PO have been reported for the treatment of refractory schizophrenia off-label.

    Children

    9 to 12 years: Safety and efficacy have not been established; however, doses up to 300 mg/day PO have been reported for the treatment of refractory schizophrenia off-label.
    Less than 9 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Use clozapine with caution in patients with hepatic disease. Modify dosage depending on clinical response and degree of hepatic impairment. If a patient develops signs or symptoms of liver problems during treatment, liver function tests (LFTs) should be measured. If LFTs are significantly elevated or if jaundice is present, treatment should be discontinued.

    Renal Impairment

    It may be necessary to reduce the dose of clozapine in patients with significant renal impairment; however, quantitative guidelines for adjustments are not available.
     
    Intermittent hemodialysis
    Hemodialysis, forced diuresis, hemoperfusion, or other methods are unlikely to be of benefit in clozapine removal.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Oral Administration

    May administer without regard to meals.

    Oral Solid Formulations

    Oral disintegrating tablets (ODT) (e.g., FazaClo):
    Keep the ODT in the unopened blister until the time of use. Just prior to use, peel the foil from the blister and gently remove the ODT. Do not push the ODT through the foil, because this could damage the tablet.
    Place tablet on the tongue, allow to dissolve, then swallow. Alternatively, the tablets may be chewed and swallowed.
    May be swallowed with saliva. No water is necessary for administration.

    Oral Liquid Formulations

    Oral Suspension (e.g., Versacloz):
    Each box contains one 1 mL oral syringe, one 9 mL oral syringe, and 1 bottle adaptor along with the suspension bottle. For each new bottle, push the provided adaptor into the bottle until the top of the adaptor is lined up with the top of the bottle.
    Prior to each use, shake well for 10 seconds.
    Fill the oral syringe (1 mL or 9 mL depending upon dose) with air and insert into the adaptor, dispelling the air into the bottle.
    If the dose is 1 mL (50 mg) or less, use the 1 mL oral syringe.
    If the dose is greater than 1 mL (50 mg), use the 9 mL oral syringe.
    Fill syringe with the prescribed dose and administer immediately. Do not save the dose in the oral syringe for later administration.
    Administer slowly into 1 side of the mouth with the patient's lips closed tightly around the syringe. The dose should be swallowed slowly.
    After use, the oral syringe may be washed with warm water and air dried in preparation for the patient's next dose.
    Close the bottle with its cap; the bottle adaptor can remain in place.
    Storage of opened bottle: The suspension is stable for 100 days after initial opening. Store at or below 25 degrees C (77 degrees F). Do not refrigerate or freeze.

    STORAGE

    Generic:
    - Store at room temperature not exceeding 86 degrees F
    Clozaril:
    - Avoid temperatures above 86 degrees F
    Fazaclo:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Versacloz:
    - Do not freeze
    - Do not refrigerate
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Clozapine is contraindicated for use in patients with a previous hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson Syndrome) or any other component of the product. Eosinophilia, defined as a blood eosinophil count of greater than 700/microL, has also occurred with clozapine treatment. Clozapine-related eosinophilia usually occurs during the first month of treatment. In some patients, it has been associated with organ involvements such as cardiac. pancreatic, hepatic, renal, and colon inflammation. Such organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS), also known as drug induced hypersensitivity syndrome (DIHS). If eosinophilia develops during clozapine treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, and organ-specific disease associated with eosinophilia. If clozapine-related systemic disease is suspected, discontinue clozapine immediately. If a cause of eosinophilia unrelated to clozapine is identified (e.g., asthma, allergies, collagen vascular disease, parasitic infections, and specific neoplasms), treat the underlying cause and continue clozapine. Clozapine-related eosinophilia has also occurred in the absence of organ involvement and can resolve without intervention. There are reports of successful rechallenge after discontinuation of clozapine, without recurrence of eosinophilia. In the absence of organ involvement, continue clozapine under careful monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt clozapine therapy and rechallenge after the eosinophil count decreases should be based on the overall clinical assessment, in consultation with an internist or hematologist.

    Agranulocytosis, bone marrow suppression, chemotherapy, fever, infection, leukemia, leukopenia, neutropenia

    Clozapine is available only through a restricted program called the Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program. All prescribers of clozapine, prescriber designees, and dispensing pharmacies must be certified in the Clozapine REMS program. Because clozapine can cause severe neutropenia (agranulocytosis), which can lead to infection and death, there is a minimum baseline neutrophil count required to initiate therapy and all patients receiving clozapine must be enrolled by the prescriber or the prescriber's designee in the clozapine REMS program. More information, including enrollment and certification requirements for providers and pharmacies, is available at: https://www.clozapinerems.com.[63913] To improve and standardize understanding, severe neutropenia replaces the previous terms severe leukopenia, severe granulocytopenia, or agranulocytosis in the clozapine product labels. The ANC is the only test result accepted in the Clozapine REMS Program to monitor for neutropenia. The mechanism by which clozapine causes neutropenia is not known, and it is not dose-dependent. Clozapine dose cannot be used as a reliable indicator for severe neutropenia risk. The risk of neutropenia generally appears greatest during the first 18 weeks and then declines, but may occur at any time. Conditions that may be associated with an increased risk for neutropenia include, but are not limited to, bone marrow suppression, leukopenia, and leukemia. A complete blood count (CBC), including the ANC value, should be obtained before initiating treatment with clozapine to ensure a normal baseline neutrophil count (ANC) of at least 1,500/microL for the general population (i.e., non-Benign Ethnic Neutropenia patients). Patients with documented Benign Ethnic Neutropenia (BEN) must have at least 2 baseline ANC levels of 1,000/microL or more before treatment can be initiated. Weekly ANC monitoring is required for all patients during the first 6 months of treatment, with modifications made to the ANC monitoring requirements after that for each individual based on clinical status, BEN status, and previous laboratory results, as outlined in the Clozapine REMS program. Treatment exclusions occur when the absolute neutrophil count (ANC) falls below the required minimum ANC as outlined in the monitoring requirements. In general, patients who develop severe neutropenia (ANC less than 500/microL) with clozapine should not be re-challenged, unless the prescriber determines that the benefit outweighs the risks. The prescriber must take into account the recommended ANC thresholds, the patient's medical/psychiatric history, the severity of the neutropenic episode, and should discuss the benefits and risks of clozapine re-challenge with the patient or his/her caregiver. Patients should report the appearance of fever, sore throat, lethargy, weakness, or other signs of bone marrow suppression or infection to their health care provider immediately. Risk factors for developing severe neutropenia from clozapine therapy, other than initial bone marrow suppression, are not known. Patients with a Jewish background, those undergoing the first 4 to 10 weeks of drug therapy, female sex, older patients, cachectic patients, or those with serious underlying medical illness may theoretically be at greater risk for severe neutropenia, but definitive data are not available. It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., chemotherapy) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased ANC monitoring and consult the treating hematologist/oncologist.[28262] [31301] [53094]

    CNS depression, coadministration with other CNS depressants, driving or operating machinery, ethanol ingestion

    Clozapine can cause somnolence, CNS depression, and impairment of cognitive and motor performance; these reactions may be particularly evident during treatment initiation and following dosage increases. Clozapine-induced somnolence may be dose-related; a dose reduction may be required in some cases. 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 or diseases that could exacerbate somnolence, including coadministration with other CNS depressants or ethanol ingestion. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Patients should be cautioned about driving or operating machinery or performing other tasks requiring mental alertness until they know how clozapine affects them.[28262] [31301] [53094]

    Seizure disorder, seizures

    Clozapine should be used cautiously in patients with a history of seizure disorder or those with risk factors that may predispose them to seizures (e.g., head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse). Clozapine lowers the seizure threshold in a dose-dependent manner, particularly at doses greater than 600 mg/day. Dosage increases in patients with a pre-existing seizure disorder should be cautious. Clozapine may induce EEG changes, myoclonic jerks or generalized seizures. Because of the substantial risk of seizure associated with clozapine use, patients should be cautioned about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving, operating complex machinery, swimming, climbing). Clozapine may potentially decrease the effectiveness of anticonvulsants in the treatment of seizure disorders. Additionally, anticonvulsants that are inducers of CYP3A4 or CYP1A2 may reduce the efficacy of clozapine, which is a substrate of CYP3A4 and CYP1A2. If seizures occur, the clozapine dosage should be reduced or discontinued, and, if necessary, anticonvulsant treatment initiated.[28262] [31301] [53094]

    Tardive dyskinesia

    Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotics; however, due to the relatively low affinity of clozapine for D2 receptors, it may be considered as a substitute when patients develop tardive dyskinesia from other antipsychotics. Periodic evaluation for movement disorders is recommended (e.g., AIMS). Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the initiation of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotics differ in their potential to cause tardive dyskinesia is unknown. 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 even arise after drug discontinuation. The syndrome may remit, partially or completely, if the antipsychotic is withdrawn. Antipsychotics may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, clozapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotics, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic therapy, the smallest dose and the shortest duration producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear, clozapine discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, cardiomyopathy, cerebrovascular disease, coronary artery disease, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, hypotension, hypovolemia, long QT syndrome, malnutrition, myocardial infarction, myocarditis, orthostatic hypotension, QT prolongation, syncope, tachycardia, thyroid disease, torsade de pointes, ventricular arrhythmias

    Similar to other antipsychotic agents, ECG repolarization changes and serious cardiac events have been reported with clozapine therapy. Treatment with clozapine has been associated with QT prolongation, ventricular arrhythmias, torsade de pointes (TdP), cardiac arrest, and sudden death. Use clozapine with caution in patients with a history of QT prolongation (including congenital long QT syndrome) or other cardiac disease or conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation. Electrolyte imbalances should be corrected prior to initiating treatment with clozapine. Baseline assessments of serum potassium and magnesium levels should be performed, as well as periodic evaluation during treatment, in patients at risk for electrolyte imbalances. Given the potential for QT prolongation, clozapine should be used cautiously with other drugs that cause QT prolongation. Prescribers should evaluate symptoms of dizziness, syncope, or palpitations. The drug should be discontinued if the QT interval measurement exceeds 500 msec. Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred during clozapine treatment and can be fatal. These symptoms are consistent with neurally mediated reflex bradycardia. The risk is highest during the initial titration period, and particularly with rapid titration. Therefore, the manufacturer's dosing titration guidelines must be followed. Orthostatic hypotension 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 orthostasis. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Clozapine should be used cautiously in patients with cardiac disease (e.g., history of myocardial infarction or ischemia, heart failure, conduction abnormalities), cerebrovascular disease, or other conditions that would predispose patients to hypotension (e.g., concurrent use of antihypertensives, dehydrated state, or hypovolemia). Cardiomyopathy or myocarditis, sometimes fatal, have occurred during clozapine use. Discontinue clozapine and obtain a cardiac evaluation if either of these reactions is suspected. Myocarditis most frequently presents within the first 2 months of treatment and cardiomyopathy symptoms usually occur after 8 weeks of treatment. Cardiomyopathy or myocarditis should be considered in patients receiving clozapine who present with unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, other signs or symptoms of heart failure, or ECG findings such as ST-T wave abnormalities or cardiac arrhythmias. It is not known whether eosinophilia is a reliable predictor of myocarditis. In patients who are diagnosed with cardiomyopathy while taking clozapine, mitral valve incompetence has been reported. These cases reported either mild or moderate mitral regurgitation on two-dimensional echocardiography. In patients with suspected cardiomyopathy, consider a 2D-echo Doppler exam to identify mitral valve incompetence. Tachycardia may occur secondary to hypotension, but has also been noted as a presenting sign in patients with myocarditis. Therefore, tachycardia during the first month of therapy warrants close monitoring for other signs of myocarditis. In general, patients with clozapine-related myocarditis or cardiomyopathy should not be re-challenged with clozapine. However, if the benefit of treatment with clozapine is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, rechallenge with clozapine may be considered in consultation with a cardiologist, after a complete cardiac evaluation, and with close monitoring.

    Thromboembolic disease, thromboembolism

    Use clozapine with caution in patients with a history of thromboembolism or thromboembolic disease. Pulmonary embolism and deep-vein thrombosis (DVT) have occurred in patients treated with clozapine. Consider the possibility of pulmonary embolism in patients who present with deep-vein thrombosis, acute dyspnea, chest pain, or with other respiratory signs and symptoms. Whether pulmonary embolus and DVT can be attributed to clozapine or some characteristic(s) of patients is not clear.

    Hepatic disease, hepatitis, hepatotoxicity, jaundice, poor metabolizers

    Clozapine exposure is likely to be increased in patients with significant hepatic disease impairment when given usual doses; therefore, a dosage reduction may be necessary for this patient population. Dose reduction may also be necessary for patients who are CYP2D6 poor metabolizers. Clozapine concentrations may be increased in these patients because clozapine is almost completely metabolized and then excreted. Clozapine may cause hepatotoxicity. Severe, life-threatening, and in some cases fatal liver injury including hepatic failure, hepatic necrosis, and hepatitis have been reported during clozapine administration. Patients should be monitored for the appearance of signs and symptoms of hepatotoxicity (e.g., fatigue, malaise, anorexia, nausea, jaundice, hyperbilirubinemia, coagulopathy, hepatic encephalopathy). Liver function tests (LFTs) should be performed if hepatotoxicity is suspected. Permanent discontinuation of treatment should be considered if the cause of the liver injury is due to clozapine.[28262] [31301] [53094]

    Renal failure, renal impairment

    Dose reduction may be necessary in patients with significant renal impairment; use particular caution in patients with renal failure. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted.

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

    Clozapine exhibits potent anticholinergic effects. Central or peripheral anticholinergic toxicity is possible. Caution is advisable during use of clozapine in conditions that can be exacerbated by anticholinergic activity, including closed-angle glaucoma, prostatic hypertrophy, urinary retention, or other conditions in which anticholinergic effects can lead to significant adverse reactions. Treatment with clozapine can result in gastrointestinal adverse reactions, including constipation, GI obstruction, fecal impaction, and paralytic ileus; such reactions can be fatal. Constipation should be initially treated by ensuring adequate hydration and use of ancillary therapy such as bulk laxatives. Consultation with a gastroenterologist is advisable in more serious cases. In addition, the anticholinergic effects of clozapine may be additive to other anticholinergic medications and close monitoring is recommended if concurrent use is required.

    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. In general, antipsychotics should be avoided in patients with Parkinson's disease due to the potential for dopamine antagonists to exacerbate the symptoms of Parkinson's disease. Although clozapine appears less likely to precipitate worsening of Parkinson's disease than most other antipsychotics, caution and close monitoring are recommended.

    Dysphagia

    Antipsychotics have been associated with esophageal dysmotility and aspiration of gastric contents, which may increase the incidence of aspiration pneumonia in certain patient populations, such as patients with advanced Alzheimer's disease. Dysphagia and aspiration have been reported during postmarketing use of clozapine. Aspiration pneumonia has occurred in the setting of clozapine overdose. Patients with dysphagia or who are at risk for aspiration pneumonia should be closely monitored while receiving clozapine.

    Diabetes mellitus, diabetic ketoacidosis, hypercholesterolemia, hyperglycemia, hyperlipidemia, hyperosmolar hyperglycemic state (HHS), hypertriglyceridemia, obesity

    Atypical antipsychotics, including clozapine, have been associated with metabolic changes that may increase cardiovascular or cerebrovascular risk over time, including loss of blood glucose control, dyslipidemia and weight gain. Monitoring of weight and evaluation of lipids at baseline and periodically throughout treatment are recommended. Patients with risk factors for diabetes mellitus (e.g., obesity, pre-diabetes, family history) should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Treatment with clozapine should be undertaken with caution in patients with pre-existing conditions such as obesity, pre-diabetes, or hyperlipidemia (e.g., hypercholesterolemia or hypertriglyceridemia). Hyperglycemia and diabetes mellitus, in some cases associated with diabetic ketoacidosis, hyperosmolar hyperglycemic state (HHS) with coma or death, have been reported in patients treated with atypical antipsychotics including clozapine. Epidemiological studies suggest an increased risk of hyperglycemia-related adverse events in patients treated with the atypical antipsychotics, although precise risk estimates are not available. An increased risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus, in general, complicates this concern. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia (polydipsia, polyuria, polyphagia, weakness). Patients with established diabetes mellitus should be monitored regularly for worsening of glucose control. Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood glucose testing. In some cases, hyperglycemia had resolved when the antipsychotic was discontinued; however, some patients required continuation of the anti-diabetic medication(s) despite discontinuation of the suspect drug.[28262] [31301] [53094]

    Ambient temperature increase, dehydration, hyperthermia, hypothermia, strenuous exercise

    During clozapine therapy, patients have experienced transient, clozapine-related fever. The peak incidence is within the first 3 weeks of treatment. While this fever is generally benign and self-limited, it may necessitate discontinuing treatment. The fever can be associated with an increase or decrease in WBC count. Carefully evaluate patients with fever to rule out severe neutropenia or infection. Consider the possibility of neuroleptic malignant syndrome (NMS), which can be fatal.[28262] [31301] [53094] 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 clozapine should be advised of conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, ambient temperature increase, or dehydration).[28262] [31301] [53094] A less frequently described alteration in thermoregulatory processes reported with both conventional and atypical antipsychotics is hypothermia. Thermoregulation is multi-factorial; however, the dopaminergic system appears to have a primary role, and serotonin may also have modulatory activity (5-HT2a receptors). Most cases of hypothermia associated with antipsychotics have occurred in conjunction with other potential precipitating factors such as hypothyroidism, sepsis, organic brain injury, or environmental temperature. Hypothermia appears to occur more frequently during the initiation of antipsychotic therapy or after dose increases.[54333]

    Tobacco smoking

    Tobacco smoking may increase the clearance of clozapine, resulting in reduced clozapine plasma concentrations and a potential loss of efficacy. Tobacco smokers may require higher doses of clozapine. Tobacco smoke contains hydrocarbons that moderately induce CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Because the effect on CYP1A2 is not related to the nicotine component of tobacco, sudden smoking cessation may result in a reduced clearance of clozapine, despite the initiation of nicotine replacement. Monitor patients carefully when changes in smoking status occur.[28262] [31301] [53094]

    Abrupt discontinuation

    Abrupt discontinuation of clozapine is not recommended (due to the potential for cholinergic rebound and recurrence of psychotic symptoms) unless required by the patient's medical condition (e.g., moderate to severe neutropenia). Otherwise, discontinuation should occur through a gradual reduction in dosage over 1 to 2 weeks. Patients should be carefully observed for the recurrence of psychotic symptoms or cholinergic rebound (e.g., headache, nausea, vomiting, or diarrhea) during drug discontinuation. For abrupt clozapine discontinuation unrelated to neutropenia, continuation of the existing absolute neutrophil count (ANC) monitoring is recommended for general population patients until their ANC is 1,500/microL or higher and for benign ethnic neutropenia (BEN) patients until their ANC is at least 1,000/microL or above their baseline. For abrupt discontinuation due to moderate to severe neutropenia, ANCs should be obtained as specified in the ANC monitoring section of the product labeling.[28262] [31301] [53094]

    Dementia, geriatric, stroke

    Geriatric patients, especially those with compromised cardiac functioning, may be more susceptible to the cardiovascular effects of clozapine, including orthostatic hypotension and tachycardia. Geriatric patients may also be more likely to experience tardive dyskinesia, severe neutropenia (agranulocytosis) or anticholinergic effects (e.g., urinary retention or constipation) due to clozapine. Lower initial doses and gradual titration of clozapine should be considered in the elderly, along with close monitoring. Atypical antipsychotics are not approved for the treatment of dementia-related psychosis in geriatric patients. All atypical antipsychotic labels include a boxed warning regarding increased morbidity and mortality (1.6 to 1.7 times vs. placebo) reported in geriatric patients with dementia receiving atypical antipsychotics. Deaths typically occurred due to 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. According to the Beers Criteria, antipsychotics are considered potentially inappropriate medications (PIMs) in elderly patients, and use should be avoided except for treating schizophrenia or bipolar disorder, and for short-term use as antiemetics during chemotherapy. Avoid use of clozapine in geriatric patients with the following conditions due to the potential for symptom exacerbation or adverse effects: lower urinary tract symptoms/benign prostatic hyperplasia in men (decreased urinary flow, urinary retention), delirium (possible new-onset or worsening delirium), dementia (adverse CNS effects), and Parkinson's disease (symptom exacerbation). There is an increased risk of stroke and a greater rate of cognitive decline and mortality in persons with dementia receiving antipsychotics. The Beers expert panel recommends avoiding antipsychotics to treat delirium- or dementia-related behavioral problems unless non-pharmacological options have failed or are not possible and the patient is a substantial threat to self or others. Avoid antipsychotics in elderly patients with a history of falls or fractures unless safer alternatives are not available since antipsychotics can cause ataxia, impaired psychomotor function, syncope, and new falls. If use is necessary, consider reducing the use of other CNS-active medications and implement other strategies to reduce fall risk. Because antipsychotics can cause or exacerbate hyponatremia and SIADH, particularly in the elderly, sodium levels should be closely monitored when starting or changing dosages of antipsychotics in older adults. While it is recommended that most dopamine-receptor antagonists be avoided in patients with Parkinson's disease due to the potential to worsen parkinsonian symptoms, clozapine appears less likely to precipitate a worsening of symptoms than other antipsychotics and is excluded from the recommendation. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). An antipsychotic should generally be used only for the conditions listed in the guidelines (e.g., schizophrenia, mood disorder, Tourette's disorder) and meet the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for use. The LTCF must identify and address all possible causes of behavioral or psychological symptoms of dementia (BPSD) before considering an antipsychotic, as there is an increased risk of morbidity and mortality in elderly patients treated with antipsychotics for dementia-related psychosis. To initiate antipsychotic therapy, the patient must either be a danger to self or others or have symptoms due to mania or psychosis, and the plan of care should document attempted behavioral interventions (except in an emergency). Limit emergency treatment to 7 days or less and evaluate/document within 7 days the contributors/causes to the symptoms. For acute conditions persisting beyond 7 days, appropriate non-pharmacologic interventions must be attempted, unless clinically contraindicated and documented. Treatment of non-acute, chronic, or prolonged BPSD must meet all of the OBRA criteria for BPSD treatment and ensure that the behavioral symptoms are not due to a treatable medical condition or correctable environmental or psychological stressors alone and the facility must provide documented evidence of persistence. The LTCF must evaluate the appropriateness of antipsychotic treatment during or within 2 weeks of admission for a newly admitted resident. OBRA provides general dosing guidance for antipsychotic treatment of BPSD. In all cases, the lowest possible dose and the shortest duration should be prescribed and the facility should monitor for ongoing effectiveness and potential adverse effects. Antipsychotics are subject to periodic review for effectiveness, medical necessity/rationale for use, and the potential for gradual dose reduction (GDR) or discontinuation. Refer to the OBRA guidelines for complete information.

    Neonates, pregnancy, pregnancy testing

    There are no adequate trials of the effect of clozapine in human pregnancy. Animal studies have produced no evidence of adverse fetal effects; however, the use of clozapine during pregnancy should be undertaken only when needed because animal data may not be indicative of a human response. Clozapine is known to have serious adverse effects that may compromise maternal health and influence pregnancy status. Neonatal effects have been reported with the use of antipsychotics during pregnancy. Extrapyramidal symptoms and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates exposed to antipsychotics during the third trimester of pregnancy. These complications have varied in severity, with some neonates recovered within hours or days without specific treatment and others requiring prolonged hospitalization. Monitor neonates for extrapyramidal and withdrawal symptoms and manage symptoms appropriately. The knowledge about long-term neurobehavioral effects in offspring is limited for all antipsychotics and requires further investigation. According to the American Psychiatric Association treatment guidelines for schizophrenia, consider pregnancy testing in women of childbearing potential before initiation of an antipsychotic. The National Pregnancy Registry for Psychiatric Medications is dedicated to evaluating the safety of psychiatric medications that may be taken by women during pregnancy to treat a wide range of mood, anxiety, or psychiatric disorders. The primary goal of this Registry is to determine the frequency of major malformations, such as heart defects, cleft lip, or neural tube defects, in babies exposed to various psychiatric drugs during pregnancy. While the research concentrates on atypical antipsychotics and antidepressant use, pregnant women using other psychiatric medications are encouraged to register. For more information, contact the registry at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry or by phone 1-866-961-2388. It is not known if antipsychotics, through their effect on prolactin, would affect labor or obstetric delivery.[28262] [31301] [53094] [43461] [49642] [61843]

    Breast-feeding

    A decision should be made whether to discontinue breast-feeding or to discontinue clozapine, taking into account the importance of the drug to the mother. Anecdotal evidence suggests that clozapine accumulates in human breast milk. An antipsychotic agent other than clozapine would be preferred due to the possibility of clozapine-induced agranulocytosis or other adverse events in the nursing infant; guidelines support that lactating women taking clozapine should not breastfeed. Although elevations in prolactin associated with clozapine are minimal relative to many other antipsychotics, interference with proper lactation is possible. Alternate medications for consideration during breast-feeding include atypical antipsychotic agents such as olanzapine or quetiapine. Data related to the safety of antipsychotics during breast-feeding are limited and chronic administration of any antipsychotic during breast-feeding should be avoided if possible. 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.[28262] [31301] [53094] [46865] [46866] [46867] [46868] [46875] [46964] [46965] [61847]

    Children, infants

    The safety and efficacy of clozapine use in children and adolescents have not been established. Limited data on the use of clozapine for resistant schizophrenia exists for children older than 9 years of age. Due to the potential for serious adverse effects from clozapine, including agranulocytosis, only consider clozapine use in children refractory to other antipsychotic medications. Routine cardiovascular monitoring has been suggested for children receiving psychotropic medications due to the potential of these agents to produce adverse cardiac effects. There is no known use of clozapine in infants. Additionally, adverse effects have been reported after delivery in newborns exposed to antipsychotics during the third trimester and some cases have included intensive care unit stays and prolonged hospitalization.[28262] [31301] [53094]

    Phenylketonuria

    Oral disintegrating clozapine tablets (e.g., FazaClo) may contain aspartame and should be used cautiously in patients with phenylketonuria. Phenylalanine is a component of aspartame. Each 25-mg orally disintegrating tablet of FazaClo contains 3.1 mg of aspartame (1.74 mg of phenylalanine), and each 100-mg oral disintegrating tablet of FazaClo contains 12.4 mg of aspartame (6.96 mg of phenylalanine).[31301]

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / 1.0-5.0
    visual impairment / Early / 5.0-5.0
    akinesia / Delayed / 4.0-4.0
    agranulocytosis / Delayed / 1.0-1.0
    neutropenia / Delayed / 1.0-1.0
    cyanosis / Early / 0-1.0
    bradycardia / Rapid / 0-1.0
    peptic ulcer / Delayed / 0-1.0
    hematemesis / Delayed / 0-1.0
    myocarditis / Delayed / 0-0.1
    tardive dyskinesia / Delayed / Incidence not known
    neuroleptic malignant syndrome / Delayed / Incidence not known
    stroke / Early / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    atrial fibrillation / Early / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    cardiac arrest / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    pericarditis / Delayed / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    pseudopheochromocytoma / Delayed / Incidence not known
    hepatic encephalopathy / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    GI obstruction / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    cirrhosis / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    diabetic ketoacidosis / Delayed / Incidence not known
    pleural effusion / Delayed / Incidence not known
    apnea / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    vasculitis / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    ocular hypertension / Delayed / Incidence not known
    water intoxication / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known

    Moderate

    sinus tachycardia / Rapid / 25.0-25.0
    constipation / Delayed / 14.0-25.0
    hypotension / Rapid / 9.0-9.0
    orthostatic hypotension / Delayed / 0-6.0
    hypertension / Early / 4.0-4.0
    leukopenia / Delayed / 3.0-3.0
    akathisia / Delayed / 3.0-3.0
    confusion / Early / 3.0-3.0
    eosinophilia / Delayed / 1.0-1.0
    anemia / Delayed / 0-1.0
    dysarthria / Delayed / 0-1.0
    ataxia / Delayed / 1.0-1.0
    pseudoparkinsonism / Delayed / 0-1.0
    phlebitis / Rapid / 0-1.0
    palpitations / Early / 0-1.0
    premature ventricular contractions (PVCs) / Early / 0-1.0
    chest pain (unspecified) / Early / 1.0-1.0
    angina / Early / 1.0-1.0
    edema / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 1.0-1.0
    urinary retention / Early / 1.0-1.0
    urinary incontinence / Early / 1.0-1.0
    impotence (erectile dysfunction) / Delayed / 0-1.0
    ejaculation dysfunction / Delayed / 1.0-1.0
    hyperthermia / Delayed / 0-1.0
    wheezing / Rapid / 0-1.0
    dyspnea / Early / 1.0-1.0
    amnesia / Delayed / 0-1.0
    depression / Delayed / 1.0-1.0
    hallucinations / Early / 0-1.0
    erythema / Early / 0-1.0
    hematoma / Early / 0-1.0
    hot flashes / Early / 0-1.0
    atopic dermatitis / Delayed / 0-1.0
    myasthenia / Delayed / 1.0-1.0
    conjunctival hyperemia / Early / 0-1.0
    nystagmus / Delayed / 0-1.0
    thrombocytosis / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    myoclonia / Delayed / Incidence not known
    EEG changes / Delayed / Incidence not known
    dystonic reaction / Delayed / Incidence not known
    tachypnea / Early / Incidence not known
    ST-T wave changes / Rapid / Incidence not known
    QT prolongation / Rapid / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    dysphagia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    steatosis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    priapism / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    psychosis / Early / Incidence not known
    delirium / Early / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    hyponatremia / Delayed / Incidence not known

    Mild

    hypersalivation / Early / 48.0-48.0
    drowsiness / Early / 39.0-46.0
    dizziness / Early / 19.0-27.0
    insomnia / Early / 2.0-20.0
    vertigo / Early / 19.0-19.0
    vomiting / Early / 3.0-17.0
    nausea / Early / 3.0-17.0
    dyspepsia / Early / 14.0-14.0
    headache / Early / 7.0-7.0
    tremor / Early / 6.0-6.0
    syncope / Early / 6.0-6.0
    xerostomia / Early / 6.0-6.0
    hyperhidrosis / Delayed / 6.0-6.0
    fever / Early / 5.0-5.0
    nightmares / Early / 4.0-4.0
    restlessness / Early / 4.0-4.0
    pyrosis (heartburn) / Early / 4.0-4.0
    agitation / Early / 4.0-4.0
    weight gain / Delayed / 4.0-4.0
    fatigue / Early / 2.0-2.0
    diarrhea / Early / 2.0-2.0
    rash / Early / 2.0-2.0
    leukocytosis / Delayed / 0-1.0
    epistaxis / Delayed / 0-1.0
    asthenia / Delayed / 1.0-1.0
    hyperkinesis / Delayed / 1.0-1.0
    lethargy / Early / 1.0-1.0
    eructation / Early / 0-1.0
    dysgeusia / Early / 0-1.0
    urinary urgency / Early / 1.0-1.0
    dysmenorrhea / Delayed / 0-1.0
    mastalgia / Delayed / 0-1.0
    increased urinary frequency / Early / 1.0-1.0
    nasal congestion / Early / 1.0-1.0
    laryngitis / Delayed / 0-1.0
    sneezing / Early / 0-1.0
    malaise / Early / 0-1.0
    infection / Delayed / 0-1.0
    hyperventilation / Early / 0-1.0
    throat irritation / Early / 1.0-1.0
    rhinorrhea / Early / 0-1.0
    chills / Rapid / 0-1.0
    hypothermia / Delayed / 0-1.0
    cough / Delayed / 0-1.0
    anxiety / Delayed / 1.0-1.0
    libido decrease / Delayed / 0-1.0
    paranoia / Early / 0-1.0
    libido increase / Delayed / 0-1.0
    irritability / Delayed / 0-1.0
    pruritus / Rapid / 0-1.0
    pallor / Early / 0-1.0
    petechiae / Delayed / 0-1.0
    urticaria / Rapid / 0-1.0
    muscle cramps / Delayed / 1.0-1.0
    back pain / Delayed / 1.0-1.0
    myalgia / Early / 1.0-1.0
    mydriasis / Early / 0-1.0
    anorexia / Delayed / 1.0-1.0
    appetite stimulation / Delayed / 0-1.0
    paresthesias / Delayed / Incidence not known
    nocturia / Early / Incidence not known
    polyuria / Early / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known
    weight loss / Delayed / Incidence not known
    polydipsia / Early / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Major) Since abarelix can cause QT prolongation, abarelix should be used cautiously, if at all, with other drugs that are associated with QT prolongation. Clozapine may induce QT prolongation.
    Abiraterone: (Moderate) Monitor for an increase in clozapine-related adverse reactions if coadministration with abiraterone is necessary; consider reducing the dose of clozapine if clinically appropriate. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. If abiraterone is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. Clozapine is a CYP2D6 substrate and abiraterone is a moderate CYP2D6 inhibitor.
    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) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Acetaminophen; Aspirin, ASA; Caffeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
    Acetaminophen; Butalbital: (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Acetaminophen; Butalbital; Caffeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention. (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Acetaminophen; Caffeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Pain medications such as dihydrocodeine, should be combined cautiously with clozapine due to the potential for additive depressant effects and possible respiratory depression or hypotension. Concurrent use of clozapine and opiates may also lead to reduced intestinal motility or bladder function.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Acetaminophen; Codeine: (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as doxylamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    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) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as clozapine, can lead to additive respiratory depression, hypotension, profound sedation, or coma. In addition, this drug combination may result in additive effects on intestinal motility or bladder function. Prior to concurrent use of oxycodone in patients taking clozapine, 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. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider using a lower clozapine dose. Monitor patients for sedation and respiratory depression.
    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) Propoxyphene should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension. Combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Acetaminophen; Tramadol: (Moderate) Concurrent use of tramadol and clozapine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. In addition, in vitro data suggest that clozapine has CYP2D6 inhibitory effects and may increase plasma concentrations of CYP2D6 substrates such as tramadol. Although the full pharmacologic impact of increased tramadol exposure is unknown, close monitoring for serious adverse effects, such as seizures, is advisable. In addition, serotonin syndrome may occur during use of tramadol with medications that impair its metabolism. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, hyperreflexia, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because the analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), CYP2D6 inhibition by clozapine may alter the analgesic response to tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and clozapine.
    Acetazolamide: (Moderate) Caution is advisable during concurrent use of clozapine and acetazolamide as electrolyte imbalance caused by diuretics may increase the risk of QT prolongation with clozapine.
    Aclidinium; Formoterol: (Moderate) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with clozapine 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.
    Ado-Trastuzumab emtansine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Albendazole: (Moderate) Albendazole induces cytochrome P450 1A. and may induce the metabolism of clozapine. Patients receiving this combination should be closely monitored when albendazole is prescribed, as albendazole may increase the clearance of clozapine. Conversely, the discontinuation of albendazole therapy may result in a reduced clearance of the clozapine, leading to an increase in serum concentrations. 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.
    Albuterol: (Minor) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with clozapine 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.
    Albuterol; Ipratropium: (Minor) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with clozapine 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.
    Aldesleukin, IL-2: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. In addition, Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS or psychotropic activity (e.g., antipsychotics). Use with caution. Patients developing mood disturbances, moderate to severe lethargy/somnolence while on aldesleukin should seek evaluation from their health care provider.
    Alemtuzumab: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Alfentanil: (Moderate) Concomitant use of alfentanil with other CNS depressants, including clozapine, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. Combining alfentanil with clozapine may also lead to additive effects on intestinal motility or bladder function. A dose reduction of one or both drugs may be warranted.
    Alfuzosin: (Moderate) Use caution when administering alfuzosin with clozapine due to the potential for QT prolongation. Alfuzosin may prolong the QT interval in a dose-dependent manner. Treatment with clozapine has been associated with QT prolongation, torsade de pointes, cardiac arrest, and sudden death.
    Aliskiren; Amlodipine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Alkylating agents: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    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. 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) Alosetron, if combined with drugs that possess anticholinergic properties like clozapine, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
    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) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Altretamine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Amantadine: (Moderate) Amantadine may exhibit anticholinergic activity. Medications with significant anticholinergic activity, such as clozapine may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects.
    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 clozapine.
    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.
    Amiodarone: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation such as amiodarone. In addition, amiodarone is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP2D6 or CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Amitriptyline; Chlordiazepoxide: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Amlodipine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Amlodipine; Atorvastatin: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Amlodipine; Benazepril: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Amlodipine; Olmesartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Amlodipine; Telmisartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Amlodipine; Valsartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Amobarbital: (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Amoxapine: (Moderate) Amoxapine exhibits some antipsychotic activity and may increase the risk of tardive dyskinesia or neuroleptic malignant syndrome (NMS) when clozapine is given concurrently. In addition, additive anticholinergic effects and sedation are possible, as well as lowering of the seizure threshold.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with clozapine. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. In addition, clarithromycin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with clozapine. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. In addition, clarithromycin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. (Moderate) The addition of omeprazole to clozapine therapy resulted in a roughly 40% reduction in clozapine plasma concentrations in at least 2 patients. Omeprazole is an inducer of CYP1A2, one of the isoenzymes reponsible for the metabolism of clozapine. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
    Amprenavir: (Moderate) Caution is advisable during concurrent use of amprenavir and clozapine. Amprenavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP2D6, or CYP3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Anagrelide: (Moderate) Caution is advisable during concurrent use of anagrelide and clozapine. Anagrelide is an inhibitor of CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP2D6, or CYP3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. When initiating clozapine or adding a mild or moderate CYP1A2 inhibitor to clozapine treatment, monitor for adverse reactions and consider reducing the clozapine dose if necessary. If the inhibitor is discontinued, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Angiotensin II receptor antagonists: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Angiotensin-converting enzyme inhibitors: (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Anticholinergics: (Moderate) Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. 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.
    Antimetabolites: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Antitumor antibiotics: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Apalutamide: (Major) Coadministration of clozapine with apalutamide is not recommended due to decreased plasma concentrations of clozapine. If concomitant use is unavoidable, the patient should be monitored for loss of efficacy; consider increasing the clozapine dose if necessary. When apalutamide is discontinued, reduce the clozapine dose based on clinical response. Clozapine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Apomorphine: (Major) Exercise caution when administering apomorphine concomitantly with clozapine as concurrent use may increase the risk of QT prolongation, decrease apomorphine efficacy, and result in additive CNS effects. Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Clozapine may block the dopamine agonist properties of apomorphine, thereby compromising apomorphine effectiveness. Apomorphine causes considerable somnolence, and concomitant administration with clozapine could result in additive CNS effects.
    Aprepitant, Fosaprepitant: (Major) Use caution if clozapine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in clozapine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Clozapine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of clozapine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Arformoterol: (Moderate) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with clozapine 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: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Clozapine is an atypical antipsychotic with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with aripiprazole. In addition, caution is advisable when aripiprazole is given in combination with other CNS depressants such as other atypical antipsychotics. 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. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent.
    Armodafinil: (Moderate) Caution is advisable during concurrent use of modafinil or armodafinil with clozapine. Modanil and armodafinil have potential to induce CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Patients receiving clozapine in combination with a CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. An interaction between modafinil and clozapine has been reported in a case report that resulted in clinical side effects. After the addition of modafinil to the drug regimen of a patient stabilized on clozapine, the patient became symptomatic with dizziness, problems with gait, and sinus tachycardia. Clozapine serum concentrations were found to be elevated. All symptoms resolved and the patient's clozapine levels returned to normal on modafinil discontinuation. The mechanism of the interaction is unclear, but may be related to changes in clozapine metabolism by modafinil. Concomitant therapy of modafinil and clozapine should be approached with close monitoring of the patient's clinical status.
    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 clozapine. In addition, it is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor and clozapine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased clozapine 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 clozapine, should be avoided. Consider ECG monitoring if clozapine must be used with or after artemether; lumefantrine treatment.
    Articaine; Epinephrine: (Moderate) Clozapine may induce significant alpha-adrenergic blockade during clozapine overdose, leading to profound hypotension. Epinephrine should generally not be used to treat clozapine-induced hypotension due to the unopposed beta-activity, which potentially could worsen the hypotension.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect, such as clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Coadministration of asenapine with clozapine may also 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: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention. (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Pain medications such as dihydrocodeine, should be combined cautiously with clozapine due to the potential for additive depressant effects and possible respiratory depression or hypotension. Concurrent use of clozapine and opiates may also lead to reduced intestinal motility or bladder function.
    Aspirin, ASA; Caffeine; Orphenadrine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties, like clozapine 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: (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention. (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Aspirin, ASA; Omeprazole: (Moderate) The addition of omeprazole to clozapine therapy resulted in a roughly 40% reduction in clozapine plasma concentrations in at least 2 patients. Omeprazole is an inducer of CYP1A2, one of the isoenzymes reponsible for the metabolism of clozapine. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as clozapine, can lead to additive respiratory depression, hypotension, profound sedation, or coma. In addition, this drug combination may result in additive effects on intestinal motility or bladder function. Prior to concurrent use of oxycodone in patients taking clozapine, 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. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider using a lower clozapine dose. Monitor patients for sedation and respiratory depression.
    Atazanavir: (Moderate) Caution is advisable during concurrent use of atazanavir and clozapine. Atazanavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Atazanavir; Cobicistat: (Moderate) Caution is advisable during concurrent use of atazanavir and clozapine. Atazanavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Atenolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Atenolol; Chlorthalidone: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Atomoxetine: (Moderate) Use clozapine with caution in combination with atomoxetine. Treatment with clozapine has been associated with QT prolongation, torwade de pointes, cardiac arrest, and sudden death. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
    Atropine; Difenoxin: (Moderate) Diphenoxylate decreases GI motility. Other drugs that also decrease GI motility, such as clozapine, may produce additive effects with diphenoxylate if used concomitantly.
    Atropine; Diphenoxylate: (Moderate) Diphenoxylate decreases GI motility. Other drugs that also decrease GI motility, such as clozapine, may produce additive effects with diphenoxylate if used concomitantly.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as phenobarbital, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Phenobarbital may also increase the metabolism of clozapine through induction of CYP1A2. Close monitoring is recommended when clozapine is administered to patients with a seizure disorder because clozapine lowers the seizure threshold. The effectiveness of phenobarbital in treating seizures may be reduced. Dosage adjustments may be necessary, and close monitoring of clinical and/or adverse effects is warranted when phenobarbital is used with clozapine. Additive sedation may be noted with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Azithromycin: (Moderate) Consider the risk of QT prolongation which can be fatal when administering azithromycin to patients on other QT prolonging agents such as clozapine. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
    Bacillus Calmette-Guerin Vaccine, BCG: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Baclofen: (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with clozapine. 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. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
    Belinostat: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as phenobarbital, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Phenobarbital may also increase the metabolism of clozapine through induction of CYP1A2. Close monitoring is recommended when clozapine is administered to patients with a seizure disorder because clozapine lowers the seizure threshold. The effectiveness of phenobarbital in treating seizures may be reduced. Dosage adjustments may be necessary, and close monitoring of clinical and/or adverse effects is warranted when phenobarbital is used with clozapine. Additive sedation may be noted with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Belladonna; Opium: (Moderate) Pain medications such as opiate agonists, should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Bendamustine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Bendroflumethiazide; Nadolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with clozapine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with clozapine 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 clozapine, reduce initial dosage and titrate to clinical response. If clozapine is initiated a patient taking an opioid agonist, use a lower initial dose of clozapine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Benzodiazepines: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Bepridil: (Major) Bepridil is associated with a well-established risk of QT prolongation and torsades de pointes and should be used cautiously in combination with other drugs that may also prolong the QT interval, including clozapine.
    Beta-adrenergic blockers: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Betaxolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Bethanechol: (Moderate) Drugs that possess antimuscarinic properties, such as clozapine, are pharmacologic opposites of bethanechol. These agents should not be used with bethanechol except when the specific intent is to counteract excessive actions of one or the other.
    Bexarotene: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Use clozapine with caution in combination with metronidazole as concurrent use may increase the risk of QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Potential QT prolongation has been reported in limited case reports with metronidazole.
    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 clozapine 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 clozapine may produce additive effects. (Moderate) Use clozapine with caution in combination with metronidazole as concurrent use may increase the risk of QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bisoprolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Blinatumomab: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Boceprevir: (Moderate) Caution is advisable during concurrent use of boceprevir and clozapine. Boceprevir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Bortezomib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Bosentan: (Moderate) Concomitant use of clozapine and bosentan can increase the risk and severity of hypotension by potentiating the effect of bosentan; monitor for hypotension. In addition, bosentan is an inducer of CYP3A4 and clozapine is partially metabolized by this isoenzyme. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP3A4 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
    Bosutinib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Brentuximab vedotin: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Brexpiprazole: (Major) Caution is advisable during concurrent use of brexpiprazole with other antipsychotics such as clozapine. 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) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Bromocriptine: (Moderate) The prolactin-lowering effect of bromocriptine at the anterior pituitary may be antagonized by medications that increase prolactin levels, such as the atypical antipsychotics. The atypical antipsychotics elevate prolactin to various degrees. Like other drugs that antagonize dopamine D2 receptors, the elevation in prolactin from atypical antipsychotics can persist during chronic administration. Monitor the patient for reduced response to bromocriptine. Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. If bromocriptine is taken for diabetes, monitor for worsening glycemic control.
    Brompheniramine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (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.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Brompheniramine; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Budesonide; Formoterol: (Moderate) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with clozapine 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 clozapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clozapine 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 clozapine 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 clozapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clozapine 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 clozapine 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) Monitor for evidence of clozapine-related adverse reactions and consider a clozapine dose reduction if necessary when coadministered with bupropion. If bupropion is discontinued after dose adjustments are made, monitor for lack of clozapine affect and consider increasing the clozapine dose if necessary. Concurrent use may result in increased clozapine exposure due to inhibition of CYP2D6 metabolism by bupropion. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. Furthermore, bupropion is associated with a dose-related risk of seizures; this risk may be increased by antipsychotics.
    Bupropion; Naltrexone: (Major) Monitor for evidence of clozapine-related adverse reactions and consider a clozapine dose reduction if necessary when coadministered with bupropion. If bupropion is discontinued after dose adjustments are made, monitor for lack of clozapine affect and consider increasing the clozapine dose if necessary. Concurrent use may result in increased clozapine exposure due to inhibition of CYP2D6 metabolism by bupropion. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. Furthermore, bupropion is associated with a dose-related risk of seizures; this risk may be increased by antipsychotics.
    Buspirone: (Moderate) The combination of buspirone and CNS depressants like the antipsychotics can increase the risk for drowsiness, sedation, and dizziness.
    Butabarbital: (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Butorphanol: (Moderate) Concomitant use of butorphanol with other CNS depressants, such as clozapine, can potentiate the effects of butorphanol on respiratory depression, CNS depression, and sedation.
    Cabergoline: (Major) The prolactin-lowering effect of cabergoline may be antagonized by medications that increase prolactin levels such as the antipsychotic drugs. In addition, cabergoline is a dopamine agonist and may diminish the effectiveness of dopamine antagonists such as the antipsychotics.
    Caffeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
    Caffeine; Ergotamine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
    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.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and atypical antipsychotics. CNS depressants can potentiate the effects of cannabidiol.
    Capsaicin; Metaxalone: (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Carbamazepine: (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as carbamazepine, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Carbamazepine may also increase the metabolism of clozapine through induction of CYP1A2. Both agents have myelosuppressive properties; patients should be monitored for and instructed about symptoms of infection. Lastly, close monitoring is recommended when clozapine is administered to patients with a seizure disorder because clozapine lowers the seizure threshold. The effectiveness of carbamazepine in treating seizures may be reduced. Dosage adjustments may be necessary and close monitoring is warranted when carbamazepine is used with clozapine.
    Carbetapentane; Chlorpheniramine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (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; Chlorpheniramine; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (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; Diphenhydramine; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (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: (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) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as pyrilamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (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) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as pyrilamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (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) Levodopa is a potent dopamine-receptor agonist. Dopamine-receptor antagonists, including the atypical antipsychotics, may reduce the effects of levodopa. In general, the atypical antipsychotics are less likely to interfere with antiparkinson treatments than traditional antipsychotic agents. Monitor for diminished effectiveness of the antiparkinson treatments, for movement disorders, and for unusual changes in moods or behavior. Certain atypical antipsychotics, such as quetiapine or pimavanserin, may be preferable to other antipsychotics in these patients.
    Carbidopa; Levodopa; Entacapone: (Moderate) Dopamine-receptor antagonists, including the atypical antipsychotics, may reduce the effects of the COMT inhibitors (e.g., entacapone, tolcapone). In general, the atypical antipsychotics are less likely to interfere with antiparkinson treatments than traditional antipsychotic agents. Monitor for diminished effectiveness of the antiparkinson treatments, for movement disorders, and for unusual changes in moods or behavior. (Moderate) Levodopa is a potent dopamine-receptor agonist. Dopamine-receptor antagonists, including the atypical antipsychotics, may reduce the effects of levodopa. In general, the atypical antipsychotics are less likely to interfere with antiparkinson treatments than traditional antipsychotic agents. Monitor for diminished effectiveness of the antiparkinson treatments, for movement disorders, and for unusual changes in moods or behavior. Certain atypical antipsychotics, such as quetiapine or pimavanserin, may be preferable to other antipsychotics in these patients.
    Carbinoxamine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as carbinoxamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as carbinoxamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as carbinoxamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as carbinoxamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Carbinoxamine; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as carbinoxamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Carbinoxamine; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as carbinoxamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Carboplatin: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Carfilzomib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Cariprazine: (Moderate) The risk of adverse effects may be increased during concurrent use of cariprazine with other antipsychotics, such as clozapine. 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.
    Carisoprodol: (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Carmustine, BCNU: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Carteolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Carvedilol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Celecoxib: (Moderate) A dosage adjustment may be warranted for clozapine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of clozapine. Celecoxib is a CYP2D6 inhibitor, and clozapine is a CYP2D6 substrate.
    Central-acting adrenergic agents: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Ceritinib: (Major) Avoid coadministration of ceritinib with clozapine 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. Additionally, consider a clozapine dose reduction and monitor for adverse reactions; if ceritinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. Clozapine is partially metabolized by CYP3A4 and has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use.
    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.
    Chlophedianol; Dexbrompheniramine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as dexbrompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as dexchlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Chlorambucil: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Chloramphenicol: (Moderate) Caution is advisable during concurrent use of chloramphenicol and clozapine. Chloramphenicol is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Chlorcyclizine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorcyclizine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Chlordiazepoxide: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Chlordiazepoxide; Clidinium: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Chloroquine: (Major) Coadminister chloroquine with other drugs known to prolong the QT interval, such as clozapine, with caution. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
    Chlorpheniramine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Chlorpheniramine; Codeine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
    Chlorpheniramine; Dextromethorphan: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Pain medications such as dihydrocodeine, should be combined cautiously with clozapine due to the potential for additive depressant effects and possible respiratory depression or hypotension. Concurrent use of clozapine and opiates may also lead to reduced intestinal motility or bladder function.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Pain medications such as dihydrocodeine, should be combined cautiously with clozapine due to the potential for additive depressant effects and possible respiratory depression or hypotension. Concurrent use of clozapine and opiates may also lead to reduced intestinal motility or bladder function.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Chlorpheniramine; Hydrocodone: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Chlorpheniramine; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Chlorpromazine: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP). In addition, coadministration of clozapine with phenothiazines 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 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 clozapine. Dosage adjustments of one or both medications may be necessary.
    Cimetidine: (Moderate) Caution is advisable during concurrent use of cimetidine and clozapine. Cimetidine is an inhibitor of CYP3A4, CYP2D6, and CYP1A2, the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, 2D6, or 3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4, CYP2D6, or CYP1A2 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cinacalcet: (Moderate) Caution is advisable during concurrent use of cinacalcet and clozapine. Cinacalcet is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Ciprofloxacin: (Major) If co-administration of clozapine and a potent inhibitor of CYP1A2 such as ciprofloxacin is necessary, the manufacturer of clozapine recommends using one-third of the usual clozapine dose. If the inhibitor is discontinued, increase the clozapine dose based on clinical response. One study of 7 schizophrenic patients has shown that concurrent therapy with ciprofloxacin (250 mg twice daily) versus placebo resulted in increased clozapine plasma concentrations (29%) and N-desmethylclozapine plasma concentrations (31%). One case study has reported elevated clozapine plasma concentrations (by 80%) during ciprofloxacin coadministration at doses of 500 mg twice daily. In addition, rare cases of QT prolongation and torsade de pointes (TdP) have been reported with both ciprofloxacin and clozapine. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP3A4, or CYP2D6 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. If quinolone administration is indicated during clozapine therapy, an alternative fluoroquinolone with minimal inhibitory effects on CYP1A2, CYP2D6, or CYP3A4 should be considered.
    Cisapride: (Severe) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Because of the potential for TdP, use of cisapride with clozapine is contraindicated.
    Cisplatin: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Citalopram: (Major) Concurrent use of clozapine and citalopram should be avoided if possible. Citalopram causes dose-dependent QT interval prolongation and clozapine is associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. 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. In addition, citalopram is a weak inhibitor of CYP2D6, and increased plasma concentrations of antipsychotics partially metabolized via CYP2D6, such as clozapine, may occur. A reduced dosage of clozapine should be considered when clozapine is combined with CYP2D6 inhibitors, due to a decrease in clozapine metabolism and a potential for clozapine-related adverse effects, such as orthostatic hypotension, seizures, or adverse cardiac effects.
    Clarithromycin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with clozapine. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. In addition, clarithromycin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Clemastine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as clemastine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    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.
    Clofarabine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Clofazimine: (Major) Monitor ECGs for QT prolongation when clofazimine is administered with clozapine. QT prolongation and torsade de pointes (TdP) have been reported in patients receiving clofazimine in combination with QT prolonging medications. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
    Clonazepam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Clorazepate: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Cobicistat: (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Codeine: (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
    Codeine; Guaifenesin: (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
    Codeine; Phenylephrine; Promethazine: (Major) Coadministration of promethazine and clozapine may increase the risk of QT prolongation and other adverse effects. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Promethazine is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine; elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Coadministration may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, and seizures. Monitor for adverse reactions if use together is not avoidable. Consideration should be given to reducing the clozapine dose if necessary. (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
    Codeine; Promethazine: (Major) Coadministration of promethazine and clozapine may increase the risk of QT prolongation and other adverse effects. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Promethazine is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine; elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Coadministration may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, and seizures. Monitor for adverse reactions if use together is not avoidable. Consideration should be given to reducing the clozapine dose if necessary. (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
    COMT inhibitors: (Moderate) Dopamine-receptor antagonists, including the atypical antipsychotics, may reduce the effects of the COMT inhibitors (e.g., entacapone, tolcapone). In general, the atypical antipsychotics are less likely to interfere with antiparkinson treatments than traditional antipsychotic agents. Monitor for diminished effectiveness of the antiparkinson treatments, for movement disorders, and for unusual changes in moods or behavior.
    Conivaptan: (Moderate) Caution is advisable during concurrent use of conivaptan and clozapine. Conivaptan is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Crizotinib: (Major) Avoid coadministration of crizotinib with clozapine due to the risk of QT prolongation; exposure to clozapine may also increase. If concomitant use is unavoidable, consider a clozapine dose reduction. Monitor ECGs for QT prolongation and monitor electrolytes; also monitor for clozapine-related adverse reactions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. If crizotinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Clozapine is partially metabolized by CYP3A4, and has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Cyclobenzaprine: (Moderate) Additive anticholinergic effects may be seen when clozapine is used concomitantly with other drugs with antimuscarinic activity such as cyclobenzaprine. Antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Particular attention should be paid to GI problems because of the possible development of paralytic ileus. Additive sedation may also occur.
    Cyclophosphamide: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Cyproheptadine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as cyproheptadine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Dacomitinib: (Moderate) Consider a clozapine dose reduction if coadministered with dacomitinib and monitor for adverse reactions. If dacomitinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Dalfopristin; Quinupristin: (Moderate) Consider a clozapine dose reduction if coadministered with dalfopristin; quinupristin and monitor for adverse reactions. If dalfopristin; quinupristin is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4. Dalfopristin; quinupristin is a weak CYP3A4 inhibitor.
    Danazol: (Moderate) Caution is advisable during concurrent use of danazol and clozapine. Danazol is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    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) Consider a clozapine dose reduction if coadministered with darifenacin and monitor for adverse reactions including anticholinergic effects. If darifenacin is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP2D6. Darifenacin is a moderate CYP2D6 inhibitor. Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like darifenacin are used concomitantly with other drugs with moderate to significant anticholinergic effects including clozapine.
    Darunavir: (Moderate) Caution is advisable during concurrent use of darunavir and clozapine. Darunavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP2D6, or CYP3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Darunavir; Cobicistat: (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. (Moderate) Caution is advisable during concurrent use of darunavir and clozapine. Darunavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP2D6, or CYP3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. (Moderate) Caution is advisable during concurrent use of darunavir and clozapine. Darunavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP2D6, or CYP3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Consider a clozapine dose adjustment if coadministered with ritonavir and monitor for efficacy and adverse reactions. If ritonavir is discontinued, monitor for lack of clozapine effect and adverse effects and adjust dose if necessary. A clinically relevant increase or decrease in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4, CYP2D6, and CYP1A2. Ritonavir is a strong CYP3A4 and weak CYP2D6 inhibitor and a moderate inducer of CYP1A2.
    Dasatinib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. Additionally, in vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). Clozapine therapy may lead to S-T segment depression and flattening or inversion of T waves. In theory, concurrent use of dasatinib and clozapine could produce clinically significant prolongation of the QTc interval.
    Deferiprone: (Major) Avoid concomitant use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis, such as clozapine; however, if this is not possible, closely monitor the absolute neutrophil count and interrupt deferiprone therapy if neutropenia develops.
    Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving clozapine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Delavirdine: (Moderate) Caution is advisable during concurrent use of delavirdine and clozapine. Delavirdine is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Denileukin Diftitox: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Desflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with clozapine. Halogenated anesthetics can prolong the QT interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Clozapine can also potentiate the actions of other CNS depressants such as the general anesthetics. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects. Neuroleptic malignant syndrome has been reported in association with antipsychotic medications, including clozapine. In the presence of high fever, the possibility of this complication should be considered.
    Deutetrabenazine: (Major) For patients taking a deutetrabenazine dosage more than 24 mg/day with clozapine, assess the QTc interval before and after increasing the dosage of either medication. Use caution during concurrent use of clozapine with medications known to prolong the QT interval. Clinically relevant QTc prolongation may occur with deutetrabenazine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. 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 clozapine is a dopamine antagonist. Additionally, concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as clozapine, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how deutetrabenazine affects them.
    Dexamethasone: (Moderate) Caution is advisable during concurrent use of dexamethasone and clozapine. Dexamethasone is an inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. According to the manufacturer, patients receiving clozapine in combination with a weak to moderate CYP3A4 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. Concurrent use with strong CYP3A4 inducers is not recommended. Topical corticosteroids are not likely to interact.
    Dexchlorpheniramine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as dexchlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as dexchlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Dexmethylphenidate: (Moderate) Atypical antipsychotics and dexmethylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Dexmethylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of dexmethylphenidate.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Dextromethorphan; Promethazine: (Major) Coadministration of promethazine and clozapine may increase the risk of QT prolongation and other adverse effects. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Promethazine is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine; elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Coadministration may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, and seizures. Monitor for adverse reactions if use together is not avoidable. Consideration should be given to reducing the clozapine dose if necessary.
    Dextromethorphan; Quinidine: (Severe) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6 as the effects on the QT interval may be increased during concurrent use of these agents. Drugs that prolong the QT and are substrates for CYP2D6 that are contraindicated with quinidine include clozapine.
    Diazepam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Diazoxide: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Digoxin: (Moderate) Because clozapine is highly protein bound, other highly protein bound medications such as digoxin can displace clozapine from its binding sites, predominantly alpha1-acid glycoprotein. Clozapine, in turn, can increase the serum concentrations of digoxin.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Pain medications such as dihydrocodeine, should be combined cautiously with clozapine due to the potential for additive depressant effects and possible respiratory depression or hypotension. Concurrent use of clozapine and opiates may also lead to reduced intestinal motility or bladder function.
    Diltiazem: (Moderate) Caution is advisable during concurrent use of diltiazem and clozapine. Diltiazem is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Dimenhydrinate: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as dimenhydrinate. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Dinutuximab: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    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) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Diphenhydramine; Ibuprofen: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Diphenhydramine; Naproxen: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Diphenhydramine; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Disopyramide: (Major) Clozapine should be used cautiously and with close monitoring with disopyramide. Disopyramide administration is associated with QT prolongation and torsade de pointes (TdP). Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Additive anticholinergic effects are also possible; both drugs exhibit significant anticholinergic activity.
    Disulfiram: (Moderate) Caution is advisable during concurrent use of disulfiram and clozapine. Disulfiram is an inhibitor of CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. When initiating clozapine or adding a mild or moderate CYP1A2 inhibitor to clozapine treatment, monitor for adverse reactions and consider reducing the clozapine dose if necessary. If the inhibitor is discontinued, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Dofetilide: (Major) Coadministration of dofetilide and clozapine 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). Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
    Dolasetron: (Moderate) Administer dolasetron with caution in combination with clozapine as concurrent use may increase the risk of QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. 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 clozapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Donepezil: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than clozapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Clozapine exhibits considerable anticholinergic activity, and is more likely than other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Donepezil; Memantine: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than clozapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Clozapine exhibits considerable anticholinergic activity, and is more likely than other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Dorzolamide; Timolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Doxazosin: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Doxylamine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as doxylamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Doxylamine; Pyridoxine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as doxylamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    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: (Severe) Concomitant use of dronedarone and clozapine is contraindicated. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death and dronedarone is associated with dose-related increases in the QTc interval. 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; concomitant use is contraindicated. In addition, dronedarone is an inhibitor of CYP2D6 and CYP3A, two of the isoenzymes responsible for the metabolism of clozapine. Coadministration of dronedarone and clozapine may result in elevated plasma concentrations of clozapine, which may potentially increase the risk of life-threatening arrhythmias or other adverse effects. According to the manufacturer of clozapine, concomitant use of clozapine and substrates or inhibitors of CYP2D6 may require lower doses of either drug.
    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 clozapine.
    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 CYP2D6 and CYP1A2, two of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP1A2, CYP3A4, or CYP2D6 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Duvelisib: (Moderate) Consider a clozapine dose reduction if coadministered with duvelisib and monitor for adverse reactions. If duvelisib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4. duvelisib is a moderate CYP3A4 inhibitor.
    Efavirenz: (Moderate) Consider alternatives to efavirenz when coadministering with clozapine as concurrent use may increase the risk of QT prolongation; decreased clozapine exposure may also occur. Monitor for loss of clozapine efficacy and consider increasing the clozapine dose if necessary. QTc prolongation has been observed with the use of efavirenz. Clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. In addition, efavirenz is an and inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Consider alternatives to efavirenz when coadministering with clozapine as concurrent use may increase the risk of QT prolongation; decreased clozapine exposure may also occur. Monitor for loss of clozapine efficacy and consider increasing the clozapine dose if necessary. QTc prolongation has been observed with the use of efavirenz. Clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. In addition, efavirenz is an and inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with clozapine as concurrent use may increase the risk of QT prolongation; decreased clozapine exposure may also occur. Monitor for loss of clozapine efficacy and consider increasing the clozapine dose if necessary. QTc prolongation has been observed with the use of efavirenz. Clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. In addition, efavirenz is an and inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
    Elagolix: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with elagolix. Consideration should be given to increasing the clozapine dose if necessary. When elagolix is discontinued, reduce the clozapine dose based on clinical response. Elagolix is a weak to moderate inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
    Elbasvir; Grazoprevir: (Moderate) Administering clozapine with grazoprevir may result in elevated clozapine plasma concentrations. Clozapine is a substrate of CYP3A4 and grazoprevir is a weak CYP3A inhibitor. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Use caution when administering ivacaftor and clozapine concurrently. Ivacaftor is an inhibitor of CYP3A and clozapine is partially metabolized by CYP3A. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Eliglustat: (Major) Coadministration of clozapine and eliglustat may result in increased plasma concentrations of clozapine and an increased risk of QT prolongation. If coadministration is necessary, use great caution and monitor closely. Consider reducing the dosage of clozapine and titrating to clinical effect. In addition, if eliglustat is discontinued while the patient is taking clozapine, monitor for a lack of antipsychotic efficacy, and increase the clozapine dose as clinically necessary. Clozapine is a CYP2D6 substrate associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Eliglustat is a CYP2D6 inhibitor that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    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; 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 clozapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering rilpivirine with clozapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Encainide: (Moderate) The manufacturer of clozapine advises that concomitant use of clozapine, a CYP2D6 substrate, with other CYP2D6 substrates, such as encainide, may require lower doses of either drug. The use of these medications together may inhibit the activity of CYP2D6 thereby increasing the risk of QT prolongation, ventricular arrhythmias, or other adverse effects.
    Encorafenib: (Major) Avoid coadministration of encorafenib and clozapine due to 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. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Enflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with clozapine. Halogenated anesthetics can prolong the QT interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Clozapine can also potentiate the actions of other CNS depressants such as the general anesthetics. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects. Neuroleptic malignant syndrome has been reported in association with antipsychotic medications, including clozapine. In the presence of high fever, the possibility of this complication should be considered.
    Entacapone: (Moderate) Dopamine-receptor antagonists, including the atypical antipsychotics, may reduce the effects of the COMT inhibitors (e.g., entacapone, tolcapone). In general, the atypical antipsychotics are less likely to interfere with antiparkinson treatments than traditional antipsychotic agents. Monitor for diminished effectiveness of the antiparkinson treatments, for movement disorders, and for unusual changes in moods or behavior.
    Entrectinib: (Major) Avoid coadministration of entrectinib with clozapine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Enzalutamide: (Major) Coadministration of clozapine with enzalutamide is not recommended due to decreased plasma concentrations of clozapine. If concomitant use is unavoidable, the patient should be monitored for loss of efficacy; consider increasing the clozapine dose if necessary. When enzalutamide is discontinued, reduce the clozapine dose based on clinical response. Clozapine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Epinephrine: (Moderate) Clozapine may induce significant alpha-adrenergic blockade during clozapine overdose, leading to profound hypotension. Epinephrine should generally not be used to treat clozapine-induced hypotension due to the unopposed beta-activity, which potentially could worsen the hypotension.
    Eplerenone: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Epoprostenol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Eribulin: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with clozapine 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) Concurrent use of erythromycin and clozapine should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death and erythromycin has an established risk of QT prolongation and TdP. A case report has documented increased serum clozapine concentrations and the occurrence of a seizure when erythromycin was added to a stable dose of clozapine. Erythromycin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Erythromycin; Sulfisoxazole: (Major) Concurrent use of erythromycin and clozapine should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death and erythromycin has an established risk of QT prolongation and TdP. A case report has documented increased serum clozapine concentrations and the occurrence of a seizure when erythromycin was added to a stable dose of clozapine. Erythromycin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Escitalopram: (Moderate) Consider a clozapine dose reduction if coadministered with escitalopram and monitor for adverse reactions, inlcuding QT prolongation. If escitalopram is discontinued, monitor for lack of clozapine effect, and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine and increased risk of QT prolongation may occur during concurrent use. Clozapine is partially metabolized by CYP2D6 and has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Escitalopram is a moderate CYP2D6 inhibitor that has been associated with a risk of QT prolongation and TdP.
    Esketamine: (Major) Closely monitor patients receiving esketamine and clozapine 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.
    Eslicarbazepine: (Moderate) Eslicarbazepine is an inducer of CYP3A4, one of the isoenzymes reponsible for the metabolism of clozapine. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP3A4 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary. In addition, clozapine can lower the seizure threshold, potentially reducing the effectiveness of eslicarbazepine in treating seizures. Monitor for increased seizure activity during concurrent use.
    Esmolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Estazolam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Estramustine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    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.
    Ethotoin: (Moderate) Ethotoin may increase the metabolism of clozapine through CYP1A2 and/or CYP3A4 induction, leading to increased clearance of clozapine. When initiating clozapine or adding a weak to moderate CYP1A2 or CYP3A4 inducer to pre-existing clozapine treatment, monitor for decreased effectiveness and consider increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions and consider reducing the clozapine dose if necessary. In addition, clozapine lowers the seizure threshold and may reduce the effectiveness of ethotoin in treating seizures. Monitor for increased seizure activity and consider alternative treatment or make dose adjustments accordingly.
    Etomidate: (Moderate) Clozapine can potentiate the actions of other CNS depressants such as the general anesthetics. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
    Etravirine: (Moderate) Caution is advisable during concurrent use of etravirine and clozapine. Etravirine is an inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. According to the manufacturer, patients receiving clozapine in combination with a weak to moderate CYP3A4 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
    Everolimus: (Moderate) Monitor for an increase in clozapine-related adverse reactions, including a risk of seizures, orthostasis, QT prolongation, if coadministration with everolimus is necessary; the effect of clozapine on neutropenia is not concentration-dependent. Clozapine is a CYP2D6 and CYP3A4 substrate, everolimus is a weak CYP3A4 and a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of clozapine.
    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) Use clozapine with caution in combination with ezogabine as concurrent use may increase the risk of QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Ezogabine has been associated with QT prolongation.
    Fedratinib: (Moderate) Consider a clozapine dose reduction if coadministered with fedratinib and monitor for adverse reactions. If fedratinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4 and CYP2D6. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6.
    Fenoldopam: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Fentanyl: (Moderate) Concomitant use of fentanyl with other CNS depressants, such as clozapine, can potentiate the effects of fentanyl on respiration, CNS depression, sedation, and hypotension. Concurrent use of clozapine and opiates may also lead to reduced intestinal motility or bladder function.
    Fesoterodine: (Moderate) Coadministration of fesoterodine and other drugs with moderate to significant anticholinergic effects such as clozapine may increase the frequency and/or severity of anticholinergic effects such as blurred vision, constipation, xerostomia, and urinary retention.
    Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with clozapine 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. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Flecainide: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Flecainide should be used cautiously and with close monitoring with clozapine. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsades de pointes (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: (Severe) Due to the risk of life-threatening arrhythmias such as torsade de pointes (TdP), coadministration of fluconazole with drugs that both prolong the QT interval and are CYP3A4 substrates, like clozapine, is contraindicated. Fluconazole has been associated with QT prolongation and rare cases of TdP. Additonally, fluconazole is an inhibitor of CYP3A4. Coadministration may result in elevated plasma concentrations of clozapine, causing an increased risk for adverse events such as QT prolongation.
    Flucytosine: (Moderate) Because of the ability of flucytosine to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants, including clozapine.
    Fluoxetine: (Moderate) Consider a clozapine dose reduction if coadministered with fluoxetine and monitor for adverse reactions including QT prolongation. If fluoxetine is discontinued, monitor for lack of clozapine effect and increase dose if necessary. Modest (less than 2-fold) elevations in concentrations of clozapine and its metabolites have been reported during concurrent use of fluoxetine. Clozapine is a CYP2D6 substrate that has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Fluoxetine is a strong CYP2D6 inhibitor; QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine.
    Fluoxetine; Olanzapine: (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. (Moderate) Consider a clozapine dose reduction if coadministered with fluoxetine and monitor for adverse reactions including QT prolongation. If fluoxetine is discontinued, monitor for lack of clozapine effect and increase dose if necessary. Modest (less than 2-fold) elevations in concentrations of clozapine and its metabolites have been reported during concurrent use of fluoxetine. Clozapine is a CYP2D6 substrate that has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Fluoxetine is a strong CYP2D6 inhibitor; QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine.
    Fluphenazine: (Moderate) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, coadministration of clozapine 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 these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent.
    Flurazepam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Fluticasone; Salmeterol: (Moderate) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with clozapine 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) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with clozapine 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) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with clozapine 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 and torsade de pointes (TdP) during concurrent use of fluvoxamine and clozapine. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death, especially at high dosages. In addition, if coadministration of clozapine and a potent inhibitor of CYP1A2 such as fluvoxamine is necessary, the manufacturer of clozapine recommends using one-third of the usual clozapine dose. If the inhibitor is discontinued, increase the clozapine dose based on clinical response. In one study, the mean concentrations of clozapine and its metabolites were increased about 3-fold compared to baseline values. Up to a 10-fold increase in plasma concentrations of clozapine and its metabolites have been noted in other evaluations. Fluvoxamine is also a moderate CYP3A4 inhibitor and a mild CYP2D6 inhibitor. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP3A4, or CYP2D6 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects.
    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. Additionally, additive CNS effects, such as sedation or CNS depression are 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, For example, the smoking of marijuana influences the metabolism of some medications in a manner similar to tobacco by inducing CYP1A2.
    Formoterol: (Moderate) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with clozapine 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) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monit