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  • CLASSES

    Anticonvulsants, Benzodiazepines
    Anxiolytics, Benzodiazepines

    BOXED WARNING

    Asthma, coadministration with other CNS depressants, pulmonary disease, respiratory depression, respiratory insufficiency, sleep apnea

    Oral diazepam tablets are contraindicated for use in patients with severe respiratory insufficiency or sleep apnea syndrome. Use extreme care when administering diazepam in patients with limited pulmonary reserve or compromised respiratory function related to concurrent pulmonary disease process (e.g., asthma, pneumonia) or neurologic damage due to the possibility of apnea or cardiac arrest. Additionally, avoid coadministration with other CNS depressants, especially opioids, unless no other alternatives are available as coadministration significantly increases the risk for profound sedation, respiratory depression, coma, and death.[28712] [43931] [43932] [61143] [64930]

    Abrupt discontinuation, alcoholism, benzodiazepine dependence, substance abuse

    Use diazepam with caution in patients with a history of alcoholism or substance abuse due to the potential for psychological dependence. The use of benzodiazepines exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive benzodiazepines routinely for development of these behaviors or conditions. A potential risk of abuse should not preclude appropriate treatment in any patient, but requires more intensive counseling and monitoring. To discourage abuse, the smallest appropriate quantity of the benzodiazepine should be prescribed, and proper disposal instructions for unused drug should be given to patients. Avoid or minimize concomitant use of CNS depressants or other medications associated with addiction or abuse. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, and death. Advise patients to seek immediate medical attention if they experience symptoms such as trouble breathing. Abrupt discontinuation or rapid dosage reduction of benzodiazepines after continued use may precipitate acute withdrawal reactions, which can be life-threatening. The risks of physiological dependence and withdrawal increase with longer treatment duration and higher daily dose. Benzodiazepine dependence can occur after administration of therapeutic doses for as few as 1 to 2 weeks and withdrawal symptoms may be seen after the discontinuation of therapy. To reduce the risk of acute withdrawal reactions, use a gradual taper to reduce the dosage or to discontinue benzodiazepines. No standard benzodiazepine tapering schedule is suitable for all patients; therefore, create a patient-specific plan to gradually reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently, decrease the dosage more slowly. Patients with a seizure history or who are taking drugs that lower the seizure threshold (e.g., certain antidepressants, phenothiazines) should not be withdrawn abruptly from benzodiazepines due to the risk of precipitating a seizure. During benzodiazepine withdrawal, the greatest risk of seizure appears to be during the first 24 to 72 hours. Diazepam is not recommended for chronic, daily use as an anticonvulsant. Chronic daily use of diazepam may increase the frequency and/or severity of tonic-clonic seizures, requiring an increase in the dosage of standard anticonvulsant medication. In such cases, abrupt withdrawal of chronic diazepam may also be associated with a temporary increase in the frequency and/or severity of seizures in patients with a seizure disorder. Tonic status epilepticus has been precipitated in patients treated with intravenous diazepam for petit mal status or petit mal variant status. Clinicians should be aware that the use of flumazenil may increase the risk of seizures.[28712]

    DEA CLASS

    Rx, schedule IV

    DESCRIPTION

    Oral, nasal, parenteral, or rectal long-acting benzodiazepine
    Used for anxiety, acute alcohol withdrawal, skeletal muscle spasm, and seizure disorders
    Increased risk of profound sedation, respiratory depression, coma, and death with concomitant opioid use

    COMMON BRAND NAMES

    Diastat, Dizac, Valium

    HOW SUPPLIED

    Diastat/Diazepam Rectal Gel: 1mL, 5mg
    Diazepam Oral Sol: 1mL, 5mg, 5mL
    Diazepam/Dizac/Valium Intramuscular Inj Sol: 1mL, 5mg
    Diazepam/Dizac/Valium Intramuscular Sol: 1mL, 5mg
    Diazepam/Dizac/Valium Intravenous Inj Sol: 1mL, 5mg
    Diazepam/Dizac/Valium Intravenous Sol: 1mL, 5mg
    Diazepam/Valium Oral Tab: 2mg, 5mg, 10mg

    DOSAGE & INDICATIONS

    For the treatment of anxiety disorders or for the short-term relief of the symptoms of anxiety.
    Oral dosage (oral solution or regular tablets)
    Adults

    2 to 10 mg PO 2 to 4 times per day depending upon the severity of the symptoms. Use lower initial adult doses for the debilitated adult patient. A maximum daily dosage has not been defined by the manufacturer, but commonly implied limit is 40 mg/day in divided doses for ambulatory use.

    Geriatric Adults

    2 to 2.5 mg PO 1 to 2 times per day, increasing the dose according to response and patient tolerability. A maximum daily dosage has not been defined, but commonly the adult limits are 40 mg/day in divided doses for ambulatory use. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of anxiolytics in long-term care facility (LTCF) residents. Max: 5 mg/day PO in residents meeting the criteria for treatment, except when documentation is provided showing that higher doses are necessary to maintain or improve the resident's functional status. In addition, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.

    Infants 6 months and older, Children, and Adolescents

    Initially, 1 to 2.5 mg PO 3 to 4 times per day. The dose may be increased as needed and tolerated.

    Intravenous and Intramuscular dosage
    Adults

    2 to 5 mg IM or IV for moderate anxiety disorders and symptoms of anxiety; repeat in 3 to 4 hours if necessary. For severe anxiety disorders and symptoms of anxiety, 5 to 10 mg IM or IV; repeat in 3 to 4 hours if necessary.

    For the treatment of acute alcohol withdrawal.
    Intravenous dosage
    Adults

    Until it is known how the patient will respond, a dose of 10 mg IV initially, followed by 5 to 10 mg IV every 3 to 4 hours as needed. Doses of 5 to 10 mg IV may be given every hour if required. Some patients may require massive doses of benzodiazepines during the acute phase of ethanol withdrawal. Intravenous doses of 270 mg over 45 minutes and 2,335 mg over a period of 4 days have been reported.

    For the treatment of muscle spasm due to local pathology such as muscle or joint inflammation or trauma; athetosis; stiff-man syndrome; tetanus; or spasticity due to upper motor neuron diseases such as cerebral palsy.
    For the treatment of muscle spasm due to tetanus.
    Intravenous and Intramuscular dosage
    Adults

    0.1 to 0.2 mg/kg/dose IV or 5 to 10 mg IV or IM every 3 to 6 hours as needed. Larger doses and up to 600 mg/day IV may be required.  

    Children and Adolescents 5 to 17 years

    0.1 to 0.2 mg/kg/dose IV or 5 to 10 mg IV or IM every 3 to 6 hours as needed.  

    Infants and Children 1 month to 4 years

    0.1 to 0.2 mg/kg/dose IV or 1 to 2 mg IV or IM every 3 to 6 hours as needed.  

    Oral dosage
    Adults

    2 to 10 mg PO 3 to 4 times daily.

    Geriatric

    2 to 2.5 mg PO 1 to 2 times daily, increasing the dose according to response and patient tolerability.

    Infants, Children, and Adolescents 6 months to 17 years

    1 to 2.5 mg PO 3 to 4 times daily. The dose may be increased as needed and tolerated.

    Intravenous and Intramuscular dosage
    Adults

    5 to 10 mg IV or IM every 3 to 4 hours as needed.

    Children and Adolescents 5 to 17 years

    5 to 10 mg IV or IM every 3 to 4 hours as needed.

    Infants and Children 1 month to 4 years

    1 to 2 mg IV or IM every 3 to 4 hours as needed.

    For the treatment of status epilepticus.
    Intravenous dosage
    Adults

    0.15 to 0.2 mg/kg/dose (Max: 10 mg/dose) IV; may repeat once in 5 minutes if needed.[58123] [61569] Alternately, 5 to 10 mg IV every 10 to 15 minutes as needed up to a maximum of 30 mg. May repeat in 2 to 4 hours, if needed.[43931]

    Children and Adolescents 5 to 17 years

    0.15 to 0.2 mg/kg/dose (Max: 10 mg/dose) IV; may repeat once in 5 minutes if needed. Alternately, 1 mg IV every 2 to 5 minutes as needed up to a maximum of 10 mg. May repeat in 2 to 4 hours, if needed.

    Infants and Children 1 month to 4 years

    0.15 to 0.2 mg/kg/dose (Max: 10 mg/dose) IV; may repeat once in 5 minutes if needed. Alternately, 0.2 to 0.5 mg IV every 2 to 5 minutes as needed up to a maximum of 5 mg. May repeat in 2 to 4 hours, if needed.

    Neonates†

    0.1 to 0.15 mg/kg/dose IV every 10 minutes as needed. Mean total dose: 0.38 mg/kg IV (range: 0.09 to 0.71 mg/kg).[45310] NOTE: Not recommended as a first-line agent due to sodium benzoate and benzoic acid in the injection.

    Rectal dosage†
    Adults

    0.2 to 0.5 mg/kg/dose (Max: 20 mg/dose) PR once.

    Children and Adolescents 12 to 17 years

    0.2 mg/kg/dose (Max: 20 mg/dose) PR once.

    Children 6 to 11 years

    0.3 mg/kg/dose (Max: 20 mg/dose) PR once.

    Children 2 to 5 years

    0.5 mg/kg/dose (Max: 20 mg/dose) PR once.

    For the treatment of intermittent, stereotypic, episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern.
    Intravenous dosage
    Adults

    5 to 10 mg IV every 10 to 15 minutes as needed up to a maximum of 30 mg. May repeat in 2 to 4 hours, if needed.

    Children and Adolescents 5 to 17 years

    1 mg IV every 2 to 5 minutes as needed up to a maximum of 10 mg. May repeat in 2 to 4 hours, if needed.

    Infants and Children 1 month to 4 years

    0.2 to 0.5 mg IV every 2 to 5 minutes as needed up to a maximum of 5 mg. May repeat in 2 to 4 hours, if needed.

    Rectal dosage

    NOTE: It is recommended that rectal diazepam be used to treat no more than 5 episodes per month and no more than 1 episode every 5 days.[43932]
    NOTE: The 2.5 mg dose may also be used as a partial replacement dose for patients who expel a portion of the first dose.[43932]

    Adults

    0.2 mg/kg/dose PR once; round dose upward to the next available dosage strength. May give a second dose 4 to 12 hours after the first dose if needed.[43932]

    Geriatric and Debilitated Adults

    0.2 mg/kg/dose PR once; round dose downward to the next available dosage strength. May give a second dose 4 to 12 hours after the first dose if needed.[43932]

    Children and Adolescents 12 to 17 years

    0.2 mg/kg/dose PR once; round dose upward to the next available dosage strength. May give a second dose 4 to 12 hours after the first dose if needed.

    Children 6 to 11 years

    0.3 mg/kg/dose PR once; round dose upward to the next available dosage strength. May give a second dose 4 to 12 hours after the first dose if needed.

    Children 2 to 5 years

    0.5 mg/kg/dose PR once; round dose upward to the next available dosage strength. May give a second dose 4 to 12 hours after the first dose if needed.

    Nasal dosage

    NOTE: The recommended weight-based dosages of diazepam nasal spray are 0.2 mg/kg for adults, adolescents, and children 12 years and 0.3 mg/kg for children 6 to 11 years. Specific dosage recommendations provide acceptable weight ranges for each dose and age category, such that patients will receive between 90% and 180% of the calculated recommended dose.

    Adults weighing 76 kg or more

    10 mg in each nostril once, for a total dose of 20 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not use to treat more than 1 episode every 5 days and more than 5 episodes per month.[64930]

    Adults weighing 51 to 75 kg

    7.5 mg in each nostril once, for a total dose of 15 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not use to treat more than 1 episode every 5 days and more than 5 episodes per month.

    Adults weighing 35 to 50 kg

    10 mg in 1 nostril once, for a total dose of 10 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not use to treat more than 1 episode every 5 days and more than 5 episodes per month.

    Adolescents weighing 76 kg or more

    10 mg in each nostril once, for a total dose of 20 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not use to treat more than 1 episode every 5 days and more than 5 episodes per month.[64930]

    Children and Adolescents 12 to 17 years weighing 51 to 75 kg

    7.5 mg in each nostril once, for a total dose of 15 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not use to treat more than 1 episode every 5 days and more than 5 episodes per month.

    Children and Adolescents 12 to 17 years weighing 28 to 50 kg

    10 mg in 1 nostril once, for a total dose of 10 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not use to treat more than 1 episode every 5 days and more than 5 episodes per month.

    Children 12 years weighing 14 to 27 kg

    5 mg in 1 nostril once, for a total dose of 5 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not use to treat more than 1 episode every 5 days and more than 5 episodes per month.

    Children 6 to 11 years weighing 56 to 74 kg

    10 mg in each nostril once, for a total dose of 20 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not use to treat more than 1 episode every 5 days and more than 5 episodes per month.[64930]

    Children 6 to 11 years weighing 38 to 55 kg

    7.5 mg in each nostril once, for a total dose of 15 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not use to treat more than 1 episode every 5 days and more than 5 episodes per month.

    Children 6 to 11 years weighing 19 to 37 kg

    10 mg in 1 nostril once, for a total dose of 10 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not use to treat more than 1 episode every 5 days and more than 5 episodes per month.

    Children 6 to 11 years weighing 10 to 18 kg

    5 mg in 1 nostril once, for a total dose of 5 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not use to treat more than 1 episode every 5 days and more than 5 episodes per month.

    For adjunctive treatment of convulsive disorders, such as partial seizures or generalized tonic-clonic seizures.
    Oral dosage (oral solution or regular tablets)
    Adults

    2 to 10 mg PO 2 to 4 times daily.

    Geriatric

    2 to 2.5 mg PO 1 to 2 times daily; increase dose gradually as needed and tolerated.

    Infants, Children, and Adolescents 6 months to 17 years

    1 to 2.5 mg PO 3 to 4 times daily; increase dose gradually as needed and tolerated.

    For amnesia induction or for procedural sedation.
    Intravenous dosage
    Adults (prior to cardioversion)

    5 to 15 mg IV 5 to 10 minutes before the procedure.

    Adults (prior to endoscopy)

    Dose may be titrated up to 20 mg IV, depending on response and patient tolerability.

    Infants†, Children†, and Adolescents†

    0.05 to 0.1 mg/kg/dose IV initially, titrate slowly to a maximum dose of 0.25 mg/kg IV.

    Oral dosage
    Adults

    10 mg PO 45 to 60 minutes before the procedure.

    Infants†, Children†, and Adolescents† (for procedures or conscious sedation)

    0.2 to 0.4 mg/kg/dose (Max: 20 mg/dose) PO 45 to 60 minutes before the procedure.

    For the treatment of benzodiazepine withdrawal†.
    Oral dosage
    Adults

    Because benzodiazepine withdrawal is more pronounced with shorter-acting agents, diazepam has been proposed as the benzodiazepine of choice for managing withdrawal. Diazepam-equivalent doses have been established for some other benzodiazepines. Diazepam should be tapered off in increments of 0.5 to 2 mg per week over a period of 4 to 16 weeks.

    For the treatment of acute chloroquine overdose† in combination with epinephrine.
    Intravenous dosage
    Adults

    Eleven cases of acute chloroquine overdose (total ingested dose ranged 5 to 12 g) were treated with diazepam 2 mg/kg IV over 30 minutes in combination with IV epinephrine, general anesthesia with thiopental, and FiO2 40%. Diazepam was continued at a dose of 1 to 2 mg/kg/day IV for 2 to 4 additional days. Other vasopressors and/or inotropic agents were used as necessary. Ten of 11 patients were discharged alive from the hospital. The one patient who died had ingested the largest total dose (15 g) of chloroquine.

    For the treatment of insomnia†.
    Oral dosage
    Adults

    2 to 10 mg PO at bedtime; individualize and titrate dosage according to patient response.

    Geriatric Adults

    2 to 10 mg PO at bedtime; individualize and titrate dosage according to patient response. Use is not recommended as a hypnotic due to the long half-life of diazepam, the availability of safer sleep agents, and the increased sensitivity to benzodiazepines (e.g., ataxia, psychomotor impairment, syncope, falls) within the geriatric population.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Dosage must be individualized. Suggested maximum doses: 40 mg/day PO in divided doses for chronic ambulatory uses. A maximum dose has not been specifically defined by the manufacturer for emergent conditions.

    Geriatric

    Dosage must be individualized. Suggested maximum dose: 40 mg/day PO in divided doses for many chronic ambulatory uses. A maximum dose has not been specifically defined by the manufacturer for emergent conditions.

    Adolescents

    Dosage must be individualized. Suggested maximum dose: 0.6 mg/kg IV in 8 hour period for acute anxiety.

    Children

    Dosage must be individualized. Suggested maximum dose: 0.6 mg/kg IV in 8 hour period for acute anxiety.

    Infants

    Maximum dosage not established.

    Neonates

    Maximum dosage not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dosage should be modified depending on clinical response and degree of hepatic impairment, but no quantitative recommendations are available.

    Renal Impairment

    Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available; active and inactive diazepam metabolites are excreted by the kidney.

    ADMINISTRATION

    Oral Administration
    Oral Liquid Formulations

    Concentrated oral solution (25 mg/5 mL)
    Use only the calibrated dropper provided with the product.
    Draw into the dropper the amount prescribed for a single dose.
    Squeeze the dropper contents into a liquid or semi-solid food such as water, juices, soda or soda-like beverages, applesauce, or puddings. Stir the liquid or food gently for a few seconds.
    Administer the entire amount of the mixture of drug and liquid or drug and food immediately. Do not store for future use.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Once the acute symptomatology has been properly controlled with diazepam injection, transition the patient to oral diazepam therapy if further treatment is required.[43931]

    Intravenous Administration

    Ensure facilities for respiratory assistance are readily available.
    Do not use small veins, such as those of the dorsum of the hand or wrist.
    Inject slowly, taking at least 1 minute for each 5 mg.
    If it is not feasible to administer diazepam directly intravenous, may inject slowly through the infusion tubing as close as possible to the vein insertion.
    Take extreme care to avoid extravasation or intraarterial administration.
    Do not dilute or mix diazepam with other solutions or drugs in syringe or infusion flask.[43931]

    Intramuscular Administration

    Inject deeply into a large muscle mass.

    Inhalation Administration
    Intranasal Inhalation Administration

    No device assembly is required.
    Do not prime or attempt to use for more than 1 administration per device.
    Place the person on their side or back where they cannot fall.
    Remove the device from the blister pack.
    Hold the device with thumb on the bottom of the plunger and first and middle fingers on either side of the nozzle.
    Gently insert the nozzle tip into the nostril until the fingers on either side of the nozzle are against the bottom of the person's nose.
    Press the bottom of the plunger firmly with thumb to deliver the dose
    Remove the device from the nose and discard.[64930]

    Rectal Administration

    Before dispensing to the patient, a pharmacist must dial in the dose and lock the rectal syringe. To do so, hold barrel of the syringe with the cap pointed downward. Grasp cap with the other hand and turn to adjust dose. Confirm prescribed dose appears in the window. Grasp and push the locking ring upward to lock both sides of the ring. Repeat steps for second syringe.
    Place the person on their side where they cannot fall.
    Get the medicine syringe. Confirm dose is visible and correct, if known. Ensure green "READY" band is visible.
    To remove protective cover from syringe, push up with thumb and pull. Ensure that both the cap and seal pin are removed.
    Lubricate rectal tip with lubricating jelly.
    Turn person on side facing you and bend upper leg forward to expose rectum. Separate buttocks to expose rectum.
    Gently insert syringe tip into rectum; rim should be snug against rectal opening. Slowly count to 3 while gently pushing the plunger in until it stops. Slowly count to 3 before removing the syringe from the rectum.
    Slowly count to 3 while holding the buttocks together to prevent leakage.
    Keep person on the side facing you. Note time given and continue to observe.
    After use, pull on the syringe plunger until it is completely removed from the syringe body. Point syringe tip over sink or toilet. Replace plunger into syringe body, gently pushing plunger until it stops. Flush toilet or rinse sink with water until gel is no longer visible.[43932]

    STORAGE

    Generic:
    - Discard opened bottle after 90 days
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Diastat:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Dizac:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Valium:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Diazepam is contraindicated in any patient with a known hypersensitivity to diazepam.[28712] [43931] [43932] [64930]

    Extravasation, intraarterial administration

    Use extreme care to avoid intraarterial administration or extravasation when administering diazepam intravenously. To reduce the possibility of venous thrombosis, phlebitis, local irritation, and rarely, vascular impairment, inject slowly and do not use small veins, such as those on the dorsum of the hand or wrist.[43931]

    Depression, psychosis, suicidal ideation

    Monitor all patients beginning treatment with antiepileptic drugs (AEDs) or currently receiving diazepam closely for emerging or worsening depression or suicidal ideation. Advise patients and caregivers of the increased risk of suicidal thoughts and behaviors and to immediately report the emergence of new or worsening of depression, suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. AEDs should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any patient may be related to the illness being treated. There is an increased risk of suicidal ideation and behavior in patients receiving AEDs to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (5 years of age and older). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks.[64930] Diazepam is not recommended in the treatment of psychosis; do not use diazepam instead of appropriate treatment.[28712]

    CNS depression, coma, driving or operating machinery, ethanol ingestion, ethanol intoxication, shock

    Benzodiazepines, including diazepam, may produce CNS depression. Advise patients against engaging in hazardous activities requiring mental alertness (e.g., driving or operating machinery or riding a bicycle) until the effects of the drug, such as drowsiness, have subsided, and their medical condition permits. Advise patients against simultaneous ethanol ingestion or ethanol intoxication as well as ingestion of other CNS depressant drugs during diazepam therapy. Do not administer diazepam injection to patients in coma or shock.[28712] [43931] [43932] [64930]

    Asthma, coadministration with other CNS depressants, pulmonary disease, respiratory depression, respiratory insufficiency, sleep apnea

    Oral diazepam tablets are contraindicated for use in patients with severe respiratory insufficiency or sleep apnea syndrome. Use extreme care when administering diazepam in patients with limited pulmonary reserve or compromised respiratory function related to concurrent pulmonary disease process (e.g., asthma, pneumonia) or neurologic damage due to the possibility of apnea or cardiac arrest. Additionally, avoid coadministration with other CNS depressants, especially opioids, unless no other alternatives are available as coadministration significantly increases the risk for profound sedation, respiratory depression, coma, and death.[28712] [43931] [43932] [61143] [64930]

    Closed-angle glaucoma

    Diazepam is contraindicated in patients with closed-angle glaucoma. It may be used in patients with open-angle glaucoma who are receiving appropriate therapy. Benzodiazepines, including diazepam, can increase intraocular pressure in patients with glaucoma.[28712] [43931] [43932] [64930]

    Hepatic disease

    Oral diazepam tablets are contraindicated in patients with severe hepatic disease. In general, use diazepam with caution in patients with liver disease. Concomitant liver disease is known to decrease the clearance of diazepam. Because of isolated reports of jaundice, periodic liver function tests are advisable during long-term diazepam therapy.[28712] [43932]

    Renal disease, renal failure, renal impairment

    Diazepam metabolites are excreted by the kidneys; to avoid their excess accumulation, use caution when administering diazepam to patients with renal disease, including renal impairment or renal failure.[43932]

    Myasthenia gravis

    Oral diazepam tablets are contraindicated in patients with myasthenia gravis.[28712]

    Neutropenia

    Because of isolated reports of neutropenia, periodic blood counts are advisable during long-term diazepam therapy.

    Dementia, geriatric

    Use diazepam with caution in the geriatric adult, especially for chronic treatment. Significant accumulation of diazepam and its major metabolite, desmethyldiazepam, has been noted in elderly subjects receiving prolonged, routine therapy. Decreased elimination may also occur in some elderly patients due to a decline in renal function and can either intensify or prolong the adverse reactions of the drug. The impairment of cognitive and motor function may be more marked in this patient group. Because diazepam can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the elderly, with the potential for subsequent severe injuries. Due to its long half-life and the availability of safer alternatives, diazepam is not recommended for the treatment of insomnia in the elderly. In geriatric and debilitated patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation and that close monitoring be employed. Use caution when administering diazepam intravenously to the elderly due to the risk of apnea and/or cardiac instability.[28712] [41506] [43931] According to the Beers Criteria, benzodiazepines are considered potentially inappropriate medications (PIMs) in geriatric patients and avoidance is generally recommended, although some agents may be appropriate for seizure disorders, rapid eye movement sleep disorders, benzodiazepine or ethanol withdrawal, severe generalized anxiety disorder, or peri-procedural anesthesia. Older adults have an increased sensitivity to benzodiazepines and slower metabolism of long-acting agents, which increases their risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents. The Beers panel recommends avoiding benzodiazepines in geriatric patients with the following conditions due to the potential for symptom exacerbation or adverse effects: delirium (new-onset or worsening delirium), dementia (adverse CNS effects), and history of falls/fractures (ataxia, impaired psychomotor function, syncope, and additional falls). If a benzodiazepine must be used in a patient with a history of falls or fractures, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. The Beers criteria are not meant to apply to patients at the end of life or receiving palliative care, when risk-benefit considerations of drug therapy can be different.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). Specific criteria for anxiolytics must be met, including 1) limiting use to indications specified in the OBRA guidelines (e.g., generalized anxiety disorder, panic disorder, significant anxiety to a situational trigger, alcohol withdrawal) which meet the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for the indication, and 2) evidence exists that other possible reasons for the individual's distress have been considered, and 3) use results in maintenance or improvement in mental, physical, and psychosocial well-being as reflected on the Minimum Data Set (MDS) or other assessment tool. Anxiolytics should be used for delirium, dementia, or other cognitive disorders only when there are associated behaviors that are 1) quantitatively and objectively documented, and 2) are persistent, and 3) are not due to preventable or correctable reasons, and 4) constitute clinically significant distress or dysfunction to the LTCF resident or represent a danger to the resident or others. There are exceptions that may warrant the use of an anxiolytic such as a long-acting benzodiazepine for withdrawal from a short-acting benzodiazepine, use for neuromuscular syndromes (e.g., tardive dyskinesia, restless legs syndrome, seizure disorder, cerebral palsy), or end of life care. The need for indefinite continuation of diazepam (e.g., seizure disorder) should be based on confirmation of the condition being treated and its potential cause(s). It should be noted that benzodiazepines may increase the risk of confusion, sedation, and falls. OBRA provides dosing guidance for diazepam as an anxiolytic. When a medication is used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.[60742]

    Children, infants, neonates

    Due to the potential for prolonged CNS depression, oral diazepam is contraindicated in neonates and infants younger than 6 months, and parenteral diazepam is not recommended for use in neonates younger than 1 month. The response of children to benzodiazepine therapy can be unpredictable. In general, the pediatric population is more sensitive to the effects of benzodiazepines. Initially, use the lowest dose of diazepam in children, with increases made according to response. When using parenteral diazepam, ensure age and size appropriate resuscitative equipment and trained personnel are readily available. The safety and efficacy of diazepam rectal gel have not been established in children younger than 2 years. The safety and efficacy of diazepam nasal spray have not been established in children younger than 6 years. Serious and fatal adverse reactions, including gasping syndrome, can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including diazepam nasal spray. The gasping syndrome is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.[28712] [43931] [43932] [64930]

    Abrupt discontinuation, alcoholism, benzodiazepine dependence, substance abuse

    Use diazepam with caution in patients with a history of alcoholism or substance abuse due to the potential for psychological dependence. The use of benzodiazepines exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive benzodiazepines routinely for development of these behaviors or conditions. A potential risk of abuse should not preclude appropriate treatment in any patient, but requires more intensive counseling and monitoring. To discourage abuse, the smallest appropriate quantity of the benzodiazepine should be prescribed, and proper disposal instructions for unused drug should be given to patients. Avoid or minimize concomitant use of CNS depressants or other medications associated with addiction or abuse. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, and death. Advise patients to seek immediate medical attention if they experience symptoms such as trouble breathing. Abrupt discontinuation or rapid dosage reduction of benzodiazepines after continued use may precipitate acute withdrawal reactions, which can be life-threatening. The risks of physiological dependence and withdrawal increase with longer treatment duration and higher daily dose. Benzodiazepine dependence can occur after administration of therapeutic doses for as few as 1 to 2 weeks and withdrawal symptoms may be seen after the discontinuation of therapy. To reduce the risk of acute withdrawal reactions, use a gradual taper to reduce the dosage or to discontinue benzodiazepines. No standard benzodiazepine tapering schedule is suitable for all patients; therefore, create a patient-specific plan to gradually reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently, decrease the dosage more slowly. Patients with a seizure history or who are taking drugs that lower the seizure threshold (e.g., certain antidepressants, phenothiazines) should not be withdrawn abruptly from benzodiazepines due to the risk of precipitating a seizure. During benzodiazepine withdrawal, the greatest risk of seizure appears to be during the first 24 to 72 hours. Diazepam is not recommended for chronic, daily use as an anticonvulsant. Chronic daily use of diazepam may increase the frequency and/or severity of tonic-clonic seizures, requiring an increase in the dosage of standard anticonvulsant medication. In such cases, abrupt withdrawal of chronic diazepam may also be associated with a temporary increase in the frequency and/or severity of seizures in patients with a seizure disorder. Tonic status epilepticus has been precipitated in patients treated with intravenous diazepam for petit mal status or petit mal variant status. Clinicians should be aware that the use of flumazenil may increase the risk of seizures.[28712]

    Labor, obstetric delivery, pregnancy

    There are no adequate data on diazepam use during human pregnancy. Consider diazepam use during pregnancy only when the clinical situation warrants the risk to the fetus. If diazepam is to be used during pregnancy or the patient becomes pregnant while taking diazepam, advise the patient of the potential hazard to the fetus. Measurable amounts of diazepam were found in cord blood, indicating placental transfer of the drug. Available data suggest that the class of benzodiazepines is not associated with marked increases in risk for congenital anomalies. A meta-analysis of 23 studies examined the effects of benzodiazepine exposure during the first trimester of pregnancy. Eleven of the 23 studies included in the meta-analysis considered the use of chlordiazepoxide and diazepam and not other benzodiazepines. Case-control and cohort studies were considered separately. The data from the cohort studies did not suggest an increased risk for major malformations (OR 0.90; 95% CI 0.61 to 1.35) or oral cleft (OR 1.19; 95% CI 0.34 to 4.15). The data from the case-control studies suggested an association between benzodiazepines and major malformations (OR 3.01, 95% CI 1.32 to 6.84) and oral cleft (OR 1.79; 95% CI 1.13 to 2.82). The limitations of this meta-analysis included the small number of reports included in the analysis, and that most cases for analyses of both oral cleft and major malformations came from only 3 studies. A follow up to that meta-analysis included 3 new cohort studies that examined risk for major malformations and 1 study that considered cardiac malformations. No new studies with an outcome of oral clefts were found. After the addition of the new studies, the odds ratio for major malformations with first trimester exposure to benzodiazepines was 1.07 (95% CI 0.91 to 1.25). There is insufficient evidence to assess the effect of benzodiazepine pregnancy exposure on neurodevelopment. In animal studies, administration of diazepam during the organogenesis period of pregnancy resulted in increased incidences of fetal malformations at doses greater than those used clinically. Data for diazepam and other benzodiazepines suggest the possibility of increased neuronal cell death and long-term effects on neurobehavioral and immunological function based on findings in animals after prenatal or early postnatal exposure at clinically relevant doses. Clinical considerations regarding exposure to benzodiazepines during the second and third trimesters of pregnancy and immediately before or during labor and obstetric delivery include decreased fetal movement and/or fetal heart rate variability, floppy infant syndrome, dependence, and withdrawal. Neonatal withdrawal syndrome and symptoms suggestive of floppy infant syndrome associated with administration of benzodiazepines during the later stages of pregnancy and peripartum have been reported. Clinical manifestations of withdrawal or neonatal abstinence syndrome may include hypertonia, hyperreflexia, hypoventilation, irritability, tremors, diarrhea, and vomiting. These complications can appear shortly after birth to 3 weeks after birth and persist from hours to several months, depending on the degree of dependence and the pharmacokinetic profile of the benzodiazepine. Symptoms may be mild and transient or severe. Standard management for neonatal withdrawal syndrome has not yet been defined. Floppy infant syndrome is characterized by lethargy, hypothermia, hypotonia, respiratory depression, and difficulty feeding. Floppy infant syndrome occurs mainly within the first hours after birth and may last up to 14 days. Observe newborns who are exposed to diazepam for symptoms of withdrawal and floppy infant syndrome and manage accordingly. The major neonatal side effects of benzodiazepines also include sedation. Data suggest that fetal exposure to benzodiazepines is also associated with the neonatal adverse events of hypotonia, respiratory problems, hypoventilation, and low Apgar score. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to diazepam; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.[28712] [64930]

    Breast-feeding

    Breast-feeding is not recommended in patients receiving oral diazepam. Because diazepam and its metabolites may be present in human breast milk for a prolonged period after acute use of rectal diazepam, advise patients not to breast-feed for an appropriate period of time after receiving rectal diazepam. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for nasal diazepam and any potential adverse effects on the breast-fed infant from diazepam or the underlying maternal condition. Diazepam is excreted in human milk. There are no data to assess the effects of diazepam on milk production. Postmarketing experience suggests that breast-fed infants of mothers taking benzodiazepines may have effects of lethargy, somnolence, and poor sucking.[28712] [43932] [64930] Diazepam concentrations were assessed in 3 breast-feeding mothers receiving diazepam 30 mg daily for 6 days after delivery. The mean concentration of diazepam and its metabolite in the mothers' sera, the breast milk, and the infants' sera at 4 days were 831 ng/mL, 79 ng/mL, and 415 ng/mL and at 6 days were 1,084 ng/mL, 130 ng/mL, and 105 ng/mL, respectively. The infants' mean serum concentration decrease from days 4 to 6 may be due to decreases in the amount of milk consumed or the onset of elimination mechanisms. None of the infants showed signs of lethargy or hypoventilation.[46133] An infant exposed to diazepam 30 mg daily at 5 days postpartum experienced weight loss, lethargy, and electroencephalogram (EEG) findings consistent with sedative medication.[46129] A small series of 9 infants exposed to diazepam at unspecified doses through breast milk found the only adverse event was mild jaundice in 3 of the infants.[46130] Previous American Academy of Pediatrics recommendations considered diazepam as a drug whose effect on the breast-feeding infant is not known but may be of concern, particularly with prolonged exposure.[27500] If occasional maternal therapy with a benzodiazepine is required, lorazepam or oxazepam may be reasonable alternatives for some patients. Some experts suggest that occasional maternal treatment with usual doses of lorazepam or oxazepam would pose little risk to a breast-feeding infant.[46105] [46341]

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 1.0
    bone fractures / Delayed / Incidence not known
    apnea / Delayed / Incidence not known
    laryngospasm / Rapid / Incidence not known
    cardiac arrest / Early / Incidence not known
    seizures / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    neonatal abstinence syndrome / Early / Incidence not known

    Moderate

    memory impairment / Delayed / 39.5-39.5
    dysarthria / Delayed / 1.0-32.1
    urinary retention / Early / 17.3-17.3
    urinary incontinence / Early / 17.3-17.3
    respiratory depression / Rapid / 9.0-9.0
    ataxia / Delayed / 2.0-5.0
    peripheral vasodilation / Rapid / 1.0-5.0
    euphoria / Early / 3.0-3.0
    anemia / Delayed / 0-1.0
    lymphadenopathy / Delayed / 0-1.0
    confusion / Early / 1.0
    hypotension / Rapid / 1.0
    myasthenia / Delayed / 1.0
    tolerance / Delayed / Incidence not known
    physiological dependence / Delayed / Incidence not known
    psychological dependence / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    amnesia / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    nystagmus / Delayed / Incidence not known
    constipation / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    mania / Early / Incidence not known
    hallucinations / Early / Incidence not known
    dyspnea / Early / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    phlebitis / Rapid / Incidence not known

    Mild

    drowsiness / Early / 23.0-84.0
    fatigue / Early / 56.8-56.8
    appetite stimulation / Delayed / 32.1-32.1
    weight gain / Delayed / 23.5-23.5
    libido decrease / Delayed / 18.5-18.5
    libido increase / Delayed / 18.5-18.5
    menstrual irregularity / Delayed / 18.4-18.4
    weight loss / Delayed / 12.3-12.3
    nasal irritation / Early / 6.0-6.0
    headache / Early / 2.0-5.0
    dizziness / Early / 2.0-5.0
    rash / Early / 2.0-5.0
    diarrhea / Early / 4.0-4.0
    epistaxis / Delayed / 3.0-3.0
    nasal congestion / Early / 3.0-3.0
    dysgeusia / Early / 2.0-2.0
    mydriasis / Early / 0-1.0
    pruritus / Rapid / 0-1.0
    vomiting / Early / 0-1.0
    anorexia / Delayed / 0-1.0
    hyperkinesis / Delayed / 0-1.0
    infection / Delayed / 0-1.0
    diaphoresis / Early / 0-1.0
    cough / Delayed / 0-1.0
    emotional lability / Early / 1.0
    vertigo / Early / 1.0
    abdominal pain / Early / 1.0
    agitation / Early / 1.0
    rhinitis / Early / 1.0
    hiccups / Early / 1.0
    tremor / Early / Incidence not known
    syncope / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    diplopia / Early / Incidence not known
    nausea / Early / Incidence not known
    hypersalivation / Early / Incidence not known
    xerostomia / Early / Incidence not known
    nightmares / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    insomnia / Early / Incidence not known
    irritability / Delayed / Incidence not known
    restlessness / Early / Incidence not known
    hyperventilation / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Acetaminophen; Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Acetaminophen; Chlorpheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Diphenhydramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Acetaminophen; Oxycodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 oxycodone is initiated in a patient taking a benzodiazepine, reduce dosages and titrate to clinical response. For acetaminophen; oxycodone extended-release tablets, start with 1 tablet PO every 12 hours, and for other oxycodone products, use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Acetaminophen; Pentazocine: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines 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 a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If parental diazepam is used with a mixed opiate agonist/antagonist, reduce the mixed opiate agonist/antagonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Acetaminophen; Propoxyphene: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. The dose of any opiate agonist administered with parenteral diazepam should be reduced by at least one-third.
    Acrivastine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS activity. Use with caution.
    Alfentanil: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Aluminum Hydroxide: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
    Aluminum Hydroxide; Magnesium Carbonate: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
    Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
    Amiodarone: (Moderate) Diazepam is metabolized by oxidative metabolism, specifically, the hepatic isozymes CYP2C19 and CYP3A4. As a result, diazepam is susceptible to interactions with drugs that inhibit these hepatic enzymes, such as amiodarone. Monitor patients closely.
    Amobarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
    Amoxapine: (Moderate) Amoxapine may enhance the response to the effects of benzodiazepines and other CNS depressants. Patients should be warned of the possibility of drowsiness that may impair performance of potentially hazardous tasks such as driving an automobile or operating machinery.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes. Clarithromycin could theoretically inhibit the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as diazepam. (Moderate) Omeprazole inhibits the CYP2C19 metabolic pathway for diazepam. Omeprazole can increase the plasma concentrations and the elimination half-life of diazepam. It is recommended that patients receiving omeprazole and diazepam concomitantly should be monitored for enhanced diazepam response. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Amphetamine; Dextroamphetamine Salts: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use dextroamphetamine with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures.
    Antacids: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
    Apalutamide: (Moderate) Monitor for diazepam withdrawal symptoms or lack of efficacy if coadministration of diazepam with apalutamide is necessary. Diazepam is a CYP3A4, CYP2C9, and CYP2C19 substrate. Apalutamide is a strong CYP3A4 and CYP2C19 inducer, as well as a weak CYP2C9 inducer.
    Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and benzodiazepines could result in additive depressant effects.
    Apraclonidine: (Minor) No specific drug interactions were identified with systemic agents and apraclonidine during clinical trials. Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as the anxiolytics, sedatives, and hypnotics, including barbiturates or benzodiazepines.
    Aprepitant, Fosaprepitant: (Major) Use caution if diazepam and aprepitant, fosaprepitant are used concurrently and monitor for an increase in diazepam-related adverse effects for several days after administration of a multi-day aprepitant regimen. If a benzodiazepine is necessary, a dosage adjustment of the multi-day regimen may be necessary depending on the clinical situation (e.g., elderly patients) and degree of monitoring available; no dosage adjustment is needed for a single 40-mg dose of aprepitant or 150-mg dose of fosaprepitant. Consider selection of an agent that is not metabolized via CYP3A4 isoenzymes (e.g., lorazepam, oxazepam, temazepam). Diazepam 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 diazepam. 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. Aprepitant is also a CYP2C9 inducer and diazepam is a CYP2C9 substrate. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.
    Aripiprazole: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics. The intensity of sedation and orthostatic hypotension is greater during concurrent use of lorazepam and oral aripiprazole and during use of a parenteral benzodiazepine and intramuscular (IM) aripiprazole compared to aripiprazole alone; therefore, patients receiving a benzodiazepine with oral or parenteral aripiprazole should be monitored for sedation and blood pressure and the dose should be adjusted accordingly. Data from the manufacturer indicate there are no clinically significant pharmacokinetic changes when aripiprazole is given with lorazepam.
    Armodafinil: (Moderate) In vitro data indicate that armodafinil is an inhibitor of CYP2C19. In theory, dosage reductions may be required for drugs that are largely eliminated via CYP2C19 metabolism such as diazepam during coadministration with armodafinil.
    Asciminib: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with asciminib is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and asciminib is a CYP3A inhibitor.
    Asenapine: (Moderate) Drugs that can cause CNS depression, if used concomitantly with asenapine, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when asenapine is given in combination with other centrally-acting medications including anxiolytics, sedatives, and hypnotics (including barbiturates), buprenorphine, buprenorphine; naloxone, butorphanol, dronabinol, THC, nabilone, nalbuphine, opiate agonists, pentazocine, acetaminophen; pentazocine, aspirin, ASA; pentazocine, and pentazocine; naloxone.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Aspirin, ASA; Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
    Aspirin, ASA; Omeprazole: (Moderate) Omeprazole inhibits the CYP2C19 metabolic pathway for diazepam. Omeprazole can increase the plasma concentrations and the elimination half-life of diazepam. It is recommended that patients receiving omeprazole and diazepam concomitantly should be monitored for enhanced diazepam response. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 oxycodone is initiated in a patient taking a benzodiazepine, reduce dosages and titrate to clinical response. For acetaminophen; oxycodone extended-release tablets, start with 1 tablet PO every 12 hours, and for other oxycodone products, use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Atazanavir; Cobicistat: (Moderate) The plasma concentrations of diazepam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; diazepam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of diazepam. These drugs used in combination may result in elevated diazepam plasma concentrations, causing an increased risk for diazepam-related adverse events.
    Atropine; Difenoxin: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as diphenoxylate/difenoxin, can potentiate the CNS effects of either agent.
    Avacopan: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with avacopan is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and avacopan is a CYP3A inhibitor.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with CNS depressants including benzodiazepines.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with CNS depressants including benzodiazepines.
    Bacitracin: (Minor) Diazepam, which has skeletal muscle relaxant properties, should be used cautiously in patients receiving systemic bacitracin. If bacitracin is administered parenterally during surgery, there may be increased skeletal muscle relaxation, and postoperative use may reinstate neuromuscular blockade.
    Barbiturates: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
    Belladonna; Opium: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Belumosudil: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with belumosudil is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and belumosudil is a CYP3A inhibitor.
    Belzutifan: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with belzutifan is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and belzutifan is a CYP3A inducer.
    Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 a benzodiazepine, reduce initial dosage and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Benztropine: (Moderate) CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of benztropine.
    Berotralstat: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with berotralstat is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and berotralstat is a CYP3A4 inhibitor.
    Bicalutamide: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with bicalutamide is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and bicalutamide is a CYP3A4 inhibitor.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering diazepam with boceprevir due to an increased potential for diazepam-related adverse events. If diazepam dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of diazepam. Diazepam is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated diazepam plasma concentrations.
    Bosentan: (Moderate) Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes, including diazepam.
    Brigatinib: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with brigatinib is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A4 substrate and brigatinib is a CYP3A4 inducer.
    Brimonidine: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Brimonidine; Brinzolamide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Brimonidine; Timolol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Brompheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Brompheniramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Brompheniramine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Buprenorphine: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines 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 a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If parental diazepam is used with an opiate agonist, reduce the mixed opiate agonist/antagonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Buprenorphine; Naloxone: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines 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 a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If parental diazepam is used with an opiate agonist, reduce the mixed opiate agonist/antagonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Buspirone: (Moderate) It is common for patients to overlap anxiety treatment when switching from benzodiazepines to buspirone. Buspirone has a slow onset of action and the drug will not block the withdrawal syndrome often seen with cessation of benzodiazepine therapy in those with benzodiazepine dependence. Therefore, before starting therapy with buspirone, withdraw patients gradually from the benzodiazepine. Alternatively, conversion to buspirone therapy may require treatment overlap to allow for the downward titration of the benzodiazepine while buspirone takes effect. It should be noted that the combination of buspirone and benzodiazepines can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Butabarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
    Butalbital; Acetaminophen: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Butorphanol: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines 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 a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If parental diazepam is used with a mixed opiate agonist/antagonist, reduce the mixed opiate agonist/antagonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Caffeine; Sodium Benzoate: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Calcium Carbonate: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
    Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
    Calcium Carbonate; Risedronate: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
    Calcium Carbonate; Simethicone: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
    Calcium, Magnesium, Potassium, Sodium Oxybates: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Cannabidiol: (Moderate) Consider a dose reduction of diazepam as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Additive sedation and somnolence may occur. Increased diazepam exposure is possible. Diazepam is a CYP2C19 substrate. In vitro data predicts inhibition of CYP2C19 by cannabidiol potentially resulting in clinically significant interactions.
    Carbamazepine: (Moderate) Carbamazepine is a potent inducer of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of diazepam. Monitor closely for signs of reduced diazepam effects.
    Carbetapentane; Chlorpheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines.
    Carbetapentane; Pyrilamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines.
    Carbinoxamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Carbinoxamine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbinoxamine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution should be used when cariprazine is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics.
    Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
    Ceritinib: (Moderate) Monitor for an increase in sedation and respiratory depression if coadministration of diazepam with ceritinib is necessary. At low concentrations, diazepam is a CYP2C19 substrate but at high concentrations, CYP3A4 is also involved. Ceritinib is a strong CYP3A4 inhibitor.
    Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with benzodiazepines 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 benzodiazepines 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.
    Chlophedianol; Dexbrompheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorcyclizine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Dextromethorphan: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorthalidone; Clonidine: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Cimetidine: (Moderate) Cimetidine can inhibit the hepatic clearance of some benzodiazepines that undergo oxidative metabolism, such as diazepam. In some cases, dosage reduction of the interacting drug will be necessary or an alternative to cimetidine should be considered.
    Ciprofloxacin: (Moderate) Ciprofloxacin is a CYP3A4 inhibitor and may reduce the metabolism of diazepam and increase the potential for benzodiazepine toxicity. Ciprofloxacin has been shown to decrease the clearance and increase the half-life of diazepam. However, no significant changes were observed in digit symbol substitution psychometric tests, tapping rate and short memory, or concentration, vigilance, and tension.
    Cisapride: (Moderate) Cisapride may enhance the sedative effects of benzodiazepines. Patients should not drive or operate heavy machinery until they know how the combination affects them. Patient counseling is important, as cisapride alone does not cause drowsiness or affect psychomotor function.
    Citalopram: (Moderate) Clinicians should use citalopram cautiously with diazepam since co-administration with citalopram could potentially result in additive pharmacodynamic effects within the CNS.
    Clarithromycin: (Moderate) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes. Clarithromycin could theoretically inhibit the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as diazepam.
    Clemastine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Clobazam: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
    Clonidine: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Clozapine: (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) The plasma concentrations of diazepam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; diazepam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of diazepam. These drugs used in combination may result in elevated diazepam plasma concentrations, causing an increased risk for diazepam-related adverse events.
    Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
    Codeine; Guaifenesin: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
    Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Codeine; Promethazine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
    Colesevelam: (Moderate) Colesevelam may decrease the absorption of anticonvulsants. To minimize potential for interactions, consider administering oral anticonvulsants at least 1 hour before or at least 4 hours after colesevelam.
    COMT inhibitors: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Conivaptan: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with conivaptan is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and conivaptan is a CYP3A inhibitor.
    Crizotinib: (Moderate) Monitor for increased diazepam-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary. Diazepam is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation.
    Cyclizine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Cyproheptadine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Dalfopristin; Quinupristin: (Moderate) Monitor for diazepam-related adverse reactions including sedation and respiratory depression if coadministration with dalfopristin; quinupristin is necessary due to increased diazepam exposure. Dalfopristin; quinupristin is a weak CYP3A4 inhibitor and diazepam is metabolized by CYP3A4.
    Danazol: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of diazepam.
    Darunavir; Cobicistat: (Moderate) The plasma concentrations of diazepam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; diazepam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of diazepam. These drugs used in combination may result in elevated diazepam plasma concentrations, causing an increased risk for diazepam-related adverse events.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) The plasma concentrations of diazepam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; diazepam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of diazepam. These drugs used in combination may result in elevated diazepam plasma concentrations, causing an increased risk for diazepam-related adverse events.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Systemic exposure of diazepam and its metabolite, nordiazepam, were decreased when a single 2 mg dose was administered concurrently with ombitasvir; paritaprevir; ritonavir. If these drugs are given together, monitor for reduced diazepam efficacy; consider increasing the diazepam dose if clinically needed.
    Delavirdine: (Moderate) Delavirdine is a potent inhibitor of the CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as diazepam, should be expected with concurrent use of delavirdine.
    Desflurane: (Moderate) Concurrent use with benzodiazepines can decrease the minimum alveolar concentration (MAC) of desflurane needed to produce anesthesia.
    Desogestrel; Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as diazepam, may have additive effects and worsen drowsiness or sedation.
    Dexbrompheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Dexbrompheniramine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Dexchlorpheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Dexmedetomidine: (Moderate) Concurrent use of dexmedetomidine and benzodiazepines may result in additive CNS depression. A reduction in dosage of dexmedetomidine or the benzodiazepine may be required.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Dicyclomine: (Moderate) Dicyclomine can cause drowsiness, so it should be used cautiously in patients receiving CNS depressants like benzodiazepines.
    Digoxin: (Moderate) Coadministration of diazepam and digoxin has been reported to increase the half-life of digoxin due to reduced urinary excretion of digoxin. Consider measuring serum digoxin concentrations before initiating diazepam. Continue monitoring during concomitant treatment and decrease the digoxin dose as necessary.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
    Diltiazem: (Moderate) Diazepam is metabolized by oxidative metabolism, specifically, the hepatic isozymes CYP2C19 and CYP3A4. As a result, diazepam is susceptible to interactions with drugs that inhibit these hepatic enzymes, such as diltiazem.
    Dimenhydrinate: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Diphenhydramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Diphenhydramine; Ibuprofen: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Diphenhydramine; Naproxen: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Diphenhydramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Diphenoxylate; Atropine: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as diphenoxylate/difenoxin, can potentiate the CNS effects of either agent.
    Disulfiram: (Moderate) Disulfiram may compete for the binding sites on hepatic cytochrome P-450 (CYP) with benzodiazepines that undergo oxidative metabolism such as diazepam, thereby slowing the metabolism of diazepam and increasing its steady-state plasma concentrations.
    Doxylamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Doxylamine; Pyridoxine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Dronabinol: (Moderate) Use caution if the use of benzodiazepines are necessary with dronabinol, and monitor for additive dizziness, confusion, somnolence, and other CNS effects.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Diazepam is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Droperidol: (Major) Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes. In December 2001, the FDA issued a black box warning regarding the use of droperidol and its association with QT prolongation and potential for cardiac arrhythmias based on post-marketing surveillance data. Risk factors for the development of prolonged QT syndrome may include the use of benzodiazepines. Also, droperidol and benzodiazepines can both cause CNS depression. If used with a benzodiazepine, droperidol should be initiated at a low dose and adjusted upward, with caution, as needed to achieve the desired effect.
    Drospirenone; Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Efavirenz: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including diazepam. In addition, efavirenz inhibits CYP2C9 in vitro; diazepam is also metabolized via this isoenzyme. Monitor patients closely for excessive side effects.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including diazepam. In addition, efavirenz inhibits CYP2C9 in vitro; diazepam is also metabolized via this isoenzyme. Monitor patients closely for excessive side effects.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including diazepam. In addition, efavirenz inhibits CYP2C9 in vitro; diazepam is also metabolized via this isoenzyme. Monitor patients closely for excessive side effects.
    Elagolix: (Minor) Coadministration of elagolix with diazepam may theoretically increase plasma concentrations of diazepam. Elagolix is a weak CYP2C19 inhibitor and diazepam is a CYP2C19 sensitive substrate. Monitor for diazepam-related adverse effects during coadministration with elagolix.
    Elagolix; Estradiol; Norethindrone acetate: (Minor) Coadministration of elagolix with diazepam may theoretically increase plasma concentrations of diazepam. Elagolix is a weak CYP2C19 inhibitor and diazepam is a CYP2C19 sensitive substrate. Monitor for diazepam-related adverse effects during coadministration with elagolix.
    Elbasvir; Grazoprevir: (Moderate) Administering diazepam with elbasvir; grazoprevir may result in elevated diazepam plasma concentrations. At high concentrations, diazepam is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Use caution when administering ivacaftor and diazepam concurrently because patients may be at increased risk for adverse effects from diazepam. Ivacaftor is a CYP3A inhibitor, and diazepam is a CYP3A substrate. Diazepam is also metabolized by CYP2C19, which is not affected by ivacaftor. Co-administration of ivacaftor with midazolam, another CYP3A substrate, increased midazolam exposure by 1.5-fold.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of diazepam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; diazepam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of diazepam. These drugs used in combination may result in elevated diazepam plasma concentrations, causing an increased risk for diazepam-related adverse events.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of diazepam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; diazepam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of diazepam. These drugs used in combination may result in elevated diazepam plasma concentrations, causing an increased risk for diazepam-related adverse events.
    Enflurane: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Enzalutamide: (Moderate) Monitor for withdrawal symptoms or lack of efficacy if coadministration of diazepam with enzalutamide is necessary. Diazepam is a CYP3A4, CYP2C9, and CYP2C19 substrate; enzalutamide is a strong CYP3A4 inducer, as well as a moderate CYP2C9 and CYP2C19 inducer.
    Ergotamine; Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Erythromycin: (Moderate) Erythromycin may inhibit the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as diazepam. Monitor patient clinically for enhanced response from diazepam.
    Erythromycin; Sulfisoxazole: (Moderate) Erythromycin may inhibit the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as diazepam. Monitor patient clinically for enhanced response from diazepam.
    Escitalopram: (Moderate) The effect of escitalopram on benzodiazepine metabolism is not known. The combined administration of citalopram with triazolam has not been reported to significantly affect the pharmacokinetics of either drug. However, clinicians should use citalopram or escitalopram cautiously with alprazolam or diazepam since coadministration could potentially result in additive pharmacodynamic effects within the CNS.
    Esketamine: (Major) Closely monitor patients receiving esketamine and benzodiazepines 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.
    Esomeprazole: (Moderate) Diazepam is a substrate for the CYP2C19 isozyme. Since esomeprazole is an inhibitor of the CYP2C19 isozyme, plasma levels of diazepam may increase. Administration of esomeprazole with diazepam resulted in a 45% reduced clearance of diazepam. According to the manufacturer, this interaction is not likely to be clinically relevant. However, it would be prudent to monitor patients more closely, particularly if other CNS depressants are prescribed. The manufacturer reports that use of diazepam does not appear to alter the pharmacokinetic profile of esomeprazole.
    Eszopiclone: (Moderate) Concomitant administration of benzodiazepines with eszopiclone can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. The concurrent use of eszopiclone with other anxiolytics, sedatives, and hypnotics at bedtime or in the middle of the night is not recommended. 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. If used together, a reduction in the dose of one or both drugs may be needed.
    Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
    Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Ethinyl Estradiol; Norelgestromin: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Ethinyl Estradiol; Norgestrel: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Ethotoin: (Moderate) Ethotoin is a hepatic enzyme inducer and thus may accelerate the metabolism of several other anticonvulsants, and can theoretically add to the CNS-depressant effects of other CNS depressants, including the anxiolytics, sedatives, and hypnotics which may be used concomitantly for seizure control or as psychotropics. Ethotoin should be used cautiously with diazepam, as decreased diazepam serum concentrations may be seen when coadministered with phenytoin. In addition, diazepam has been reported to have an unpredictable effect on phenytoin serum concentrations (e.g., to increase, decrease, or cause no change in phenytoin serum concentrations). Conflicting results may have been observed due to saturable phenytoin metabolism and/or other conditions associated with the reported data. Since definitive controlled trial data are lacking, phenytoin concentrations should be monitored more closely when diazepam is added or discontinued.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Etomidate: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Etonogestrel; Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Etravirine: (Moderate) Etravirine is an inhibitor of CYP2C19. Coadministration of etravirine and diazepam, a CYP2C19 substrate, may result in increased diazepam plasma concentrations. Coadminister these drugs with caution, closely monitoring the patient for adverse effects related to diazepam; a decrease in diazepam dose may be needed.
    Everolimus: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and everolimus is a CYP3A4 inhibitor.
    Fedratinib: (Moderate) Monitor for increased diazepam-related adverse reactions including sedation and respiratory depression if coadministration with fedratinib is necessary. Diazepam is a CYP3A4 and CYP2C19 substrate and fedratinib is a moderate CYP3A and CYP2C19 inhibitor. Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation.
    Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and benzodiazepines. Concurrent use may result in additive CNS depression.
    Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as diazepam, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of diazepam during coadministration with fenofibric acid.
    Fentanyl: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Fluconazole: (Moderate) Fluconazole could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, such as diazepam. Coadminister these drugs with caution.
    Flumazenil: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor is competitive and flumazenil has a much shorter duration of action than do most benzodiazepines, it is possible for the effects of flumazenil to dissipate sooner than the effects of the benzodiazepine. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause dysphoria, agitation, and possibly increased adverse effects. If administered to patients who have received a benzodiazepine chronically, abrupt interruption of benzodiazepine agonism by flumazenil can induce benzodiazepine withdrawal including seizures. Flumazenil has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
    Fluoxetine: (Moderate) Diazepam is metabolized by CYP2C19 and CYP3A4. Fluoxetine impairs both of these pathways at therapeutic doses. This can result in substantial increases in the half-life of diazepam, and the psychomotor and physiological response may be altered.
    Fluvoxamine: (Major) Fluvoxamine decreases the oxidative hepatic metabolism of diazepam. Diazepam is metabolized by CYP2C19 and CYP3A4 and fluvoxamine inhibits these CYP isoenzymes and appears to have a significant effect on diazepam exposure, clearance, and elimination half-life. Monitor the patient closely for sedation, CNS depression, and prolonged benzodiazepine effects. Dose reduction may be necessary. In a study with healthy volunteers, concurrent fluvoxamine intake was associated with increased mean peak plasma diazepam concentrations (from 108 to 143 ng/mL, geometric means, difference not significant), with a marked reduction in apparent oral diazepam clearance (significant difference, p less than 0.01) and with a prolongation in diazepam half-life (from 51 to 118 hours; p less than 0.01). N-Desmethyldiazepam AUC values were also significantly increased. These data suggest the interaction is likely to have clinical significance.
    Food: (Major) Coadministration of marijuana with benzodiazepines may result in an exaggerated sedative effect. Instruct patients receiving these medications concurrently not to drive or operate machinery.
    Fosphenytoin: (Moderate) Phenytoin is a hepatic enzyme inducer and thus may accelerate the metabolism of several other anticonvulsants, and can theoretically add to the CNS-depressant effects of other CNS depressants, including the anxiolytics, sedatives, and hypnotics which may be used concomitantly for seizure control or as psychotropics. Fosphenytoin should be used cautiously with clonazepam and diazepam, as decreased clonazepam or diazepam serum concentrations may be seen. In addition, diazepam has been reported to have an unpredictable effect on phenytoin serum concentrations (e.g., to increase, decrease, or cause no change in phenytoin serum concentrations).
    Fospropofol: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Gabapentin: (Major) Concomitant use of benzodiazepines with gabapentin may cause excessive sedation, somnolence, and respiratory depression. If concurrent use is necessary, initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
    General anesthetics: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Grapefruit juice: (Major) Orally-administered diazepam may interact with grapefruit juice. Grapefruit juice has been shown to increase diazepam peak serum concentrations (Cmax) and exposure (AUC) by 1.5-fold and 3.2-fold, respectively, when diazepam was administered orally. Grapefruit juice contains furano-coumarins and certain flavonoids which may inhibit the CYP3A4 isozyme. Increased sedation or other CNS effects may be possible. To prevent this interaction, it would be prudent to avoid taking oral diazepam with grapefruit juice.
    Green Tea: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products, such as green tea, prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Guanabenz: (Moderate) Guanabenz is associated with sedative effects. Guanabenz can potentiate the effects of CNS depressants such as benzodiazepines, when administered concomitantly.
    Guanfacine: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Haloperidol: (Moderate) Haloperidol can potentiate the actions of other CNS depressants, such as benzodiazepines, Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
    Halothane: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Homatropine; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants such as barbiturates, benzodiazepines, opiate agonists, or phenothiazines when administered concomitantly.
    Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Hydromorphone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 hydromorphone is initiated in a patient taking a benzodiazepine, reduce the initial dosage of hydromorphone and titrate to clinical response; for hydromorphone extended-release tablets, use 1/3 to 1/2 of the estimated hydromorphone starting dose. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as diazepam. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
    Hydroxyzine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Ibuprofen; Oxycodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 oxycodone is initiated in a patient taking a benzodiazepine, reduce dosages and titrate to clinical response. For acetaminophen; oxycodone extended-release tablets, start with 1 tablet PO every 12 hours, and for other oxycodone products, use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with diazepam, a CYP3A substrate, as diazepam toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with iloperidone, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when iloperidone is given in combination with other centrally-acting medications including anxiolytics, sedatives, and hypnotics.
    Imatinib: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including diazepam.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with diazepam may result in increased serum concentrations of diazepam. Diazepam is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoflurane: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Isoniazid, INH: (Moderate) Concurrent use of isoniazid, INH and diazepam can increase serum concentrations of diazepam due to alterations in the half-life and clearance of diazepam. Patients should be observed for signs of altered diazepam effects if isoniazid therapy is initiated or discontinued.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of diazepam. Patients receiving rifampin may require higher doses of diazepam to achieve the desired clinical effect. (Moderate) Concurrent use of isoniazid, INH and diazepam can increase serum concentrations of diazepam due to alterations in the half-life and clearance of diazepam. Patients should be observed for signs of altered diazepam effects if isoniazid therapy is initiated or discontinued.
    Isoniazid, INH; Rifampin: (Major) Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of diazepam. Patients receiving rifampin may require higher doses of diazepam to achieve the desired clinical effect. (Moderate) Concurrent use of isoniazid, INH and diazepam can increase serum concentrations of diazepam due to alterations in the half-life and clearance of diazepam. Patients should be observed for signs of altered diazepam effects if isoniazid therapy is initiated or discontinued.
    Itraconazole: (Moderate) Monitor for increased and prolonged sedation if coadministration of itraconazole and diazepam is necessary. A dose reduction of diazepam may be necessary. Diazepam is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and diazepam concurrently because patients may be at increased risk for adverse effects from diazepam. Ivacaftor is a CYP3A inhibitor, and diazepam is a CYP3A substrate. Diazepam is also metabolized by CYP2C19, which is not affected by ivacaftor. Co-administration of ivacaftor with midazolam, another CYP3A substrate, increased midazolam exposure by 1.5-fold.
    Ketamine: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Ketoconazole: (Moderate) Ketoconazole could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines such as diazepam.
    Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes. Clarithromycin could theoretically inhibit the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as diazepam.
    Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and benzodiazepines. Concurrent use may result in additive CNS depression.
    Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during use of lemborexant with benzodiazepines. Dosage adjustments may be necessary when administered together because of potentially additive CNS effects. Use of more than 2 hypnotics should be avoided due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with lemborexant, a reduction in dose of one or both agents may be needed. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.
    Letermovir: (Moderate) Plasma concentrations of diazepam could be increased when administered concurrently with letermovir. The magnitude of this interaction may be elevated in patients who are also receiving cyclosporine. If these drugs are given together, closely monitor for reduced diazepam efficacy and diazepam-related adverse events. Diazepam is a substrate of CYP3A4. Letermovir is a moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with benzodiazepines 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.
    Levomethadyl: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including opiate agonists, can potentiate the CNS effects of either agent.
    Levomilnacipran: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Levonorgestrel; Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Levorphanol: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 levorphanol is initiated in a patient taking a benzodiazepine, reduce the initial dose of levorphanol by approximately 50% or more. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Lisdexamfetamine: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use lisdexamfetamine with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.
    Lithium: (Moderate) Because lithium has the potential to impair cognitive and motor skills, caution is advisable during concurrent use of other medications with centrally-acting effects including anxiolytics, sedatives, and hypnotics.
    Lofexidine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
    Lonafarnib: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with lonafarnib is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 and CYP2C19 substrate and lonafarnib is a CYP2C19 and strong CYP3A4 inhibitor.
    Lorlatinib: (Moderate) Monitor for diazepam withdrawal symptoms or lack of efficacy if coadministration with lorlatinib is necessary. Lorlatinib is a moderate CYP3A4 inducer and diazepam is a primarily metabolized by CYP2C19 at low concentrations, but at higher concentrations CYP3A4 is also involved. Coadministration may result in decreased plasma concentrations of diazepam.
    Luliconazole: (Moderate) Theoretically, luliconazole may increase the side effects of diazepam, which is a CYP2C19 and CYP3A4 substrate. Monitor patients for adverse effects of diazepam, such as CNS effects and respiratory depression. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP2C19 and CYP3A4 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of diazepam by decreasing its systemic exposure. If used together, monitor patients closely for loss of diazepam efficacy; a diazepam dosage adjustment may be required to obtain the desired therapeutic effect. Diazepam is primarily metabolized by CYP2C19 and CYP3A4, and to a lesser extent by CYP2B6 and CYP2C9. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce CYP2B6 and CYP2C19, and induce and/or inhibit CYP2C9. (Moderate) Use caution when administering ivacaftor and diazepam concurrently because patients may be at increased risk for adverse effects from diazepam. Ivacaftor is a CYP3A inhibitor, and diazepam is a CYP3A substrate. Diazepam is also metabolized by CYP2C19, which is not affected by ivacaftor. Co-administration of ivacaftor with midazolam, another CYP3A substrate, increased midazolam exposure by 1.5-fold.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of diazepam by decreasing its systemic exposure. If used together, monitor patients closely for loss of diazepam efficacy; a diazepam dosage adjustment may be required to obtain the desired therapeutic effect. Diazepam is primarily metabolized by CYP2C19 and CYP3A4, and to a lesser extent by CYP2B6 and CYP2C9. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce CYP2B6 and CYP2C19, and induce and/or inhibit CYP2C9.
    Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Lurasidone: (Moderate) Due to the CNS effects of lurasidone, caution should be used when lurasidone is given in combination with other centrally acting medications such as anxiolytics, sedatives, and hypnotics, including benzodiazepines. In one study, co-administration of lurasidone and midazolam increased the Cmax and AUC of midazolam by about 21% and 44%, respectively, compared to midazolam alone; however, dosage adjustment of midazolam based upon pharmacokinetic parameters is not required during concurrent use of lurasidone.
    Magnesium Hydroxide: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
    Magnesium Salts: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as benzodiazepines. Caution should be exercised when using these agents concurrently.
    Maprotiline: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Meclizine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Mefloquine: (Moderate) Coadministration of mefloquine and anticonvulsants may result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the anticonvulsant serum concentration is recommended. Dosage adjustments may be required during and after therapy with mefloquine.
    Melatonin: (Major) Use caution when combining melatonin with the benzodiazepines; when the benzodiazepine is used for sleep, co-use of melatonin should be avoided. Use of more than 1 agent for hypnotic purposes may increase the risk for over-sedation, CNS effects, or sleep-related behaviors. Be alert for unusual changes in moods or behaviors. Use caution when combining melatonin with benzodiazepines for other uses. Patients reporting unusual sleep-related behaviors should likely discontinue melatonin use. In animal studies, melatonin has been shown to increase benzodiazepine binding to receptor sites. In one case report, a benzodiazepine-dependent woman with an 11 year history of insomnia weaned and discontinued her benzodiazepine prescription within a few days without rebound insomnia or apparent benzodiazepine withdrawal when melatonin was given. In another case report, the ingestion of excessive melatonin along with normal doses of chlordiazepoxide and an antidepressant resulted in lethargy and short-term amnestic responses. Both cases suggest additive pharmacodynamic effects. In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between melatonin and another hypnotic agent one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and coordination compared to the hypnotic agent alone.
    Mepenzolate: (Moderate) CNS depression can be increased when mepenzolate is combined with other CNS depressants such as skeletal muscle relaxants.
    Meperidine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Meperidine; Promethazine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Mephobarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
    Meprobamate: (Moderate) Concomitant administration of benzodiazepines with meprobamate can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed.
    Mestranol; Norethindrone: (Minor) Oral contraceptives can increase the effects of diazepam because they inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to diazepam.
    Methadone: (Major) Concurrent use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If methadone is initiated for pain in an opioid-naive patient taking a benzodiazepine, use an initial methadone dose of 2.5 mg PO every 12 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial benzodiazepine dose and titrate to response. In patients treated with methadone for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia during methadone maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation. If parenteral diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Methocarbamol: (Moderate) Concurrent use of benzodiazepines and other CNS active medications including skeletal muscle relaxants, can potentiate the CNS effects of either agent. Lower doses of one or both agents may be required. The severity of this interaction may be increased when additional CNS depressants are given.
    Methohexital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
    Methscopolamine: (Moderate) CNS depression can be increased when methscopolamine is combined with other CNS depressants such as any anxiolytics, sedatives, and hypnotics.
    Methyldopa: (Moderate) Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants such as barbiturates, benzodiazepines, opiate agonists, or phenothiazines when administered concomitantly.
    Metoclopramide: (Minor) Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as benzodiazepines, should be used with caution. Additive drowsiness and/or dizziness is possible.
    Metyrosine: (Moderate) The concomitant administration of metyrosine with benzodiazepines can result in additive sedative effects.
    Milnacipran: (Moderate) Concurrent use of many CNS-active drugs with milnacipran or levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with these medications.
    Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as benzodiazepines. Caution should be exercised when using these agents concurrently.
    Mirtazapine: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Mitotane: (Major) Use caution if mitotane and diazepam are used concomitantly, and monitor for decreased efficacy of diazepam and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer; diazepam is predominantly metabolized by CYP2C19, but at high concentrations, CYP3A4 is also involved. Coadministration may result in decreased plasma concentrations of diazepam. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with diazepam.
    Mobocertinib: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with mobocertinib is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and mobocertinib is a CYP3A inducer.
    Modafinil: (Moderate) Modafinil has demonstrated an inhibition of the CYP2C19 hepatic microsomal isoenzyme at pharmacologically relevant concentrations. Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, may have prolonged elimination upon co-administration of modafinil.
    Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
    Monoamine oxidase inhibitors: (Moderate) The CNS depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. In addition, MAOIs can cause a variable change in seizure patterns, so careful monitoring of patients with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Morphine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Morphine; Naltrexone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Nabilone: (Major) Nabilone should not be taken with benzodiazepines or other sedative/hypnotic agents because these substances can potentiate the central nervous system effects of nabilone. Additive drowsiness and CNS depression can occur.
    Nalbuphine: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines 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 a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If parental diazepam is used with a mixed opiate agonist/antagonist, reduce the mixed opiate agonist/antagonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Naproxen; Esomeprazole: (Moderate) Diazepam is a substrate for the CYP2C19 isozyme. Since esomeprazole is an inhibitor of the CYP2C19 isozyme, plasma levels of diazepam may increase. Administration of esomeprazole with diazepam resulted in a 45% reduced clearance of diazepam. According to the manufacturer, this interaction is not likely to be clinically relevant. However, it would be prudent to monitor patients more closely, particularly if other CNS depressants are prescribed. The manufacturer reports that use of diazepam does not appear to alter the pharmacokinetic profile of esomeprazole.
    Nefazodone: (Moderate) Diazepam is metabolized by oxidative metabolism, specifically, the hepatic isozymes CYP2C19 and CYP3A4. As a result, diazepam is susceptible to interactions with drugs that inhibit these hepatic enzymes including nefazodone.
    Nevirapine: (Moderate) Nevirapine may induce the metabolism of certain benzodiazepines that are metabolized through the cytochrome P450 system, including diazepam.
    Nicardipine: (Moderate) Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including diazepam.
    Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as benzodiazepines. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with benzodiazepines.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Norethindrone; Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Norgestimate; Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Odevixibat: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with odevixibat is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
    Olanzapine: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
    Olanzapine; Fluoxetine: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine. (Moderate) Diazepam is metabolized by CYP2C19 and CYP3A4. Fluoxetine impairs both of these pathways at therapeutic doses. This can result in substantial increases in the half-life of diazepam, and the psychomotor and physiological response may be altered.
    Olanzapine; Samidorphan: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
    Oliceridine: (Major) Concomitant use of oliceridine with diazepam may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with diazepam 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 injectable diazepam is used with oliceridine, reduce the oliceridine dosage by at least one-third.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Systemic exposure of diazepam and its metabolite, nordiazepam, were decreased when a single 2 mg dose was administered concurrently with ombitasvir; paritaprevir; ritonavir. If these drugs are given together, monitor for reduced diazepam efficacy; consider increasing the diazepam dose if clinically needed.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Systemic exposure of diazepam and its metabolite, nordiazepam, were decreased when a single 2 mg dose was administered concurrently with ombitasvir; paritaprevir; ritonavir. If these drugs are given together, monitor for reduced diazepam efficacy; consider increasing the diazepam dose if clinically needed.
    Omeprazole: (Moderate) Omeprazole inhibits the CYP2C19 metabolic pathway for diazepam. Omeprazole can increase the plasma concentrations and the elimination half-life of diazepam. It is recommended that patients receiving omeprazole and diazepam concomitantly should be monitored for enhanced diazepam response. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Omeprazole; Amoxicillin; Rifabutin: (Moderate) Omeprazole inhibits the CYP2C19 metabolic pathway for diazepam. Omeprazole can increase the plasma concentrations and the elimination half-life of diazepam. It is recommended that patients receiving omeprazole and diazepam concomitantly should be monitored for enhanced diazepam response. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole. (Moderate) Rifabutin induces hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by CYP3A4 and CYP2C8/9, such as diazepam, may require dosage adjustments when administered concurrently with rifabutin.
    Omeprazole; Sodium Bicarbonate: (Moderate) Omeprazole inhibits the CYP2C19 metabolic pathway for diazepam. Omeprazole can increase the plasma concentrations and the elimination half-life of diazepam. It is recommended that patients receiving omeprazole and diazepam concomitantly should be monitored for enhanced diazepam response. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole. (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
    Oritavancin: (Moderate) Coadministration of oritavancin and diazepam may result in increases or decreases in diazepam exposure and may increase side effects or decrease efficacy of diazepam. Diazepam is metabolized by CYP3A4, CYP2C9, and CYP2C19. Oritavancin weakly induces CYP3A4, while weakly inhibiting CYP2C9 and CYP2C19. If these drugs are administered concurrently, monitor the patient for signs of toxicity or lack of efficacy.
    Oxybutynin: (Moderate) Additive CNS depression may occur when oxybutynin is used concomitantly with other CNS-depressant drugs, including anxiolytics, sedatives, and hypnotics.
    Oxycodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 oxycodone is initiated in a patient taking a benzodiazepine, reduce dosages and titrate to clinical response. For acetaminophen; oxycodone extended-release tablets, start with 1 tablet PO every 12 hours, and for other oxycodone products, use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Oxymorphone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 oxymorphone is initiated in a patient taking a benzodiazepine, use an initial dose of oxymorphone at 1/3 to 1/2 the usual dosage and titrate to clinical response. If the extended-release oxymorphone tablets are used concurrently with a CNS depressant, use an initial dosage of 5 mg PO every 12 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Paliperidone: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
    Papaverine: (Moderate) Concurrent use of papaverine with potent CNS depressants such as benzodiazepines could lead to enhanced sedation.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and diazepam, a CYP3A4 substrate, may cause an increase in systemic concentrations of diazepam. Use caution when administering these drugs concomitantly.
    Pemoline: (Moderate) A reduction in seizure threshold has been reported following concomitant administration of pemoline with anticonvulsant agents.
    Pentazocine: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines 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 a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If parental diazepam is used with a mixed opiate agonist/antagonist, reduce the mixed opiate agonist/antagonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Pentazocine; Naloxone: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines 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 a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If parental diazepam is used with a mixed opiate agonist/antagonist, reduce the mixed opiate agonist/antagonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Pentobarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
    Perampanel: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Pexidartinib: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with pexidartinib is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A4 substrate and pexidartinib is a CYP3A4 inducer.
    Phenobarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers. (Moderate) Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
    Phenothiazines: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Phentermine; Topiramate: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Phenytoin: (Moderate) Phenytoin is a hepatic enzyme inducer and thus may accelerate the metabolism of several other anticonvulsants, and can theoretically add to the CNS-depressant effects of other CNS depressants, including the anxiolytics, sedatives, and hypnotics which may be used concomitantly for seizure control or as psychotropics. Phenytoin should be used cautiously with diazepam, as decreased diazepam serum concentrations may be seen. In addition, diazepam has been reported to have an unpredictable effect on phenytoin serum concentrations (e.g., to increase, decrease, or cause no change in phenytoin serum concentrations). Conflicting results may have been observed due to saturable phenytoin metabolism and/or other conditions associated with the reported data. Since definitive controlled trial data are lacking, phenytoin concentrations should be monitored more closely when diazepam is added or discontinued.
    Pimozide: (Moderate) Due to the effects of pimozide on cognition, it should be used cautiously with other CNS depressants including benzodiazepines.
    Posaconazole: (Moderate) Diazepam is a substrate of CYP2C19 and CYP3A4, and inhibition of metabolism by posaconazole could lead to elevated diazepam blood levels.
    Pramipexole: (Major) Concomitant administration of benzodiazepines with CNS-depressant drugs, including pramipexole, can potentiate the CNS effects.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Prasterone, dehydroepiandrosterone, DHEA may inhibit the metabolism of benzodiazepines (e.g., alprazolam, estazolam, midazolam) which undergo CYP3A4-mediated metabolism. In one study of elderly volunteers, half of the patients received DHEA 200 mg/day PO for 2 weeks, followed by a single dose of triazolam 0.25 mg. Triazolam clearance was reduced by close to 30% in the DHEA-pretreated patients vs. the control group; however, the effect of DHEA on CYP3A4 metabolism appeared to vary widely among subjects. While more study is needed, benzodiazepine-induced CNS sedation and other adverse effects might be increased in some individuals if DHEA is co-administered.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Prasterone, dehydroepiandrosterone, DHEA may inhibit the metabolism of benzodiazepines (e.g., alprazolam, estazolam, midazolam) which undergo CYP3A4-mediated metabolism. In one study of elderly volunteers, half of the patients received DHEA 200 mg/day PO for 2 weeks, followed by a single dose of triazolam 0.25 mg. Triazolam clearance was reduced by close to 30% in the DHEA-pretreated patients vs. the control group; however, the effect of DHEA on CYP3A4 metabolism appeared to vary widely among subjects. While more study is needed, benzodiazepine-induced CNS sedation and other adverse effects might be increased in some individuals if DHEA is co-administered.
    Pregabalin: (Major) Concomitant use of benzodiazepines with pregabalin may cause excessive sedation, somnolence, and respiratory depression. If concurrent use is necessary, initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
    Primidone: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
    Procarbazine: (Minor) CNS depressants benzodiazepines can potentiate the CNS depression caused by procarbazine therapy, so these drugs should be used together cautiously.
    Promethazine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Propofol: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Propoxyphene: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. The dose of any opiate agonist administered with parenteral diazepam should be reduced by at least one-third.
    Protease inhibitors: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of diazepam and increase the potential for benzodiazepine toxicity. Prolonged sedation and respiratory depression can occur. A decrease in the diazepam dose may be needed
    Pseudoephedrine; Triprolidine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Pyrilamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Quetiapine: (Moderate) Somnolence is a commonly reported adverse effect of quetiapine; coadministration of quetiapine with anxiolytics, sedatives, and hypnotics, or other CNS depressants may result in additive sedative effects.
    Ramelteon: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Ranolazine: (Moderate) CYP3A4 inhibitors, like ranolazine, may reduce the metabolism of diazepam and increase the potential for benzodiazepine toxicity.
    Rasagiline: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including buprenorphine, butorphanol, dronabinol, THC, nabilone, nalbuphine, and anxiolytics, sedatives, and hypnotics. Use these drugs cautiously with MAOIs; warn patients to not drive or perform other hazardous activities until they know how a particular drug combination affects them. In some cases, the dosages of the CNS depressants may need to be reduced.
    Remifentanil: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Remimazolam: (Major) The sedative effect of remimazolam can be accentuated by diazepam. Titrate the dose of remimazolam to the desired clinical response and continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation.
    Ribociclib: (Moderate) Monitor for an increase in diazepam-related adverse reactions if coadministration with ribociclib is necessary; decrease the dose of diazepam if necessary. At low concentrations, diazepam is primarily metabolized by CYP2C19; however, CYP3A4 is also involved at higher concentrations. Ribociclib is a strong CYP3A4 inhibitor.
    Ribociclib; Letrozole: (Moderate) Monitor for an increase in diazepam-related adverse reactions if coadministration with ribociclib is necessary; decrease the dose of diazepam if necessary. At low concentrations, diazepam is primarily metabolized by CYP2C19; however, CYP3A4 is also involved at higher concentrations. Ribociclib is a strong CYP3A4 inhibitor.
    Rifabutin: (Moderate) Rifabutin induces hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by CYP3A4 and CYP2C8/9, such as diazepam, may require dosage adjustments when administered concurrently with rifabutin.
    Rifampin: (Major) Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of diazepam. Patients receiving rifampin may require higher doses of diazepam to achieve the desired clinical effect.
    Rifapentine: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with rifapentine is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A4 substrate and rifapentine is a CYP3A4 inducer.
    Risperidone: (Moderate) Due to the primary CNS effects of risperidone, caution should be used when risperidone is given in combination with other centrally acting medications including anxiolytics, sedatives, and hypnotics.
    Ropinirole: (Moderate) Concomitant use of ropinirole with other CNS depressants can potentiate the sedation effects of ropinirole.
    Rotigotine: (Major) Concomitant use of rotigotine with other CNS depressants, such as benzodiazepines, can potentiate the sedative effects of rotigotine.
    Rucaparib: (Moderate) Monitor for an increase in diazepam-related adverse reactions including sedation and respiratory depression if coadministration with rucaparib is necessary. Diazepam is a CYP2C19 substrate and rucaparib is a weak CYP2C19 inhibitor. Concomitant use may increase plasma concentrations of diazepam.
    Safinamide: (Moderate) Dopaminergic medications, including safinamide, may cause a sudden onset of somnolence which sometimes has resulted in motor vehicle accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. Because of possible additive effects, advise patients about the potential for increased somnolence during concurrent use of safinamide with other sedating medications, such as benzodiazepines.
    Scopolamine: (Moderate) Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
    Secobarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
    Sedating H1-blockers: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Segesterone Acetate; Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Selegiline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of selegiline and benzodiazepines. Concurrent use may result in additive CNS depression.
    Selpercatinib: (Moderate) Monitor for an increase in diazepam-related adverse reactions if coadministration with selpercatinib is necessary; decrease the dose of diazepam if necessary. Concurrent use may increase exposure of diazepam. At low concentrations, diazepam is primarily metabolized by CYP2C19; however, CYP3A4 is also involved at higher concentrations. Selpercatinib is a weak CYP3A4 inhibitor.
    Sevoflurane: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of diazepam, which is a CYP3A4 substrate. Monitor patients for adverse effects of diazepam, such as CNS effects and respiratory depression.
    Sincalide: (Moderate) Sincalide-induced gallbladder ejection fraction may be affected by benzodiazepines. False study results are possible in patients with drug-induced hyper- or hypo-responsiveness; thorough patient history is important in the interpretation of procedure results.
    Skeletal Muscle Relaxants: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Sodium Bicarbonate: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
    Sodium Oxybate: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as benzodiazepines. Caution should be exercised when using these agents concurrently.
    Sotorasib: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with sotorasib is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A4 substrate and sotorasib is a CYP3A4 inducer.
    Spironolactone: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with spironolactone is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and spironolactone is a CYP3A inhibitor.
    Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with spironolactone is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and spironolactone is a CYP3A inhibitor.
    St. John's Wort, Hypericum perforatum: (Major) St. John's Wort may induce the hepatic CYP3A4 metabolism of diazepam which is metabolized by oxidation. It would be prudent to avoid co-administration of St. John's Wort with diazepam. Benzodiazepines that are not metabolized by CYP3A4 such as oxazepam or lorazepam may be alternatives if a benzodiazepine is required in combination with St. John's Wort.
    Streptogramins: (Moderate) Monitor for diazepam-related adverse reactions including sedation and respiratory depression if coadministration with dalfopristin; quinupristin is necessary due to increased diazepam exposure. Dalfopristin; quinupristin is a weak CYP3A4 inhibitor and diazepam is metabolized by CYP3A4.
    Sufentanil: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Tacrine: (Major) Tacrine is an inhibitor of CYP1A2 and could potentially increase plasma concentrations of diazepam. However, clinical documentation of interactions is lacking.
    Tapentadol: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 tapentadol is initiated in a patient taking a benzodiazepine, a reduced initial dosage of tapentadol is recommended. If the extended-release tapentadol tablets are used concurrently with a benzodiazepine, use an initial tapentadol dose of 50 mg PO every 12 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Teduglutide: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering diazepam with telaprevir due to an increased potential for diazepam-related adverse events. If diazepam dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of diazepam. Diazepam is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated diazepam plasma concentrations.
    Telithromycin: (Moderate) Diazepam is metabolized by oxidative metabolism which may be decreased by telithromycin and caution is recommended. Patients should be monitored for needed dosage adjustments in accordance with response.
    Telotristat Ethyl: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with telotristat is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A4 and CYP2B6 substrate. Telotristat is a weak CYP3A4 inducer and based on in vitro studies, Potential induction of CYP2B6 in vivo by telotristat cannot be ruled out.
    Tetrabenazine: (Moderate) Concurrent use of tetrabenazine and drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Tezacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and diazepam concurrently because patients may be at increased risk for adverse effects from diazepam. Ivacaftor is a CYP3A inhibitor, and diazepam is a CYP3A substrate. Diazepam is also metabolized by CYP2C19, which is not affected by ivacaftor. Co-administration of ivacaftor with midazolam, another CYP3A substrate, increased midazolam exposure by 1.5-fold.
    Thalidomide: (Major) The use of benzodiazepine anxiolytics, sedatives, or hypnotics with thalidomide may cause an additive sedative effect and should be avoided. Thalidomide frequently causes drowsiness and somnolence. Dose reductions may be required. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. Advise patients as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks, such as driving a car or operating other complex or dangerous machinery.
    Theophylline, Aminophylline: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
    Thiopental: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
    Thiothixene: (Moderate) Thiothixene can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Tiagabine: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Tizanidine: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Topiramate: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Tramadol: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Tramadol; Acetaminophen: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Trandolapril; Verapamil: (Moderate) Verapamil inhibits CYP3A4 metabolism, and therefore may inhibit the metabolism of oxidized benzodiazepines, including diazepam.
    Trazodone: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Tricyclic antidepressants: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as tricyclic antidepressants, can potentiate the CNS effects of either agent. Tricyclic antidepressants may also lower the seizure threshold leading to pharmacodynamic interactions with anticonvulsant benzodiazepines (i.e., clobazam, clonazepam, diazepam, and lorazepam). The plasma concentrations of imipramine and desipramine may increase an average of 31% and 20%, respectively, when administered concurrently with alprazolam. The significance of this interaction has not been described; therefore, patients should be monitored closely for symptoms of tricyclic toxicity during coadministration of these agents with alprazolam.
    Trihexyphenidyl: (Moderate) CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of trihexyphenidyl.
    Trimethobenzamide: (Moderate) The concurrent use of trimethobenzamide with other medications that cause CNS depression, like the benzodiazepines, may potentiate the effects of either trimethobenzamide or the benzodiazepine.
    Triprolidine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Tucatinib: (Moderate) Monitor for an increase in diazepam-related adverse reactions if coadministration with tucatinib is necessary; decrease the dose of diazepam if necessary. Concurrent use may increase exposure of diazepam. At low concentrations, diazepam is primarily metabolized by CYP2C19; however, CYP3A4 is also involved at higher concentrations. Tucatinib is a strong CYP3A4 inhibitor.
    Valdecoxib: (Moderate) Coadministration of diazepam and valdecoxib may result in increased exposure to diazepam. Although the magnitude of the change in diazepam exposure does not necessitate a dosage change, patients may experience increased sedative effects due to the increase in diazepam exposure.
    Valerian, Valeriana officinalis: (Major) Any substances that act on the CNS, including psychoactive drugs and drugs used as anesthetic adjuvants (e.g., barbiturates, benzodiazepines), may theoretically interact with valerian, Valeriana officinalis. The valerian derivative, dihydrovaltrate, binds at barbiturate binding sites; valerenic acid has been shown to inhibit enzyme-induced breakdown of GABA in the brain; the non-volatile monoterpenes (valepotriates) have sedative activity. These interactions are probably pharmacodynamic in nature. There is a possibility of interaction with valerian at normal prescription dosages of anxiolytics, sedatives, and hypnotics (including barbiturates and benzodiazepines). Patients who are taking barbiturates or other sedative/hypnotic drugs should avoid concomitant administration of valerian. Patients taking medications such as tricyclic antidepressants, lithium, MAOIs, skeletal muscle relaxants, SSRIs and serotonin norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine) should discuss the use of herbal supplements with their health care professional prior to consuming valerian; combinations should be approached with caution in the absence of clinical data. Patients should not abruptly stop taking their prescribed psychoactive medications.
    Valproic Acid, Divalproex Sodium: (Minor) The administration of valproic acid to patients receiving diazepam can cause an increase in diazepam serum concentrations. If therapeutic effect is altered in patients receiving these medications, an alternative anticonvulsant should be instituted.
    Vemurafenib: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as diazepam, could be expected with concurrent use. Use caution, and monitor therapeutic effects of diazepam when coadministered with vemurafenib.
    Verapamil: (Moderate) Verapamil inhibits CYP3A4 metabolism, and therefore may inhibit the metabolism of oxidized benzodiazepines, including diazepam.
    Vigabatrin: (Moderate) Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given in combination with benzodiazepines.
    Vilazodone: (Moderate) Due to the CNS effects of vilazodone, caution should be used when vilazodone is given in combination with other centrally acting medications such as the benzodiazepines.
    Viloxazine: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with viloxazine is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and viloxazine is a CYP3A4 inhibitor.
    Voriconazole: (Moderate) Monitor for an increase in diazepam-related adverse reactions if coadministration with voriconazole is necessary; decrease the dose of diazepam if necessary. At low concentrations, diazepam is primarily metabolized by CYP2C19; however, CYP3A4 is also involved at higher concentrations. Voriconazole is a strong CYP3A4.
    Voxelotor: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with voxelotor is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and voxelotor is a CYP3A4 inhibitor.
    Zafirlukast: (Moderate) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as diazepam.
    Zaleplon: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Zileuton: (Moderate) Diazepam is metabolized by oxidative metabolism, specifically, the hepatic isozymes CYP2C19 and CYP3A4. As a result, diazepam is susceptible to interactions with drugs that inhibit these hepatic enzymes. Zileuton may inhibit the metabolism of diazepam. While diazepam clearance may be inhibited, diazepam pharmacodynamics are not always affected. Consider dose reduction of diazepam if clinically indicated. Monitor for an increase in CNS or respiratory depression.
    Ziprasidone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Zolpidem: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate data on diazepam use during human pregnancy. Consider diazepam use during pregnancy only when the clinical situation warrants the risk to the fetus. If diazepam is to be used during pregnancy or the patient becomes pregnant while taking diazepam, advise the patient of the potential hazard to the fetus. Measurable amounts of diazepam were found in cord blood, indicating placental transfer of the drug. Available data suggest that the class of benzodiazepines is not associated with marked increases in risk for congenital anomalies. A meta-analysis of 23 studies examined the effects of benzodiazepine exposure during the first trimester of pregnancy. Eleven of the 23 studies included in the meta-analysis considered the use of chlordiazepoxide and diazepam and not other benzodiazepines. Case-control and cohort studies were considered separately. The data from the cohort studies did not suggest an increased risk for major malformations (OR 0.90; 95% CI 0.61 to 1.35) or oral cleft (OR 1.19; 95% CI 0.34 to 4.15). The data from the case-control studies suggested an association between benzodiazepines and major malformations (OR 3.01, 95% CI 1.32 to 6.84) and oral cleft (OR 1.79; 95% CI 1.13 to 2.82). The limitations of this meta-analysis included the small number of reports included in the analysis, and that most cases for analyses of both oral cleft and major malformations came from only 3 studies. A follow up to that meta-analysis included 3 new cohort studies that examined risk for major malformations and 1 study that considered cardiac malformations. No new studies with an outcome of oral clefts were found. After the addition of the new studies, the odds ratio for major malformations with first trimester exposure to benzodiazepines was 1.07 (95% CI 0.91 to 1.25). There is insufficient evidence to assess the effect of benzodiazepine pregnancy exposure on neurodevelopment. In animal studies, administration of diazepam during the organogenesis period of pregnancy resulted in increased incidences of fetal malformations at doses greater than those used clinically. Data for diazepam and other benzodiazepines suggest the possibility of increased neuronal cell death and long-term effects on neurobehavioral and immunological function based on findings in animals after prenatal or early postnatal exposure at clinically relevant doses. Clinical considerations regarding exposure to benzodiazepines during the second and third trimesters of pregnancy and immediately before or during labor and obstetric delivery include decreased fetal movement and/or fetal heart rate variability, floppy infant syndrome, dependence, and withdrawal. Neonatal withdrawal syndrome and symptoms suggestive of floppy infant syndrome associated with administration of benzodiazepines during the later stages of pregnancy and peripartum have been reported. Clinical manifestations of withdrawal or neonatal abstinence syndrome may include hypertonia, hyperreflexia, hypoventilation, irritability, tremors, diarrhea, and vomiting. These complications can appear shortly after birth to 3 weeks after birth and persist from hours to several months, depending on the degree of dependence and the pharmacokinetic profile of the benzodiazepine. Symptoms may be mild and transient or severe. Standard management for neonatal withdrawal syndrome has not yet been defined. Floppy infant syndrome is characterized by lethargy, hypothermia, hypotonia, respiratory depression, and difficulty feeding. Floppy infant syndrome occurs mainly within the first hours after birth and may last up to 14 days. Observe newborns who are exposed to diazepam for symptoms of withdrawal and floppy infant syndrome and manage accordingly. The major neonatal side effects of benzodiazepines also include sedation. Data suggest that fetal exposure to benzodiazepines is also associated with the neonatal adverse events of hypotonia, respiratory problems, hypoventilation, and low Apgar score. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to diazepam; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.[28712] [64930]

    MECHANISM OF ACTION

    Benzodiazepines act at the level of the limbic, thalamic, and hypothalamic regions of the CNS and can produce any level of CNS depression required including sedation, hypnosis, skeletal muscle relaxation, and anticonvulsant activity. Recent evidence indicates that benzodiazepines exert their effects through enhancement of the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex. GABA is an inhibitory neurotransmitter that exerts its effects at specific receptor subtypes designated GABA-A and GABA-B. GABA-A is the primary receptor subtype in the CNS and is thought to be involved in the actions of anxiolytics and sedatives.
     
    Specific benzodiazepine receptor subtypes are thought to be coupled to GABA-A receptors. Three types of BNZ receptors are located in the CNS and other tissues; the BNZ1 receptors are located in the cerebellum and cerebral cortex, the BNZ2 receptors in the cerebral cortex and spinal cord, and the BNZ3 receptors in peripheral tissues. Activation of the BNZ1 receptor is thought to mediate sleep while the BNZ2 receptor affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. Benzodiazepines bind nonspecifically to BNZ1 and BNZ2 which ultimately enhances the effects of GABA. Unlike barbiturates which augment GABA responses by increasing the length of time that chloride channels are open, benzodiazepines enhance the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.
     
    The antianxiety action of benzodiazepines may be a result of their ability to block cortical and limbic arousal following stimulation of the reticular pathways while muscle relaxation properties are mediated by inhibiting both mono- and polysynaptic pathways. Benzodiazepine can also depress muscle and motor nerve function directly. Animal studies of the anticonvulsant actions suggest that benzodiazepines augment presynaptic inhibition of neurons, thereby limiting the spread of electrical activity, although they do not actually inhibit the abnormally discharging focus. Benzodiazepines alleviate insomnia by decreasing the latency to sleep and increasing sleep continuity and total sleep time through their effects on GABA.
     
    Benzodiazepines may also have other actions. For example, diazepam has been shown to counteract the cardiovascular toxicity of chloroquine. It is thought that diazepam increases the urinary clearance of chloroquine by improving electrocardiographic and hemodynamic function.

    PHARMACOKINETICS

    Diazepam is administered orally, nasally, parenterally, and rectally. Both diazepam and its major active metabolite, desmethyldiazepam, bind extensively to plasma proteins (95% to 98%). Diazepam and its metabolite cross the blood-brain barrier. In young healthy males, the volume of distribution at steady-state is 0.8 to 1 L/kg. Metabolism of diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4), followed by glucuronidation. Diazepam is extensively metabolized to 1 major active metabolite, desmethyldiazepam, and 2 minor active metabolites, temazepam (3-hydroxydiazepam) and oxazepam (3-hydroxy-N-diazepam). At therapeutic doses, desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam while oxazepam and temazepam are usually undetectable. The initial distribution phase is followed by a prolonged terminal elimination phase (half-life up to 48 hours). The terminal elimination half-life of N-desmethyldiazepam is up to 100 hours. Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates. The clearance of diazepam is 20 to 30 mL/minute in young adults. Diazepam accumulates upon multiple dosing, and there is some evidence that the terminal elimination half-life is slightly prolonged. The marked interindividual variability in the clearance of diazepam is probably attributable to variability of CYP2C19, which is known to exhibit genetic polymorphism, and CYP3A4.[28712] [43932] [64930]
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP2C19, CYP3A4
    Diazepam is metabolized by the hepatic isozymes CYP2C19 and CYP3A4.[64930]

    Oral Route

    After oral administration, more than 90% of diazepam is absorbed. Tmax is 1 to 1.5 hours, with a range of 0.25 to 2.5 hours. The decline in the plasma-concentration time profile after oral administration is biphasic. The initial distribution phase has a half-life of approximately 1 hour, although it may range up to more than 3 hours. Absorption is delayed and decreased when administered with a moderate fat meal. In the presence of food, mean lag times are approximately 45 minutes as compared with 15 minutes when fasting. There is also an increase in Tmax to about 2.5 hours in the presence of food as compared with 1.25 hours when fasting. An average decrease in Cmax of 20% in addition to a 27% decrease in AUC (range 15% to 50%) occurs when diazepam is administered with food.[28712]

    Inhalation Route

    After administration of diazepam nasal spray in healthy adult subjects, Tmax was 1.5 hours. The estimated volume of distribution at steady-state is 0.8 to 1 L/kg. The absolute bioavailability of diazepam nasal spray relative to intravenous diazepam was 97%. The mean elimination half-life of diazepam after administration of a 10 mg dose of nasal spray was about 49.2 hours. Diazepam plasma exposures (Cmax and AUC) increased approximately proportional to dose from 5 to 20 mg. In a relative bioavailability study of diazepam nasal spray and rectal gel 15 and 20 mg in healthy adult subjects, diazepam Cmax and AUC were 2- to 4-fold less variable for nasal spray and within the range of those seen with rectal gel. Pharmacokinetic parameters were similar between seizure and non-seizure states in patients with epilepsy.[64930]

    Other Route(s)

    Rectal Route
    Diazepam is well absorbed after rectal administration. Tmax after administration of diazepam rectal gel is 1.5 hours. The absolute bioavailability of diazepam rectal gel relative to intravenous diazepam is 90%. The volume of distribution of diazepam rectal gel is approximately 1 L/kg. The mean elimination half-lives of diazepam and desmethyldiazepam after administration of a 15 mg dose of diazepam rectal gel are approximately 46 hours and 71 hours, respectively.[43932]