Clobazam is a long-acting benzodiazepine used for the adjunct treatment of seizures associated with Lennox-Gastaut syndrome. Clobazam has a distinct chemical structure separating it from other available benzodiazepines, with nitrogen atoms in the 1 and 5 position of the heterocyclic ring, instead of at the 1 and 4 positions. Its unique chemical design was an attempt to decrease adverse reactions traditionally associated with benzodiazepines while maintaining or improving efficacy. Although sedative effects are still common, clobazam appears to have a less sedating effect than other benzodiazepines. Antiepileptic drugs (AEDs) such as clobazam increase the risk of suicidal ideation and behavior; monitor all patients receiving clobazam for emerging or worsening suicidal thoughts/behavior or depression. Additionally, clobazam has been associated with rare but serious reactions, such as Drug Reaction with eosinophilia and systemic symptoms (DRESS). Clobazam is recommended as a first-line anticonvulsant in children with Dravet syndrome, although seizure response is often insufficient when used as monotherapy. Evidence for this practice is weak; recommendations are predominantly based on expert consensus of anecdotal evidence. Outside the US, clobazam has been available since 1970 and is used for anxiety and the adjunctive treatment of epilepsy. Off-label use is recommended in patients with Dravet syndrome, which presents in the first year of life, at suspected diagnosis.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH (Draft) 2020 List: Table 2
-Approved by FDA after NIOSH 2016 list published.
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/film will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.
Route-Specific Administration
Oral Administration
-May be taken with or without food.
Oral Solid Formulations
-Tablets may be administered whole, broken in half along the score, or crushed and mixed in applesauce.
Oral Liquid Formulations
-Shake suspension well prior to use.
-Only the oral dosing syringes provided with the product should be used to measure the dose. Use only 1 of the 2 syringes provided for dosing; reserve the second syringe as a replacement in case the first syringe is damaged or lost.
-Insert the provided adapter firmly into the neck of the bottle before first use and keep the adapter in place for the duration of the usage of the bottle.
-To withdraw the dose, insert the dosing syringe into the adapter and invert the bottle then slowly pull back the plunger to prescribed dose.
-The measured dose should be squirted into the corner of the patient's mouth.
-Storage: Store clobazam oral suspension in its original bottle in an upright position at controlled room temperature. Use within 90 days of first opening the bottle.
Other Oral Formulations
Oral film
-Apply to top of the tongue where it adheres and dissolves.
-Do not administer with liquids.
-As the film dissolves, swallow saliva in a normal manner. Do not chew, spit, or talk during dissolution.
-Take only 1 oral film at a time; if a second film is needed to complete the dosage, take it after the first film has completely dissolved.
Drowsiness (16% to 25%), sedation (2% to 9%), lethargy (5% to 15%), drooling (up to 14%), ataxia (2% to 10%), psychomotor hyperactivity or restlessness (3% to 5%), dysarthria (2% to 5%), and insomnia (2% to 7%) were reported in patients receiving clobazam more often than those taking placebo during clinical trials. Treatment discontinuation was reported in at least 1% of patients due to lethargy, drowsiness, ataxia, or insomnia. Elderly or debilitated patients are generally more susceptible to sedation and ataxia from benzodiazepines. Because clobazam 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.
Aggression (3% to 14% vs. 5%) and irritability (3% to 11% vs. 5%) were reported in patients receiving clobazam more often than those taking placebo during clinical trials. Treatment discontinuation was reported in at least 1% of patients due to aggression. Other psychiatric effects reported during postmarket use include agitation, anxiety, apathy, confusion, delirium, delusions, depression, and hallucinations. Anticonvulsants are thought to carry an increased risk of suicidal ideation and behavior. An analysis by the FDA of previously gathered drug data showed that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor. The increased risk of suicidal ideation and behavior occurred between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association with the drug since most studies included in the analysis did not continue beyond 24 weeks. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening suicidal thoughts/behavior, depression, or other changes in mood or behavior. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior.
Vomiting (5% to 9% vs. 5%), constipation (2% to 10% vs. 0%), dysphagia (0% to 5% vs. 0%), decreased appetite/anorexia (0% to 7% vs. 3%), and appetite stimulation (2% to 5% vs. 0%) were reported in patients receiving clobazam more often than those taking placebo during clinical trials. Abdominal distention has been reported during postmarket use.
Fatigue occurred in 3% to 5% of patients receiving clobazam and in 2% of patients receiving placebo during clinical trials. Fatigue was associated with treatment discontinuation in at least 1% of study patients.
Diplopia and blurred vision have been reported during postmarketing use of clobazam; however, frequencies are unknown, and causality has not been established.
Anemia, eosinophilia, leukopenia, and thrombocytopenia have been reported with postmarketing use of clobazam; however, frequencies are unknown, and causality has not been established.
Muscle cramps (muscle spasms) have been reported with postmarketing use of clobazam; however, the frequency is unknown, and causality has not been established.
Elevated hepatic enzymes have been reported during postmarketing use of clobazam; however, the frequency is unknown. It should be noted that clobazam undergoes extensive hepatic metabolism and dosage adjustments are recommended in patients with hepatic impairment.
Upper respiratory tract infection (10% to 14%), pneumonia (3% to 7%), urinary tract infection (2% to 5%), bronchitis (0% to 5%), cough (3% to 7%), and pyrexia or fever (10% to 17%) were reported in patients receiving clobazam and more often than with placebo during clinical trials. Aspiration has been reported postmarketing.
Urinary retention has occurred during postmarketing use of clobazam; however, the frequency is unknown, and causality has not been established.
Hypothermia has occurred during postmarketing use of clobazam; however, the frequency is unknown, and causality has not been established.
Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with clobazam during postmarketing experience. Closely monitor for signs and symptoms of serious dermatologic reactions, especially during the first 8 weeks of treatment initiation or when re-introducing therapy. Discontinue clobazam at the first sign of rash, unless the rash is clearly not drug related. Do not resume clobazam and consider alternative therapy if signs or symptoms suggest SJS/TEN. Additionally, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), which can be fatal or life-threatening, particularly if diagnosis and treatment do not occur as early as possible, has been reported with clobazam. DRESS can develop 2 to 8 weeks after starting therapy and typically presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection; other organ systems may be involved. Eosinophilia is often present. Early manifestations of hypersensitivity, such as fever and lymphadenopathy, may be present without evidence of a rash. Evaluate such signs or symptoms immediately and discontinue clobazam if an alternative etiology for the signs and symptoms cannot be identified. Rash, urticaria, angioedema, and facial and lip edema have also been reported during postmarketing use of clobazam.
Tolerance to clobazam may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of clobazam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.
Prolonged use of benzodiazepines can produce physiological dependence with or without psychological dependence. The risk of psychological dependence increases in those with a history of alcohol or substance 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. Caution is advised when considering the use of benzodiazepines in patients with a known or suspected history of substance abuse. To discourage abuse, prescribe the smallest appropriate quantity of the benzodiazepine and provide proper disposal instructions for unused drug. Avoid or minimize concomitant use of CNS depressants or other medications associated with addiction or abuse. Clinically significant physiological dependence may occur with continued use of benzodiazepines. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of benzodiazepines after continued use may precipitate acute withdrawal reactions, which can be life-threatening. Withdrawal symptoms may range from mild dysphoria and insomnia to a major withdrawal syndrome including abdominal and muscle cramps, vomiting, sweating, tremors, and seizures. During clinical trials of clobazam in healthy volunteers, withdrawal symptoms most often included headache, tremor, insomnia, anxiety, irritability, drug withdrawal syndrome, palpitations, and diarrhea. In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Use a gradual dosage taper to lower the risk of withdrawal reactions when reducing the dose or discontinuing therapy.
Respiratory depression has been reported during postmarketing use of clobazam. Respiratory depression can occur with benzodiazepine therapy, particularly with misuse, coadministration with other CNS depressants, or overdosage. Concomitant use of benzodiazepines and opioids or alcohol may result in profound sedation, respiratory depression, coma, and death.
Benzodiazepines cross the placenta and may produce sedation, hypotonia, lethargy, and neonatal respiratory depression at birth. Monitor neonates exposed during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Neonatal withdrawal or a neonatal abstinence syndrome has also been reported following the ingestion of therapeutic doses of benzodiazepines during the last weeks of pregnancy. Clinical manifestations of neonatal withdrawal may include hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties. These complications can appear shortly after delivery to 3 weeks after birth and persist from hours to several months, depending on the degree of dependence and pharmacokinetic profile of the benzodiazepine. Observe neonates who are exposed to benzodiazepines in utero during the later stages of pregnancy for symptoms of withdrawal and manage appropriately. Benzodiazepines should be withdrawn cautiously and slowly, using a very gradual dosage-tapering schedule.
Clobazam may be associated with reproductive risk and infertility. Administration of clobazam to male and female rats prior to and during mating and early gestation resulted in adverse effects on fertility and early embryonic development, including increases in abnormal sperm and pre-implantation loss, at plasma exposures for clobazam and its major metabolite, N-desmethylclobazam, below those in humans at the maximum recommended human dose (MRHD) of 40 mg/day.
Clobazam is contraindicated in patients with a hypersensitivity to clobazam or any of its ingredients; serious dermatological reactions have occurred. Clobazam is a benzodiazepine derivative. It is not clear if cross-sensitivity occurs with this agent and other benzodiazepines; however, some product labeling from other countries outside the US state benzodiazepine hypersensitivity as a condition under which clobazam should not be used.
There is an increased risk of suicidal ideation and behavior in patients receiving antiepileptic drugs (AEDs). Suicidal ideation or behavior has occurred as early as 1 week after AED initiation and may occur at any time during treatment. Closely monitor patients treated with clobazam for emerging or worsening depression or suicidal thoughts/behavior. Inform patients, caregivers, and families of the increased risk of suicidal thoughts and behaviors and advise them to immediately report the emergence or worsening of depression, the emergence of 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 to reduce the risk of overdose. A pooled analysis 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 or older) was conducted. 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.
Avoid clobazam coadministration with other CNS depressants, especially opioids, unless other alternatives are not available as coadministration significantly increases the risk of respiratory depression, low blood pressure, and death. Similar to other benzodiazepines, clobazam may also cause drowsiness and dizziness when used alone. Patients should be advised to avoid driving or operating machinery or performing other tasks that require mental alertness until they are aware of whether clobazam adversely affects their cognitive and/or motor performance. As with other benzodiazepines, use with caution in patients with pre-existing respiratory insufficiency, such as sleep apnea. Sedation and dizziness are most likely to occur during the first month of treatment, during dosage increases, or with concomitant use of other CNS depressant drugs, including alcohol. Avoid ethanol ingestion and ethanol intoxication; alcohol increases the bioavailability of clobazam by 50% and thus may increase the risk of side effects such as sedation, respiratory depression, and further impairs function. Because clobazam 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.
Use clobazam 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 history of a seizure disorder should not be withdrawn abruptly from benzodiazepines due to the risk of precipitating seizures; status epilepticus has also been reported. Clinicians should be aware that the use of flumazenil may increase the risk of seizures, particularly in long-term users of benzodiazepines.
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. When discontinuing, taper the clobazam dosage every week by 5 to 10 mg/day to minimize the risk of precipitating seizures, seizure exacerbation, status epilepticus, or withdrawal. 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 history of a seizure disorder should not be withdrawn abruptly from benzodiazepines due to the risk of precipitating seizures; status epilepticus has also been reported. Clinicians should be aware that the use of flumazenil may increase the risk of seizures, particularly in long-term users of benzodiazepines.
Clobazam should be used cautiously in patients with renal impairment. Dosage adjustments are not required in patients with mild to moderate renal impairment. However, there are no dosage recommendations for patients with end-stage renal disease (renal failure) or those receiving dialysis because there is inadequate data on the use of clobazam in these patient populations.
Clobazam should be used cautiously in patients with hepatic disease because the drug is hepatically metabolized. Dosage adjustments are recommended in patients with mild to moderate hepatic impairment. However, there are no dosage recommendations for patients with severe hepatic impairment because there are inadequate data on the use of clobazam in this patient population. Dosage adjustments are recommended in those patients who are genetically poor metabolizers of CYP2C19.
Use clobazam with caution in the geriatric patient; dosage adjustments and care in dosage titration are recommended. Geriatric adults are generally more susceptible to the effects of benzodiazepines. Because clobazam 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. According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If clobazam must be used, consider reducing the use of other CNS-active medications and implement other strategies to reduce fall risk. 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. When possible, avoid use in those with the following conditions due to the potential for symptom exacerbation or adverse effects: delirium (new-onset or worsening delirium) and dementia (adverse CNS effects).
There are no adequate data on the effects clobazam use during human pregnancy. Recent case-control and cohort studies of benzodiazepine use during human pregnancy have not confirmed increased risks of congenital malformations previously reported with early studies of benzodiazepines, including diazepam and chlordiazepoxide. Available animal data suggest developmental toxicity, including an increased incidence of fetal abnormalities, at plasma exposures for clobazam and its major active metabolite below those expected at the maximum recommended human dose of 40 mg/day. Data suggest the possibility of long-term effects on neurobehavioral and immunological functions in animals after prenatal benzodiazepine exposure at clinically relevant doses. Clobazam should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Monitor neonates exposed to benzodiazepines during pregnancy, labor, or obstetric delivery for signs of sedation, respiratory depression, or lethargy, and manage accordingly. Use of benzodiazepines late in pregnancy may result in a neonatal abstinence syndrome (NAS) or floppy infant syndrome (FIS). Monitor the neonate for hypotonia and withdrawal symptoms, including hyperreflexia, irritability, restlessness, tremors, inconsolable crying, or feeding difficulties and manage accordingly. The incidence, time to onset, and duration of NAS or FIS symptoms is multi-factorial (e.g., duration of use, drug lipophilicity, placental disposition, degree of accumulation in neonatal tissues). FIS typically occurs after chronic fetal exposure to long-acting benzodiazepines (e.g., chlordiazepoxide), or when benzodiazepines are administered shortly before delivery, resulting in newborn toxicity of variable severity and duration. FIS primarily occurs within the first few hours after labor and may last for up to 14 days. If a benzodiazepine is required during pregnancy, avoid first trimester administration if possible, consider short-acting agents, limit treatment to the shortest possible duration and lowest effective dose, and discontinue the drug well before delivery. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to clobazam; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.
Clobazam is excreted into human breast milk. Monitor breastfed infants exposed to benzodiazepines through breast milk for sedation, poor feeding, and poor weight gain. The effect of clobazam on milk production is not known. Consider the developmental and health benefits of breast-feeding along with the clinical need for clobazam and any potential adverse effects on the breastfed infant from clobazam or the underlying maternal condition. Data from a study of 6 patients indicate that maternal doses of clobazam up to 30 mg daily produce low concentrations in milk. Short-term use would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. Milk concentrations of clobazam plus its active metabolite, N-desmethylclobazam, were 0.125 mg/L on day 2 and 0.152 mg/L on day 5. Milk samples were taken 2 hours after each dose on days 2 and 5 of drug administration. The highest recorded clobazam plus N-desmethylclobazam milk concentrations were 0.33 mg/L on day 2 and 0.25 mg/L on day 5. The weight-adjusted infant dosages were an average of 4.6% and a maximum of 7.5% of the maternal dosage. Previous American Academy of Pediatrics (AAP) recommendations did not evaluate the use of clobazam in breast-feeding; however, the AAP considered other benzodiazepines to be drugs whose effect on the nursing infant is not known but may be of concern, particularly with prolonged exposure.
Clobazam may be associated with reproductive risk and infertility. Administration of clobazam to male and female rats prior to and during mating and early gestation resulted in adverse effects on fertility and early embryonic development, including increases in abnormal sperm and pre-implantation loss, at plasma exposures for clobazam and its major metabolite, N-desmethylclobazam, below those in humans at the maximum recommended human dose (MRHD) of 40 mg/day.
For the adjunct treatment of seizures associated with Lennox-Gastaut syndrome:
NOTE: Clobazam has been designated an orphan drug for this indication by the FDA.
Oral dosage:
Adults: 5 mg PO twice daily initially. Titrate to 10 mg PO twice daily on Day 7, then 20 mg PO twice daily on Day 14. Individualize dose based on clinical efficacy and tolerability. In patients who are poor metabolizers of CYP2C19, initiate dosing at 5 mg PO once daily and titrate to 5 mg PO twice daily on Day 7, 10 mg PO twice daily on Day 14, then 20 mg PO twice daily on Day 21, as tolerated. Upon treatment discontinuation in any patient, decrease the total daily dose by 5 to 10 mg/day on a weekly basis until discontinued.
Geriatric Adults weighing more than 30 kg: 5 mg PO once daily initially. Titrate to 5 mg PO twice daily on Day 7, 10 mg PO twice daily on Day 14, then 20 mg PO twice daily on Day 21 if required. Individualize dose based on clinical efficacy and tolerability. Upon treatment discontinuation, decrease the total daily dose by 5 to 10 mg/day on a weekly basis until discontinued.
Geriatric Adults weighing 30 kg or less: 5 mg PO once daily initially. Titrate to 5 mg PO twice daily on Day 14, then 10 mg PO twice daily on Day 21 if required. Individualize dose based on clinical efficacy and tolerability. Upon treatment discontinuation, decrease the total daily dose by 5 to 10 mg/day on a weekly basis until discontinued.
Children and Adolescents 2 to 17 years weighing more than 30 kg: 5 mg PO twice daily initially. Titrate to 10 mg PO twice daily on Day 7, then 20 mg PO twice daily on Day 14. Individualize dose based on clinical efficacy and tolerability. In patients who are poor metabolizers of CYP2C19, initiate dosing at 5 mg PO once daily and titrate to 5 mg PO twice daily on Day 7, 10 mg PO twice daily on Day 14, then 20 mg PO twice daily on Day 21, as tolerated. Upon treatment discontinuation in any patient, decrease the total daily dose by 5 to 10 mg/day on a weekly basis until discontinued.
Children and Adolescents 2 to 17 years weighing 30 kg or less: 5 mg PO once daily initially. Titrate to 5 mg PO twice daily on Day 7, then 10 mg PO twice daily on Day 14. Individualize dose based on clinical efficacy and tolerability. In patients who are poor metabolizers of CYP2C19, initiate dosing at 5 mg PO once daily and titrate to 5 mg PO twice daily on Day 14, then 10 mg PO twice daily on Day 21, as tolerated. Upon treatment discontinuation in any patient, decrease the total daily dose by 5 to 10 mg/day on a weekly basis until discontinued.
For the treatment of seizures associated with Dravet syndrome*:
Oral dosage:
Infants, Children, and Adolescents: 0.2 to 0.3 mg/kg/day PO divided twice daily initially; increase to a target dose of 0.5 to 1 mg/kg/day over 2 to 3 weeks. Max: 2 mg/kg/day. Clobazam and valproic acid are the optimal first-line medications in Dravet syndrome. Initiate treatment with 1 and add the other if control remains suboptimal.
Maximum Dosage Limits:
-Adults
40 mg/day PO.
-Geriatric
40 mg/day PO.
-Adolescents
Weighing more than 30 kg: 40 mg/day PO.
Weighing 30 kg or less: 20 mg/day PO.
-Children
2 to 12 years weighing more than 30 kg: 40 mg/day PO.
2 to 12 years weighing 30 kg or less: 20 mg/day PO.
1 year: Safety and efficacy have not been established; however, doses up to 2 mg/kg/day PO have been recommended for Dravet syndrome.
-Infants
Safety and efficacy have not been established; however, doses up to 2 mg/kg/day PO have been recommended for Dravet syndrome.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Patients weighing more than 30 kg with mild to moderate hepatic impairment (Child-Pugh score 5 to 9): Initiate dosing at 5 mg PO once daily and titrate to 5 mg PO twice daily on Day 7, 10 mg PO twice daily on Day 14, then 20 mg PO twice daily on Day 21, as tolerated.
Patients weighing 30 kg or less with mild to moderate hepatic impairment (Child-Pugh score 5 to 9): Initiate dosing at 5 mg PO once daily and titrate to 5 mg PO twice daily on Day 14, then 10 mg PO twice daily on Day 21, as tolerated.
Patients with severe hepatic impairment: No dosing recommendation is available due to inadequate data.
Patients with Renal Impairment Dosing
No dose adjustment is necessary for patients with mild to moderate renal impairment; patients with severe renal impairment were not studied in clinical trials.
Intermittent Hemodialysis
No dosage recommendations are available. It is not known if clobazam or its active metabolite is dialyzable.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with clobazam; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Clobazam is a weak inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
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 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; Caffeine; Pyrilamine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Acetaminophen; Chlorpheniramine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme. (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme. (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme. (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
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 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: (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme. (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Acetaminophen; Diphenhydramine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
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. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, co-administration of hydrocodone and a CYP2D6 inhibitor, such as clobazam, may result in a reduction in the analgesic effect of hydrocodone. Avoid opiate cough medications in patients taking benzodiazepines.
Acetaminophen; Oxycodone: (Major) Concomitant use of oxycodone with clobazam may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with clobazam to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of oxycodone with clobazam may decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of clobazam may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Clobazam induces CYP3A4; oxycodone is a CYP3A4 substrate.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Acrivastine; Pseudoephedrine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
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 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: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Amitriptyline: (Moderate) A dosage reduction of CYP2D6 substrates, such tricyclic antidepressants, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. Additive CNS depressant effects are possible when clobazam is administered concurrently with tricyclic antidepressants.
Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as clobazam, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Amlodipine; Atorvastatin: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as clobazam, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Amlodipine; Benazepril: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as clobazam, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Amlodipine; Celecoxib: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as clobazam, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Amlodipine; Olmesartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as clobazam, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Amlodipine; Valsartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as clobazam, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as clobazam, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Amobarbital: (Moderate) Concomitant of clobazam with other CNS-depressant drugs including barbiturates can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. The primary metabolic pathway of clobazam is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. Results of a population pharmacokinetic analysis showed that concurrent use of phenobarbital, a CYP3A4 and CYP2C9 inducer, did not significantly alter the kinetics of clobazam or its active metabolite N-desmethylclobazam at steady-state. It should be noted that because clobazam is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase its clearance.
Amoxapine: (Moderate) Amoxapine may enhance the response to 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) A dosage reduction of clobazam may be necessary during co-administration of omeprazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and omeprazole is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Anxiolytics; Sedatives; and Hypnotics: (Moderate) Concomitant administration of clobazam with other CNS depressant drugs including sedatives and hypnotics, can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent.
Aprepitant, Fosaprepitant: (Major) Use caution if clobazam and aprepitant, fosaprepitant are used concurrently and monitor for a possible decrease in the efficacy of aprepitant as well as an increase in clobazam-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). After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Clobazam 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 clobazam. 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. Additionally, clobazam is a weak CYP3A4 inducer and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for weak-to-moderate inducers.
Aripiprazole: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Armodafinil: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of armodafinil. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and armodafinil is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Asenapine: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Concomitant of clobazam with other CNS-depressant drugs including barbiturates can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. The primary metabolic pathway of clobazam is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. Results of a population pharmacokinetic analysis showed that concurrent use of phenobarbital, a CYP3A4 and CYP2C9 inducer, did not significantly alter the kinetics of clobazam or its active metabolite N-desmethylclobazam at steady-state. It should be noted that because clobazam is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase its clearance.
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 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; Omeprazole: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of omeprazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and omeprazole is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Aspirin, ASA; Oxycodone: (Major) Concomitant use of oxycodone with clobazam may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with clobazam to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of oxycodone with clobazam may decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of clobazam may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Clobazam induces CYP3A4; oxycodone is a CYP3A4 substrate.
Atazanavir: (Major) Coadministration of atazanavir with clobazam is not recommended. There is a potential for elevated clobazam concentrations and altered atazanavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a substrate of CYP3A4. Clobazam is also a weak inducer of CYP3A4. The active metabolite of clobazam, N-desmethylclobazam, is a dose-dependent inducer of CYP3A4. Atazanavir is an inhibitor/substrate of CYP3A4.
Atazanavir; Cobicistat: (Major) Coadministration of atazanavir with clobazam is not recommended. There is a potential for elevated clobazam concentrations and altered atazanavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a substrate of CYP3A4. Clobazam is also a weak inducer of CYP3A4. The active metabolite of clobazam, N-desmethylclobazam, is a dose-dependent inducer of CYP3A4. Atazanavir is an inhibitor/substrate of CYP3A4. (Major) Coadministration of cobicistat with clobazam is not recommended. There is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a weak inducer of CYP3A4. Cobicistat is a substrate of CYP3A4.
Atogepant: (Major) Avoid use of atogepant and clobazam when atogepant is used for chronic migraine. Use an atogepant dose of 30 or 60 mg PO once daily for episodic migraine if coadministered with clobazam. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and clobazam is a weak CYP3A inducer. Coadministration with a weak CYP3A inducer resulted in a 25% reduction in atogepant overall exposure and a 24% reduction in atogepant peak concentration.
Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with clobazam can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
atypical antipsychotic: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Barbiturates: (Moderate) Concomitant of clobazam with other CNS-depressant drugs including barbiturates can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. The primary metabolic pathway of clobazam is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. Results of a population pharmacokinetic analysis showed that concurrent use of phenobarbital, a CYP3A4 and CYP2C9 inducer, did not significantly alter the kinetics of clobazam or its active metabolite N-desmethylclobazam at steady-state. It should be noted that because clobazam is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase its clearance.
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 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.
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. Educate patients about the risks and symptoms of respiratory depression and sedation.
Benzodiazepines: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Brexpiprazole: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Brompheniramine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme. (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Brompheniramine; Phenylephrine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Brompheniramine; Pseudoephedrine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme. (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
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 in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist 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 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.
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 in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist 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 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.
Buspirone: (Moderate) Concomitant administration of benzodiazepines like clobazam with CNS-depressant drugs, including buspirone, may potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Butalbital; Acetaminophen: (Moderate) Concomitant of clobazam with other CNS-depressant drugs including barbiturates can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. The primary metabolic pathway of clobazam is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. Results of a population pharmacokinetic analysis showed that concurrent use of phenobarbital, a CYP3A4 and CYP2C9 inducer, did not significantly alter the kinetics of clobazam or its active metabolite N-desmethylclobazam at steady-state. It should be noted that because clobazam is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase its clearance.
Butalbital; Acetaminophen; Caffeine: (Moderate) Concomitant of clobazam with other CNS-depressant drugs including barbiturates can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. The primary metabolic pathway of clobazam is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. Results of a population pharmacokinetic analysis showed that concurrent use of phenobarbital, a CYP3A4 and CYP2C9 inducer, did not significantly alter the kinetics of clobazam or its active metabolite N-desmethylclobazam at steady-state. It should be noted that because clobazam is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase its clearance.
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 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) Concomitant of clobazam with other CNS-depressant drugs including barbiturates can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. The primary metabolic pathway of clobazam is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. Results of a population pharmacokinetic analysis showed that concurrent use of phenobarbital, a CYP3A4 and CYP2C9 inducer, did not significantly alter the kinetics of clobazam or its active metabolite N-desmethylclobazam at steady-state. It should be noted that because clobazam is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase its clearance.
Butalbital; Aspirin; 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 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) Concomitant of clobazam with other CNS-depressant drugs including barbiturates can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. The primary metabolic pathway of clobazam is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. Results of a population pharmacokinetic analysis showed that concurrent use of phenobarbital, a CYP3A4 and CYP2C9 inducer, did not significantly alter the kinetics of clobazam or its active metabolite N-desmethylclobazam at steady-state. It should be noted that because clobazam is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase its clearance.
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 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.
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 dosage reduction of clobazam if adverse reactions known to occur with clobazam are experienced when coadministered with cannabidiol and consider discontinuation or dosage adjustment of clobazam if hepatic enzyme elevations occur. Concomitant use of cannabidiol and clobazam increased the incidence of elevated hepatic enzymes. Pneumonia has been observed more frequently in patients receiving cannabidiol and concomitant clobazam. Additive sedation and somnolence may also occur. Coadministration produces a 3-fold increase in plasma concentrations of N-desmethylclobazam, the active metabolite of clobazam. Clobazam is a CYP2C19 substrate and cannabidiol is a CYP2C19 inhibitor.
Carbamazepine: (Moderate) Carbamazepine induces CYP3A4 and clobazam is metabolized by CYP3A4; therefore, carbamazepine may potentially accelerate the hepatic metabolism of clobazam. Close monitoring of anticonvulsant efficacy and clinical effects is warranted.
Carbidopa; Levodopa; Entacapone: (Moderate) An enhanced CNS depressant effect may occur when clobazam is combined with entacapone, a COMT inhibitor. Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. COMT inhibitors may cause drowsiness and 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.
Carbinoxamine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Cariprazine: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Celecoxib; 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 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. Additionally, in vivo data suggest clobazam is a CYP2D6 inhibitor. Because the analgesic activity of tramadol is due to both the parent drug and O-desmethyltramadol (M1), inhibition of CYP2D6 by clobazam may affect the analgesic response to tramadol. Reduced analgesic effects of tramadol are possible, and the risk for serious adverse effects such as seizures may be increased.
Cenobamate: (Moderate) Consider a dose reduction of clobazam when coadministered with cenobamate due to the potential for increased clobazam exposure and adverse effects. Also, concomitant use of cenobamate with clobazam may increase the risk of neurological adverse reactions, including sedation and somnolence. Clobazam is a CYP2C19 substrate; cenobamate is a moderate CYP2C19 inhibitor. Moderate inhibitors of CYP2C19 may cause up to a 5-fold increase in exposure to N-desmethylclobazam, the active metabolite of clobazam.
Chlophedianol; Dexbrompheniramine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Chloramphenicol: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of chloramphenicol. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and chloramphenicol is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicate that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Chlorcyclizine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Chlordiazepoxide: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Chlordiazepoxide; Amitriptyline: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression. (Moderate) A dosage reduction of CYP2D6 substrates, such tricyclic antidepressants, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. Additive CNS depressant effects are possible when clobazam is administered concurrently with tricyclic antidepressants.
Chlordiazepoxide; Clidinium: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Chlorpheniramine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
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 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) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Chlorpheniramine; Dextromethorphan: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme. (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme. (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme. (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
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. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, co-administration of hydrocodone and a CYP2D6 inhibitor, such as clobazam, may result in a reduction in the analgesic effect of hydrocodone. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Chlorpheniramine; Phenylephrine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Chlorpheniramine; Pseudoephedrine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Chlorpromazine: (Major) A dose reduction of CYP2D6 substrates, such as chlorpromazine, may be necessary during coadministration of clobazam. Clobazam is a weak inhibitor of CYP2D6. Elevated concentrations of chlorpromazine occurring through inhibition of CYP2D6 may increase the risk of QT prolongation, torsade de pointes, or other serious adverse effects. Phenothiazines may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant.
Cimetidine: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of cimetidine. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and cimetidine is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Clemastine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Clomipramine: (Moderate) A dosage reduction of CYP2D6 substrates, such tricyclic antidepressants, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. Additive CNS depressant effects are possible when clobazam is administered concurrently with tricyclic antidepressants.
Clonazepam: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Clorazepate: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Clozapine: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Cobicistat: (Major) Coadministration of cobicistat with clobazam is not recommended. There is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a weak inducer of CYP3A4. Cobicistat is a substrate of CYP3A4.
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 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 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 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) A dose reduction of CYP2D6 substrates, such as promethazine, may be necessary during coadministration of clobazam. Clobazam is a weak inhibitor of CYP2D6. Elevated concentrations of promethazine occurring through inhibition of CYP2D6 may increase the risk of extrapyramidal symptoms, somnolence, or other serious adverse effects. In addition, phenothiazines may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant. (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. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
Codeine; Promethazine: (Major) A dose reduction of CYP2D6 substrates, such as promethazine, may be necessary during coadministration of clobazam. Clobazam is a weak inhibitor of CYP2D6. Elevated concentrations of promethazine occurring through inhibition of CYP2D6 may increase the risk of extrapyramidal symptoms, somnolence, or other serious adverse effects. In addition, phenothiazines may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant. (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. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
Colesevelam: (Major) The manufacturer for colesevelam suggests monitoring serum drug concentrations and/or clinical effects for those drugs for which alterations in serum blood concentrations have a clinically significant effect on safety or efficacy. To minimize potential for interactions, consider administering oral anticonvulsants such as clobazam at least 4 hours before colesevelam.
Conjugated Estrogens: (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Conjugated Estrogens; Bazedoxifene: (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Conjugated Estrogens; Medroxyprogesterone: (Major) The addition of non-hormonal forms of contraception are recommended during concurrent use of clobazam and hormonal contraceptives. Concurrent administration of clobazam, a weak CYP3A4 inducer, with progestins may increase the elimination of these hormones. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Patients taking these hormones for indications other than contraception may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy. (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Cyproheptadine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Darunavir: (Major) Coadministration of darunavir with clobazam is not recommended. There is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a weak inducer of CYP3A4. Darunavir is a substrate of CYP3A4.
Darunavir; Cobicistat: (Major) Coadministration of cobicistat with clobazam is not recommended. There is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a weak inducer of CYP3A4. Cobicistat is a substrate of CYP3A4. (Major) Coadministration of darunavir with clobazam is not recommended. There is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a weak inducer of CYP3A4. Darunavir is a substrate of CYP3A4.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of cobicistat with clobazam is not recommended. There is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a weak inducer of CYP3A4. Cobicistat is a substrate of CYP3A4. (Major) Coadministration of darunavir with clobazam is not recommended. There is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a weak inducer of CYP3A4. Darunavir is a substrate of CYP3A4.
Delavirdine: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of delavirdine. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and delavirdine is an inhibitor of CYP2C19 in vitro. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Desipramine: (Moderate) A dosage reduction of CYP2D6 substrates, such tricyclic antidepressants, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. Additive CNS depressant effects are possible when clobazam is administered concurrently with tricyclic antidepressants.
Desogestrel; Ethinyl Estradiol: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as clobazam, may have additive effects and worsen drowsiness or sedation.
Dexbrompheniramine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Dexbrompheniramine; Pseudoephedrine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Dexchlorpheniramine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme. (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Dextromethorphan: (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Dextromethorphan; Bupropion: (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme. (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Dextromethorphan; Guaifenesin: (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Dextromethorphan; Quinidine: (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Diazepam: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Dienogest; Estradiol valerate: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy. (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Dimenhydrinate: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Diphenhydramine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Diphenhydramine; Ibuprofen: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Diphenhydramine; Naproxen: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Diphenhydramine; Phenylephrine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Diphenoxylate; Atropine: (Moderate) Concurrent administration of diphenoxylate/difenoxin with clobazam can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
Dolutegravir: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with clobazam; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Clobazam is a weak inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Dolutegravir; Lamivudine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with clobazam; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Clobazam is a weak inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Dolutegravir; Rilpivirine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with clobazam; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Clobazam is a weak inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Doravirine: (Minor) Concurrent administration of doravirine and clobazam may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; clobazam is a weak CYP3A4 inducer.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Minor) Concurrent administration of doravirine and clobazam may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; clobazam is a weak CYP3A4 inducer.
Doxepin: (Moderate) A dosage reduction of CYP2D6 substrates, such tricyclic antidepressants, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. Additive CNS depressant effects are possible when clobazam is administered concurrently with tricyclic antidepressants.
Doxorubicin Liposomal: (Major) Avoid coadministration of doxorubicin and clobazam due to the potential for altered doxorubicin exposure. Doxorubicin is a major substrate of CYP3A4 and CYP2D6. Clobazam is a weak inhibitor of CYP2D6 and a weak inducer of CYP3A4. Clinically significant interactions have been reported with inhibitors of CYP2D6 resulting in increased concentration and clinical effect of doxorubicin while inducers of CYP3A4 may decrease the concentration of doxorubicin.
Doxorubicin: (Major) Avoid coadministration of doxorubicin and clobazam due to the potential for altered doxorubicin exposure. Doxorubicin is a major substrate of CYP3A4 and CYP2D6. Clobazam is a weak inhibitor of CYP2D6 and a weak inducer of CYP3A4. Clinically significant interactions have been reported with inhibitors of CYP2D6 resulting in increased concentration and clinical effect of doxorubicin while inducers of CYP3A4 may decrease the concentration of doxorubicin.
Doxylamine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Doxylamine; Pyridoxine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Dronabinol: (Moderate) Use caution if coadministration of dronabinol with clobazam is necessary due to the potential for additive dizziness, confusion, somnolence, and other CNS effects.
Droperidol: (Major) Central nervous system (CNS) depressants (e.g., clobazam) have additive or potentiating effects with droperidol. Following administration of droperidol, the dose of the other CNS depressant should be reduced. Furthermore, according to the manufacturer, ethanol abuse and the use of benzodiazepines and intravenous opiates are risk factors for the development of prolonged QT syndrome in patients receiving droperidol.
Drospirenone: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Drospirenone; Estetrol: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Drospirenone; Estradiol: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy. (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Drospirenone; Ethinyl Estradiol: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Elagolix; Estradiol; Norethindrone acetate: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy. (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Eliglustat: (Moderate) In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of clobazam and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily. Clobazam is a weak CYP2D6 inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration with CYP2D6 inhibitors, such as clobazam, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration of cobicistat with clobazam is not recommended. There is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a weak inducer of CYP3A4. Cobicistat is a substrate of CYP3A4. (Major) Coadministration of elvitegravir with clobazam is not recommended. There is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a weak inducer of CYP3A4. Elvitegravir is a substrate of CYP3A4.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of cobicistat with clobazam is not recommended. There is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a weak inducer of CYP3A4. Cobicistat is a substrate of CYP3A4. (Major) Coadministration of elvitegravir with clobazam is not recommended. There is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a weak inducer of CYP3A4. Elvitegravir is a substrate of CYP3A4.
Entacapone: (Moderate) An enhanced CNS depressant effect may occur when clobazam is combined with entacapone, a COMT inhibitor. Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. COMT inhibitors may cause drowsiness and 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.
Eslicarbazepine: (Moderate) Eslicarbazepine may inhibit the CYP2C19-mediated metabolism of clobazam resulting in increased concentrations of clobazam. Metabolism of the active metabolite of clobazam occurs primarily through CYP2C19. Extrapolation of pharmacogenomic data indicates that concurrent administration of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated. A dosage reduction of clobazam may be necessary during co-administration of eslicarbazepine.
Esomeprazole: (Moderate) Coadministration may increase serum concentrations of clobazam; a dosage reduction of clobazam may be necessary during coadministration of esomeprazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and esomeprazole is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Estazolam: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Esterified Estrogens: (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Esterified Estrogens; Methyltestosterone: (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Estradiol: (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Estradiol; Levonorgestrel: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy. (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Estradiol; Norethindrone: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy. (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Estradiol; Norgestimate: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy. (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Estradiol; Progesterone: (Major) The addition of non-hormonal forms of contraception are recommended during concurrent use of clobazam and hormonal contraceptives. Concurrent administration of clobazam, a weak CYP3A4 inducer, with progestins may increase the elimination of these hormones. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Patients taking these hormones for indications other than contraception may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy. (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Estramustine: (Major) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Estropipate: (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Eszopiclone: (Moderate) Concomitant administration of clobazam with other CNS depressant drugs including sedatives and hypnotics, can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent.
Ethanol: (Major) Advise patients to avoid alcohol-containing beverages while taking clobazam. Concomitant administration of clobazam with other CNS depressants including alcohol can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. In addition, consumption of alcohol increases the maximum plasma exposure of clobazam by about 50%. (Major) Concomitant administration of clobazam with other CNS depressants including alcohol can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. In addition, consumption of alcohol increases the maximum plasma exposure of clobazam by about 50%. Patients should be advised of the potential hazards of consuming alcohol during treatment with clobazam, including excessive sedation and resultant effects on ability to drive or operate machinery.
Ethinyl Estradiol; Norelgestromin: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy. (Major) The addition of non-hormonal forms of contraception are recommended during concurrent use of clobazam and hormonal contraceptives. Concurrent administration of clobazam, a weak CYP3A4 inducer, with progestins may increase the elimination of these hormones. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Patients taking these hormones for indications other than contraception may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Ethinyl Estradiol; Norethindrone Acetate: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Ethinyl Estradiol; Norgestrel: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Etomidate: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Potentiation of CNS effects (i.e., increased sedation or respiratory depression) may occur when clobazam is combined with other CNS depressants such as general anesthetics.
Etonogestrel: (Major) The addition of non-hormonal forms of contraception are recommended during concurrent use of clobazam and hormonal contraceptives. Concurrent administration of clobazam, a weak CYP3A4 inducer, with progestins may increase the elimination of these hormones. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Patients taking these hormones for indications other than contraception may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Etonogestrel; Ethinyl Estradiol: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy. (Major) The addition of non-hormonal forms of contraception are recommended during concurrent use of clobazam and hormonal contraceptives. Concurrent administration of clobazam, a weak CYP3A4 inducer, with progestins may increase the elimination of these hormones. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Patients taking these hormones for indications other than contraception may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Fedratinib: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of omeprazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and fedratinib is a moderate inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam.
Felbamate: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of felbamate. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and felbamate is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated. It should be noted that results of a population pharmacokinetic analysis showed that concurrent use of felbamate and clobazam did not significantly alter the kinetics of clobazam or its active metabolite at steady-state.
Fenfluramine: (Moderate) Limit fenfluramine dose increases to 0.05 mg/kg/dose every 7 days up to a maximum of 0.2 mg/kg/dose PO twice daily (Max: 17 mg/day) in patients also receiving stiripentol and clobazam. Monitor for excessive sedation and somnolence; additive CNS depression may occur. Coadministration increases fenfluramine plasma concentrations and decreases its metabolite, norfenfluramine, due to the inhibition of the metabolism of fenfluramine. The effect of stiripentol plus clobazam on fenfluramine exposure is greater when fenfluramine is at steady-state than for the first dose of fenfluramine. Coadministration of existing stiripentol plus clobazam is expected to increase the exposure of the first fenfluramine dose by up to 42%. At steady-state, coadministration is expected to result in a 166% increase in fenfluramine exposure and a 38% decrease in norfenfluramine exposure.
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 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.
Fexinidazole: (Moderate) Monitor for an increase in clobazam-related adverse effects if concomitant use with fexinidazole is necessary; a clobazam dosage reduction may be required based on response. Concomitant use may increase clobazam exposure. Clobazam is a CYP2C19 substrate and fexinidazole is a moderate CYP2C19 inhibitor.
Flecainide: (Moderate) A dosage reduction of CYP2D6 substrates, such as flecainide, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. If these agents are used in combination, it is advisable to monitor the patient for flecainide-related adverse reactions.
Fluconazole: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of fluconazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and fluconazole is a potent inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Flumazenil: (Major) Flumazenil and benzodiazepines are pharmacologic opposites. The use of flumazenil is not indicated in epileptic patients receiving benzodiazepines. The antagonistic action of flumazenil may precipitate seizures in epileptic patients receiving benzodiazepines such as clobazam.
Fluoxetine: (Moderate) A dosage reduction of clobazam and/or fluoxetine may be necessary during co-administration of clobazam and fluoxetine. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and fluoxetine is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated. In addition, fluoxetine is a substrate of CYP2D6 and limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. A dosage reduction of CYP2D6 substrates may be necessary during co-administration of clobazam. It should be noted that because fluoxetine is metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease its clearance.
Fluphenazine: (Major) A dose reduction of CYP2D6 substrates, such as fluphenazine, may be necessary during coadministration of clobazam. Clobazam is a weak inhibitor of CYP2D6. Elevated concentrations of fluphenazine occurring through inhibition of CYP2D6 may increase the risk of extrapyramidal symptoms, somnolence, or other serious adverse effects. In addition, phenothiazines may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant.
Flurazepam: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Fluvoxamine: (Moderate) A dosage reduction of clobazam and/or fluvoxamine may be necessary during co-administration of clobazam and fluvoxamine. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and fluvoxamine is a potent inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated. In addition, fluvoxamine is a substrate of CYP2D6 and limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. A dosage reduction of CYP2D6 substrates may be necessary during co-administration of clobazam.
Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
Fosphenytoin: (Moderate) Concomitant administration of clobazam with other CNS-depressant drugs including fosphenytoin (prodrug of phenytoin) can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent.
Gabapentin: (Major) Concomitant use of clobazam 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) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Potentiation of CNS effects (i.e., increased sedation or respiratory depression) may occur when clobazam is combined with other CNS depressants such as general anesthetics.
Haloperidol: (Major) A dosage reduction of CYP2D6 substrates, such as haloperidol, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. Elevated concentrations of haloperidol occurring through inhibition of CYP2D6 may increase the risk of adverse effects, including QT prolongation and torsade de pointes. Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects which may be potentiated during concurrent use of conventional antipsychotics including phenothiazines, haloperidol, loxapine, thiothixene, or molindone. Antipsychotics may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant.
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. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, co-administration of hydrocodone and a CYP2D6 inhibitor, such as clobazam, may result in a reduction in the analgesic effect of hydrocodone. Avoid opiate cough medications in patients taking benzodiazepines.
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. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, co-administration of hydrocodone and a CYP2D6 inhibitor, such as clobazam, may result in a reduction in the analgesic effect of hydrocodone. 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. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, co-administration of hydrocodone and a CYP2D6 inhibitor, such as clobazam, may result in a reduction in the analgesic effect of hydrocodone. 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. 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 clobazam. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
Hydroxyzine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Ibuprofen; Oxycodone: (Major) Concomitant use of oxycodone with clobazam may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with clobazam to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of oxycodone with clobazam may decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of clobazam may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Clobazam induces CYP3A4; oxycodone is a CYP3A4 substrate.
Idelalisib: (Moderate) Monitor for increased clobazam-related adverse effects if coadministered with idelalisib due to potential for increased clobazam exposure. Clobazam is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration of clobazam with another strong CYP3A4 inhibitor increased clobazam AUC by 54%, with an insignificant effect on clobazam Cmax.
Iloperidone: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Imipramine: (Moderate) A dosage reduction of CYP2D6 substrates, such tricyclic antidepressants, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. Additive CNS depressant effects are possible when clobazam is administered concurrently with tricyclic antidepressants.
Isavuconazonium: (Moderate) Coadministration of isavuconazonium with clobazam may decrease isavuconazonium concentrations. Decreased isavuconazonium concentrations may lead to a reduction of antifungal efficacy and the potential for treatment failure. Clobazam is a weak inducer of CYP3A4. Isavuconazole, the active moiety of isavuconazonium, is a sensitive CYP3A4 substrate.
Isoflurane: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Potentiation of CNS effects (i.e., increased sedation or respiratory depression) may occur when clobazam is combined with other CNS depressants such as general anesthetics.
Isoniazid, INH: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of isoniazid, INH. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and isoniazid is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of isoniazid, INH. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and isoniazid is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Isoniazid, INH; Rifampin: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of isoniazid, INH. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and isoniazid is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Ketamine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Potentiation of CNS effects (i.e., increased sedation or respiratory depression) may occur when clobazam is combined with other CNS depressants such as general anesthetics.
Ketoconazole: (Moderate) During co-administration of ketoconazole and clobazam, the AUC of clobazam was increased by 54%. However, there were no significant changes in AUC and Cmax of N-desmethylclobazam, the active metabolite of clobazam. No dosage adjustments are recommended by the manufacturer during concurrent use of these agents.
Lansoprazole: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of lansoprazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and lansoprazole is an inhibitor of CYP2C19 in vitro. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of lansoprazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and lansoprazole is an inhibitor of CYP2C19 in vitro. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and clobazam. Dosage adjustments of lemborexant and clobazam may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.
Letermovir: (Moderate) Plasma concentrations of clobazam could be increased when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Monitor for clobazam-related adverse events. Clobazam is a substrate of CYP3A4. Letermovir is a moderate inhibitor of CYP3A4; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Leuprolide; Norethindrone: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Levamlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as clobazam, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Levoketoconazole: (Moderate) During co-administration of ketoconazole and clobazam, the AUC of clobazam was increased by 54%. However, there were no significant changes in AUC and Cmax of N-desmethylclobazam, the active metabolite of clobazam. No dosage adjustments are recommended by the manufacturer during concurrent use of these agents.
Levonorgestrel: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Levonorgestrel; Ethinyl Estradiol: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
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. Educate patients about the risks and symptoms of respiratory depression and sedation.
Lofexidine: (Moderate) Monitor for excessive sedation during coadministration of lofexidine and clobazam, a benzodiazepine. Lofexidine can potentiate the effects of CNS depressants.
Lopinavir; Ritonavir: (Moderate) Monitor for decreased response to lopinavir during concurrent use with clobazam. Coadministration may result in decreased lopinavir plasma concentrations. Clobazam is a weak inducer of CYP3A4. Lopinavir is a substrate of CYP3A4. (Moderate) Monitor for reduced response to ritonavir and increased adverse effects from both clobazam and ritonavir during concurrent use. Coadministration may result in elevated plasma concentrations of clobazam and altered concentrations of ritonavir. Clobazam is a substrate of CYP3A4, weak inducer of CYP3A4, and an inhibitor of CYP2D6. Ritonavir is a substrate of CYP3A4 and CYP2D6. Ritonavir is also a strong inhibitor of CYP3A4.
Lorazepam: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Loxapine: (Major) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects which may be potentiated during concurrent use of conventional antipsychotics including loxapine. Antipsychotics may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant.
Lumacaftor; Ivacaftor: (Moderate) Although the clinical significance of this interaction is unknown, lumacaftor; ivacaftor may reduce the efficacy of clobazam by decreasing its systemic exposure; a dosage increase of clobazam may be necessary during co-administration of lumacaftor; ivacaftor. Do not exceed the maximum recommended dose. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and in vitro data suggest that lumacaftor may induce CYP2C19. Clobazam and its active metabolite are also substrates of the drug transporter P-glycoprotein (P-gp) and in vitro data suggest that lumacaftor; ivacaftor may inhibit and/or induce P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
Lumacaftor; Ivacaftor: (Moderate) Although the clinical significance of this interaction is unknown, lumacaftor; ivacaftor may reduce the efficacy of clobazam by decreasing its systemic exposure; a dosage increase of clobazam may be necessary during co-administration of lumacaftor; ivacaftor. Do not exceed the maximum recommended dose. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and in vitro data suggest that lumacaftor may induce CYP2C19. Clobazam and its active metabolite are also substrates of the drug transporter P-glycoprotein (P-gp) and in vitro data suggest that lumacaftor; ivacaftor may inhibit and/or induce P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
Lumateperone: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Lurasidone: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Maprotiline: (Moderate) These drugs may be used together with caution. You may feel drowsy or more tired when taking these drugs together. Do not drive or operate machinery until you know how these drugs affect you. Notify your health care provider if you notice that your medication is not working as well for you, or if you experience confusion, dizziness, falls, unsteadiness, or other troublesome side effects. A dosage reduction of CYP2D6 substrates, such as maprotiline, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. If these agents are used in combination, it is advisable to monitor the patient for maprotiline-related adverse reactions.
Maraviroc: (Minor) Use caution if coadministration of maraviroc with clobazam is necessary, due to a possible decrease in maraviroc exposure. Maraviroc is a CYP3A substrate and clobazam is a weak CYP3A4 inducer. Monitor for a decrease in efficacy with concomitant use.
Meclizine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Medroxyprogesterone: (Major) The addition of non-hormonal forms of contraception are recommended during concurrent use of clobazam and hormonal contraceptives. Concurrent administration of clobazam, a weak CYP3A4 inducer, with progestins may increase the elimination of these hormones. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Patients taking these hormones for indications other than contraception may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
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 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.
Meprobamate: (Moderate) Concomitant administration of clobazam with other CNS depressant drugs including sedatives and hypnotics, can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent.
Methadone: (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 methadone is initiated in a patient taking a benzodiazepine, reduced dosages are recommended; in opioid-naive adults, use an initial dose of methadone 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 dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Methohexital: (Moderate) Concomitant of clobazam with other CNS-depressant drugs including barbiturates can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. The primary metabolic pathway of clobazam is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. Results of a population pharmacokinetic analysis showed that concurrent use of phenobarbital, a CYP3A4 and CYP2C9 inducer, did not significantly alter the kinetics of clobazam or its active metabolite N-desmethylclobazam at steady-state. It should be noted that because clobazam is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase its clearance.
Mexiletine: (Moderate) A dosage reduction of CYP2D6 substrates, such as mexiletine, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. If these agents are used in combination, it is advisable to monitor the patient for mexiletine-related adverse reactions.
Midazolam: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Modafinil: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of modafinil or armodafinil. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and modafinil and armodafinil are inhibitors of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Molindone: (Major) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects which may be potentiated during concurrent use of conventional antipsychotics including molindone. Antipsychotics may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant. Additionally, 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.
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. 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. Educate patients about the risks and symptoms of respiratory depression and sedation.
Nabilone: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Potentiation of CNS effects (i.e., increased sedation or respiratory depression) may occur when clobazam is combined with other CNS depressants such as nabilone.
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 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.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with clobazam is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and clobazam is a weak CYP3A4 inducer.
Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor for reduced sirolimus efficacy if sirolimus is coadministered with clobazam. Concomitant use may decrease sirolimus exposure. Sirolimus is a CYP3A substrate and clobazam is a weak CYP3A inducer.
Naproxen; Esomeprazole: (Moderate) Coadministration may increase serum concentrations of clobazam; a dosage reduction of clobazam may be necessary during coadministration of esomeprazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and esomeprazole is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Nirmatrelvir; Ritonavir: (Major) Consider withholding clobazam, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the clobazam dose. However, do not stop clobazam abruptly or rapidly reduce the dose as this may precipitate an acute withdrawal reaction, especially in patients who have been receiving high doses over an extended period. Coadministration may increase clobazam exposure resulting in increased toxicity and excessive sedation. Clonazepam is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. Also, concurrent use may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and clobazam is a weak CYP3A inducer. (Moderate) Monitor for reduced response to ritonavir and increased adverse effects from both clobazam and ritonavir during concurrent use. Coadministration may result in elevated plasma concentrations of clobazam and altered concentrations of ritonavir. Clobazam is a substrate of CYP3A4, weak inducer of CYP3A4, and an inhibitor of CYP2D6. Ritonavir is a substrate of CYP3A4 and CYP2D6. Ritonavir is also a strong inhibitor of CYP3A4.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with clobazam due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and clobazam is a mild CYP3A4 inducer. Coadministration with a CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Norethindrone: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Norethindrone; Ethinyl Estradiol: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Norgestimate; Ethinyl Estradiol: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Norgestrel: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Nortriptyline: (Moderate) A dosage reduction of CYP2D6 substrates, such tricyclic antidepressants, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. Additive CNS depressant effects are possible when clobazam is administered concurrently with tricyclic antidepressants.
Olanzapine: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Olanzapine; Fluoxetine: (Moderate) A dosage reduction of clobazam and/or fluoxetine may be necessary during co-administration of clobazam and fluoxetine. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and fluoxetine is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated. In addition, fluoxetine is a substrate of CYP2D6 and limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. A dosage reduction of CYP2D6 substrates may be necessary during co-administration of clobazam. It should be noted that because fluoxetine is metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease its clearance. (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Olanzapine; Samidorphan: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Oliceridine: (Major) Concomitant use of oliceridine with clobazam may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with clobazam 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.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as clobazam, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Omeprazole: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of omeprazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and omeprazole is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of omeprazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and omeprazole is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Omeprazole; Sodium Bicarbonate: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of omeprazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and omeprazole is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Opicapone: (Major) An enhanced CNS depressant effect may occur when clobazam is combined with opicapone, a COMT inhibitor. Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. COMT inhibitors may cause drowsiness and 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.
Oral Contraceptives: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy.
Oxazepam: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Oxycodone: (Major) Concomitant use of oxycodone with clobazam may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with clobazam to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of oxycodone with clobazam may decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of clobazam may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Clobazam induces CYP3A4; oxycodone is a CYP3A4 substrate.
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. Educate patients about the risks and symptoms of respiratory depression and sedation.
Paliperidone: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Paroxetine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with clobazam is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and clobazam is a weak CYP2D6 inhibitor. Coadministration with a weak CYP2D6 inhibitor increased paroxetine overall exposure by 50%.
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 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) Concomitant of clobazam with other CNS-depressant drugs including barbiturates can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. The primary metabolic pathway of clobazam is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. Results of a population pharmacokinetic analysis showed that concurrent use of phenobarbital, a CYP3A4 and CYP2C9 inducer, did not significantly alter the kinetics of clobazam or its active metabolite N-desmethylclobazam at steady-state. It should be noted that because clobazam is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase its clearance.
Perindopril; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as clobazam, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Perphenazine: (Major) A dose reduction of CYP2D6 substrates, such as perphenazine, may be necessary during coadministration of clobazam. Clobazam is a weak inhibitor of CYP2D6. Elevated concentrations of perphenazine occurring through inhibition of CYP2D6 may increase the risk of extrapyramidal symptoms, somnolence, or other serious adverse effects. In addition, phenothiazines may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant.
Perphenazine; Amitriptyline: (Major) A dose reduction of CYP2D6 substrates, such as perphenazine, may be necessary during coadministration of clobazam. Clobazam is a weak inhibitor of CYP2D6. Elevated concentrations of perphenazine occurring through inhibition of CYP2D6 may increase the risk of extrapyramidal symptoms, somnolence, or other serious adverse effects. In addition, phenothiazines may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant. (Moderate) A dosage reduction of CYP2D6 substrates, such tricyclic antidepressants, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. Additive CNS depressant effects are possible when clobazam is administered concurrently with tricyclic antidepressants.
Phenobarbital: (Moderate) Concomitant of clobazam with other CNS-depressant drugs including barbiturates can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. The primary metabolic pathway of clobazam is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. Results of a population pharmacokinetic analysis showed that concurrent use of phenobarbital, a CYP3A4 and CYP2C9 inducer, did not significantly alter the kinetics of clobazam or its active metabolite N-desmethylclobazam at steady-state. It should be noted that because clobazam is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase its clearance.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Concomitant of clobazam with other CNS-depressant drugs including barbiturates can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. The primary metabolic pathway of clobazam is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. Results of a population pharmacokinetic analysis showed that concurrent use of phenobarbital, a CYP3A4 and CYP2C9 inducer, did not significantly alter the kinetics of clobazam or its active metabolite N-desmethylclobazam at steady-state. It should be noted that because clobazam is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase its clearance.
Phenytoin: (Moderate) Concomitant administration of clobazam with other CNS-depressant drugs including phenytoin can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent.
Pimozide: (Major) A dosage reduction of CYP2D6 substrates, such as pimozide, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. Elevated concentrations of pimozide occurring through inhibition of CYP2D6 may increase the risk of pimozide-related adverse effects, including QT prolongation and torsade de pointes. Antipsychotics may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant. Additive CNS effects, including somnolence, are also likely to occur.
Pramipexole: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Potentiation of CNS effects (i.e., increased sedation or respiratory depression) may occur when clobazam is combined with other CNS depressants such as pramipexole.
Pregabalin: (Major) Concomitant use of clobazam 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) Concomitant of clobazam with other CNS-depressant drugs including barbiturates can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. The primary metabolic pathway of clobazam is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. Results of a population pharmacokinetic analysis showed that concurrent use of phenobarbital, a CYP3A4 and CYP2C9 inducer, did not significantly alter the kinetics of clobazam or its active metabolite N-desmethylclobazam at steady-state. It should be noted that because clobazam is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase its clearance.
Prochlorperazine: (Major) A dose reduction of CYP2D6 substrates, such as prochlorperazine, may be necessary during coadministration of clobazam. Clobazam is a weak inhibitor of CYP2D6. Elevated concentrations of prochlorperazine occurring through inhibition of CYP2D6 may increase the risk of extrapyramidal symptoms, somnolence, or other serious adverse effects. In addition, phenothiazines may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant.
Progesterone: (Major) The addition of non-hormonal forms of contraception are recommended during concurrent use of clobazam and hormonal contraceptives. Concurrent administration of clobazam, a weak CYP3A4 inducer, with progestins may increase the elimination of these hormones. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Patients taking these hormones for indications other than contraception may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Promethazine: (Major) A dose reduction of CYP2D6 substrates, such as promethazine, may be necessary during coadministration of clobazam. Clobazam is a weak inhibitor of CYP2D6. Elevated concentrations of promethazine occurring through inhibition of CYP2D6 may increase the risk of extrapyramidal symptoms, somnolence, or other serious adverse effects. In addition, phenothiazines may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant.
Promethazine; Dextromethorphan: (Major) A dose reduction of CYP2D6 substrates, such as promethazine, may be necessary during coadministration of clobazam. Clobazam is a weak inhibitor of CYP2D6. Elevated concentrations of promethazine occurring through inhibition of CYP2D6 may increase the risk of extrapyramidal symptoms, somnolence, or other serious adverse effects. In addition, phenothiazines may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant. (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Promethazine; Phenylephrine: (Major) A dose reduction of CYP2D6 substrates, such as promethazine, may be necessary during coadministration of clobazam. Clobazam is a weak inhibitor of CYP2D6. Elevated concentrations of promethazine occurring through inhibition of CYP2D6 may increase the risk of extrapyramidal symptoms, somnolence, or other serious adverse effects. In addition, phenothiazines may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant.
Propafenone: (Moderate) A dosage reduction of CYP2D6 substrates, such as propafenone, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. If these agents are used in combination, it is advisable to monitor the patient for propafenone-related adverse reactions.
Propofol: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Potentiation of CNS effects (i.e., increased sedation or respiratory depression) may occur when clobazam is combined with other CNS depressants such as general anesthetics.
Propranolol: (Moderate) A dosage reduction of CYP2D6 substrates, such as propranolol, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. If propranolol is used in combination, it is advisable to monitor the patient for adverse reactions related to beta-blockers.
Protriptyline: (Moderate) A dosage reduction of CYP2D6 substrates, such tricyclic antidepressants, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. Additive CNS depressant effects are possible when clobazam is administered concurrently with tricyclic antidepressants.
Pseudoephedrine; Triprolidine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Quazepam: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Quetiapine: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Quinine: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of quinine. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and quinine is an inhibitor of CYP2C19 in vitro. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Rabeprazole: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of rabeprazole. Metabolism of the active metabolite of clobazam occurs primarily through CYP2C19 and rabeprazole is an inhibitor of CYP2C19 in vitro. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Relugolix; Estradiol; Norethindrone acetate: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy. (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
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. Educate patients about the risks and symptoms of respiratory depression and sedation.
Remimazolam: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Risperidone: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Ritonavir: (Moderate) Monitor for reduced response to ritonavir and increased adverse effects from both clobazam and ritonavir during concurrent use. Coadministration may result in elevated plasma concentrations of clobazam and altered concentrations of ritonavir. Clobazam is a substrate of CYP3A4, weak inducer of CYP3A4, and an inhibitor of CYP2D6. Ritonavir is a substrate of CYP3A4 and CYP2D6. Ritonavir is also a strong inhibitor of CYP3A4.
Ropinirole: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Potentiation of CNS effects (e.g., increased sedation) may occur when clobazam is combined with other CNS depressants such as ropinirole.
Secobarbital: (Moderate) Concomitant of clobazam with other CNS-depressant drugs including barbiturates can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. The primary metabolic pathway of clobazam is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. Results of a population pharmacokinetic analysis showed that concurrent use of phenobarbital, a CYP3A4 and CYP2C9 inducer, did not significantly alter the kinetics of clobazam or its active metabolite N-desmethylclobazam at steady-state. It should be noted that because clobazam is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase its clearance.
Sedating H1-blockers: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Segesterone Acetate; Ethinyl Estradiol: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy. (Major) The addition of non-hormonal forms of contraception are recommended during concurrent use of clobazam and hormonal contraceptives. Concurrent administration of clobazam, a weak CYP3A4 inducer, with progestins may increase the elimination of these hormones. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Patients taking these hormones for indications other than contraception may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
Sevoflurane: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Potentiation of CNS effects (i.e., increased sedation or respiratory depression) may occur when clobazam is combined with other CNS depressants such as general anesthetics.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of clobazam. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and clobazam is a weak CYP3A inducer.
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.
Sufentanil: (Major) Concomitant use of sufentanil with clobazam may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with clobazam to only patients for whom alternative treatment options are inadequate. Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if clobazam must be administered. If concurrent use of sufentanil injection is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of sufentanil with clobazam may decrease sufentanil plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of clobazam may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Clobazam induces CYP3A4; sufentanil is a CYP3A4 substrate.
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. 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.
Telmisartan; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as clobazam, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Temazepam: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Thioridazine: (Contraindicated) Clobazam is a mild inhibitor of CYP2D6 and the use of thioridazine concomitantly with CYP2D6 inhibitors is contraindicated due to the possible risk of QT prolongation and subsequent arrhythmias, or other serious side effects, occurring from elevated serum concentrations of thioridazine.
Thiothixene: (Major) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects which may be potentiated during concurrent use of conventional antipsychotics including thiothixene. Antipsychotics may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant.
Tolcapone: (Moderate) An enhanced CNS depressant effect may occur when clobazam is combined with tolcapone, a COMT inhibitor. Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. COMT inhibitors may cause drowsiness and 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.
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 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. Additionally, in vivo data suggest clobazam is a CYP2D6 inhibitor. Because the analgesic activity of tramadol is due to both the parent drug and O-desmethyltramadol (M1), inhibition of CYP2D6 by clobazam may affect the analgesic response to tramadol. Reduced analgesic effects of tramadol are possible, and the risk for serious adverse effects such as seizures may be increased.
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 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. Additionally, in vivo data suggest clobazam is a CYP2D6 inhibitor. Because the analgesic activity of tramadol is due to both the parent drug and O-desmethyltramadol (M1), inhibition of CYP2D6 by clobazam may affect the analgesic response to tramadol. Reduced analgesic effects of tramadol are possible, and the risk for serious adverse effects such as seizures may be increased.
Triazolam: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Tricyclic antidepressants: (Moderate) A dosage reduction of CYP2D6 substrates, such tricyclic antidepressants, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. Additive CNS depressant effects are possible when clobazam is administered concurrently with tricyclic antidepressants.
Trifluoperazine: (Major) A dose reduction of CYP2D6 substrates, such as trifluoperazine, may be necessary during coadministration of clobazam. Clobazam is a weak inhibitor of CYP2D6. Elevated concentrations of trifluoperazine occurring through inhibition of CYP2D6 may increase the risk of extrapyramidal symptoms, somnolence, or other serious adverse effects. In addition, phenothiazines may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant.
Trimipramine: (Moderate) A dosage reduction of CYP2D6 substrates, such tricyclic antidepressants, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. Additive CNS depressant effects are possible when clobazam is administered concurrently with tricyclic antidepressants.
Triprolidine: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme.
Ubrogepant: (Major) Increase the initial and second dose of ubrogepant to 100 mg if coadministered with clobazam as concurrent use may decrease ubrogepant exposure and reduce its efficacy. Ubrogepant is a CYP3A4 substrate; clobazam is a weak CYP3A4 inducer.
Ulipristal: (Moderate) Clobazam is a weak CYP3A4 inducer. As ulipristal is metabolized by CYP3A4, its effectiveness may be diminished when given with clobazam. Strong CYP3A4 inducers should be avoided with ulipristal. Monitor the patient for the desired clinical effect if ulipristal must be administered to a patient taking clobazam.
Valerian, Valeriana officinalis: (Major) Any substances that act on the CNS, including benzodiazepines, may interact with valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature. Patients taking clobazam should avoid concomitant administration of valerian.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with clobazam is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Clobazam is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zaleplon: (Moderate) Concomitant administration of clobazam with other CNS depressant drugs including sedatives and hypnotics, can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent.
Ziprasidone: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Zolpidem: (Moderate) Concomitant administration of clobazam with other CNS depressant drugs including sedatives and hypnotics, can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent.
Zuranolone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Benzodiazepines such as clobazam 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, anxiolytic activity, anticonvulsant effects, and coma. Similar to other benzodiazepines, the action of clobazam is thought to be mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Central benzodiazepine receptors interact allosterically with GABA receptors, potentiating the effects of this inhibitory neurotransmitter.
Results from an electrocardiogram study indicate that clobazam does not have clinically significant effects on the QTc interval.
Clobazam is administered orally. Clobazam is lipophilic and distributes rapidly, with an apparent Vd at steady state of about 100 L. Plasma protein binding of clobazam and its active metabolite are about 80% to 90% and 70%, respectively. Clobazam is extensively metabolized in the liver, with about 2% of the dose excreted in urine and 1% in feces as the parent compound. The primary metabolic pathway is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. N-desmethylclobazam, the primary metabolite, has biologic activity that ranges from as low as 20% of the potency of clobazam to equivalent potency with clobazam. Plasma concentrations of N-desmethylclobazam are 3 to 5 times higher than those of the parent compound. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. The mean elimination half-lives of clobazam and N-desmethylclobazam are 36 to 42 hours and 71 to 82 hours, respectively. N-desmethylclobazam and its metabolites account for about 94% of a dose recovered in urine. After a single oral dose, about 11% of the dose was excreted in the feces and 82% was excreted in the urine.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2B6, CYP2D6, CYP2C9, CYP2C19, UGT1A4, UGT1A6, UGT2B4, P-gp
Clobazam is extensively metabolized in the liver, primarily via CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. In vitro, clobazam and N-desmethylclobazam induce CYP3A4 activity in a concentration-dependent manner. N-desmethylclobazam is a weak inhibitor of CYP2C9, UGT1A4, UGT1A6, and UGT2B4. Both are P-glycoprotein (P-gp) substrates. Clobazam is a weak inducer of CYP3A4 and in vivo data suggest it is an inhibitor of CYP2D6.
Systemic exposure of clobazam is similar for both poor and extensive metabolizers of CYP2C19. Plasma concentrations of N-desmethylclobazam are 3- to 5-fold higher and 2-fold higher in CYP2C19 poor metabolizers and intermediate metabolizers, respectively, than in extensive metabolizers. Urine concentrations of N-desmethylclobazam are 2- to 3-fold higher in poor metabolizers than extensive metabolizers.
-Route-Specific Pharmacokinetics
Oral Route
Clobazam is rapidly and extensively absorbed after oral administration. Tmax ranges from 0.5 to 4 hours after tablet administration and 0.33 to 4 hours after oral film administration. The relative bioavailability of the tablet formulation compared to the oral suspension is about 100%. Bioavailability is not affected by food.
-Special Populations
Hepatic Impairment
There are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of clobazam. The Cmax and mean plasma clearance of clobazam and the Cmax of N-desmethylclobazam were not significantly different in patients with hepatic impairment compared to healthy controls in a small, single-dose pharmacokinetic study (n = 15). The AUC of N-desmethylclobazam in these patients was not available.
Renal Impairment
There were no significant changes in Cmax (3% to 24%) and AUC (13% or less) for clobazam or N-desmethylclobazam in patients with mild (CrCl 51 to 80 mL/minute; n = 6) or moderate (30 to 50 mL/minute; n = 6) renal impairment compared to healthy controls (n = 6) in a multiple-dose pharmacokinetic study. Patients with severe renal impairment or end-stage renal dysfunction were not included.
Pediatrics
Clobazam metabolism is 53% to 69% faster in children compared to adults. Elimination half-life in children with epilepsy is approximately 16 hours.
Geriatric
The clearance of clobazam is lower in geriatrics compared to other age groups (younger than 64 years).
Gender Differences
There is no difference in the clearance of clobazam between men and women.
Ethnic Differences
There is no clinically significant difference in the clearance of clobazam between Caucasians, African Americans, and Asians. However, it should be noted that the prevalence of CYP2C19 poor metabolism differs depending on race. Plasma concentrations of N-desmethylclobazam are 3- to 5-fold higher and 2-fold higher in CYP2C19 poor metabolizers and intermediate metabolizers, respectively, than in extensive metabolizers. Urine concentrations of N-desmethylclobazam are 2- to 3-fold higher in poor metabolizers than extensive metabolizers.