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Clobazam

Class: Benzodiazepines
VA Class: CN400
Chemical Name: 7-Chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione
Molecular Formula: C16H13ClN2O2
CAS Number: 22316-47-8
Brands: Onfi, Sympazan

Medically reviewed by Drugs.com on Nov 23, 2020. Written by ASHP.

Warning

Special Alerts:

[Posted 09/23/2020]

TOPIC: Benzodiazepine Drug Class: Drug Safety Communication - Boxed Warning Updated to Improve Safe Use

AUDIENCE: Patient, Health Professional, Pharmacy

ISSUE: The FDA is requiring the Boxed Warning, FDA's most prominent warning, be updated by adding other information to the prescribing information for all benzodiazepine medicines. This information will describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class. The FDA is also requiring updates to the existing patient Medication Guides to help educate patients and caregivers about these risks.

Other changes are also being required to several sections of the prescribing information, including to the Warnings and Precautions, Drug Abuse and Dependence, and Patient Counseling Information sections.

BACKGROUND: Benzodiazepines are a class of medicines approved to treat generalized anxiety disorder, insomnia, seizures, social phobia, and panic disorder.

RECOMMENDATION:

Health Care Professionals

  • Consider the patient's condition and the other medicines being taken, and assess the risk of abuse, misuse, and addiction, available at: [Web].

  • Limit the dosage and duration of each medicine to the minimum needed to achieve the desired clinical effect when prescribing benzodiazepines, alone or in combination with other medicines.

  • Use a gradual taper to reduce the dosage or to discontinue benzodiazepines to reduce the risk of acute withdrawal reactions.

  • Take precautions when benzodiazepines are used in combination with opioid addiction medications, available at: [Web].

Patients, Parents, and Caregivers

  • Always tell your health care professionals about all the prescription and over-the-counter (OTC) medicines you are taking or any other substances you are using, including alcohol.

  • Take benzodiazepines and all medicines exactly as prescribed by your health care professional

  • Discuss a plan for slowly decreasing the dose and frequency of your benzodiazepine(s) with your health care professional.

  • Contact your health care professional if you experience withdrawal symptoms or your medical condition worsens.

  • Go to an emergency room or call 911 if you have trouble breathing or other serious side effects such as seizures.

For more information visit the FDA website at: [Web] and [Web].

Warning

    Concomitant Use with Opiates
  • Concomitant use of benzodiazepines and opiates may result in profound sedation, respiratory depression, coma, and death.

  • Reserve concomitant use for patients in whom alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy and monitor closely for respiratory depression and sedation. (See Specific Drugs under Interactions.)

Introduction

Anticonvulsant that also demonstrates anxiolytic properties; a 1,5-benzodiazepine.

Uses for Clobazam

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Seizure Disorders

Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients ≥2 years of age. Designated an orphan drug by FDA for use in this condition.

Also has been used as adjunctive therapy in many other seizure disorders, sometimes refractory, including partial, generalized, and myoclonic seizures. Has been used with some success in partial onset seizures; additional studies needed to more clearly determine role in the adjunctive treatment of other refractory seizure disorders.

Has been used in the treatment of seizures associated with Dravet syndrome. Although evidence from controlled studies limited, considered a first-line therapy for this condition.

Anxiety Disorders

Has been used for short-term (2–4 weeks) treatment of anxiety disorders in some countries outside the US. Currently not FDA-labeled for the treatment of anxiety disorders in the US.

Clobazam Dosage and Administration

General

  • Withdraw gradually to minimize potential for increased seizure frequency and status epilepticus. (See Dosage under Dosage and Administration and also see Discontinuance of Therapy under Cautions.)

  • Closely monitor for emergence or worsening of suicidal thoughts or behavior or depression. (See Suicidality Risk under Cautions.)

Administration

Oral Administration

Administer orally as tablets, oral suspension, or oral film. Administer daily dosages >5 mg in divided doses twice daily; may administer 5-mg daily dosage as a single daily dose.

May administer with or without food.

Tablets

Administer tablets whole, broken in half, or crushed and mixed in applesauce.

Oral Suspension

Shake oral suspension well prior to administration. Administer using bottle adapter and calibrated oral dosing syringe supplied by manufacturer. Firmly insert bottle adapter into neck of bottle before first use and keep in place for duration of use (up to 90 days). To dispense dose, insert oral dosing syringe into adapter, then invert bottle and withdraw appropriate dose into syringe. Administer dose slowly and directly into corner of patient's mouth.

Oral Film

Place oral film on the surface of tongue and allow to dissolve completely. Do not administer with liquids. As film dissolves, swallow saliva in a normal manner; avoid chewing, spitting, or talking. Only one oral film should be taken at a time; if a second film is needed to complete the dose, take after first film has completely dissolved.

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Pediatric Patients

Seizure Disorders
Adjunctive Therapy in Lennox-Gastaut Syndrome
Oral

Individualize dosage based on patient response and tolerability. Although all recommended dosages have demonstrated efficacy, efficacy is dose related; titrate to maximum tolerability until adequate seizure control attained. Increase dosage no more frequently than once a week to allow sufficient time for steady-state concentrations to be achieved at each dosage level.

Children ≥2 years of age weighing ≤30 kg: Initially, 5 mg daily as a single daily dose. May increase to 10 mg daily (in 2 divided doses) after 7 days, and to recommended maximum of 20 mg daily (in 2 divided doses) after an additional 7 days if clinically indicated and tolerated.

Children ≥2 years of age weighing >30 kg: Initially, 10 mg daily in 2 divided doses. May increase to 20 mg daily (in 2 divided doses) after 7 days, and to recommended maximum of 40 mg daily (in 2 divided doses) after an additional 7 days if clinically indicated and tolerated.

Reduce dosage gradually (by decreasing total daily dosage by 5–10 mg at weekly intervals) when discontinuing therapy. (See Discontinuance of Therapy under Cautions.)

Seizures Associated with Dravet Syndrome†
Oral

Initial dosages of 0.2–0.3 mg/kg daily (in 2 divided doses) with target daily dosages of 0.5–2 mg/kg (in 2 divided doses) have been used.

Adults

Seizure Disorders
Adjunctive Therapy in Lennox-Gastaut Syndrome
Oral

Individualize dosage based on patient response and tolerability. Although all recommended dosages have demonstrated efficacy, efficacy is dose related; titrate to maximum tolerability until adequate seizure control attained. Increase dosage no more frequently than once a week to allow sufficient time for steady-state concentrations to be achieved at each dosage level.

Patients weighing ≤30 kg: Initially, 5 mg daily as a single daily dose. May increase to 10 mg daily (in 2 divided doses) after 7 days, and to recommended maximum of 20 mg daily (in 2 divided doses) after an additional 7 days if clinically indicated and tolerated.

Patients weighing >30 kg: Initially, 10 mg daily in 2 divided doses. May increase to 20 mg daily (in 2 divided doses) after 7 days, and to recommended maximum of 40 mg daily (in 2 divided doses) after an additional 7 days if clinically indicated and tolerated.

Reduce dosage gradually (by decreasing total daily dosage by 5–10 mg at weekly intervals) when discontinuing therapy. (See Discontinuance of Therapy under Cautions.)

Seizures Associated with Dravet Syndrome†
Oral

Initial dosages of 0.2–0.3 mg/kg daily (in 2 divided doses) with target daily dosages of 0.5–2 mg/kg (in 2 divided doses) have been used.

Anxiety Disorders†
Short-term Treatment of Severe, Disabling, or Intolerable Anxiety†
Oral

Usual dosage: 20–30 mg daily in divided doses or as a single dose in the evening. Dosages of up to 60 mg daily have been used for severe anxiety in hospitalized patients.

Prescribing Limits

Pediatric Patients

Seizure Disorders
Adjunctive Therapy in Lennox-Gastaut Syndrome
Oral

Children ≥2 years of age: Maximum 20 mg daily in those weighing ≤30 kg and 40 mg daily in those weighing >30 kg.

Adults

Seizure Disorders
Adjunctive Therapy in Lennox-Gastaut Syndrome
Oral

Maximum 20 mg daily in those weighing ≤30 kg and 40 mg daily in those weighing >30 kg.

Special Populations

Hepatic Impairment

Adjunctive Therapy in Lennox-Gastaut Syndrome

Limited pharmacokinetic data; titrate dosage slowly.

Mild to moderate hepatic impairment (Child-Pugh class A or B): Initially, 5 mg daily regardless of body weight. Subsequently titrate dosage according to weight, but to half of the usual recommended dosage as tolerated. May initiate an additional titration to maximum dosage of 20 mg daily (in patients weighing ≤30 kg) or 40 mg daily (in patients weighing >30 kg) at 3 weeks if necessary and based on clinical response. (See Hepatic Impairment under Cautions.)

Severe hepatic impairment (Child-Pugh class C): Data currently insufficient to make dosage recommendations.

Renal Impairment

Adjunctive Therapy in Lennox-Gastaut Syndrome

Mild or moderate renal impairment (Clcr 30–80 mL/minute): No dosage adjustment necessary.

Severe renal impairment or end-stage renal disease: Not systematically evaluated. (See Renal Impairment under Cautions.)

Geriatric Patients

Adjunctive Therapy in Lennox-Gastaut Syndrome

Initially, 5 mg daily regardless of body weight. Subsequently titrate dosage slowly according to weight, but to half of the usual recommended dosage as tolerated. May initiate an additional titration to maximum dosage of 20 mg daily (in patients weighing ≤30 kg) or 40 mg daily (in patients weighing >30 kg) at 3 weeks if necessary and based on clinical response. (See Geriatric Use under Cautions.)

Pharmacogenomic Considerations

Adjunctive Therapy in Lennox-Gastaut Syndrome

Initially, 5 mg daily regardless of body weight. (See CYP2C19 Poor Metabolizers under Cautions.) Subsequently titrate dosage slowly according to weight, but to half of the usual recommended dosage as tolerated. May initiate an additional titration to maximum dosage of 20 mg daily (in patients weighing ≤30 kg) or 40 mg daily (in patients weighing >30 kg) at 3 weeks if necessary and based on clinical response.

Cautions for Clobazam

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Known hypersensitivity to clobazam or any ingredient in the formulation. (See Serious Dermatologic Reactions under Cautions.)

Warnings/Precautions

Warnings

Concomitant Use with Opiates

Concomitant use of benzodiazepines, including clobazam, and opiates may result in profound sedation, respiratory depression, coma, and death. Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.

Reserve concomitant use of clobazam and opiates for patients in whom alternative treatment options are inadequate. (See Specific Drugs under Interactions.)

Other Warnings and Precautions

Concomitant Use of CNS Depressants

Risk of potentiated CNS depressant effects. (See Concomitant Use with Opiates and also Somnolence and Sedation under Cautions.)

Somnolence and Sedation

Somnolence and sedation commonly occur. Generally occur within first month of treatment and may diminish with continued therapy. Observed at all clinically effective dosages and appear to be dose related.

Monitor for somnolence and sedation, particularly during concomitant use of other CNS depressants (e.g., alcohol, opiate agonists, tricyclic antidepressants [TCAs], sedating antihistamines, other benzodiazepines).

Discontinuance of Therapy

Avoid abrupt discontinuance and rapid dosage reduction to minimize the risk of precipitating or exacerbating seizures and status epilepticus.

Withdrawal symptoms (e.g., convulsions, psychosis, hallucinations, behavioral disorders, tremor, anxiety, irritability, dysphoria, insomnia, headache, palpitations, diarrhea) also can occur following abrupt discontinuance; risk of withdrawal symptoms is greater with increasing dosage and duration of treatment.

When discontinuing therapy, decrease dosage gradually (i.e., by 5–10 mg daily at weekly intervals).

Serious Dermatologic Reactions

Serious and sometimes life-threatening dermatologic reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), reported rarely in pediatric and adult patients during postmarketing experience worldwide. May occur at any time during therapy, but risk is greater during first 8 weeks of therapy or when clobazam is discontinued and then reinitiated. Hospitalization was required in all cases; one case resulted in blindness and at least one death occurred.

Closely monitor patients for signs and symptoms of SJS and TEN, particularly during the initial 8 weeks of treatment or when reinitiating therapy. Discontinue therapy at the first sign of a rash unless clearly not drug related (see Discontinuance of Therapy under Cautions); if manifestations suggest SJS or TEN, do not reinitiate clobazam and consider alternative therapies. When switching from one anticonvulsant to another, consider that other anticonvulsants also may be associated with serious dermatologic reactions.

Physical and Psychological Dependence

Possible physical and/or psychological dependence. While the risk is greater with increasing dosage and duration of therapy, some patients can become physically or psychologically dependent even with short-term use (i.e., a few weeks) at recommended dosages.

As with all benzodiazepines, tolerance to the therapeutic effects of clobazam reported, and may be a concern with long-term use.

Carefully monitor patients with a history of substance abuse because of their predisposition to habituation and dependence.

Avoid abrupt discontinuance or rapid dosage reduction, which can precipitate withdrawal symptoms in patients with physical dependence. (See Discontinuance of Therapy under Cautions.)

Suicidality Risk

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%). Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks. Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.

Balance risk of suicidality with risk of untreated illness. Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality. If suicidal thoughts or behavior emerges during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself. (See Advice to Patients.)

Abuse Potential

Abuse potential expected to be similar to that of other benzodiazepines (e.g., diazepam).

Specific Populations

Pregnancy

North American Antiepileptic Drug (NAAED) Pregnancy Registry (for patients or caregivers) at 888-233-2334 or [Web].

No adequate data in pregnant women. Based on animal data, may cause fetal harm. Use during pregnancy only if potential benefits justify potential risks to the fetus.

Possible dependence and subsequent withdrawal syndrome, ranging from mild to severe, in neonates exposed to benzodiazepines during the second and third trimesters. Manifestations include hypertonia, hyperreflexia, hypoventilation, irritability, tremors, diarrhea, or vomiting, and appear shortly after delivery or up to 3 weeks after birth, and can persist from hours to several months. Observe neonates for symptoms of withdrawal and manage as clinically appropriate.

Floppy infant syndrome reported in neonates exposed to benzodiazepines immediately prior to or during birth; symptoms include lethargy, hypothermia, hypotonia, respiratory depression, and difficulty feeding. Occurs mainly within the first hours after birth and may last up to 14 days. Observe neonates for symptoms and manage as clinically appropriate.

Lactation

Clobazam and its active metabolite are distributed into human milk; effects on milk production or the breast-fed infant not known. Consider benefits of breast-feeding and importance of clobazam to the woman; also consider potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Monitor infants exposed to clobazam through breast milk for potential adverse reactions; lethargy, somnolence, and poor sucking reported in breast-fed infants whose mothers were taking benzodiazepines.

Fertility

May impair fertility, based on studies in male and female rats.

Pediatric Use

Safety and efficacy not established in pediatric patients <2 years of age.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.

Because of the possibility of decreased clearance in geriatric patients, initiate therapy with a low dosage and titrate slowly. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Extensively metabolized by the liver; however, effects of hepatic impairment on pharmacokinetics of clobazam not fully characterized.

Initiate therapy at 5 mg daily (regardless of patient weight) and titrate slowly in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Insufficient information in patients with severe hepatic impairment. (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Systemic exposure to clobazam or its active metabolite not substantially altered in patients with mild (Clcr >50–80 mL/minute) or moderate (Clcr 30–50 mL/minute) renal impairment. No experience in patients with severe renal impairment or end-stage renal disease.

Not known whether clobazam or its active N-desmethylclobazam metabolite is dialyzable. (See Renal Impairment under Dosage and Administration and also see Absorption: Special Populations, under Pharmacokinetics.)

CYP2C19 Poor Metabolizers

Genetic polymorphism of CYP2C19 can affect pharmacokinetic and pharmacodynamic response to clobazam. CYP2C19 is the principal enzyme involved in the metabolism of N-desmethylclobazam, the pharmacologically active metabolite of clobazam. Plasma concentrations of N-desmethylclobazam are higher in poor CYP2C19 metabolizers compared with extensive CYP2C19 metabolizers.

Dosage adjustment is necessary in known poor CYP2C19 metabolizers. (See Pharmacogenomic Considerations under Dosage and Administration.)

Common Adverse Effects

Adverse effects generally similar to those observed with other benzodiazepines.

Somnolence or sedation, lethargy, drooling, vomiting, constipation, dysphagia, decreased or increased appetite, cough, upper respiratory tract infection, pneumonia, bronchitis, urinary tract infection, aggression, insomnia, irritability, ataxia, psychomotor hyperactivity, dysarthria, pyrexia, fatigue.

Interactions for Clobazam

Metabolized principally by CYP3A4, and to a lesser extent by CYP2C19 and CYP2B6. Clobazam's active metabolite, N-desmethylclobazam, is metabolized principally by CYP2C19.

Clobazam and N-desmethylclobazam induce CYP3A4 in a concentration-dependent manner; N-desmethylclobazam also is a weak inhibitor of CYP2C9. Clobazam also appears to inhibit CYP2D6.

Does not inhibit CYP1A2, 2C8, 2C9, 2C19, and 3A4 nor substantially induce CYP1A2 and CYP2C19 in vitro.

Clobazam does not inhibit uridine diphosphate-glucuronosyltransferase (UGT) 1A1, 1A4, 1A6, or 2B4 in vitro. N-desmethylclobazam is a weak inhibitor of UGT 1A4, 1A6, and 2B4.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP2D6 substrates: Potential pharmacokinetic interaction (increased plasma concentrations of substrate); dosage adjustment of drugs metabolized by CYP2D6 may be necessary.

CYP3A4 substrates: Potential pharmacokinetic interaction (decreased plasma concentrations of substrate); however, manufacturer states dosage adjustment of drugs principally metabolized by CYP3A4 not necessary.

CYP1A2 substrates: Pharmacokinetic interaction not likely.

CYP2C9 substrates: Pharmacokinetic interaction not likely.

Drugs Affecting Hepatic Microsomal Enzymes

Potent or moderate CYP2C19 inhibitors: Potential pharmacokinetic interaction (increased exposure to N-desmethylclobazam and possible toxicity); clobazam dosage adjustment may be necessary.

Potent CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased exposure to clobazam).

Specific Drugs

Drug

Interaction

Comments

Alcohol

Increased maximum plasma exposure of clobazam by approximately 50%; pharmacokinetics of alcohol not altered

Possible potentiation of CNS depressant effects

Avoid concomitant use

Cannabidiol

Increased risk of hepatic enzyme elevations

Increased peak plasma concentrations and AUC of N-desmethylclobazam by approximately threefold; may increase risk of clobazam-related adverse reactions

Increased peak plasma concentrations and AUC of active cannabidiol metabolite

If hepatic enzyme elevations occur, consider dosage reduction or discontinuance of clobazam

Consider dosage reduction of clobazam if adverse reactions occur during concomitant use

Carbamazepine

Population pharmacokinetic analysis suggests steady-state pharmacokinetics of clobazam and N-desmethylclobazam not substantially altered; however, decreased clobazam and increased N-desmethylclobazam concentrations observed in some studies

Possible increased metabolism of carbamazepine

Cimetidine

Increased AUC and prolonged half-life of clobazam; no substantial effect on peak plasma concentrations of clobazam; plasma concentrations of N-desmethylclobazam not substantially affected

Pharmacokinetic changes unlikely to be clinically important

CNS depressants (e.g., TCAs, sedating antihistamines, other benzodiazepines)

Possible additive CNS effects (e.g., somnolence, sedation)

Generally avoid concomitant use

Contraceptives, hormonal

Possible reduced efficacy of some hormonal contraceptives

Additional nonhormonal contraceptive methods recommended during clobazam therapy and for 28 days following discontinuance

Dextromethorphan

Increased peak plasma concentrations and AUC of dextromethorphan

Dosage adjustment of dextromethorphan may be necessary

Felbamate

Population pharmacokinetic analysis suggests steady-state pharmacokinetics of clobazam and N-desmethylclobazam not substantially altered; however, increased N-desmethylclobazam concentrations observed in some studies

Fluconazole

Possible increased exposure to N-desmethylclobazam

Clobazam dosage adjustment may be necessary

Ketoconazole

Increased AUC of clobazam with no substantial alterations in peak plasma concentrations of the drug; no substantial change in pharmacokinetics of N-desmethylclobazam

Clinically important effects not expected

Lamotrigine

Population pharmacokinetic analysis indicates exposure to lamotrigine unaffected

Midazolam

Decreased AUC of midazolam and its 1-hydroxymidazolam metabolite

Dosage adjustment not necessary

Omeprazole

Increased AUC and peak plasma concentrations of N-desmethylclobazam; pharmacokinetics of clobazam not substantially affected

Clinically important effects not observed

Clobazam dosage adjustment may be necessary

Opiate agonists and partial agonists

Risk of profound sedation, respiratory depression, coma, or death

Whenever possible, avoid concomitant use

Opiate analgesics: Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression and sedation

In patients receiving clobazam, initiate opiate analgesic, if required, at reduced dosage and titrate based on clinical response

In patients receiving an opiate analgesic, initiate clobazam, if required for any indication other than epilepsy, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response

Opiate antitussives: Avoid concomitant use

Consider offering naloxone to patients receiving benzodiazepines and opiates concomitantly

Oxcarbazepine

Population pharmacokinetic analysis suggests steady-state pharmacokinetics of clobazam and N-desmethylclobazam not substantially altered

Phenobarbital

Population pharmacokinetic analysis suggests steady-state pharmacokinetics of clobazam and N-desmethylclobazam not substantially altered; however, decreased clobazam and increased N-desmethylclobazam concentrations observed in some studies

Phenytoin

Population pharmacokinetic analysis suggests steady-state pharmacokinetics of clobazam and N-desmethylclobazam not substantially altered; however, decreased clobazam and increased N-desmethylclobazam concentrations observed in some studies

SSRIs (fluoxetine, fluvoxamine, paroxetine)

Possible increased plasma concentrations of SSRIs metabolized by CYP2D6 (e.g., fluoxetine, paroxetine)

Fluvoxamine (a potent CYP2C19 inhibitor): Possible increased exposure to N-desmethylclobazam

Dosage adjustment of SSRIs metabolized by CYP2D6 (e.g., fluoxetine, paroxetine) may be necessary

Fluvoxamine: Clobazam dosage adjustment may be necessary

Stiripentol

Increased plasma concentrations of clobazam and N-desmethylclobazam; may increase risk of clobazam-related adverse reactions

If somnolence occurs, consider initial 25% reduction in dosage of clobazam

If somnolence persists, consider additional 25% reduction in dosage of clobazam along with adjustments to other concomitant anticonvulsants that can cause sedation

Ticlopidine

Possible increased exposure to N-desmethylclobazam

Clobazam dosage adjustment may be necessary

Tolbutamide

No clinically important interaction observed

Valproic acid

Some studies have shown no substantial interaction; others suggest clobazam may inhibit metabolism of valproic acid

Clobazam Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed following oral administration; peak plasma concentrations achieved within 0.5–4 hours after single- or multiple-dose administration of clobazam tablets under fasting conditions. Peak plasma concentrations achieved within 0.5–2 hours following single-dose administration of the oral suspension under fasting conditions.

Bioavailability of oral suspension similar to that of tablets under fasting conditions. Oral films and tablets are bioequivalent following administration of single doses of 10 or 20 mg.

Median time to disintegration of oral film following placement on tongue is 82 seconds (range 18–245 seconds) for the 10-mg film and 105 seconds (range: 45–300 seconds) for the 20-mg film.

At therapeutic dosages, plasma concentrations of N-desmethylclobazam (an active metabolite) are approximately 3–5 times higher than those of clobazam.

Food

Food does not appear to substantially affect absorption from tablets; although not evaluated, food also unlikely to affect bioavailability of the oral suspension or oral film.

Special Populations

Limited data indicate no substantial pharmacokinetic differences between patients with hepatic impairment and healthy individuals.

No substantial pharmacokinetic differences between patients with mild (Clcr >50–80 mL/minute) or moderate (Clcr 30–50 mL/minute) renal impairment and those with normal renal function. Not known if clobazam or N-desmethylclobazam is dialyzable; limited evidence suggests clobazam concentrations are unaffected by hemodialysis.

Systemic exposure to N-desmethylclobazam is approximately 3–5 times higher in poor CYP2C19 metabolizers and approximately 2 times higher in intermediate CYP2C19 metabolizers than in extensive CYP2C19 metabolizers (See CYP2C19 Poor Metabolizers under Cautions.)

Distribution

Extent

Highly lipophilic and distributes rapidly throughout the body.

Crosses the blood-brain barrier.

Distributes into human milk.

Plasma Protein Binding

Clobazam: Approximately 80–90%.

N-desmethylclobazam: Approximately 70%.

Elimination

Metabolism

Extensively metabolized in liver, primarily via N-demethylation (principally by CYP3A4 and, to a lesser extent, by CYP2C19 and CYP2B6) to pharmacologically active metabolite, N-desmethylclobazam. Potency of N-desmethylclobazam may be similar to or somewhat less than parent drug; therefore, active metabolite may contribute to efficacy and safety.

N-Desmethylclobazam is further metabolized by CYP2C19 to an inactive derivative.

Metabolism is subject to genetic polymorphism of CYP2C19. (See Actions.)

Elimination Route

Eliminated mainly in urine (82%) as metabolites; only about 2% of dose is excreted as unchanged drug.

Half-life

Approximately 36–42 hours for clobazam and 71–82 hours for N-desmethylclobazam.

Special Populations

Some data suggest that clobazam may be more rapidly and extensively metabolized in children than in adults.

Decreased clearance observed in geriatric patients compared with younger age groups (ages 2–64).

Stability

Storage

Oral

Oral Film

20–25°C (may be exposed to 15–30°C).

Tablets

20–25°C.

Suspension

20–25°C. Store bottle in upright position; use within 90 days of opening.

Actions

  • 1,5-benzodiazepine with anticonvulsant and anxiolytic properties.

  • Exact mechanism of anticonvulsant and anxiolytic actions unknown, but thought to involve allosteric binding of clobazam to the benzodiazepine site of the GABA type A (GABAA) receptor, which in turn potentiates the inhibitory effects of GABA.

  • Structurally similar to the 1,4-benzodiazepines (e.g., clonazepam, diazepam, lorazepam), but appears to have a broader spectrum of anticonvulsant activity and an improved adverse effect profile (e.g., less sedative effects).

  • Metabolism of the drug is subject to genetic polymorphism of CYP2C19. Individuals with the CYP2C19*2/*2 genotype are described as poor metabolizers; those with the CYP2C19*1/*2 genotype are intermediate metabolizers, and those with CYP2C19*1/*1 are extensive metabolizers. Prevalence of poor CYP2C19 metabolizers in general population varies based on ethnic and racial background.

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of providing patient or caregiver with copy of written patient information (medication guide) each time clobazam is dispensed. Importance of advising patients or caregivers to read the medication guide before start of therapy and each time the prescription is refilled.

  • Importance of taking clobazam only as prescribed.

  • Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with opiates either therapeutically or illicitly. Avoid concomitant use of opiate antitussives; also avoid concomitant use of opiate analgesics unless use is supervised by clinician.

  • Risk of potentiated CNS depression with concurrent use of alcohol or other CNS depressants. Advise patients or caregivers to avoid concomitant use of alcohol and to check with their clinician before using clobazam concomitantly with other CNS depressants (e.g., other benzodiazepines, TCAs, sedating antihistamines).

  • Risk of somnolence or sedation. Caution patients against driving or operating hazardous machinery until they are reasonably certain that clobazam does not adversely affect their judgment, thinking, or motor skills.

  • Risk of rare but serious skin reactions, including SJS and TEN. Advise patient or caregivers to seek immediate medical attention at first appearance of a skin rash or other signs of hypersensitivity (e.g., blistering or peeling of skin, mouth sores, hives) while receiving clobazam. Drug discontinuance may be required; advise patients or caregivers not to discontinue without first consulting with their clinician.

  • Risk of suicidality (anticonvulsants, including clobazam, may increase risk of suicidal thoughts or actions in about 1 in 500 people). Importance of patients, family members, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).

  • Importance of advising patients or caregivers to consult their clinician before increasing or decreasing the dosage or abruptly discontinuing the drug. Sudden discontinuance can cause serious problems (e.g., increased risk of seizures, withdrawal symptoms).

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of clinicians informing women about the existence of and encouraging enrollment in the pregnancy registry (see Pregnancy under Cautions).

  • Importance of informing women that clobazam may cause some hormonal contraceptives (e.g., oral contraceptives, patches, rings, implants, injections, intrauterine devices) to be less effective; importance of advising women to use additional nonhormonal forms of contraception during clobazam therapy and for 28 days after discontinuance of the drug.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., kidney or liver disease, respiratory problems, depression or other mood disorders).

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

cloBAZam

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Oral film

5 mg

Sympazan (C-IV)

Aquestive

10 mg

Sympazan (C-IV)

Aquestive

20 mg

Sympazan (C-IV)

Aquestive

Suspension

2.5 mg/mL*

Clobazam Oral Suspension

Onfi (C-IV)

Lundbeck

Tablets

10 mg*

Clobazam Oral Suspension

Onfi (C-IV; scored)

Lundbeck

20 mg*

Clobazam Oral Suspension

Onfi (C-IV; scored)

Lundbeck

AHFS DI Essentials™. © Copyright 2021, Selected Revisions November 23, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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