AHFS Class:

• Benzodiazepines 28:12.08

Generic Name(s):

• cloBAZam

Clobazam, a 1,5-benzodiazepine, is an anticonvulsant that also demonstrates anxiolytic properties.1,2,3,6,7,9,14,19,34,36,44

Seizure Disorders

Seizures Associated with Lennox-Gastaut Syndrome

Clobazam is used for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older.1,2,3,5,6,9,17,19,22,36,49 The drug has been designated an orphan drug by FDA for use in this condition.5,9,19

Lennox-Gastaut syndrome is a rare and severe type of childhood epilepsy that is characterized by a classic triad of manifestations including multiple seizure types, an EEG pattern of slow spike and wave activity, and cognitive impairment; many patients also develop comorbid behavioral and psychiatric disorders.6,7,8,9,15,16,18,19,36 Tonic and atypical absence seizures are the most common types of seizures in Lennox-Gastaut syndrome; at least 50% of patients experience sudden tonic or atonic falls (drop seizures; also known as “drop attacks”), which can result in substantial injury.7,8,15,16,18,20,36

Management of Lennox-Gastaut syndrome can be difficult given the multiple seizure types that can occur and the refractory nature of the condition.7,8,9,15,16,18,19,20 Although several drugs (e.g., clobazam, clonazepam, felbamate, lamotrigine, levetiracetam†, rufinamide, topiramate, valproic acid, zonisamide†) have been used to treat Lennox-Gastaut syndrome,1,2,3,6,7,8,9,15,18,19,20,21,22,35 no single anticonvulsant has been shown to be completely effective in controlling seizures and a combination of anticonvulsant agents often is required.3,7,9,15,19,36 When selecting an appropriate regimen, clinicians should consider anticonvulsant combinations that maximize seizure control and improve quality of life while minimizing adverse effects and potential drug interactions; treatment should be individualized based on the expected benefits and risks of each therapy.3,6,7,8,15,18

Efficacy and safety of adjunctive clobazam therapy in patients with Lennox-Gastaut syndrome have been established in 2 randomized, multicenter, double-blind studies.1,2,3 Patients younger than 11 years of age at the onset of Lennox-Gastaut syndrome were included in these studies; valproic acid, lamotrigine, levetiracetam, and topiramate were the most commonly used anticonvulsant agents at baseline.1,2,3 Both studies consisted of a 4-week baseline period followed by a 3-week titration period and then a 12- or 4-week maintenance period; at the end of the double-blind treatment periods, patients either discontinued therapy or continued into open-label extensions of the studies.1,2,3,17 Efficacy of clobazam was evaluated principally by the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic) from the 4-week baseline period to the maintenance period of each study.1,2,3

In the first study (CONTAIN trial), a total of 238 pediatric and adult patients (age range: 2-54 years) were stratified into 2 groups by weight (12.5-30 kg or more than 30 kg) and then randomized to receive adjunctive therapy with placebo or one of 3 target maintenance dosages of clobazam: low dosage (5 mg daily in those weighing up to 30 kg or 10 mg daily in those weighing more than 30 kg), medium dosage (10 mg daily in those weighing up to 30 kg or 20 mg daily in those weighing more than 30 kg), or high dosage (20 mg daily in those weighing up to 30 kg or 40 mg daily in those weighing more than 30 kg).1,2 A substantial reduction in the weekly drop seizure rate from baseline to the 12-week maintenance period was observed in patients receiving clobazam in all dosage groups (mean reduction of approximately 41, 49, and 68% for the low-, medium-, and high-dosage groups, respectively) compared with those receiving placebo (approximately 12%); this effect appeared to be dose dependent.1,2 The average weekly rate of total (drop and nondrop) seizures, a secondary efficacy end point, also was reduced with clobazam in a dose-dependent manner.2 In addition, the responder rate (percentage of patients with a 50% or greater decrease from baseline to maintenance period in average weekly rate of drop seizures) was approximately 32% for the placebo group compared with approximately 43, 59, and 78% for the low-, medium-, and high-dosage clobazam groups, respectively.2 Patients who received clobazam also had improved symptoms (based on investigator- and caregiver-rated global evaluation scores) compared with those who received placebo.2

The second study was a dose comparison study; in this study, 68 patients (age range: 2-25 years) were stratified by weight (12.5-30 kg or more than 30 kg) and then randomized to receive adjunctive therapy with either a low clobazam dosage (5 mg daily in those weighing up to 30 kg or 10 mg daily in those weighing more than 30 kg) or a high clobazam dosage (20 mg daily in those weighing up to 30 kg or 40 mg daily in those weighing more than 30 kg).1,3 The average weekly rate of drop seizures was substantially reduced from baseline to the 4-week maintenance period in both dosage groups; however, the reduction was substantially greater with the higher versus the lower dosage (median reductions of 93 versus 29%, respectively).1,3 The rate of nondrop seizures, a secondary measure of efficacy, also was reduced with clobazam treatment in a dose-dependent manner.3 In addition, patients who received high-dosage clobazam had greater improvements in overall symptoms (based on investigator and parent/caregiver global evaluation scores) compared with those who received the low-dosage regimen.3

Tolerance to the therapeutic effects of benzodiazepines, including clobazam, may develop over time and result in partial or complete loss of anticonvulsant activity.19,23,24,25,26,31,41 To evaluate the potential for tolerance with clobazam, seizure frequencies were assessed during the initial, middle, and last 4 weeks of the maintenance period in the placebo-controlled efficacy study of the drug in patients with Lennox-Gastaut syndrome.13 The anticonvulsant effects of clobazam generally persisted during each of the time periods suggesting that substantial tolerance to clobazam does not develop, at least for the 3-month maintenance period that was studied.1,13,19 In addition, clobazam was shown to maintain clinical benefit for up to 2 years in the long-term, open-label extension of the 2 principal efficacy studies of the drug.17 In a preliminary analysis of those results, patients who continued to receive up to 2 years of clobazam therapy had median reductions in drop seizure frequency of 71.1% at 3 months and 91.6% at 24 months; dosage requirements generally were similar across various durations of treatment.17

Seizures Associated with Dravet Syndrome

Clobazam has been used in the treatment of seizures associated with Dravet syndrome† (also known as severe myoclonic epilepsy of infancy), a rare and severe type of epilepsy characterized by early onset of multiple refractory seizure types, frequent episodes of status epilepticus, and developmental delay with cognitive and psychomotor impairment.310,311,312,314 Although evidence from controlled studies is limited,311,314,315,316 experts generally recommend initial treatment with either clobazam† or valproic acid†, followed by a combination of both drugs; however, adequate seizure control is rarely achieved with these drugs alone, and most patients will require additional anticonvulsant agents.310,311,312,314 For additional information about Dravet syndrome, see Dravet Syndrome under Uses: Epilepsy Syndromes, in the Anticonvulsants General Statement 28:12.

Other Seizure Disorders

Clobazam has demonstrated broad anticonvulsant activity and has been used extensively in adults and pediatric patients with a wide range of other seizure disorders, which have sometimes been refractory, including partial, generalized, and myoclonic seizures†.6,13,14,23,24,25,26,41,44 In several randomized controlled trials, clobazam, when used as adjunctive therapy, reduced the frequency of refractory seizures and was particularly useful in patients with partial onset seizures.14,24 However, these were short-term trials and were substantially different in terms of their study design and methodology, making it difficult to determine the practical implications of these findings.14,24 Additional studies, including large-scale randomized studies of longer duration, are needed to more clearly determine the role of clobazam in the adjunctive treatment of other refractory seizure disorders.14

Anxiety Disorders

Clobazam has been used in the treatment of anxiety disorders† and has been labeled for the short-term (2-4 weeks) treatment of anxiety in some countries outside the US.6,13,36,42,44 However, the drug currently is not FDA-labeled for the treatment of anxiety disorders in the US.1

Administration

Clobazam is administered orally as tablets, oral suspension, or oral film without regard to meals.1,49 Daily dosages greater than 5 mg should be administered in divided doses twice daily; the 5-mg daily dosage can be administered as a single daily dose.1,19

Clobazam therapy should be withdrawn gradually (i.e., by tapering the daily dosage by 5-10 mg every week) to minimize the risk of precipitating or exacerbating seizures, status epilepticus, or withdrawal symptoms.1,4,49

Patients currently receiving or beginning therapy with clobazam and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.1,4

Tablets

Clobazam tablets may be swallowed whole, broken in half, or crushed and mixed in applesauce.1

Oral Suspension

Clobazam oral suspension should be shaken well prior to administration.1 The bottle adapter and calibrated oral dosing syringe supplied by the manufacturer should be used to administer the suspension.1 The adapter should be inserted firmly into the neck of the bottle before first use and should remain in place as long as the bottle is in use (up to 90 days).1 A dose is dispensed by inserting the oral dosing syringe into the adapter, and then inverting the bottle and slowly withdrawing the appropriate dose into the syringe.1 The dose should then be slowly administered directly into the corner of the patient's mouth.1

Oral Film

Clobazam oral film should be placed on the surface of the tongue and allowed to dissolve completely (median time to disintegration 82-105 seconds; see Description);49,50 the oral film should not be administered with liquids.49 As the film dissolves, saliva should be swallowed naturally; chewing, spitting, or talking should be avoided.49 Only one film should be administered at a time; if a second film is needed for the complete dose, it should not be taken until the first film has completely dissolved.49

Dosage

Seizures Associated with Lennox-Gastaut Syndrome

For the adjunctive treatment of Lennox-Gastaut syndrome in adults and children 2 years of age or older, clobazam dosage should be based on patient body weight.1,49 Within each body weight group, the dosage should be individualized based on clinical response and tolerability (see Table 1).1,49 Although each dosage in Table 1 has been shown to be effective, the clinical efficacy of clobazam is dose related and increases with increasing dosage.1,2,3,13,49 Clobazam dosage should therefore be titrated to maximum tolerability until adequate seizure control is attained; in some patients, this may be achieved with less than the recommended total daily dosage.13,49 Dosage should not be increased more frequently than once weekly to allow sufficient time for steady-state concentrations of the drug and its active metabolite to be achieved.1,49

Seizures Associated with Dravet Syndrome

For the treatment of seizures associated with Dravet syndrome†, initial clobazam dosages of 0.2-0.3 mg/kg daily (given in 2 divided doses) with target daily dosages of 0.5-2 mg/kg (given in 2 divided doses) have been used.311,314

Anxiety Disorders

For the short-term (2-4 weeks) relief of anxiety that is severe, disabling, or causes unacceptable distress†, the usual dosage of clobazam is 20-30 mg daily given either in divided doses or as a single daily dose in the evening.44 Dosages of up to 60 mg daily have been used in the treatment of severe anxiety in hospitalized patients.44

Special Populations

Dosage in Patients with Hepatic Impairment

Because of limited pharmacokinetic data, the manufacturers recommend slow titration of clobazam dosage in patients with hepatic impairment.1,49 For patients with mild to moderate hepatic impairment (Child-Pugh class A or B), an initial clobazam dosage of 5 mg daily is recommended regardless of body weight.1,49 Dosage should be titrated slowly according to weight, but to half of the recommended dosage presented in Table 1 as tolerated.1,49 If necessary and based on clinical response, an additional titration to the maximum recommended dosage of 20 mg daily (in patients weighing 30 kg or less) or 40 mg daily (in patients weighing more than 30 kg) may be initiated at 3 weeks.1,49 Data currently are insufficient to make specific dosage recommendations for patients with severe hepatic impairment (Child-Pugh class C).1,49

Dosage in Patients with Renal Impairment

Dosage adjustment is not required in patients with mild (creatinine clearance greater than 50-80 mL/minute) or moderate (creatinine clearance of 30-50 mL/minute) renal impairment.1,49 Clobazam has not been systematically evaluated in patients with severe renal impairment or end-stage renal disease.1,49 It is also not known if clobazam or its active N -desmethylclobazam metabolite is dialyzable;1,49 however, limited evidence suggests that clobazam concentrations are unaffected by hemodialysis.40

Dosage in Geriatric Patients

Because clobazam plasma concentrations at any given dosage are generally higher in geriatric patients, the manufacturers recommend slow dosage titration in such patients.1,49 All geriatric patients should receive an initial dosage of 5 mg daily regardless of their body weight.1,49 Dosage should then be titrated at weekly intervals according to weight, but to half of the recommended dosage presented in Table 1.1,49 If necessary and based on clinical response, an additional titration to the maximum dosage of 20 mg daily (in patients weighing 30 kg or less) or 40 mg daily (in patients weighing more than 30 kg) may be initiated at 3 weeks.1,49

Pharmacogenomic Considerations

Patients known to be poor metabolizers of cytochrome P-450 (CYP) 2C19 substrates should receive an initial clobazam dosage of 5 mg daily regardless of their body weight.1,49 Dosage should then be titrated slowly at weekly intervals according to weight, but to half of the recommended dosage presented in Table 1 as tolerated.1,49 If necessary and based on clinical response, an additional titration to the maximum dosage of 20 mg daily (in patients weighing 30 kg or less) or 40 mg daily (in patients weighing more than 30 kg) may be initiated at 3 weeks.1,49

Contraindications

Known hypersensitivity to clobazam or any ingredient in the formulation.1,49

Warnings/Precautions

Warnings

A boxed warning has been included in the prescribing information for all benzodiazepines describing the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions associated with all drugs in this class.900 Abuse and misuse can result in overdose or death, especially when benzodiazepines are combined with other medicines, such as opioid pain relievers, alcohol, or illicit drugs.900 Frequent follow-up with patients receiving benzodiazepines is important.900 Reassess patients regularly to manage their medical conditions and any withdrawal symptoms.900 Clinicians should assess a patient's risk of abuse, misuse, and addiction. 900 Standardized screening tools are available ([Web]).900 To reduce the risk of acute withdrawal reactions, use a gradual dose taper when reducing the dosage or discontinuing benzodiazepines.900 Take precautions when benzodiazepines are used in combination with opioid medications.900

Concomitant Use with Opiates

Concomitant use of benzodiazepines, including clobazam, and opiate agonists or opiate partial agonists may result in profound sedation, respiratory depression, coma, and death.1,49,700,701,703,705,706,707 Concomitant use of such drugs should be reserved for patients in whom alternative treatment options are inadequate; the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.1,49,700,703

Other Warnings and Precautions

Concomitant Use of CNS Depressants

Since clobazam has a CNS depressant effect, patients or their caregivers should be cautioned against concomitant use of other CNS depressant drugs or alcohol and cautioned that the effects of other CNS depressants or alcohol may be potentiated.1,4

Somnolence and Sedation

Somnolence and sedation are among the most common adverse effects associated with clobazam therapy.1,2,3,6,19 These effects generally begin within the first month of treatment and may diminish with continued therapy.1,6,19 In a placebo-controlled study of patients with Lennox-Gastaut syndrome, somnolence or sedation was reported in 26% of patients who received clobazam compared with 15% of those who received placebo.1 Somnolence and sedation were observed at all effective dosages and were dose related.1,2 The sedative effect of clobazam is reportedly less pronounced than that of other commercially available benzodiazepines.2,6,19,39

Patients should be monitored for somnolence and sedation during clobazam therapy, particularly if other CNS depressants (e.g., alcohol, opiate agonists, tricyclic antidepressants, sedating antihistamines, other benzodiazepines) are administered concomitantly.1

Discontinuance of Therapy

Abrupt discontinuance and rapid dosage reduction of clobazam should be avoided to minimize the risk of precipitating or exacerbating seizures, status epilepticus, and withdrawal symptoms.1 When therapy is discontinued, dosage of the drug should be decreased gradually (i.e., by 5-10 mg daily at weekly intervals).1,49

Withdrawal symptoms (e.g., convulsions, psychosis, hallucinations, behavioral disorders, tremor, anxiety, irritability, dysphoria, insomnia, headache, palpitations, diarrhea) have been reported following abrupt discontinuance of benzodiazepines, including clobazam; the risk of withdrawal symptoms is greater with increasing dosage and duration of treatment.1,36 Such withdrawal reactions occur in patients who have developed physical dependence on these drugs.1 More severe withdrawal symptoms usually are limited to patients who abruptly discontinue therapy after receiving excessive dosages of benzodiazepines for an extended period of time.1 Milder withdrawal symptoms (e.g., dysphoria, anxiety, insomnia) generally have been reported following abrupt discontinuance of benzodiazepines in patients continuously receiving therapeutic dosages for several months.1

Serious Dermatologic Reactions

Serious and sometimes life-threatening dermatologic reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported rarely in both pediatric patients and adults treated with clobazam during postmarketing experience worldwide.1,47,48 Although such reactions may occur at any time during clobazam therapy, the risk is greater during the first 8 weeks of therapy or when clobazam is discontinued and then reinitiated.47,48 TEN developed in skin areas exposed to sunlight in one published case.48 FDA states that, as of December 2013, 21 cases of SJS or TEN associated with clobazam were identified.47 Hospitalization was required in all of the patients; one case resulted in blindness and at least one death occurred.47 The majority of the patients were receiving concomitant therapy with other drugs associated with an increased risk of SJS and TEN (e.g., other anticonvulsant agents, beta-lactam antibiotics, sulfasalazine); however, the available evidence, including a close temporal relationship (within 2 months) between initiation of clobazam and development of the serious skin reaction in most cases, suggests that clobazam was the likely cause of the skin reactions.47 In addition, patients in many of the cases improved after clobazam was discontinued and, in some cases, despite continuing or reinitiating the other suspected medications.47

Patients receiving clobazam therapy should be closely monitored for signs and symptoms of SJS and TEN, particularly during the initial 8 weeks of treatment or when therapy with the drug is reinitiated.1,47 Clobazam should be discontinued at the first sign of a rash unless the rash is clearly not drug related.1,47 If clinical manifestations suggestive of SJS or TEN occur, clobazam therapy should not be resumed and alternative therapy should be considered.1,47 When switching from one anticonvulsant drug to another, clinicians should consider that other anticonvulsants also may be associated with a risk of serious dermatologic reactions.47

Physical and Psychological Dependence

Physical and/or psychological dependence may occur in patients receiving clobazam.1,36 While the risk of dependence is greater with increasing dosage and duration of therapy, some patients can become physically or psychologically dependent even with short-term use of the drug (i.e., a few weeks) at recommended dosages.1 The risk of dependence also is increased in patients with a history of alcohol or substance abuse.1 As with all benzodiazepines, tolerance to the therapeutic effects of clobazam has been reported and may be a concern with long-term use of the drug.19,23,24,25,26,31,41

Patients with a history of substance abuse should be carefully monitored while receiving clobazam or other psychotropic therapy because of their predisposition to habituation and dependence.1 Abrupt discontinuance of therapy or rapid dosage reduction can precipitate withdrawal symptoms in patients with physical dependence on the drug, and should therefore be avoided.1

Suicidality Risk

Suicidal behavior and ideation have been reported in patients receiving anticonvulsants, including clobazam.1 An increased risk of suicidality (suicidal behavior or ideation) was observed in an analysis of 199 placebo-controlled studies involving 11 anticonvulsants (i.e., carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); results of the analysis found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).1 This increased suicidality risk was observed as early as one week after beginning therapy and continued through 24 weeks.1 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1

Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality with anticonvulsant therapy; all patients currently receiving or beginning therapy with any anticonvulsant should be closely monitored for notable changes that may indicate the emergence or worsening of suicidal thoughts or behavior or depression.1

Clinicians who prescribe clobazam or any other anticonvulsant should balance the risk of suicidality with the clinical need for the drug and the risk associated with untreated illness.1 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.1 If suicidal thoughts or behavior emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.1

Abuse Potential

Clobazam is subject to control as a schedule IV (C-IV) drug.1,13 Because of its pharmacologic similarity to other benzodiazepines, particularly its potentiating effects on γ-aminobutyric acid (GABA) through the GABA_A receptor, the abuse potential of clobazam is expected to be similar to that of other benzodiazepines (e.g., diazepam).1 Cases of abuse, misuse, and overdosage associated with clobazam have been reported to the World Health Organization (WHO).1

Specific Populations

Pregnancy

North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 (for patients or caregivers); NAAED registry information also is available on the website [Web].1,4

Based on animal data, clobazam may cause fetal harm.1 There are no adequate data on the developmental risks associated with the use of clobazam in pregnant women.1 Clobazam produced developmental toxicity (e.g., fetal malformations and mortality) when administered orally to pregnant animals at exposure levels lower than those expected in humans at the recommended dosage.1 The drug should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.1

Maternal use of benzodiazepines during the later stages of pregnancy (i.e., second and third trimester) can result in dependence and subsequent withdrawal syndrome in neonates during the postnatal period.1 Manifestations (e.g., hypertonia, hyperreflexia, hypoventilation, irritability, tremors, diarrhea, vomiting) may be mild to severe and appear shortly after delivery or up to 3 weeks after birth, and can persist from hours to several months, depending on the degree of dependence and pharmacokinetic profile of the benzodiazepine.1 Neonates who have been exposed to clobazam in utero during the later stages of pregnancy should be observed for symptoms of withdrawal and managed as clinically appropriate.1

Maternal use of benzodiazepines immediately prior to or during childbirth can result in a floppy infant syndrome, characterized by lethargy, hypothermia, hypotonia, respiratory depression, and difficulty feeding in the infant.1 Floppy infant syndrome occurs mainly within the first hours after birth and may last up to 14 days.1 Neonates exposed to benzodiazepines should be observed for such symptoms and managed as clinically appropriate.1

For further information on the use of anticonvulsants and benzodiazepines during pregnancy, see Cautions: Pregnancy and Lactation in the Anticonvulsants General Statement 28:12 and also see Cautions: Pregnancy and Lactation in the Benzodiazepines General Statement 28:24.08.

Lactation

Clobazam and N -desmethylclobazam are distributed into human milk.1 The benefits of breast-feeding should be considered along with the importance of clobazam to the woman and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1 Because lethargy, somnolence, and poor sucking have been reported in breast-fed infants whose mothers were taking benzodiazepines, infants exposed to clobazam through breast milk should be monitored for potential adverse effects.1

The effects of clobazam on milk production are not known.1

Fertility

Clobazam may impair fertility, based on studies in male and female rats administered clobazam at exposure levels lower than those expected in humans at the maximum recommended dosage.1

Pediatric Use

Safety and efficacy of clobazam have not been established in pediatric patients younger than 2 years of age.1,4

Geriatric Use

Clinical trials of clobazam did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger patients.1 Based on a population pharmacokinetic analysis, geriatric patients appear to eliminate clobazam more slowly than younger patients (2-64 years of age).1 Therefore, clobazam should be initiated at a low dosage and titrated slowly in geriatric patients.1

Hepatic Impairment

Clobazam is extensively metabolized in the liver; however, the effects of hepatic impairment on the pharmacokinetics of the drug have not been fully characterized.1,13,45 Results of a small single-dose study showed no substantial pharmacokinetic differences (i.e., in peak plasma concentrations and plasma clearance of clobazam and peak plasma concentrations of N -desmethylclobazam) between patients with hepatic impairment and healthy individuals; however, because of limitations of the data, definitive conclusions cannot be drawn from this study.1,13,45

Clobazam therapy should be initiated at a dosage of 5 mg daily (regardless of patient weight) and titrated slowly in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1,36 There is insufficient information regarding the metabolism of clobazam in patients with severe hepatic impairment.1

Renal Impairment

Results of a pharmacokinetic study showed no substantial differences in systemic exposure to clobazam or its active N -desmethylclobazam metabolite between patients with mild (creatinine clearance exceeding 50-80 mL/minute) or moderate (creatinine clearance of 30-50 mL/minute) renal impairment and those with normal renal function.1

Dosage adjustment is not required in patients with mild or moderate renal impairment.1 There is no experience with clobazam in patients with severe renal impairment or end-stage renal disease.1 It is not known whether the drug or its active N -desmethylclobazam metabolite is dialyzable;1 however, limited evidence suggests that clobazam concentrations are unaffected by hemodialysis.40

Poor CYP2C19 Metabolizers

Genetic polymorphism of the cytochrome P-450 (CYP) isoenzyme 2C19 can affect the pharmacokinetic and pharmacodynamic response to clobazam.1,27,31,32,33 CYP2C19 is the principal enzyme involved in the metabolism of N -desmethylclobazam, the pharmacologically active metabolite of clobazam.1 Individuals with genetic variants of this enzyme may have reduced enzymatic activity and higher than expected plasma concentrations of N -desmethylclobazam, predisposing them to a higher risk of adverse effects.1,27,31,32,33

Higher concentrations of N -desmethylclobazam have been observed in poor CYP2C19 metabolizers compared with extensive CYP2C19 metabolizers.1,27,31,32,33 Dosage adjustment of clobazam is therefore recommended in patients known to be poor metabolizers of CYP2C19.1

Common Adverse Effects

Adverse effects associated with clobazam generally are similar to those observed with other benzodiazepines.6,9,13,19

Adverse effects reported in at least 5% of patients receiving clobazam and more frequently with clobazam than with placebo include somnolence or sedation,1,2 lethargy,1,2 drooling,1,2 vomiting,1 constipation,1,2 dysphagia,1 decreased or increased appetite,1 cough,1 upper respiratory tract infection,1 pneumonia,1 bronchitis,1 urinary tract infection,1 aggression,1,3 insomnia,1 irritability,1 ataxia,1 psychomotor hyperactivity,1 dysarthria,1 pyrexia,1,2 and fatigue.1

Drugs Affecting Hepatic Microsomal Enzymes

Clobazam is metabolized principally by cytochrome P-450 (CYP) isoenzyme CYP3A4, and to a lesser extent by CYP2C19 and CYP2B6.1,27,42 The active metabolite, N -desmethylclobazam, is metabolized principally by CYP2C19.1,27 Pharmacokinetic interactions are possible when clobazam is used concomitantly with drugs that inhibit or induce CYP3A4 or CYP2C19.1,27,30

Concomitant use of clobazam with potent (e.g., fluconazole, fluvoxamine, ticlopidine) or moderate (e.g., omeprazole) inhibitors of CYP2C19 may increase exposure to N -desmethylclobazam by up to fivefold (based on extrapolation of pharmacogenomic data) and possibly increase adverse effects.1,36,42 Therefore, clobazam dosage adjustment may be necessary when the drug is administered concomitantly with potent or moderate CYP2C19 inhibitors.1

Concomitant use of clobazam with a potent CYP3A4 inhibitor (e.g., ketoconazole) increased exposure to clobazam, but did not substantially affect pharmacokinetics of N -desmethylclobazam.1,42

Population pharmacokinetic analysis of data from clinical trials showed no substantial alterations in steady-state pharmacokinetics of clobazam or its active metabolite when the drug was used concomitantly with anticonvulsants that induce CYP3A4 (carbamazepine, phenobarbital, phenytoin), induce CYP2C9 (carbamazepine, phenobarbital, phenytoin, valproate), or inhibit CYP2C9 (felbamate, oxcarbazepine).1,42

Drugs Metabolized by Hepatic Microsomal Enzymes

In vitro studies indicate that clobazam and its active metabolite ( N -desmethylclobazam) induce CYP3A4 in a concentration-dependent manner; in vitro studies also indicate that N -desmethylclobazam is a weak inhibitor of CYP2C9.1 Clobazam does not appear to inhibit CYP isoenzymes 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 nor substantially induce CYP1A2 and CYP2C19 in vitro.1

The potential for clobazam to inhibit or induce various CYP isoenzymes in vivo was evaluated in a study using probe substrates for CYP2D6 (dextromethorphan), CYP3A4 (midazolam), CYP1A2 (caffeine), and CYP2C9 (tolbutamide).1,42 In contrast to in vitro observations, clobazam increased peak plasma concentrations and area under the concentration-time curve (AUC) of dextromethorphan by 59 and 90%, respectively, indicating inhibition of CYP2D6; therefore, dosage adjustment of drugs metabolized by CYP2D6 (e.g., dextromethorphan, fluoxetine, paroxetine) may be necessary when they are used concomitantly with clobazam.1,36,42 Clobazam decreased systemic exposure to midazolam by 27% and increased exposure to its 1-hydroxymidazolam metabolite by approximately fourfold; however, the manufacturer states that the extent of interaction does not warrant dosage adjustment of concomitantly used drugs that are metabolized principally by CYP3A4.1,42 Clobazam had no effect on the pharmacokinetics of caffeine or tolbutamide.1,42

Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase

Clobazam does not inhibit uridine diphosphate-glucuronosyltransferase (UGT) 1A1, 1A4, 1A6, or 2B4 in vitro.1 Clobazam's active metabolite, N -desmethylclobazam, was shown to be a weak inhibitor of UGT 1A4, 1A6, and 2B4.1 Clobazam and N -desmethylclobazam also increased UGT1A1 messenger RNA (mRNA), but at concentrations much higher than therapeutic concentrations.1 However, a population pharmacokinetic analysis indicated that clobazam does not affect the exposure of a UGT substrate (lamotrigine).1

CNS Depressants

Additive CNS effects can occur when clobazam is administered concomitantly with other CNS depressants (e.g., opiate agonists, tricyclic antidepressants, sedating antihistamines, alcohol, other benzodiazepines).1 Therefore, concomitant use of clobazam and other CNS depressants generally should be avoided.1

Opiate Agonists and Opiate Partial Agonists

Concomitant use of benzodiazepines, including clobazam, and opiate agonists or opiate partial agonists may result in profound sedation, respiratory depression, coma, and death.1,700,701,703,705,706,707 Whenever possible, such concomitant use should be avoided.708,709,710,711 Opiate antitussive agents should be avoided in patients receiving benzodiazepines,700,704 and concomitant use of opiate analgesics and benzodiazepines should be reserved for patients in whom alternative treatment options are inadequate.1,700,703 The lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.1,700,703

If clobazam is required for any indication other than epilepsy in a patient receiving opiate therapy, the drug should be initiated at a lower dosage than indicated in the absence of opiate therapy and titrated based on clinical response.700 If an opiate analgesic is required in a patient receiving clobazam, the opiate analgesic should be initiated at a reduced dosage and titrated based on clinical response.700 For further information on potential interactions between benzodiazepines and opiates, see Opiate Agonists and Opiate Partial Agonists under Drug Interactions: CNS Agents, in the Benzodiazepines General Statement 28:24.08.

Alcohol

Alcohol consumption has been reported to increase the maximum plasma exposure of clobazam by approximately 50%; clobazam does not appear to alter the pharmacokinetics of alcohol.1,36,37 Alcohol also can potentiate the CNS depressant effects of clobazam (e.g., sedation, somnolence).1,36 Concomitant use of clobazam and alcohol may therefore be hazardous and should be avoided.1,700

Anticonvulsants

Cannabidiol

Concomitant use of clobazam and cannabidiol can increase the risk of hepatic enzyme elevations.52 The manufacturer of cannabidiol states that if hepatic enzyme elevations occur in a patient receiving clobazam and cannabidiol concomitantly, dosage reduction or discontinuance of clobazam should be considered.52

Concomitant administration of clobazam and cannabidiol increases peak plasma concentrations and AUC of N -desmethylclobazam by approximately threefold, which may increase the risk of clobazam-related adverse reactions.52 In addition, peak plasma concentrations and AUC of the active cannabidiol metabolite are increased by 73 and 47%, respectively.52 The manufacturer of cannabidiol states that dosage reduction of clobazam should be considered if clobazam-related adverse reactions occur during concomitant use with cannabidiol.52

Carbamazepine, Phenobarbital, and Phenytoin

Concomitant administration of clobazam and carbamazepine was shown in one study to moderately increase metabolism of carbamazepine and result in higher concentrations of the carbamazepine 10,11-epoxide (CBZ-E) and trans -10,11-dihydro-10,11-dihydroxycarbamazepine (CBZ-T) metabolites.38

Some studies have shown that CYP enzyme-inducing anticonvulsants (carbamazepine, phenobarbital, phenytoin) can reduce concentrations of clobazam and increase metabolic transformation to its active metabolite, thereby increasing the risk of adverse effects (e.g., sedation).6,28,29 However, results of a population pharmacokinetic analysis indicate that the steady-state pharmacokinetics of clobazam and N -desmethylclobazam are not substantially altered by concurrent use of anticonvulsants that are CYP3A4 or CYP2C9 inducers (carbamazepine, phenobarbital, phenytoin).1,42

Felbamate

There is some evidence suggesting that N -desmethylclobazam concentrations may be increased via CYP2C19 inhibition in patients receiving clobazam and felbamate concomitantly.29,33 However, results from a population pharmacokinetic analysis indicate that steady-state pharmacokinetics of clobazam and its active metabolite are not substantially altered by felbamate.1,42

Lamotrigine

Results from a population pharmacokinetic analysis indicate that clobazam does not substantially affect exposure of lamotrigine.1,42

Stiripentol

Concomitant administration of clobazam and stiripentol results in increased plasma concentrations of clobazam and N -desmethylclobazam by approximately twofold and fivefold, respectively; this may increase the risk of clobazam-related adverse reactions.51 If somnolence occurs during concomitant therapy with clobazam and stiripentol, an initial 25% reduction in dosage of clobazam should be considered.51 If somnolence persists, an additional 25% reduction in the dosage of clobazam should be considered along with adjustments to other concomitant anticonvulsants that can also cause sedation.51

Valproate

Some studies have shown no substantial interaction with clobazam and valproate,1,28,42 while others suggest that clobazam may inhibit the metabolism of valproate and increase the potential for valproate-related toxicities.6 Results from a population pharmacokinetic analysis indicate that clobazam does not substantially affect exposure of valproate.1,42

Cimetidine

In a pharmacokinetic study, administration of single-dose clobazam and multiple-dose cimetidine in healthy males produced small increases in the systemic exposure and elimination half-life of clobazam; plasma concentrations of N -desmethylclobazam were not substantially affected.6,43 These changes were not considered clinically important.43

Hormonal Contraceptives

Clobazam is a weak CYP3A4 inducer and may reduce the efficacy of some hormonal contraceptives that are metabolized by CYP3A4.1,36 To ensure contraceptive reliability, the manufacturer recommends that women receiving hormonal contraceptives also use nonhormonal forms of contraception during clobazam therapy and for 28 days following discontinuance of the drug.1

Ketoconazole

Concomitant administration of clobazam and ketoconazole (a potent CYP3A4 inhibitor) in healthy individuals increased systemic exposure of clobazam by 54%, but did not substantially alter peak plasma concentrations of clobazam; pharmacokinetics of N -desmethylclobazam were unaffected.1,42 The observed increase in clobazam exposure is not expected to be clinically important.42

Omeprazole

Concomitant administration of clobazam and omeprazole (a moderate CYP2C19 inhibitor) in healthy individuals increased peak plasma concentrations and systemic exposure of N -desmethylclobazam by 15 and 36%, respectively, but did not substantially affect the pharmacokinetics of clobazam.1,36,42 Clinically important effects were not observed;42 however, the manufacturer states that clobazam dosage adjustment may be necessary when the drug is used concomitantly with potent or moderate CYP2C19 inhibitors such as omeprazole.1

Description

Clobazam is a 1,5-benzodiazepine that has anticonvulsant as well as anxiolytic properties.1,2,3,6,9,14,19,34,36,44 The exact mechanism of clobazam's anticonvulsant and anxiolytic actions has not been fully elucidated, but is thought to involve allosteric binding of the drug to the benzodiazepine site of the γ-aminobutyric acid type A (GABA_A) receptor, which in turn potentiates the inhibitory effects of GABA.1,6,9,19,34,36,46 Although structurally similar to the 1,4-benzodiazepines (e.g., clonazepam, diazepam, lorazepam), clobazam appears to have a broader spectrum of anticonvulsant activity and an improved adverse effect profile (e.g., less sedative effects), which have been attributed to differences in binding affinity for the GABA_A receptor.6,14,19,25,31,34,39

Clobazam is rapidly and almost completely absorbed following oral administration; peak plasma concentrations of the drug are achieved within 0.5-4 hours after single- or multiple-dose administration of the tablets and within 0.5-2 hours following single-dose administration of the oral suspension under fasting conditions.1,6,13,19,25,36,39,42,45 Bioavailability of the oral suspension is similar to that of the tablets under fasting conditions.1 Clobazam oral film and tablets are bioequivalent following administration of single doses of 10 or 20 mg.49,50 After the oral film is placed on the tongue, the median time to disintegration is 82 seconds (range: 18-245 seconds) for the 10-mg film and 105 seconds (range: 45-300 seconds) for the 20-mg film.50 Food does not appear to substantially affect absorption of clobazam tablets;1,6,13,19 although not evaluated, bioavailability of the oral suspension and oral film also are unlikely to be altered by food.1,49 Because clobazam is highly lipophilic, it distributes rapidly throughout the body.1,25 Clobazam is extensively metabolized in the liver where it undergoes N -demethylation and hydroxylation; approximately 2% and 1% of an orally administered dose is present in urine and feces, respectively, as unchanged drug.1,27 At least 14 metabolites of clobazam have been identified.1,19 The main circulating metabolite, N -desmethylclobazam, is pharmacologically active with potency estimates ranging from one-fifth to equal potency of the parent drug; therefore, the active metabolite may contribute to the efficacy and safety of the drug.1,6,13,19,25,31,32,42 At therapeutic dosages, plasma concentrations of N -desmethylclobazam are approximately 3-5 times higher than those of clobazam.1,42 Biotransformation of clobazam to N -desmethylclobazam is mediated by the cytochrome P-450 (CYP) enzyme system, principally by CYP3A4, and to a lesser extent by CYP2C19 and CYP2B6; N -desmethylclobazam is further metabolized by CYP2C19 to an inactive derivative.1,6,9,27,31,32,33 Both clobazam and N -desmethylclobazam are substrates of P-glycoprotein, but do not inhibit the transport protein.1 Both the drug and its active metabolite also exhibit a high degree of protein binding (80-90 and 70%, respectively).1,25 Clobazam is eliminated mainly through renal excretion; following administration of a single radiolabeled dose of clobazam, approximately 82% of the dose was recovered in urine and 11% in feces.1 The mean elimination half-life of clobazam is approximately 36-42 hours and the mean elimination half-life of N -desmethylclobazam is approximately 71-82 hours.1

Genetic polymorphism of the CYP2C19 isoenzyme can affect the metabolism of N -desmethylclobazam and result in possible increased concentrations of the active metabolite.1,9,27,31,32,33,42 Individuals with 2 copies of the CYP2C19*2 allele (the *2/*2 genotype) are described as poor metabolizers, those with 1 copy (the *1/*2 genotype) are intermediate metabolizers, and those homozygous for the wild-type CYP2C19*1 allele (the *1/*1 genotype) are described as extensive metabolizers.1,33 Systemic exposure to N -desmethylclobazam is approximately 3-5 and 2 times higher in poor and intermediate CYP2C19 metabolizers, respectively, than in extensive metabolizers.1 Systemic exposure of clobazam is similar for both poor and extensive metabolizers of CYP2C19 substrates.1 The prevalence of poor CYP2C19 metabolizers in the general population varies depending on ethnic and racial background and has been reported to be as high as 15-30% among Asians, with a lower prevalence in Caucasians.1,9,27,31,33

Advice to Patients

Importance of providing patient or caregiver with copy of written patient information (medication guide) each time clobazam is dispensed.1,4 Importance of advising patients or caregivers to read the medication guide before the start of therapy and each time the prescription is refilled.1,4

Importance of taking clobazam only as prescribed.1,4

Risk of somnolence or sedation.1,4 Patients should be cautioned against driving or operating hazardous machinery until they are reasonably certain that clobazam does not adversely affect their judgment, thinking, or motor skills.1,4

Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if benzodiazepines, including clobazam, are used concomitantly with opiates either therapeutically or illicitly.700,703 Risk of potentiated CNS depression with concurrent use of alcohol or other CNS depressants.1,4 Importance of advising patients receiving clobazam to avoid concomitant use of opiate antitussives700,704 and to also avoid concomitant use of opiate analgesics unless such use is supervised by a clinician.700,703 Importance of advising patients or caregivers to avoid concomitant use of clobazam and alcohol700 and to check with their clinician before using clobazam concomitantly with other CNS depressants (e.g., other benzodiazepines, TCAs, sedating antihistamines).1,4

Risk of rare but serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.1,47,48 Importance of advising patient or caregivers to seek immediate medical attention at the first appearance of a skin rash or other signs of hypersensitivity (e.g., blistering or peeling of skin, mouth sores, hives) while receiving clobazam.1,47 Drug discontinuance may be required; however, patients should be advised not to stop the drug without first consulting with their clinician.1,47

Importance of patients, family members, and caregivers being aware that anticonvulsants, including clobazam, may increase the risk of having suicidal thoughts or actions in a very small number of people (about 1 in 500).1,4 Advise patients, family members, and caregivers to pay close attention to any day-to-day changes in mood, behavior, and actions; these changes can happen very quickly.1,4 They should also be aware of common warning signs that may signal suicide risk (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).1,4 Advise patients, family members, and caregivers to contact the responsible clinician immediately if these or any other new and worrisome behaviors occur.1,4

Importance of advising patients or caregivers to consult their clinician before increasing or decreasing the dosage of clobazam or abruptly discontinuing the drug.1,4 Patients or caregivers should be informed that sudden discontinuance of clobazam can cause serious problems, including an increased risk of seizures and withdrawal symptoms.1,4

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,4 Importance of clinicians informing women about the existence of and encouraging enrollment in the pregnancy registry.1,4

Importance of informing women that clobazam may cause some hormonal contraceptives (e.g., birth control pills, patches, rings, implants, injections, intrauterine devices) to be less effective; women should be advised to use additional nonhormonal forms of contraception during clobazam therapy and for 28 days after discontinuance to ensure continued contraceptive reliability.1,4

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).1,4

Importance of informing patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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