- Tablets, oral 5 mg
- Tablets, oral 10 mg
- Tablets, oral 20 mg
Binds to the benzodiazepine site of the GABA A receptor and potentiates GABAergic neurotransmission.
Rapidly and extensively absorbed. Bioavailability is approximately 100%. T max is 0.5 to 4 h. Administration with food or when crushed in applesauce does not affect absorption.
Vd is approximately 100 L. Protein binding is 80% to 90% (clobazam) and 70% (N-desmethylclobazam).
Extensively metabolized in the liver by N-demethylation, primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. The active metabolite, N-desmethylclobazam, is the major circulating metabolite; it is extensively metabolized, primarily by CYP2C19.
The half-life is 36 to 42 h (71 to 82 h for N-desmethylclobazam). Approximately 82% is excreted in the urine and 11% in the feces (2% in the urine and 1% in the feces as unchanged drug).
Special PopulationsRenal Function Impairment
Insignificant changes in C max (3% to 24%) and AUC (13% or less) were seen in patients with mild or moderate renal impairment compared with healthy controls. Patients with severe renal impairment or ESRD were not evaluated.Hepatic Function Impairment
Limited pharmacokinetic data are available. C max and plasma Cl were not significantly different in patients with hepatic impairment compared with healthy controls; AUC values were not available.Elderly
Cl is lower in elderly patients.Gender
No difference in Cl was observed between women and men.Race
There is no evidence of clinically significant effect of race on Cl of clobazam.CYP2C19 poor metabolizers
AUC and C max of active metabolite are approximately 3 to 5 times higher in poor metabolizers compared with extensive metabolizers.
Indications and Usage
Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome.
None well documented.
Dosage and AdministrationAdults and children 2 y and older More than 30 kg
PO Start with 10 mg/day. Dose escalation should not proceed more rapidly than weekly. Increase dosage to 20 mg/day on day 7 and then to 40 mg/day on day 14, if needed.30 kg or less
PO Start with 5 mg/day. Dose escalation should not proceed more rapidly than weekly. Increase dosage to 10 mg/day on day 7 and then to 20 mg/day on day 14, if needed.Elderly
Initial dosage should be 5 mg/day. Titrate dose according to weight as previously described, but to half the recommended dose, as tolerated. If necessary based on clinical response, an additional titration to the maximum dose (20 mg/day for patients 30 kg or less and 40 mg/day for patients more than 30 kg) may be started on day 21.Hepatic impairment
In patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9), initial dosage should be 5 mg/day. Titrate dose according to weight as previously described, but to half the recommended dose, as tolerated. If necessary based on clinical response, an additional titration to the maximum dose (20 mg/day for patients 30 kg or less and 40 mg/day for patients more than 30 kg) may be started on day 21.CYP2C19 poor metabolizers
Initial dosage should be 5 mg/day. Titrate dose according to weight as previously described, but to half the recommended dose, as tolerated. If necessary based on clinical response, an additional titration to the maximum dose (20 mg/day for patients 30 kg or less and 40 mg/day for patients more than 30 kg) may be started on day 21.Discontinuation of therapy
Withdraw therapy gradually; taper by decreasing the total daily dose by 5 to 10 mg/day on a weekly basis until discontinued.
- Administer in divided doses twice daily; the 5 mg dose may be administered as a single daily dose.
- Administer tablets whole or crush and mix with applesauce. May be taken without regard to meals.
Store between 68° and 77°F.
Drug InteractionsCNS depressants (eg, alcohol, opioids, tricyclic antidepressants)
Concomitant use may cause additive CNS depression. Alcohol increases the maximum plasma exposure of clobazam by approximately 50%. Avoid concomitant use.CYP2C19 inhibitors (eg, fluconazole, fluvoxamine, ticlopidine, omeprazole)
CYP2C19 inhibitors may increase exposure to N-desmethylclobazam. Dosage adjustment may be needed.CYP2D6 substrates (eg, dextromethorphan)
Clobazam may increase the exposure of CYP2D6 substrates. Lower doses of some drugs metabolized by CYP2D6 may be required.CYP3A4 substrates (eg, midazolam, some hormonal contraceptives)
Clobazam may decrease the exposure of CYP3A4 substrates. Dosage adjustment generally not needed. Hormonal contraceptives that are metabolized by CYP3A4 may have their effectiveness diminished when given with clobazam. Additional nonhormonal forms of contraception are recommended.Ketoconazole
Ketoconazole (a strong CYP3A4 inhibitor) increased clobazam AUC by 54%, with an insignificant effect on clobazam C max .
The following adverse reactions were reported for clobazam when used as adjunctive therapy.
Somnolence or sedation (32%); somnolence (25%); lethargy (15%); aggression, drooling (14%); irritability (11%); ataxia (10%); sedation (9%); insomnia (7%); dysarthria, fatigue, psychomotor hyperactivity (5%); agitation, anxiety, apathy, confusional state, delirium, delusion, depression, hallucination (postmarketing).
Rash, Stevens-Johnson syndrome and TEN, urticaria (postmarketing).
Blurred vision, diplopia (postmarketing).
Constipation (10%); vomiting (9%); dysphagia (5%); abdominal distension (postmarketing).
Anemia, eosinophilia, leukopenia, thrombocytopenia (postmarketing).
Hepatic enzyme increased (postmarketing).
Decreased appetite (7%); increased appetite (5%).
Muscle spasms (postmarketing).
Upper respiratory tract infection (14%); cough, pneumonia (7%); bronchitis (5%); aspiration, respiratory depression (postmarketing).
Pyrexia (17%); UTI (5%).
Monitor patients for somnolence and sedation, particularly with concomitant use of other CNS depressants. Carefully monitor patients with a history of substance abuse because of the predisposition of such patients to habituation and dependence. Monitor patients for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Category C . Neonatal flaccidity, respiratory and feeding difficulties, hypothermia, and withdrawal symptoms have been reported in infants born to mothers who received clobazam.
Excreted in breast milk.
Safety and efficacy not established in patients younger than 2 y.
Dosage adjustment required in mild and moderate hepatic impairment. Inadequate information is available for patients with severe hepatic impairment and no dosing recommendations can be made for these patients.
Patients should not engage in hazardous activities requiring mental alertness (eg, operating machinery or motor vehicles) until the effect of clobazam is known.
May occur and risk is present even with use at recommended doses over a period of only a few weeks.
Elderly or debilitated patients
Initial dose should be small and gradually increased. Give drug with extreme care to elderly or very ill patients with limited respiratory reserve.
Reported in clinical trials at all effective doses and is dose-related. In general, somnolence and sedation begin within the first month of treatment and may diminish with continued treatment.
Suicidal behavior and ideation
Antiepileptic drugs increase the risk of suicidal thoughts or behavior.
Avoid abrupt discontinuation of clobazam; withdrawal symptoms may occur with abrupt discontinuation, and risk and severity of symptoms are greater with higher doses. Withdrawal gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus.
Ataxia, coma, confusion, CNS depression, death, drowsiness, hypotension, lethargy, respiratory depression.
- Advise patient to read the Medication Guide before starting therapy and with each refill.
- Advise patient to check with health care provider before taking with other CNS depressants, including alcohol.
- Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that clobazam does not affect them adversely (eg, impair judgement, thinking, or motor skills).
- Inform patients to consult their health care provider before changing the dose or abruptly discontinuing clobazam. Advise patients or caregivers that abrupt withdrawal may increase their seizure risk.
- Counsel women to also use nonhormonal methods of contraception when clobazam is used with hormonal contraceptives and to continue these alternative methods for 28 days after discontinuing treatment to ensure contraceptive reliability.
- Counsel patients, caregivers, and families that antiepileptic drugs may increase the risk of suicidal thoughts and behaviors and advise them of the need to be alert for the emergence of worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Instruct them to immediately report behaviors of concern.
- Instruct patients to notify their health care provider if they become pregnant or intend to become pregnant during therapy. Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant.
- Instruct patients to notify their health care provider if they are breast-feeding or intend to breast-feed during therapy.
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