Clobazam

Pronunciation

Pronunciation: KLOE-ba-zam
Class: Benzodiazepine

Trade Names

Onfi
- Tablets, oral 5 mg
- Tablets, oral 10 mg
- Tablets, oral 20 mg

Pharmacology

Binds to the benzodiazepine site of the GABA A receptor and potentiates GABAergic neurotransmission.

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Pharmacokinetics

Absorption

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.

Distribution

Vd is approximately 100 L. Protein binding is 80% to 90% (clobazam) and 70% (N-desmethylclobazam).

Metabolism

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.

Elimination

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 Populations

Renal 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.

Contraindications

None well documented.

Dosage and Administration

Adults 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.

General Advice

  • 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.

Storage/Stability

Store between 68° and 77°F.

Drug Interactions

CNS 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 .

Adverse Reactions

The following adverse reactions were reported for clobazam when used as adjunctive therapy.

CNS

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).

Dermatologic

Rash, Stevens-Johnson syndrome and TEN, urticaria (postmarketing).

EENT

Blurred vision, diplopia (postmarketing).

GI

Constipation (10%); vomiting (9%); dysphagia (5%); abdominal distension (postmarketing).

Hematologic

Anemia, eosinophilia, leukopenia, thrombocytopenia (postmarketing).

Hepatic

Hepatic enzyme increased (postmarketing).

Metabolic-Nutritional

Decreased appetite (7%); increased appetite (5%).

Musculoskeletal

Muscle spasms (postmarketing).

Respiratory

Upper respiratory tract infection (14%); cough, pneumonia (7%); bronchitis (5%); aspiration, respiratory depression (postmarketing).

Miscellaneous

Pyrexia (17%); UTI (5%).

Precautions

Monitor

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.


Pregnancy

Category C . Neonatal flaccidity, respiratory and feeding difficulties, hypothermia, and withdrawal symptoms have been reported in infants born to mothers who received clobazam.

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established in patients younger than 2 y.

Hepatic Function

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.

Hazardous Tasks

Patients should not engage in hazardous activities requiring mental alertness (eg, operating machinery or motor vehicles) until the effect of clobazam is known.

Dependence

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.

Somnolence/Sedation

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.

Withdrawal

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.

Overdosage

Symptoms

Ataxia, coma, confusion, CNS depression, death, drowsiness, hypotension, lethargy, respiratory depression.

Patient Information

  • 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.

Copyright © 2009 Wolters Kluwer Health.

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