Prescription Drug Information: Clobazam (Page 4 of 7)

8.3 Females and Males of Reproductive Potential

Administration of clobazam to rats prior to and during mating and early gestation resulted in adverse effects on fertility and early embryonic development at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those in humans at the MRHD [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness in patients less than 2 years of age have not been established.

In a study in which clobazam (0, 4, 36, or 120 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 14 to 48), adverse effects on growth (decreased bone density and bone length) and behavior (altered motor activity and auditory startle response; learning deficit) were observed at the high dose. The effect on bone density, but not on behavior, was reversible when drug was discontinued. The no-effect level for juvenile toxicity (36 mg/kg/day) was associated with plasma exposures (AUC) to clobazam and its major active metabolite, N-desmethylclobazam, less than those expected at therapeutic doses in pediatric patients.

8.5 Geriatric Use

Clinical studies of clobazam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, elderly subjects appear to eliminate clobazam more slowly than younger subjects based on population pharmacokinetic analysis. For these reasons, the initial dose in elderly patients should be 5 mg/day. Patients should be titrated initially to 10 to 20 mg/day. Patients may be titrated further to a maximum daily dose of 40 mg if tolerated [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

8.6 CYP2C19 Poor Metabolizers

Concentrations of clobazam’s active metabolite, N-desmethylclobazam, are higher in CYP2C19 poor metabolizers than in extensive metabolizers. For this reason, dosage modification is recommended [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

8.7 Renal Impairment

The pharmacokinetics of clobazam were evaluated in patients with mild and moderate renal impairment. There were no significant differences in systemic exposure (AUC and Cmax ) between patients with mild or moderate renal impairment and healthy subjects. No dose adjustment is required for patients with mild and moderate renal impairment. There is essentially no experience with clobazam in patients with severe renal impairment or ESRD. It is not known if clobazam or its active metabolite, N-desmethylclobazam, is dialyzable [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].

8.8 Hepatic Impairment

Clobazam is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of clobazam. For this reason, dosage adjustment is recommended in patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9). There is inadequate information about metabolism of clobazam in patients with severe hepatic impairment [see Dosage and Administration (2.7), Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Clobazam tablets contain clobazam, a Schedule IV controlled substance.

9.2 Abuse

Clobazam is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.

Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2)].

The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.

The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

The World Health Organization epidemiology database contains reports of drug abuse, misuse, and overdoses associated with clobazam.

9.3 Dependence

Physical Dependence

Clobazam may produce physical dependence from continued therapy. Physical Dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3)]. In clinical trials, cases of dependency were reported following abrupt discontinuation of clobazam.

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Clobazam or reduce the dosage [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)].

Acute Withdrawal Signs and Symptoms

Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment,muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality.

Protracted Withdrawal Syndrome

Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.

Tolerance

Tolerance to Clobazam may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of Clobazam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

10 OVERDOSAGE

10.1 Signs and Symptoms of Overdosage

Overdose and intoxication with benzodiazepines, including clobazam, may lead to CNS depression, associated with drowsiness, confusion and lethargy, possibly progressing to ataxia, respiratory depression, hypotension, and, rarely, coma or death. The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including opioids and alcohol.

10.2 Management of Overdosage

The management of clobazam overdose may include gastric lavage and/or administration of activated charcoal, intravenous fluid replenishment, early control of airway and general supportive measures, in addition to monitoring level of consciousness and vital signs. Hypotension can be treated by replenishment with plasma substitutes and, if necessary, with sympathomimetic agents.

The efficacy of supplementary administration of physostigmine (a cholinergic agent) or of flumazenil (a benzodiazepine antagonist) in clobazam overdose has not been assessed. The administration of flumazenil in cases of benzodiazepine overdose can lead to withdrawal and adverse reactions. Its use in patients with epilepsy is typically not recommended.

11 DESCRIPTION

Table 4. Description

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(click image for full-size original)

Clobazam is a white or almost white, crystalline powder with a slightly bitter taste; is freely soluble in dichloromethane. The melting range of clobazam is from 178ºC to 185ºC. The molecular formula is C16 H13 O2 N2 Cl and the molecular weight is 300.7.

Each clobazam tablet contains 10 mg or 20 mg of clobazam. Tablets also contain as inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The exact mechanism of action for clobazam, a 1,5-benzodiazepine, is not fully understood but is thought to involve potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABAA receptor.

12.2 Pharmacodynamics

Effects on Electrocardiogram

The effect of clobazam tablets 20 mg and 80 mg administered twice daily on QTc interval was evaluated in a randomized, evaluator-blinded, placebo-, and active-controlled (moxifloxacin 400 mg) parallel thorough QT study in 280 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on the Fridericia correction method was below 10 ms, the threshold for regulatory concern. Thus, at a dose two times the maximum recommended dose, clobazam did not prolong the QTc interval to any clinically relevant extent.

12.3 Pharmacokinetics

The peak plasma levels (Cmax) and the area under the curve (AUC) of clobazam are doseproportional over the dose range of 10 to 80 mg following single- or multiple-dose administration of clobazam tablets. Based on a population pharmacokinetic analysis, the pharmacokinetics of clobazam are linear from 5 to 160 mg/day. Clobazam is converted to Ndesmethylclobazam which has about 1/5 the activity of clobazam. The estimated mean elimination half-lives (t½) of clobazam and N-desmethylclobazam were 36 to 42 hours and 71 to 82 hours, respectively.

Absorption

Clobazam is rapidly and extensively absorbed following oral administration. The time to peak concentrations (Tmax) of clobazam tablets under fasted conditions ranged from 0.5 to 4 hours after single- or multiple-dose administrations. The relative bioavailability of clobazam tablets compared to an oral solution is approximately 100%. After single dose administration of the oral suspension under fasted conditions, the Tmax ranged from 0.5 to 2 hours. Based on exposure (Cmax and AUC) of clobazam, clobazam tablets and suspension were shown to have similar bioavailability under fasted conditions. The administration of clobazam tablets with food or when crushed in applesauce does not affect absorption. Although not studied, the oral bioavailability of the oral suspension is unlikely to be affected under fed conditions.

Distribution

Clobazam is lipophilic and distributes rapidly throughout the body. The apparent volume of distribution at steady state was approximately 100 L. The in vitro plasma protein binding of clobazam and N-desmethylclobazam is approximately 80 to 90% and 70%, respectively.

Metabolism and Excretion

Clobazam is extensively metabolized in the liver, with approximately 2% of the dose recovered in urine and 1% in feces as unchanged drug. The major metabolic pathway of clobazam involves N-demethylation, primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. Ndesmethylclobazam, an active metabolite, is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations are 3 to 5 times higher than those of the parent compound. Based on animal and in vitro receptor binding data, estimates of the relative potency of N-desmethylclobazam compared to parent compound range from 1/5 to equal potency. Ndesmethylclobazam is extensively metabolized, mainly by CYP2C19. N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine. Following a single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine.

The polymorphic CYP2C19 is the major contributor to the metabolism of the pharmacologically active N desmethylclobazam [see Clinical Pharmacology (12.5)]. In CYP2C19 poor metabolizers, levels of N-desmethylclobazam were 5-fold higher in plasma and 2- to 3-fold higher in the urine than in CYP2C19 extensive metabolizers.

Pharmacokinetics in Specific Populations

Age:

Population pharmacokinetic analyses showed that the clearance of clobazam is lower in elderly subjects compared to other age groups (ages 2 to 64). Dosing should be adjusted in the elderly [see Dosage and Administration (2.4)].

Sex:

Population pharmacokinetic analyses showed no difference in the clearance of clobazam between women and men.

Race:

Population pharmacokinetic analyses including Caucasian (75%), African American (15%), and Asian (9%) subjects showed that there is no evidence of clinically significant effect of race on the clearance of clobazam.

Renal Impairment:

The effect of renal impairment on the pharmacokinetics of clobazam was evaluated in patients with mild (creatinine clearance [CLCR] >50 to 80 mL/min; N=6) and moderate (CLCR=30 to 50 mL/min; N=6) renal dysfunction, with matching healthy controls (N=6), following administration of multiple doses of clobazam 20 mg/day. There were insignificant changes in Cmax (3 to 24%) and AUC (≤13%) for clobazam or N-desmethylclobazam in patients with mild or moderate renal impairment compared to patients with normal renal function. Patients with severe renal impairment or ESRD were not included in this study.

Hepatic Impairment:

There are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of clobazam. In a small study, the pharmacokinetics of a 20 mg single oral dose of clobazam in 9 patients with liver impairment were compared to healthy controls (N=6). The Cmax and the mean plasma clearance of clobazam, as well as the Cmax of N-desmethylclobazam, showed no significant change compared to the healthy controls. The AUC values of N-desmethylclobazam in these patients were not available. Adjust dosage in patients with hepatic impairment [see Dosage and Administration (2.7)].

Drug Interaction Studies

In vitro studies:

Clobazam did not inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A4, UGT1A6, or UGT2B4 in vitro. N-desmethylclobazam showed weak inhibition of CYP2C9, UGT1A4, UGT1A6 and UGT2B4. Clobazam and N-desmethylclobazam did not significantly increase CYP1A2 or CYP2C19 activities, but did induce CYP3A4 activity in a concentration-dependent manner. Clobazam andN-desmethylclobazam also increased UGT1A1 mRNA but at concentrations much higher than therapeutic levels. The potential for clobazam or N-desmethylclobazam to induce CYP2B6 and CYP2C8 has not been evaluated. Clobazam and N-desmethylclobazam do not inhibit P-glycoprotein (P-gp), but are P-gp substrates.

In vivo studies:

Potential for clobazam to Affect Other Drugs

The effect of repeated 40 mg once-daily doses of clobazam on the pharmacokinetic profiles of single-dose dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 substrate), caffeine (CYP1A2 substrate), and tolbutamide (CYP2C9 substrate), was studied when these probe substrates were given as a drug cocktail (N=18). Clobazam increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively, reflecting its inhibition of CYP2D6 in vivo. Drugs metabolized by CYP2D6 may require dose adjustment when used with clobazam.

Clobazam decreased the AUC and Cmax of midazolam by 27% and 24%, respectively, and increased the AUC and Cmax of the metabolite 1-hydroxymidazolam by 4-fold and 2-fold, respectively. This level of induction does not call for dosage adjustment of drugs that are primarily metabolized by CYP3A4 when used concomitantly with clobazam. Some hormonal contraceptives are metabolized by CYP3A4 and their effectiveness may be diminished when given with clobazam [see Drug Interactions (7.3)]. Repeated clobazam doses had no effect on caffeine and tolbutamide.

A population pharmacokinetic analysis indicated clobazam did not affect the exposure of valproic acid (a CYP2C9/2C19 substrate) or lamotrigine (a UGT substrate).

Potential for Other Drugs to Affect Clobazam

Co-administration of ketoconazole (a strong CYP3A4 inhibitor) 400 mg once-daily for 5 days increased clobazam AUC by 54%, with an insignificant effect on clobazam Cmax. There was no significant change in AUC and Cmax of N-desmethylclobazam (N=18).

Strong (e.g., fluconazole, fluvoxamine, ticlopidine) and moderate (e.g., omeprazole) inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam, the active metabolite of clobazam, based on extrapolation from pharmacogenomic data [see Clinical Pharmacology (12.5)]. Dosage adjustment of clobazam may be necessary when co-administered with strong or moderate CYP2C19 inhibitors [see Drug Interactions (7.4)].

The effects of concomitant antiepileptic drugs that are CYP3A4 inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C19 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), and CYP2C19 inhibitors (felbamate and oxcarbazepine) were evaluated using data from clinical trials. Results of population pharmacokinetic analysis show that these concomitant antiepileptic drugs did not significantly alter the pharmacokinetics of clobazam or N-desmethylclobazam at steady-state.

Alcohol has been reported to increase the maximum plasma exposure of clobazam by approximately 50%. Alcohol may have additive CNS depressant effects when taken with clobazam [see Warnings and Precautions (5.2), Drug Interactions (7.2)].

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