CLOBAMAX
Clobazam
PRESENTATION
Dosage Form: Tablets
Generic Name: clobazam
Pharmacopoeia: IP
Strength: 5/10 MG
Pack Size: 10*10
Packing: Blister
Group: KHA
CLINICAL PARTICULARS
Indications
CLOBAMAX (clobazam) is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older.
DOSAGE AND ADMINISTRATION
Dosing Information
A daily dose of CLOBAMAX greater than 5 mg should be administered in divided doses twice daily; a 5 mg daily dose can be administered as a single dose. Dose patients according to body weight. Individualize dosing within each body weight group, based on clinical efficacy and tolerability. Each dose in Table 1 (e.g. 5 to 20 mg in ≤30 kg weight group) has been shown to be effective, although effectiveness increases with increasing dose Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady-state.
Table 1. Recommended Total Daily Dosing by Weight Group
|
|
≤30 kg Body Weight |
>30 kg Body Weight |
|
Starting Dose |
5 mg |
10 mg |
|
Starting Day 7 |
10 mg |
20 mg |
|
Starting Day 14 |
20 mg |
40 mg |
Gradual Withdrawal
As with all antiepileptic drugs and benzodiazepines, withdraw CLOBAMAX gradually. Taper by decreasing the total daily dose by 5-10 mg/day on a weekly basis until discontinued.
Dosage Adjustments in Geriatric Patients
Plasma concentrations at any given dose are generally higher in the elderly: proceed slowly with dose escalation. The starting dose should be 5 mg/day for all elderly patients. Then titrate elderly patients according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on weight) may be started on day 21.
Dosage Adjustments in CYP2C19 Poor Metabolizers
In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam’s active metabolite, will be increased. Therefore, in patients known to be CYP2C19 poor metabolizers, the starting dose should be 5 mg/day and dose titration should proceed slowly according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group) may be started on day 21.
Patients with Renal Impairment
No dose adjustment is required for patients with mild and moderate renal impairment.
There is no experience with CLOBAMAX in patients with severe renal impairment or end stage renal disease (ESRD). It is not known if clobazam or its active metabolite, N-desmethylclobazam, is dialyzable.
Dosage Adjustments in Patients with Hepatic Impairment
CLOBAMAX is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of CLOBAMAX. For this reason, proceed slowly with dosing escalations. For patients with mild to moderate hepatic impairment (Child-Pugh score 5-9), the starting dose should be 5 mg/day in both weight groups.
Then titrate patients according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, start an additional titration on day 21 to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group). There is inadequate information about metabolism of CLOBAMAX in patients with severe hepatic impairment. Therefore no dosing recommendation in those patients can be.
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
Risks from Concomitant Use with Opioids
Concomitant use of benzodiazepines, including CLOBAMAX, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe CLOBAMAX concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when CLOBAMAX is used with opioids.
Potentiation of Sedation from Concomitant Use with Central Nervous System
Depressants
Since CLOBAMAX has a central nervous system (CNS) depressant effect, patients or their caregivers should be cautioned against simultaneous use with other CNS depressant drugs or alcohol, and cautioned that the effects of other CNS depressant drugs or alcohol may be potentiated.
Somnolence or Sedation
CLOBAMAX causes somnolence and sedation. In clinical trials, somnolence or sedation was reported at all effective doses and was dose-related.
In general, somnolence and sedation begin within the first month of treatment and may diminish with continued treatment. Prescribers should monitor patients for somnolence and sedation, particularly with concomitant use of other central nervous system depressants. Prescribers should caution patients against engaging in hazardous activities requiring mental alertness, such as operating dangerous machinery or motor vehicles, until the effect of CLOBAMAX is known.
Withdrawal Symptoms
Abrupt discontinuation of CLOBAMAX should be avoided. CLOBAMAX should be tapered by decreasing the dose every week by 5-10 mg/day until discontinuation.
Withdrawal symptoms occurred following abrupt discontinuation of CLOBAMAX; the risk of withdrawal symptoms is greater with higher doses.
As with all antiepileptic drugs, CLOBAMAX should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus.
Withdrawal symptoms (e.g., convulsions, psychosis, hallucinations, behavioral disorder, tremor, and anxiety) have been reported following abrupt discontinuance of benzodiazepines. The more severe withdrawal symptoms have usually been limited to patients who received excessive doses over an extended period of time, followed by an abrupt discontinuation. Generally milder withdrawal symptoms (e.g., dysphoria, anxiety, and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic doses for several months.
Serious Dermatological Reactions
Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with CLOBAMAX in both children and adults during the post-marketing period. Patients should be closely monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment initiation or when re-introducing therapy. CLOBAMAX should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.
Physical and Psychological Dependence
Patients with a history of substance abuse should be under careful surveillance when receiving CLOBAMAX or other psychotropic agents because of the predisposition of such patients to habituation and dependence.
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including CLOBAMAX, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% cCLOBAMAXdence interval [CI]: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing CLOBAMAX or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
ADVERSE REACTIONS
Clinically significant adverse reactions that appear in other sections of the labeling include the following:
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Gastrointestinal Disorders
General Disorders and Administration Site Conditions
Upper Respiratory Tract Infection
Metabolism and Nutrition Disorders
Nervous System Disorders
Psychiatric Disorders
Respiratory Disorders
DRUG INTERACTIONS
Opioids
The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.
Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation.
CNS Depressants and Alcohol
Concomitant use of CLOBAMAX with other CNS depressants may increase the risk of sedation and somnolence.
Alcohol, as a CNS depressant, will interact with CLOBAMAX in a similar way and also increases clobazam’s maximum plasma exposure by approximately 50%. Therefore, caution patients or their caregivers against simultaneous use with other CNS depressant drugs or alcohol, and caution that the effects of other CNS depressant drugs or alcohol may be potentiated.
Effect of CLOBAMAX on Other Drugs
Hormonal Contraceptives
CLOBAMAX is a weak CYP3A4 inducer. As some hormonal contraceptives are metabolized by CYP3A4, their effectiveness may be diminished when given with CLOBAMAX.
Drugs Metabolized by CYP2D6
CLOBAMAX inhibits CYP2D6. Dose adjustment of drugs metabolized by CYP2D6 may be necessary.
Effect of Other Drugs on CLOBAMAX
Strong and Moderate Inhibitors of CYP2C19
Strong and moderate inhibitors of CYP2C19 may result in increased exposure to
N-desmethylclobazam, the active metabolite of clobazam. This may increase the risk of dose-related adverse reactions. Dosage adjustment of CLOBAMAX may be necessary when co-administered with strong CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, ticlopidine) or moderate CYP2C19 inhibitors (e.g., omeprazole).
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C.
There are no adequate and well-controlled studies of CLOBAMAX in pregnant women. In animal studies, administration of clobazam during pregnancy resulted in developmental toxicity, including increased incidences of fetal malformations, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients. CLOBAMAX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Available human data on the risk of teratogenicity associated with benzodiazepines are inconclusive. There is insufficient evidence in humans to assess the effect of benzodiazepine exposure during pregnancy on neurodevelopment. Administration of benzodiazepines immediately prior to or during childbirth can result in a syndrome of hypothermia, hypotonia, respiratory depression, and difficulty feeding. In addition, infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period.
Data for other benzodiazepines suggest the possibility of adverse developmental effects (including long-term effects on neurobehavioral and immunological function) in animals following prenatal exposure to benzodiazepines at clinically relevant doses.
In a study in which clobazam (150, 450, or 750 mg/kg/day) was orally administered to pregnant rats throughout the period of organogenesis, embryo fetal mortality and incidences of fetal skeletal variations were increased at all doses. The low effect dose for embryo fetal developmental toxicity in rats (150 mg/kg/day) was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, lower than those in humans at the maximum recommended human dose (MRHD) of 40 mg/day.
Oral administration of clobazam (10, 30, or 75 mg/kg/day) to pregnant rabbits throughout the period of organogenesis resulted in decreased fetal body weights, and increased incidences of fetal malformations (visceral and skeletal) at the mid and high doses, and an increase in embryo fetal mortality at the high dose. Incidences of fetal variations were increased at all doses. The highest dose tested was associated with maternal toxicity (ataxia and decreased activity). The low effect dose for embryo fetal developmental toxicity in rabbits (10 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD.
Oral administration of clobazam (50, 350, or 750 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased embryo fetal mortality at the high dose, decreased pup survival at the mid and high doses and alterations in offspring behavior (loco motor activity) at all doses. The low effect dose for adverse effects on pre- and postnatal development in rats (50 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD.
Nursing Mothers
CLOBAMAX is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from CLOBAMAX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in patients less than 2 years of age have not been established.
In a study in which clobazam (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.
Geriatric Use
Clinical studies of CLOBAMAX 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 10-20 mg/day.
Patients may be titrated further to a maximum daily dose of 40 mg if tolerated.
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.
Renal Impairment
The pharmacokinetics of CLOBAMAX 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 CLOBAMAX in patients with severe renal impairment or ESRD.
It is not known if clobazam or its active metabolite, N-desmethylclobazam, is dialyzable.
Hepatic Impairment
CLOBAMAX is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of CLOBAMAX. For this reason, dosage adjustment is recommended in patients with mild to moderate hepatic impairment (Child-Pugh score 5-9). There is inadequate information about metabolism of CLOBAMAX in patients with severe hepatic impairment.
DRUG ABUSE AND DEPENDENCE
Controlled Substance
CLOBAMAX contains clobazam which is a controlled substance.
Abuse
CLOBAMAX can be abused in a similar manner as other benzodiazepines, such as diazepam.
The pharmacological profile of CLOBAMAX is similar to that of other benzodiazepines, particularly in its potentiation of GABAergic transmission through its action on GABAA receptors, which leads to sedation and somnolence.
The World Health Organization epidemiology database contains reports of drug abuse, misuse, and overdoses associated with clobazam.
Drug abuse is the intentional non-therapeutic use of a drug, repeatedly or even sporadically, for its rewarding psychological or physiological effects.
Dependence
Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood levels of the drug, and/or administration of an antagonist. In clinical trials, cases of dependency were reported following abrupt discontinuation of CLOBAMAX.
The risk of dependence is present even with use of CLOBAMAX at the recommended dose range over periods of only a few weeks. The risk of dependence increases with increasing dose and duration of treatment. The risk of dependence is increased in patients with a history of alcohol or drug abuse.
Withdrawal
Abrupt discontinuation of CLOBAMAX causes withdrawal symptoms. As with other benzodiazepines, CLOBAMAX should be withdrawn gradually.
In CLOBAMAX clinical pharmacology trials in healthy volunteers, the most common withdrawal symptoms after abrupt discontinuation were headache, tremor, insomnia, anxiety, irritability, drug withdrawal syndrome, palpitations, and diarrhea.
Other withdrawal reactions to clobazam reported in the literature include restlessness, panic attacks, profuse sweating, difficulty in concentrating, nausea and dry retching, weight loss, blurred vision, photophobia, and muscle pain and stiffness. In general, benzodiazepine withdrawal may cause seizures, psychosis, and hallucinations.
OVERDOSAGE
Signs and Symptoms of Over Dosage
Overdose and intoxication with benzodiazepines, including CLOBAMAX, 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 alcohol.
Management of Over Dosage
The management of CLOBAMAX 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 CLOBAMAX 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.
CLINICAL PHARMACOLOGY
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.
Pharmacodynamics
Effects on Electrocardiogram
The effect of CLOBAMAX 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% CLOBAMAX 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, CLOBAMAX did not prolong the QTc interval to any clinically relevant extent.
Pharmacokinetics
The peak plasma levels (Cmax) and the area under the curve (AUC) of clobazam are dose-proportional over the dose range of 10-80 mg following single- or multiple-dose administration of CLOBAMAX. Based on a population pharmacokinetic analysis, the pharmacokinetics of clobazam are linear from 5-160 mg/day. Clobazam is converted to N-desmethylclobazam which has about 1/5 the activity of clobazam. The estimated mean elimination half-lives (t½) of clobazam and N-desmethylclobazam were 36-42 hours and 71-82 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, CLOBAMAX tablets and suspension were shown to have similar bioavailability under fasted conditions. The administration of CLOBAMAX 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 80-90% 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. N-desmethylclobazam, an active metabolite, is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations are 3-5 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. N-desmethylclobazam 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. 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.
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 CLOBAMAX 20 mg/day. There were insignificant changes in Cmax (3-24%) 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 CLOBAMAX 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.
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 and N-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 CLOBAMAX to Affect Other Drugs
The effect of repeated 40 mg once-daily doses of CLOBAMAX 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 CLOBAMAX.
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 CLOBAMAX. Some hormonal contraceptives are metabolized by CYP3A4 and their effectiveness may be diminished when given with CLOBAMAX. Repeated CLOBAMAX 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 CLOBAMAX
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 pharmacogenomics data. Dosage adjustment of CLOBAMAX may be necessary when co-administered with strong or moderate CYP2C19 inhibitors.
The effects of concomitant antiepileptic drugs that are CYP3A4 inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C9 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), and CYP2C9 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.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
The carcinogenic potential of clobazam has not been adequately assessed. In a limited study in rats, oral administration of clobazam (4, 20, and 100 mg/kg/day) for 2 years resulted in an increased incidence of thyroid follicular cell adenomas in males at the high dose.
Mutagenesis
Clobazam and the major active metabolite, N-desmethylclobazam, were negative for genotoxicity, based on data from a battery of in vitro (bacteria reverse mutation, mammalian clastogenicity) and in vivo (mouse micronucleus) assays.
Impairment of Fertility
In a study in which clobazam (50, 350, or 750 mg/kg/day) was orally administered to male and female rats prior to and during mating and continuing in females to gestation day 6, increases in abnormal sperm and pre-implantation loss were observed at the highest dose tested. The no effect level for fertility and early embryonic development in rats was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than those in humans at the maximum recommended human dose of 40 mg/day.
Special Precautions for Storage
Store protected from light, moisture and temperature not exceeding 30 degree Celsius.