Clobazam

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# Overview
Clobazam is a Benzodiazepine that is FDA approved for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older.   Common adverse reactions include constipation, somnolence or sedation, pyrexia, lethargy, and drooling.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Seizures associated with Lennox-Gastaut syndrome (LGS)
- A daily dose of clobazam greater than 5 mg should be administered in divided doses twice daily
- 5 mg daily dose can be administered as a single dose.
- Dose patients according to body weight.
- 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.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Clobazam in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Clobazam in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)

### Seizures associated with Lennox-Gastaut syndrome (LGS) (2 years of age or older)
- A daily dose of clobazam greater than 5 mg should be administered in divided doses twice daily
- 5 mg daily dose can be administered as a single dose.
- Dose patients according to body weight.
- 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.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Clobazam in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Clobazam in pediatric patients.

# Contraindications
- Clobazam is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients.
- Hypersensitivity reactions have included serious dermatological reactions.

# Warnings

### Somnolence or Sedation
- Clobazam 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 clobazam is known.

### Potentiation of Sedation from Concomitant Use with Central Nervous System Depressants
- Since clobazam 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.

### Withdrawal Symptoms
- Abrupt discontinuation of clobazam should be avoided.
- Clobazam should be tapered by decreasing the dose every week by 5-10 mg/day until discontinuation.
- Withdrawal symptoms (Benzodiazepine withdrawal syndrome) occurred following abrupt discontinuation of clobazam; the risk of withdrawal symptoms is greater with higher doses.
- As with all antiepileptic drugs, clobazam 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 clobazam 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.
- Clobazam 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 clobazam or other psychotropic agents because of the predisposition of such patients to habituation and dependence.

### Suicidal Behavior and Ideation
- Antiepileptic drugs (AEDs), including clobazam, 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% cclobazamdence interval : 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 clobazam 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

## 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.
- During its development for the adjunctive treatment of seizures associated with LGS, clobazam was administered to 333 healthy volunteers and 300 patients with a current or prior diagnosis of LGS, including 197 patients treated for 12 months or more.
- The conditions and duration of exposure varied greatly and included single- and multiple-dose clinical pharmacology studies in healthy volunteers and two double-blind studies in patients with LGS (Study 1 and 2). Only Study 1 included a placebo group, allowing comparison of adverse reaction rates on clobazam at several doses to placebo.
Adverse Reactions Leading to Discontinuation in an LGS Placebo Controlled Clinical Trial (Study 1)
- The adverse reactions associated with clobazam treatment discontinuation in 1% of patients in decreasing order of frequency included lethargy, somnolence, ataxia, aggression, fatigue, and insomnia.
Most Common Adverse Reactions in an LGS Placebo Controlled Clinical Trial (Study 1)
Table 3 lists the adverse reactions that occurred in 5% of clobazam treated patients (at any dose), and at a rate greater than placebo treated patients, in the randomized, double-blind, placebo-controlled, parallel group clinical study of adjunctive AED therapy for 15 weeks (Study 1).

## Postmarketing Experience
These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure. 
Adverse reactions are categorized by system organ class.

### Blood Disorders
- Anemia
- Eosinophilia
- Leukopenia
- Thrombocytopenia

### Eye Disorders
- Diplopia
- Vision blurred

### Gastrointestinal Disorders
- Abdominal distention

### General Disorders and Administration Site Conditions
- Hypothermia

### Investigations
- Hepatic enzyme increased

### Musculoskeletal
- Muscle spasms

### Psychiatric Disorders
- Agitation
- Anxiety
- Apathy
- Confusional state
- Depression
- Delirium
- Delusion
- Hallucination

### Renal and Urinary Disorders
- Urinary retention

### Respiratory Disorders
- Aspiration
- Respiratory depression

### Skin and Subcutaneous Tissue Disorders
- Rash
- Urticaria
- Angioedema
- Facial and lip edema

# Drug Interactions

### Effect of clobazam on Other Drugs
- Clobazam is a weak CYP3A4 inducer.
- As some hormonal contraceptives are metabolized by CYP3A4, their effectiveness may be diminished when given with clobazam.
- Additional non-hormonal forms of contraception are recommended when using clobazam.
- Clobazam inhibits CYP2D6.
- Dose adjustment of drugs metabolized by CYP2D6 may be necessary.
- 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 clobazam may be necessary when co-administered with strong CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, ticlopidine) or moderate CYP2C19 inhibitors (e.g., omeprazole).

### CNS Depressants and Alcohol
- Concomitant use of clobazam with other CNS depressants may increase the risk of sedation and somnolence.
- Alcohol, as a CNS depressant, will interact with clobazam 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.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of clobazam 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. Clobazam 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, embryofetal mortality and incidences of fetal skeletal variations were increased at all doses.
- The low effect dose for embryofetal 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 embryofetal 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 embryofetal 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 embryofetal mortality at the high dose, decreased pup survival at the mid and high doses and alterations in offspring behavior (locomotor 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.
Pregnancy Category (AUS): C
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clobazam in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Clobazam during labor and delivery.

### Nursing Mothers
- Clobazam is excreted in human milk.
- Because of the potential for serious adverse reactions in nursing infants from clobazam, 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.

### Geriatic Use
- 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.
- 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.

### Gender
- 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
- No dose adjustment is required for patients with mild and moderate renal impairment.
- There is no experience with clobazam 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.

### 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, 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 clobazam in patients with severe hepatic impairment.
- Therefore no dosing recommendation in those patients can be given.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Clobazam in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Clobazam in patients who are immunocompromised.

### 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.

# Administration and Monitoring

### Administration
- Oral
- Instruct patients to read the "Instructions for Use" carefully for complete directions on how to properly dose and administer clobazam oral suspension.

### clobazam Tablet Oral Administration
- Clobazam tablets can be taken with or without food.
- Clobazam tablets can be administered whole, broken in half along the score, or crushed and mixed in applesauce.

### Clobazam Oral Suspension Oral Administration
- Clobazam oral suspension can be taken with or without food.
- Shake clobazam Oral Suspension well before every administration.
- When administering the oral suspension, use only the oral dosing syringe provided with the product.
- Each carton includes two syringes, but only one syringe should be used for dosing.
- The second oral syringe is reserved as a replacement in case the first syringe is damaged or lost.
- Insert the provided adapter firmly into the neck of the bottle before first use and keep the adapter in place for the duration of the usage of the bottle. *To withdraw the dose, insert the dosing syringe into the adapter and invert the bottle then slowly pull back the plunger to prescribed dose.
- After removing the syringe from the bottle adapter, slowly squirt clobazam Oral Suspension into the corner of the patient's mouth.
- Replace the cap after each use.
- The cap fits over the adapter when the adapter is properly placed.

### Monitoring
- Monitor for central nervous system (CNS) depression.
- Monitor patients with a history of substance abuse for signs of habituation and dependence.
- Monitor for suicidal thoughts or behaviors.
- Monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment initiation or when re-introducing therapy.

# IV Compatibility
There is limited information regarding the compatibility of Clobazam and IV administrations.

# Overdosage

### 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 alcohol.

### 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.

# 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.

## Structure
- Clobazam is a white or almost white, crystalline powder with a slightly bitter taste; is slightly soluble in water, sparingly soluble in ethanol, and freely soluble in methylene chloride.
- The melting range of clobazam is from 182oC to 185oC.
- The molecular formula is C16H13O2N2Cl and the molecular weight is 300.7.

## Pharmacodynamics

### Effects on Electrocardiogram
- The effect of clobazam 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% cclobazamdence 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.

## 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 clobazam.
- 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 (t1/2) 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, 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 80-90% 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
- 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.
- Population pharmacokinetic analyses showed no difference in the clearance of clobazam between women and men.
- 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.
- The effect of renal impairment on the pharmacokinetics of clobazam was evaluated in patients with mild (creatinine clearance  >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 (3-24%) 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.
- 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.

### Drug Interaction 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 CYP2B6and CYP2C8 has not been evaluated.
- Clobazam and N-desmethylclobazam do not inhibit P-glycoprotein (P-gp), but are P-gp substrates.
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. 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.
- Dosage adjustment of clobazam 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 clobazam.

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility
- 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.
- 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.
- 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.

# Clinical Studies
The effectiveness of clobazam for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome was established in two multicenter controlled studies (Study 1 and Study 2). Both studies were similar in terms of disease characteristics and concomitant AED treatments. The most common concomitant AED treatments at baseline included: valproate, lamotrigine, levetiracetam, and topiramate.

### Study 1
Study 1 (N=238) was a randomized, double-blind, placebo-controlled study consisting of a 4-week baseline period followed by a 3-week titration period and 12-week maintenance period. Patients age 2-54 years with a current or prior diagnosis of LGS were stratified into 2 weight groups (12.5 kg to 30 kg or >30 kg) and then randomized to placebo or one of three target maintenance doses of clobazam according to Table 5.
Doses above 5 mg/day were administered in two divided doses.
The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to 12-week maintenance period.
The pre-dosing baseline mean weekly drop seizure frequency was 98, 100, 61, and 105 for the placebo, low-, medium-, and high-dose groups, respectively. Figure 1 presents the mean percent reduction in weekly drop seizures from this baseline. All dose groups of clobazam were statistically superior (p0.05) to the placebo group. This effect appeared to be dose dependent.
Figure 2 shows changes from baseline in weekly drop seizure frequency by category for patients treated with clobazam and placebo in Study 1. Patients in whom the seizure frequency increased are shown at left as "worse." Patients in whom the seizure frequency decreased are shown in five categories.
There was no evidence that tolerance to the therapeutic effect of clobazam developed during the 3-month maintenance period.

### Study 2
Study 2 (N=68) was a randomized, double-blind comparison study of high- and low-dose clobazam, consisting of a 4-week baseline period followed by a 3-week titration period and 4-week maintenance period. Patients age 2-25 years with a current or prior diagnosis of LGS were stratified by weight, then randomized to either a low or high dose of clobazam, and then entered a 3-week titration period.
The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to the 4-week maintenance period.
A statistically significantly greater reduction in seizure frequency was observed in the high-dose group compared to the low-dose group (median percent reduction of 93% vs 29%; p<0.05).

# How Supplied

### Clobazam- Tablets
Each clobazam tablet contains 10 mg or 20 mg of clobazam.
- It is a white to off-white, oval tablet with a functional score on one side and either a "1" and "0" or a "2" and "0" debossed on the other side.
NDC 67386-314-01: 10 mg scored tablet, Bottles of 100
NDC 67386-315-01: 20 mg scored tablet, Bottles of 100
- NDC 67386-314-01: 10 mg scored tablet, Bottles of 100
- NDC 67386-315-01: 20 mg scored tablet, Bottles of 100

### Clobazam- Oral suspension
- Clobazam oral suspension is a berry flavored off-white liquid supplied in a bottle with child-resistant closure.
- The oral suspension is packaged with a dispenser set which contains two calibrated oral dosing syringes and a bottle adapter.
NDC 67386-313-21: 2.5 mg/mL supplied in a bottle containing 120 mL of suspension.
- NDC 67386-313-21: 2.5 mg/mL supplied in a bottle containing 120 mL of suspension.

## Storage

### Clobazam Tablets
- Store tablets and oral suspension at 20C to 25C (68F to 77F). See USP controlled room temperature.

### Clobazam Oral suspension
- Store and dispense clobazam oral suspension in its original bottle in an upright position.
- Use within 90 days of first opening the bottle, then discard any remainder
- Store tablets and oral suspension at 20C to 25C (68F to 77F). See USP controlled room temperature.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information

### Hypersensitivity
Inform patients or caregivers that clobazam is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients.

### Somnolence or Sedation
Advise patients or caregivers to check with their healthcare provider before clobazam is taken with other CNS depressants such as other benzodiazepines, opioids, tricyclic antidepressants, sedating antihistamines, or alcohol.
If applicable, caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that clobazam does not affect them adversely (e.g., impair judgment, thinking or motor skills).

### Increasing or Decreasing the clobazam Dose
Inform patients or caregivers to consult their healthcare provider before increasing the clobazam dose or abruptly discontinuing clobazam. Advise patients or caregivers that abrupt withdrawal of AEDs may increase their risk of seizure.

### Interactions with Hormonal Contraceptives
Counsel women to also use non-hormonal methods of contraception when clobazam is used with hormonal contraceptives and to continue these alternative methods for 28 days after discontinuing clobazam to ensure contraceptive reliability.

### Serious Dermatological Reactions
Advise patients or caregivers that serious skin reactions have been reported in patients taking clobazam.  Serious skin reactions, including SJS/TEN, may need to be treated in a hospital and may be life-threatening. If a skin reaction occurs while taking clobazam, patients or caregivers should consult with healthcare providers immediately.

### Suicidal Thinking and Behavior
Counsel patients, their caregivers, and their families that AEDs, including clobazam, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Patients should report behaviors of concern immediately to healthcare providers.

### Use in Pregnancy
Instruct patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy.

### Use in Nursing
Instruct patients to notify their physician if they are breast feeding or intend to breast feed during therapy.

# Precautions with Alcohol
- Since clobazam 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.

# Brand Names
- ONFI

# Look-Alike Drug Names
There is limited information regarding Clobazam Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price