Clobazam

RECENT MAJOR CHANGES Warnings and Precautions ( 5.7 ) 3/2024

1 INDICATIONS AND USAGE Clobazam tablets are indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. Clobazam tablets are a benzodiazepine indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. ( 1 )

2 DOSAGE AND ADMINISTRATION • For doses above 5 mg/day administer in two divided doses ( 2.1 ) • Patients ≤30 kg body weight: Initiate at 5 mg daily and titrate as tolerated up to 20 mg daily ( 2.1 ) • Patients >30 kg body weight: Initiate at 10 mg daily and titrate as tolerated up to 40 mg daily ( 2.1 ) • Dosage adjustment needed in following groups: o Geriatric patients ( 2.4 , 8.5 ) o Known CYP2C19 poor metabolizers ( 2.5 ) o Mild or moderate hepatic impairment; no information for severe hepatic impairment ( 2.7 , 8.8 ) • Tablets: Administer whole, broken in half along the score, or crush and mix in applesauce ( 2.3 ) • Tablets: Can be taken with or without food ( 2.3 ) 2.1 Dosing Information A daily dose of clobazam tablets 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 mg to 20 mg in ≤30 kg weight group) has been shown to be effective, although effectiveness increases with increasing dose [see Clinical Studies ( 14 )]. 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 2.2 Discontinuation or Dosage Reduction of Clobazam Tablets To reduce the risk of withdrawal reactions, increased seizure frequency, and status epilepticus, use a gradual taper to discontinue clobazam tablets or reduce the dosage. Taper by decreasing the total daily dose by 5 to 10 mg/day on a weekly basis until discontinued. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly [see Warnings and Precautions ( 5.3 ) and Drug Abuse and Dependence ( 9.3 )] . 2.3 Important Administration Instructions 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. 2.4 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 [see Use in Specific Populations ( 8.5 )]. 2.5 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 [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.5 )]. 2.6 Patients with Renal Impairment No dose adjustment is required for patients with mild and moderate renal impairment. There is no experience with clobazam tablets 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 [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. 2.7 Dosage Adjustments in Patients with Hepatic Impairment …

3 DOSAGE FORMS AND STRENGTHS Tablets: 10 mg and 20 mg with a functional score for oral administration. Clobazam tablets, 10 mg are white to off-white, oval tablet with a functional score on one side, debossed with a “C” on the left side of the score and “2” on the right side of the score and plain on other side. Clobazam tablets, 20 mg are white to off-white, oval tablet with a functional score on one side, debossed with a “C” on the left side of the score and “3” on the right side of the score and plain on other side. Tablet: 10 mg and 20 mg with a functional score. ( 3 )

4 CONTRAINDICATIONS Clobazam tablets are contraindicated in patients with a history of hypersensitivity to the drug or its ingredients. Hypersensitivity reactions have included serious dermatological reactions [see Warnings and Precautions ( 5.6 , 5.7 )] . History of hypersensitivity to the drug or its ingredients ( 4 )

6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include the following: • Risks from Concomitant Use with Opioids [see Warnings and Precautions ( 5.1 )] • Abuse, Misuse, and Addiction [see Warnings and Precautions ( 5.2 )] • Dependence and Withdrawal Reactions [see Warnings and Precautions ( 5.3 )] • Potentiation of Sedation from Concomitant Use with Central Nervous System Depressants [see Warnings and Precautions ( 5.4 )] • Somnolence or Sedation [see Warnings and Precautions ( 5.5 )] • Serious Dermatological Reactions [see Contraindications ( 4 ), Warnings and Precautions ( 5.6 )] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions ( 5.7 )] • Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.8 )] • Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions ( 5.9 )] Adverse reactions that occurred at least 10% more frequently than placebo in any clobazam dose included constipation, somnolence or sedation, pyrexia, lethargy, and drooling ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 tablets 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) [see Clinical Studies ( 14 )] . Only Study 1 included a placebo group, allowing comparison of adverse reaction rates on clobazam tablets 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 tablets 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 tablets-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). Table 3. Adverse Reactions Reported for ≥5% of Patients and More Frequently than Placebo in Any Treatment Group Placebo N=59 % Clobazam Dose Level All Clobazam N=179 % Low a N=58 % Medium b N=62 % High c N=59 % Gastrointestinal Disorders Vomiting 5 9 5 7 7 Constipation 0 2 2 10 5 Dysphagia 0 0 0 5 2 General Disorders and Administration Site Conditions Pyrexia 3 17 10 12 13 Irritability 5 3 11 5 7 Fatigue 2 5 5 3 5 Infections and Infestations Upper respiratory tract infection 10 10 13 14 12 Pneumonia 2 3 3 7 4 Urinary tract infection 0 2 5 5 4 Bronchitis 0 2 0 5 2 Metabolism and Nutrition Disorders Decreased appetite 3 3 0 7 3 Increased appetite 0 2 3 5 3 Nervous System Disorders Somnolence or Sedation 15 17 27 32 26 Somnolence 12 16 24 25 22 Sedation 3 2 3 9 5 Lethargy 5 10 5 15 10 Drooling 3 0 13 14 9 Ataxia 3 3 2 10 5 Psychomotor hyperactivity 3 3 3 5 4 Dysarthria 0 2 2 5 3 Psychiatric Disorders Aggression 5 3 8 14 8 Insomnia 2 2 5 7 5 Respiratory Disorders Cough 0 3 5 7 5 a Maximum daily dose of 5 mg for ≤30 kg body weight; 10 mg for >30 kg body weight b Maximum daily dose of 10 mg for ≤30 kg body weight; 20 mg f …

7 DRUG INTERACTIONS • Alcohol: Increases blood levels of clobazam by about 50% ( 7.2 ) • Drugs metabolized by CYP2D6: Lower doses of these drugs may be required when used concomitantly with clobazam ( 7.3 ) • Strong or Moderate CYP2C19 Inhibitors: Dosage adjustment of clobazam tablet may be necessary ( 7.4 ) 7.1 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 GABA A 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 [see Warnings and Precautions ( 5.1 )] . 7.2 CNS Depressants and Alcohol Concomitant use of clobazam with other CNS depressants may increase the risk of sedation and somnolence [see Warnings and Precautions ( 5.4 )] . 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 [see Warnings and Precautions ( 5.4 )] . 7.3 Effect of Clobazam Tablets on Other Drugs Hormonal Contraceptives 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 [see Clinical Pharmacology ( 12.3 ), Patient Counseling Information ( 17 )] . Drugs Metabolized by CYP2D6 Clobazam inhibits CYP2D6. Dose adjustment of drugs metabolized by CYP2D6 may be necessary [see Clinical Pharmacology ( 12.3) ] . 7.4 Effect of Other Drugs on Clobazam Tablets 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) [see Clinical Pharmacology ( 12.3 )] .

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1 ) 8.1 Pregnancy Pregnancy Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as clobazam, during pregnancy. Healthcare providers are encouraged to recommend that pregnant women taking clobazam enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or online at http://www.aedpregnancyregistry.org/. Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions ( 5.9 ) and Clinical Considerations] . Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data) . Administration of clobazam to pregnant rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation resulted in developmental toxicity, including increased incidences of fetal malformations and mortality, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients [see Animal Data] . Data for other benzodiazepines suggest the possibility of long-term effects on neurobehavioral and immunological function in animals following prenatal exposure to benzodiazepines at clinically relevant doses. Clobazam should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Advise a pregnant woman and women of childbearing age of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to clobazam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to clobazam during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions ( 5.9 )] . Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings. Animal Data In a study in which clobazam (0, 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 (0, 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. …

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 GABA A receptor.

11 DESCRIPTION Table 4. Description Established Name: Clobazam Tablets Dosage Form: Tablet Route of Administration: Oral Established Pharmacologic Class of Drug: Benzodiazepine Chemical Name: 7-Chloro-1-methyl-5-phenyl-1H-1,5 benzodiazepine-2,4( 3H,5H )-dione Structural Formula: 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 182°C to 185°C. The molecular formula is C 16 H 13 O 2 N 2 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: corn starch, crospovidone, lactose monohydrate, magnesium stearate, povidone, silicon dioxide, and talc. Chemical Structure

10 OVERDOSAGE Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions ( 5.2 )] . Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING Clobazam Tablets, 10 mg are white to off-white, oval shaped tablets with a functional score line on one face and "1" and "0" debossed on the other face. Each tablet contains 10 mg of clobazam. Bottles of 30 NDC 42571-315-30 Bottles of 90 NDC 42571-315-90 Bottles of 100 NDC 42571-315-01 Bottles of 500 NDC 42571-315-05 Carton of (Alu-Alu blister) 100 (10 x 10) Unit-dose Tablets NDC 42571-315-11 Carton of (Alu-PVC/ACLAR blister) 100 (10 x 10) Unit-dose Tablets NDC 42571-315-91 Clobazam Tablets, 20 mg are white to off-white, oval shaped tablets with a functional score line on one face and "2" and "0" debossed on the other face. Each tablet contains 20 mg of clobazam. Bottles of 30 NDC 42571-316-30 Bottles of 90 NDC 42571-316-90 Bottles of 100 NDC 42571-316-01 Carton of (Alu-Alu blister) 100 (10 x 10) Unit-dose Tablets NDC 42571-316-11 Carton of (Alu-PVC/ACLAR blister) 100 (10 x 10) Unit-dose Tablets NDC 42571-316-91 Store tablets at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].