CLOBAZAM

Table 4. Description Proprietary Name: Not Applicable Established Name: Clobazam Tablets Dosage Forms: Tablet Route of Administration: Oral Established Pharmacologic Class of Drug: Benzodiazepine Chemical Name: 7-Chloro-1-methyl-5-phenyl-1 H -1,5- benzodiazepine-2,4(3 H ,5 H )-dione Structural Formula: Clobazam is a white or almost white, crystalline powder; is freely soluble in dichloromethane. The melting range of clobazam is from 180ºC to 182ºC. The molecular formula is C 16 H 13 ClN 2 O 2 and the molecular weight is 300.74. Each clobazam tablet contains 10 mg or 20 mg of clobazam. Tablets also contain as inactive ingredients: colloidal silicon dioxide, granulated corn starch, lactose monohydrate, magnesium stearate and talc. ClobazamStucture

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

• 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 Clobazam tablet is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of clobazam tablets. For this reason, proceed slowly with dosing escalations. For patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 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 tablets in patients with severe hepatic impairment. Therefore no dosing recommendation in those patients can be given [see Use in Specific Populations ( 8.8 ), Clinical Pharmacology ( 12.3 )].

Clobazam tablet is 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 )

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 for >30 kg body weight c Maximum daily dose of 20 mg for ≤30 kg body weight; 40 mg for >30 kg body weight 6.2 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, and facial and lip edema

• 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 tablets ( 7.3 ) • Strong or Moderate CYP2C19 Inhibitors: Dosage adjustment of clobazam 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 tablets 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 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 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 )].