- 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)]
- Suicidal Behavior and Ideation [see Warnings and Precautions (5.7)]
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) [see Clinical Studies (14)]. 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).
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
|Clobazam Dose Level|
|Placebo N=59 %||Lowa N=58 %||Mediumb N=62 %||Highc N=59 %||All Clobazam N=179 %|
|General Disorders and Administration Site Conditions|
|Infections and Infestations|
|Upper respiratory tract infection||10||10||13||14||12|
|Urinary tract infection||0||2||5||5||4|
|Metabolism and Nutrition Disorders|
|Nervous System Disorders|
|Somnolence or Sedation||15||17||27||32||26|
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
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 [see Warnings and Precautions (5.1)].
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)].
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)].
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)].
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