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)]

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. The following adverse events have been reported in clinical trials of patients treated with clobazam, the active ingredient of SYMPAZAN®.

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).

Table 3: Adverse Reactions Reported for ≥5% of Patients and More Frequently than Placebo in Any Treatment Group
			Clobazam Dose Level				All Clobazam N=179 %
		Placebo N=59 %	Lowa N=58 %	Mediumb N=62 %		Highc 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

The following adverse reactions have been identified during post-approval use of clobazam tablets. 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