6 ADVERSE REACTIONS

The following serious and otherwise important adverse reactions are described elsewhere in labeling:

Permanent Vision Loss [see BOXED WARNING and Warnings and Precautions (5.1)]
Magnetic Resonance Imaging (MRI) Abnormalities in Infants [see Warnings and Precautions (5.3)]
Neurotoxicity [see Warnings and Precautions (5.4)]
Suicidal Behavior and Ideation [see Warnings and Precautions (5.5)]
Withdrawal of Antiepileptic Drugs (AEDs) [see Warnings and Precautions (5.6)]
Anemia [see Warnings and Precautions (5.7)]
Somnolence and Fatigue [see Warnings and Precautions (5.8)]
Peripheral Neuropathy [see Warnings and Precautions (5.9)]
Weight Gain [see Warnings and Precautions (5.10)]
Edema [see Warnings and Precautions (5.11)]

6.1 Clinical Trial 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.

In U.S. and primary non-U.S. clinical studies of 4,079 SABRIL-treated patients, the most common (≥5%) adverse reactions associated with the use of SABRIL in combination with other AEDs were headache, somnolence, fatigue, dizziness, convulsion, nasopharyngitis, weight gain, upper respiratory tract infection, visual field defect, depression, tremor, nystagmus, nausea, diarrhea, memory impairment, insomnia, irritability, abnormal coordination, blurred vision, diplopia, vomiting, influenza, pyrexia, and rash.

The adverse reactions most commonly associated with SABRIL treatment discontinuation in ≥1% of patients were convulsion and depression.

In patients with infantile spasms, the adverse reactions most commonly associated with SABRIL treatment discontinuation in ≥1% of patients were infections, status epilepticus, developmental coordination disorder, dystonia, hypotonia, hypertonia, weight gain, and insomnia.

Refractory Complex Partial Seizures
Adults
Table 5 lists the adverse reactions that occurred in ≥2% and more than one patient per SABRIL-treated group and that occurred more frequently than in placebo patients from 2 U.S. adjunctive clinical studies of refractory CPS in adults.

Table 5. Adverse Reactions in Pooled, Adjunctive Trials in Adults with Refractory Complex Partial Seizures
	SABRIL dosage (mg/day)
Body System Adverse Reaction	3000 [N=134] %	6000 [N=43] %	Placebo [N=135] %
Ear Disorders
Tinnitus	2	0	1
Vertigo	2	5	1
Eye Disorders
Blurred vision	13	16	5
Diplopia	7	16	3
Asthenopia	2	2	0
Eye pain	0	5	0
Gastrointestinal Disorders
Diarrhea	10	16	7
Nausea	10	2	8
Vomiting	7	9	6
Constipation	8	5	3
Upper abdominal pain	5	5	1
Dyspepsia	4	5	3
Stomach discomfort	4	2	1
Abdominal pain	3	2	1
Toothache	2	5	2
Abdominal distension	2	0	1
General Disorders
Fatigue	23	40	16
Gait disturbance	6	12	7
Asthenia	5	7	1
Edema peripheral	5	7	1
Fever	4	7	3
Chest pain	1	5	1
Thirst	2	0	0
Malaise	0	5	0
Infections
Nasopharyngitis	14	9	10
Upper respiratory tract infection	7	9	6
Influenza	5	7	4
Urinary tract infection	4	5	0
Bronchitis	0	5	1
Injury
Contusion	3	5	2
Joint sprain	1	2	1
Muscle strain	1	2	1
Wound secretion	0	2	0
Metabolism and Nutrition Disorders
Increased appetite	1	5	1
Weight gain	6	14	3
Musculoskeletal Disorders
Arthralgia	10	5	3
Back pain	4	7	2
Pain in extremity	6	2	4
Myalgia	3	5	1
Muscle twitching	1	9	1
Muscle spasms	3	0	1
Nervous System Disorders
Headache	33	26	31
Somnolence	22	26	13
Dizziness	24	26	17
Nystagmus	13	19	9
Tremor	15	16	8
Memory impairment	7	16	3
Abnormal coordination	7	16	2
Disturbance in attention	9	0	1
Sensory disturbance	4	7	2
Hyporeflexia	4	5	1
Paraesthesia	7	2	1
Lethargy	4	7	2
Hyperreflexia	4	2	3
Hypoaesthesia	4	5	1
Sedation	4	0	0
Status epilepticus	2	5	0
Dysarthria	2	2	1
Postictal state	2	0	1
Sensory loss	0	5	0
Psychiatric Disorders
Irritability	7	23	7
Depression	6	14	3
Confusional state	4	14	1
Anxiety	4	0	3
Depressed mood	5	0	1
Abnormal thinking	3	7	0
Abnormal behavior	3	5	1
Expressive language disorder	1	7	1
Nervousness	2	5	2
Abnormal dreams	1	5	1
Reproductive System
Dysmenorrhea	9	5	3
Erectile dysfunction	0	5	0
Respiratory and Thoracic Disorders
Pharyngolaryngeal pain	7	14	5
Cough	2	14	7
Pulmonary congestion	0	5	1
Sinus headache	6	2	1
Skin and Subcutaneous Tissue Disorders
Rash	4	5	4

Pediatrics 2 to 16 years of age
Table 6 lists adverse reactions from controlled clinical studies of pediatric patients receiving SABRIL or placebo as adjunctive therapy for refractory complex partial seizures. Adverse reactions that are listed occurred in at least 2% of SABRIL-treated patients and more frequently than placebo. The median SABRIL dose was 49.4 mg/kg (range of 8.0 – 105.9 mg/kg).

Table 6. Adverse Reactions in Pooled, Adjunctive Trials in Pediatric Patients 3 to 16 Years of Age with Refractory Complex Partial Seizures
Body System Adverse Reaction	All SABRIL [N=165] %	Placebo [N=104] %
Eye Disorders
Diplopia	3	2
Blurred vision	2	0
Gastrointestinal Disorders
Upper abdominal pain	4	3
Constipation	2	1
General Disorders
Fatigue	10	7
Infections and Infestations
Upper respiratory tract infection	15	11
Influenza	7	3
Otitis media	6	4
Streptococcal pharyngitis	4	3
Viral gastroenteritis	2	0
Investigations
Weight gain	15	2
Nervous System Disorders
Somnolence	6	5
Nystagmus	4	3
Tremor	4	2
Status epilepticus	2	1
Psychiatric Disorders
Abnormal behavior	7	6
Aggression	6	2
Disorientation	3	0

Safety of SABRIL for the treatment of refractory CPS in patients 2 years of age is expected to be similar to pediatric patients 3 to 16 years of age.

Infantile Spasms
In a randomized, placebo-controlled IS study with a 5 day double-blind treatment phase (n=40), the adverse reactions that occurred in >5% of patients receiving SABRIL and that occurred more frequently than in placebo patients were somnolence (SABRIL 45%, placebo 30%), bronchitis (SABRIL 30%, placebo 15%), ear infection (SABRIL 10%, placebo 5%), and acute otitis media (SABRIL 10%, placebo 0%).

In a dose response study of low-dose (18-36 mg/kg/day) versus high-dose (100-148 mg/kg/day) SABRIL, no clear correlation between dose and incidence of adverse reactions was observed. The adverse reactions (≥5% in either dose group) are summarized in Table 7.

Table 7. Adverse Reactions in a Placebo-Controlled Trial in Patients with Infantile Spasms
	SABRIL Low Dose	SABRIL High Dose
Body System Adverse Reaction	[N=114] %	[N=108] %
Eye Disorders (other than field or acuity changes)
Strabismus	5	5
Conjunctivitis	5	2
Gastrointestinal Disorders
Vomiting	14	20
Constipation	14	12
Diarrhea	13	12
General Disorders
Fever	29	19
Infections
Upper respiratory tract infection	51	46
Otitis media	44	30
Viral infection	20	19
Pneumonia	13	11
Candidiasis	8	3
Ear infection	7	14
Gastroenteritis viral	6	5
Sinusitis	5	9
Urinary tract infection	5	6
Influenza	5	3
Croup infectious	5	1
Metabolism & Nutrition Disorders
Decreased appetite	9	7
Nervous System Disorders
Sedation	19	17
Somnolence	17	19
Status epilepticus	6	4
Lethargy	5	7
Convulsion	4	7
Hypotonia	4	6
Psychiatric Disorders
Irritability	16	23
Insomnia	10	12
Respiratory Disorders
Nasal congestion	13	4
Cough	3	8
Skin and Subcutaneous Tissue Disorders
Rash	8	11

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of SABRIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are categorized by system organ class.

Birth Defects: Congenital cardiac defects, congenital external ear anomaly, congenital hemangioma, congenital hydronephrosis, congenital male genital malformation, congenital oral malformation, congenital vesicoureteric reflux, dentofacial anomaly, dysmorphism, fetal anticonvulsant syndrome, hamartomas, hip dysplasia, limb malformation, limb reduction defect, low set ears, renal aplasia, retinitis pigmentosa, supernumerary nipple, talipes

Ear Disorders: Deafness

Endocrine Disorders: Delayed puberty

Gastrointestinal Disorders: Gastrointestinal hemorrhage, esophagitis

General Disorders: Developmental delay, facial edema, malignant hyperthermia, multi-organ failure

Hepatobiliary Disorders: Cholestasis

Nervous System Disorders: Dystonia, encephalopathy, hypertonia, hypotonia, muscle spasticity, myoclonus, optic neuritis, dyskinesia

Psychiatric Disorders: Acute psychosis, apathy, delirium, hypomania, neonatal agitation, psychotic disorder

Respiratory Disorders: Laryngeal edema, pulmonary embolism, respiratory failure, stridor

Skin and Subcutaneous Tissue Disorders: Angioedema, maculo-papular rash, pruritus, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), alopecia