SABRIL (Page 5 of 11)

5.10 Weight Gain

SABRIL causes weight gain in adult and pediatric patients.

Data pooled from randomized controlled trials in adults found that 17% (77/443) of SABRIL patients versus 8% (22/275) of placebo patients gained ≥7% of baseline body weight. In these same trials, the mean weight change among SABRIL patients was 3.5 kg compared to 1.6 kg for placebo patients.

Data pooled from randomized controlled trials in pediatric patients with refractory complex partial seizures found that 47% (77/163) of SABRIL patients versus 19% (19/102) of placebo patients gained ≥7% of baseline body weight.

In all epilepsy trials, 0.6% (31/4855) of SABRIL patients discontinued for weight gain. The long term effects of SABRIL related weight gain are not known. Weight gain was not related to the occurrence of edema.

5.11 Edema

SABRIL causes edema in adults. Pediatric clinical trials were not designed to assess edema, but observed incidence of edema based pooled data from controlled pediatric studies appeared similar for pediatric patients on vigabatrin and placebo.

Pooled data from controlled trials demonstrated increased risk among SABRIL patients compared to placebo patients for peripheral edema (SABRIL 2%, placebo 1%), and edema (SABRIL 1%, placebo 0%). In these studies, one SABRIL and no placebo patients discontinued for an edema related AE. In adults, there was no apparent association between edema and cardiovascular adverse events such as hypertension or congestive heart failure. Edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function.

6 ADVERSE REACTIONS

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

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. add-on clinical studies of refractory CPS in adults.

Table 5. Adverse Reactions in Pooled, Add-On 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 10 to 16 years of age
Table 6 lists adverse reactions from controlled clinical studies of pediatric patients receiving SABRIL or placebo as add-on 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, Add-On Trials in Pediatric Patients 10 to 16 Years of Age with Refractory Complex Partial Seizures
Body System Adverse Reaction All SABRIL[N=109] % Placebo[N=46]%
Eye Disorders
Diplopia 5 0
Blurred vision 3 0
Gastrointestinal Disorders
Diarrhea 6 2
Upper abdominal pain 3 0
Constipation 3 2
General Disorders
Fatigue 9 4
Infections and Infestations
Upper respiratory tract infection 10 4
Influenza 6 2
Otitis media 6 2
Investigations
Weight gain 17 2
Nervous System Disorders
Somnolence 6 2
Tremor 6 0
Nystagmus 5 2
Psychomotor hyperactivity 4 2
Psychiatric Disorders
Abnormal behavior 6 2
Aggression 5 0
Disorientation 4 0
Reproduction and Breast Disorders
Dysmenorrhea 3 0
Skin and Subcutaneous Tissue Disorders
Acne 3 0

Infantile SpasmsIn 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

Body System

Adverse Reaction

SABRILLow Dose

[N=114]

%

SABRIL High Dose

[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

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