Gabapentin (Page 3 of 8)

5.9 Sudden and Unexplained Death in Patients with Epilepsy

During the course of premarketing development of gabapentin, 8 sudden and unexplained deaths were recorded among a cohort of 2203 epilepsy patients treated (2103 patient-years of exposure) with gabapentin.

Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0038 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving gabapentin (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical trial population similar to that in the gabapentin program, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or raise further concern depends on comparability of the populations reported upon to the gabapentin cohort and the accuracy of the estimates provided.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections:

· Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.1)]

· Anaphylaxis and Angioedema [see Warnings and Precautions (5.2)]

· Somnolence/Sedation and Dizziness [see Warnings and Precautions (5.4)]

· Withdrawal Precipitated Seizure, Status Epilepticus [see Warnings and Precautions (5.5)]

· Suicidal Behavior and Ideation [see Warnings and Precautions (5.6)]

· Neuropsychiatric Adverse Reactions (Pediatric Patients 3 to 12 Years of Age) [see Warnings and Precautions (5.7]

· Sudden and Unexplained Death in Patients with Epilepsy [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.

Epilepsy with Partial Onset Seizures (Adjunctive Therapy)

The most common adverse reactions with gabapentin in combination with other antiepileptic drugs in patients >12 years of age, not seen at an equivalent frequency among placebo-treated patients, were somnolence, dizziness, ataxia, fatigue, and nystagmus.

The most common adverse reactions with gabapentin in combination with other antiepileptic drugs in pediatric patients 3 to 12 years of age, not seen at an equal frequency among placebo-treated patients, were viral infection, fever, nausea and/or vomiting, somnolence, and hostility [see Warnings and Precautions (5.7)].

Approximately 7% of the 2074 patients >12 years of age and approximately 7% of the 449 pediatric patients 3 to 12 years of age who received gabapentin in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with withdrawal in patients >12 years of age were somnolence (1.2%), ataxia (0.8%), fatigue (0.6%), nausea and/or vomiting (0.6%), and dizziness (0.6%). The adverse reactions most commonly associated with withdrawal in pediatric patients were emotional lability (1.6%), hostility (1.3%), and hyperkinesia (1.1%).

Table 4 lists adverse reactions that occurred in at least 1% of gabapentin-treated patients >12 years of age with epilepsy participating in placebo-controlled trials and were numerically more common in the gabapentin group. In these studies, either gabapentin or placebo was added to the patient’s current antiepileptic drug therapy.

TABLE 4. Adverse Reactions in Pooled Placebo-Controlled Add-On Trials In Epilepsy Patients >12 years of age

Gabapentina N=543 %

Placeboa N=378 %

Body as a Whole

Fatigue

11

5

Increased Weight

3

2

Back Pain

2

1

Peripheral Edema

2

1

Cardiovascular

Vasodilatation

1

0

Digestive System

Dyspepsia

2

1

Dry Mouth or Throat

2

1

Constipation

2

1

Dental Abnormalities

2

0

Nervous System

Somnolence

19

9

Dizziness

17

7

Ataxia

13

6

Nystagmus

8

4

Tremor

7

3

Dysarthria

2

1

Amnesia

2

0

Depression

2

1

Abnormal thinking

2

1

Abnormal coordination

1

0

Respiratory System

Pharyngitis

3

2

Coughing

2

1

Skin and Appendages

Abrasion

1

0

Urogenital System

Impotence

2

1

Special Senses

Diplopia

6

2

Amblyopiab

4

1

a Plus background antiepileptic drug therapy

b Amblyopia was often described as blurred vision.

Among the adverse reactions occurring at an incidence of at least 10% in gabapentin-treated patients, somnolence and ataxia appeared to exhibit a positive dose-response relationship.

The overall incidence of adverse reactions and the types of adverse reactions seen were similar among men and women treated with gabapentin. The incidence of adverse reactions increased slightly with increasing age in patients treated with either gabapentin or placebo. Because only 3% of patients (28/921) in placebo-controlled studies were identified as nonwhite (black or other), there are insufficient data to support a statement regarding the distribution of adverse reactions by race.

Table 5 lists adverse reactions that occurred in at least 2% of gabapentin-treated patients, age 3 to 12 years of age with epilepsy participating in placebo-controlled trials, and which were numerically more common in the gabapentin group.

TABLE 5. Adverse Reactions in a Placebo-Controlled Add-On Trial in Pediatric Epilepsy Patients Age 3 to 12 Years

Gabapentina N=119 %

Placeboa N=128 %

Body as a Whole

Viral Infection

11

3

Fever

10

3

Increased Weight

3

1

Fatigue

3

2

Digestive System

Nausea and/or Vomiting

8

7

Nervous System

Somnolence

8

5

Hostility

8

2

Emotional Lability

4

2

Dizziness

3

2

Hyperkinesia

3

1

Respiratory System

Bronchitis

3

1

Respiratory Infection

3

1

a Plus background antiepileptic drug therapy

Other reactions in more than 2% of pediatric patients 3 to 12 years of age but equally or more frequent in the placebo group included: pharyngitis, upper respiratory infection, headache, rhinitis, convulsions, diarrhea, anorexia, coughing, and otitis media.

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