Neurontin (Page 3 of 7)

5.7 Neuropsychiatric Adverse Reactions (Pediatric Patients 3 to 12 Years of Age)

Gabapentin use in pediatric patients with epilepsy 3 to 12 years of age is associated with the occurrence of CNS related adverse reactions. The most significant of these can be classified into the following categories: 1) emotional lability (primarily behavioral problems), 2) hostility, including aggressive behaviors, 3) thought disorder, including concentration problems and change in school performance, and 4) hyperkinesia (primarily restlessness and hyperactivity). Among the gabapentin-treated patients, most of the reactions were mild to moderate in intensity.

In controlled clinical epilepsy trials in pediatric patients 3 to 12 years of age, the incidence of these adverse reactions was: emotional lability 6% (gabapentin-treated patients) versus 1.3% (placebo-treated patients); hostility 5.2% versus 1.3%; hyperkinesia 4.7% versus 2.9%; and thought disorder 1.7% versus 0%. One of these reactions, a report of hostility, was considered serious. Discontinuation of gabapentin treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of gabapentin-treated patients reporting hostility and thought disorder. One placebo-treated patient (0.4%) withdrew due to emotional lability.

5.8 Tumorigenic Potential

In an oral carcinogenicity study, gabapentin increased the incidence of pancreatic acinar cell tumors in rats [see Nonclinical Toxicology (13.1)] . The clinical significance of this finding is unknown. Clinical experience during gabapentin’s premarketing development provides no direct means to assess its potential for inducing tumors in humans.

In clinical studies in adjunctive therapy in epilepsy comprising 2,085 patient-years of exposure in patients >12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of NEURONTIN. Without knowledge of the background incidence and recurrence in a similar population not treated with NEURONTIN, it is impossible to know whether the incidence seen in this cohort is or is not affected by treatment.

5.9 Sudden and Unexplained Death in Patients with Epilepsy

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

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 NEURONTIN (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical trial population similar to that in the NEURONTIN 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 NEURONTIN cohort and the accuracy of the estimates provided.

6 ADVERSE REACTIONS

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

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.

Postherpetic Neuralgia

The most common adverse reactions associated with the use of NEURONTIN in adults, not seen at an equivalent frequency among placebo-treated patients, were dizziness, somnolence, and peripheral edema.

In the 2 controlled trials in postherpetic neuralgia, 16% of the 336 patients who received NEURONTIN and 9% of the 227 patients who received placebo discontinued treatment because of an adverse reaction. The adverse reactions that most frequently led to withdrawal in NEURONTIN-treated patients were dizziness, somnolence, and nausea.

Table 3 lists adverse reactions that occurred in at least 1% of NEURONTIN-treated patients with postherpetic neuralgia participating in placebo-controlled trials and that were numerically more frequent in the NEURONTIN group than in the placebo group.

TABLE 3. Adverse Reactions in Pooled Placebo-Controlled Trials in Postherpetic Neuralgia
NEURONTIN N=336 % Placebo N=227 %
*
Reported as blurred vision
Body as a Whole
Asthenia 6 5
Infection 5 4
Accidental injury 3 1
Digestive System
Diarrhea 6 3
Dry mouth 5 1
Constipation 4 2
Nausea 4 3
Vomiting 3 2
Metabolic and Nutritional Disorders
Peripheral edema 8 2
Weight gain 2 0
Hyperglycemia 1 0
Nervous System
Dizziness 28 8
Somnolence 21 5
Ataxia 3 0
Abnormal thinking 3 0
Abnormal gait 2 0
Incoordination 2 0
Respiratory System
Pharyngitis 1 0
Special Senses
Amblyopia * 3 1
Conjunctivitis 1 0
Diplopia 1 0
Otitis media 1 0

Other reactions in more than 1% of patients but equally or more frequent in the placebo group included pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and flu syndrome.

There were no clinically important differences between men and women in the types and incidence of adverse reactions. Because there were few patients whose race was reported as other than white, there are insufficient data to support a statement regarding the distribution of adverse reactions by race.

Epilepsy with Partial Onset Seizures (Adjunctive Therapy)

The most common adverse reactions with NEURONTIN 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 NEURONTIN 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 NEURONTIN 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 NEURONTIN-treated patients >12 years of age with epilepsy participating in placebo-controlled trials and were numerically more common in the NEURONTIN group. In these studies, either NEURONTIN 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
NEURONTIN *N=543 % Placebo *N=378 %
*
Plus background antiepileptic drug therapy
Amblyopia was often described as blurred vision.
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
Amblyopia 4 1

Among the adverse reactions occurring at an incidence of at least 10% in NEURONTIN-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 NEURONTIN. The incidence of adverse reactions increased slightly with increasing age in patients treated with either NEURONTIN 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 NEURONTIN-treated patients, age 3 to 12 years of age with epilepsy participating in placebo-controlled trials, and which were numerically more common in the NEURONTIN group.

TABLE 5. Adverse Reactions in a Placebo-Controlled Add-On Trial in Pediatric Epilepsy Patients Age 3 to 12 Years
NEURONTIN *N=119 % Placebo *N=128 %
*
Plus background antiepileptic drug therapy
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

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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