FDA label 3b89d1e5-f686-2d3e-e054-00144ff8d46c

WARNINGS WARNINGS Neuropsychiatric Adverse Events-Pediatric Patients 3-12 Years Of Age: Gabapentin use in pediatric patients with epilepsy 3-12 years of age is associated with the occurrence of central nervous system related adverse events. 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 events were mild to moderate in intensity. In controlled trials in pediatric patients 3-12 years of age, the incidence of these adverse events was: emotional lability 6% (gabapentin-treated patients) vs 1.3% (placebo-treated patients); hostility 5.2% vs 1.3%; hyperkinesia 4.7% vs 2.9%; and thought disorder 1.7% vs 0%. One of these events, 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. Withdrawal Precipitated Seizure, Status Epilepticus: Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency. In the placebo-controlled studies in patients >12 years of age, the incidence of status epilepticus in patients receiving gabapentin was 0.6% (3 of 543) versus 0.5% in patients receiving placebo (2 of 378). Among the 2074 patients >12 years of age treated with gabapentin across all studies (controlled and uncontrolled) 31 (1.5%) had status epilepticus. Of these, 14 patients had no prior history of status epilepticus either before treatment or while on other medications. Because adequate historical data are not available, it is impossible to say whether or not treatment with gabapentin is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with gabapentin. Tumorigenic Potential: In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility .) 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 2085 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 pre-existing tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of gabapentin. Without knowledge of the background incidence and recurrence in a similar population not treated with gabapentin, it is impossible to know whether the incidence seen in this cohort is or is not affected by treatment. 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 patients treated (2103 patient-years of exposure). 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.

ADVERSE REACTIONS Postherpetic Neuralgia The most commonly observed adverse events associated with the use of Gabapentin Capsules in adults, not seen at an equivalent frequency among placebo-treated patients, were dizziness, somnolence, and peripheral edema. In the 2 controlled studies in postherpetic neuralgia, 16% of the 336 patients who received Gabapentin Capsules and 9% of the 227 patients who received placebo discontinued treatment because of an adverse event. The adverse events that most frequently led to withdrawal in -Gabapentin Capsule-treated patients were dizziness, somnolence, and nausea. Incidence in Controlled Clinical Trials Table 3 lists treatment-emergent signs and symptoms that occurred in at least 1% of Gabapentin Capsule- treated patients with postherpetic neuralgia participating in placebo-controlled trials and that were numerically more frequent in the Gabapentin Capsules group than in the placebo group. Adverse events were usually mild to moderate in intensity. TABLE 3. Treatment-Emergent Adverse Event Incidence in Controlled Trials in Postherpetic Neuralgia (Events in at least 1% of Gabapentin Capsule-Treated Patients and Numerically More Frequent Than in the Placebo Group) Body SystemGabapentin CapsulesPlaceboPreferred TermN=336N=227%%Body as a WholeAsthenia5.74.8Infection5.13.5Headache3.33.1Accidental injury3.31.3Abdominal pain2.72.6Digestive SystemDiarrhea5.73.1Dry mouth4.81.3Constipation3.91.8Nausea3.93.1Vomiting3.31.8Flatulence2.11.8Metabolic and Nutritional DisordersPeripheral edema8.32.2Weight gain1.80.0Hyperglycemia1.20.4Nervous SystemDizziness28.07.5Somnolence21.45.3Ataxia3.30.0Thinking Abnormal2.70.0Abnormal gait1.50.0Incoordination1.50.0Amnesia1.20.9Hypesthesia1.20.9Respiratory SystemPharyngitis1.20.4Skin and AppendagesRash1.20.9Special SensesAmblyopiaa2.70.9Conjunctivitis1.20.0Diplopia1.20.0Otitis media1.20.0aReported as blurred vision Other events 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 events. 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 events by race. Epilepsy The most commonly observed adverse events associated with the use of Gabapentin Capsules 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 commonly observed adverse events reported with the use of Gabapentin Capsules 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, Neuropsychiatric Adverse Events). 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 Capsules in premarketing clinical trials discontinued treatment because of an adverse event. The adverse events 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 events most commonly associated with withdrawal in pediatric patients were emotional lability (1.6%), hostility (1.3%), and hyperkinesia (1.1%). Incidence in Controlled Clinical Trials Table 4 lists treatment-emergent signs and symptoms that occurred in at least 1% of Gabapentin Capsule-treated patients >12 years of age with epilepsy participating in placebo-controlled trials and were numerically more common in the Gabapentin Capsules group. In these studies, either Gabapentin Capsules or placebo was added to the patient's current antiepileptic drug therapy. Adverse events were usually mild to moderate in intensity. The prescriber should be aware that these figures, obtained when Gabapentin Capsules was added to concurrent antiepileptic drug therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied. TABLE 4. Treatment-Emergent Adverse Event Incidence in Controlled Add-On Trials in >12 years of age (Events in at least 1% of Gabapentin Capsules patients and numerically more in the placebo group frequent than Patients. Body System /Gabapentin CapsulesaPlaceboa N=378 %Adverse EventN=543N=378%%Body as a WholeFatigue11.05.0Weight Increase2.91.6Back Pain1.80.5Peripheral Edema1.70.5CardiovascularVasodilatation1.10.3Digestive SystemDyspepsia2.20.5Mouth or Throat Dry1.70.5Constipation1.50.8Dental Abnormalities1.50.3Increased Appetite1.10.8Hematologic and Lymphatic SystemsLeukopenia1.10.5Musculoskeletal SystemMyalgia2.01.9Fracture1.10.8Nervous SystemSomnolence19.38.7Dizziness17.16.9Ataxia12.55.6Nystagmus8.34.0Tremor6.83.2Nervousness2.41.9Dysarthria2.40.5Amnesia2.20.0Depression1.81.1Thinking Abnormal1.71.3Twitching1.30.5Coordination Abnormal1.10.3Respiratory SystemRhinitis4.13.7Pharyngitis2.81.6Coughing1.81.3Skin and AppendagesAbrasion1.30.0Pruritus1.30.5Urogenital SystemImpotence1.51.1Special SensesDiplopia5.91.9Amblyopiab4.21.1Laboratory DeviationsWBC Decreased1.10.5a Plus background antoepileptic drug therapy bAmblyopia was often describes as blured vision Other events in more than 1% of patients >12 years of age but equally or more frequent in the placebo group included: headache, viral infection, fever, nausea and/or vomiting, abdominal pain, diarrhea, convulsions, confusion, insomnia, emotional lability, rash, acne. Among the treatment-emergent adverse events occurring at an incidence of at least 10% of Gabapentin Capsule-treated patients, somnolence and ataxia appeared to exhibit a positive dose-response relationship. The overall incidence of adverse events and the types of adverse events seen were similar among men and women treated with Gabapentin Capsules. The incidence of adverse events increased slightly with increasing age in patients treated with either Gabapentin Capsules 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 events by race. Table 5 lists treatment-emergent signs and symptoms that occurred in at least 2% of Gabapentin Capsule-treated patients age 3 to 12 years of age with epilepsy participating in placebo-controlled trials and were numerically more common in the Gabapentin Capsules group. Adverse events were usually mild to moderate in intensity. TABLE 5. TreatmentEmergent Adverse Event Incidence in Pediatric Patients Age 3 to 12 Years in a Controlled Add-On Trial (Events in at least 2% of Gabapentin Capsules patients and numerically more frequent than in the placebo group) Body System/Gabapentin CapsulesaPlaceboaAdverse EventN=119N=128%%Body as a WholeViral Infection10.93.1Fever10.13.1Weight Increase3.40.8Fatigue3.41.6Digestive SystemNausea and / or Vomiting8.47.0Nervous SystemSomnolence8.44.7Hostility7.62.3Emotional Lability4.21.6Dizziness2.51.6Hyperkinesia2.50.8Respiratory SystemBronchitis3.40.8Respiratory Infection2.50.8a Plus background antiepileptic drug therapy Other events 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. Other Adverse Events Observed During All Clinical Trials Clinical Trials in Adults and Adolescents (Except Clinical Trials in Neuropathic Pain) Gabapentin Capsules has been administered to 4717 patients >12 years of age during all adjunctive therapy clinical trials (except clinical trials in patients with neuropathic pain), only some of which were placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. These categories are used in the listing below. The frequencies presented represent the proportion of the 4717 patients >12 years of age exposed to Gabapentin Capsules who experienced an event of the type cited on at least one occasion while receiving Gabapentin Capsules. All reported events are included except those already listed in Table 4, those too general to be informative, and those not reasonably associated with the use of the drug. Endocrine System: Rare: hyperthyroid, hypothyroid, goiter, hypoestrogen, ovarian failure, epididymitis, swollen testicle, cushingoid appearance. Clinical trials in Pediatric Patients With Epilepsy Adverse events occurring during epilepsy clinical trials in 449 pediatric patients 3 to 12 years of age treated with gabapentin that were not reported in adjunctive trials in adults are: Body as a Whole: dehydration, infectious mononucleosis Digestive System: hepatitis Hemic and Lymphatic System: coagulation defect Nervous System: aura disappeared, occipital neuralgia Psychobiologic Function: sleepwalking Respiratory System: pseudocroup, hoarseness Clinical Trials in Adults With Neuropathic Pain of Various Etiologies Safety information was obtained in 1173 patients during double-blind and open-label clinical trials including neuropathic pain conditions for which efficacy has not been demonstrated. Adverse events reported by investigators were grouped into standardized categories using modified COSTART IV terminology. Listed below are all reported events except those already listed in Table 3 and those not reasonably associated with the use of the drug. Endocrine System: Infrequent: diabetes mellitus. Postmarketing and Other Experience In addition to the adverse experiences reported during clinical testing of Gabapentin Capsules, the following adverse experiences have been reported in patients receiving marketed Gabapentin Capsules. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose fluctuation, breast hypertrophy, erythema multiforme, elevated liver function tests, fever, hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome. Adverse events following the abrupt discontinuation of gabapentin have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain and sweating.