5 WARNINGS AND PRECAUTIONS
5.1 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with NEURONTIN. Some of these reactions have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved.
It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. NEURONTIN should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
5.2 Anaphylaxis and Angioedema
NEURONTIN can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms in reported cases have included difficulty breathing, swelling of the lips, throat, and tongue, and hypotension requiring emergency treatment. Patients should be instructed to discontinue NEURONTIN and seek immediate medical care should they experience signs or symptoms of anaphylaxis or angioedema.
5.3 Effects on Driving and Operating Heavy Machinery
Patients taking NEURONTIN should not drive until they have gained sufficient experience to assess whether NEURONTIN impairs their ability to drive. Driving performance studies conducted with a prodrug of gabapentin (gabapentin enacarbil tablet, extended-release) indicate that gabapentin may cause significant driving impairment. Prescribers and patients should be aware that patients' ability to assess their own driving competence, as well as their ability to assess the degree of somnolence caused by NEURONTIN, can be imperfect. The duration of driving impairment after starting therapy with NEURONTIN is unknown. Whether the impairment is related to somnolence [see Warnings and Precautions (5.4)] or other effects of NEURONTIN is unknown.
Moreover, because NEURONTIN causes somnolence and dizziness [see Warnings and Precautions (5.4)], patients should be advised not to operate complex machinery until they have gained sufficient experience on NEURONTIN to assess whether NEURONTIN impairs their ability to perform such tasks.
5.4 Somnolence/Sedation and Dizziness
During the controlled epilepsy trials in patients older than 12 years of age receiving doses of NEURONTIN up to 1800 mg daily, somnolence, dizziness, and ataxia were reported at a greater rate in patients receiving NEURONTIN compared to placebo: i.e., 19% in drug versus 9% in placebo for somnolence, 17% in drug versus 7% in placebo for dizziness, and 13% in drug versus 6% in placebo for ataxia. In these trials somnolence, ataxia and fatigue were common adverse reactions leading to discontinuation of NEURONTIN in patients older than 12 years of age, with 1.2%, 0.8% and 0.6% discontinuing for these events, respectively.
During the controlled trials in patients with post-herpetic neuralgia, somnolence, and dizziness were reported at a greater rate compared to placebo in patients receiving NEURONTIN, in dosages up to 3600 mg per day: i.e., 21% in NEURONTIN-treated patients versus 5% in placebo-treated patients for somnolence and 28% in NEURONTIN-treated patients versus 8% in placebo-treated patients for dizziness. Dizziness and somnolence were among the most common adverse reactions leading to discontinuation of NEURONTIN.
Patients should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence and sedation, when NEURONTIN is used with other drugs with sedative properties because of potential synergy. In addition, patients who require concomitant treatment with morphine may experience increases in gabapentin concentrations and may require dose adjustment [see Drug Interactions (7.2)].
5.5 Withdrawal Precipitated Seizure, Status Epilepticus
Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency.
In the placebo-controlled epilepsy studies in patients >12 years of age, the incidence of status epilepticus in patients receiving NEURONTIN 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 NEURONTIN across all epilepsy 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 NEURONTIN is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with NEURONTIN.
5.6 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including NEURONTIN, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5–100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
|Indication||Placebo Patients with Events Per 1,000 Patients||Drug Patients with Events Per 1,000 Patients||Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients||Risk Difference: Additional Drug Patients with Events Per 1,000 Patients|
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing NEURONTIN or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
5.8 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.
5.9 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.
5.10 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.