NEURONTIN Capsule / Film-coated tablet / Solution Ref.[10600] Active ingredients: Gabapentin

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 (7.1)].

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.

Table 2. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis:

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.

5.7 Respiratory Depression

There is evidence from case reports, human studies, and animal studies associating gabapentin with serious, life-threatening, or fatal respiratory depression when coadministered with CNS depressants, including opioids, or in the setting of underlying respiratory impairment. When the decision is made to co-prescribe NEURONTIN with another CNS depressant, particularly an opioid, or to prescribe NEURONTIN to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating NEURONTIN at a low dose. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including NEURONTIN).

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.

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)]
• Respiratory Depression [see Warnings and Precautions (5.7)]
• Neuropsychiatric Adverse Reactions (Pediatric Patients 3 to 12 Years of Age) [see Warnings and Precautions (5.8)]
• Sudden and Unexplained Death in Patients with Epilepsy [see Warnings and Precautions (5.10)]

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:

^* Reported as blurred vision

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 (5.8)].

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:

^* Plus background antiepileptic drug therapy
^† Amblyopia was often described as blurred vision

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:

^* 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.

The following adverse reactions have been identified during postmarketing use of NEURONTIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hepatobiliary disorders: jaundice

Investigations: elevated creatine kinase, elevated liver function tests

Metabolism and nutrition disorders: hyponatremia

Musculoskeletal and connective tissue disorder: rhabdomyolysis

Nervous system disorders: movement disorder

Psychiatric disorders: agitation

Reproductive system and breast disorders: breast enlargement, changes in libido, ejaculation disorders and anorgasmia

Skin and subcutaneous tissue disorders: angioedema [see Warnings and Precautions (5.2)], bullous pemphigoid, erythema multiforme, Stevens-Johnson syndrome.

There are postmarketing reports of life-threatening or fatal respiratory depression in patients taking NEURONTIN with opioids or other CNS depressants, or in the setting of underlying respiratory impairment [see Warnings and Precautions (5.7)].

Adverse reactions following the abrupt discontinuation of gabapentin have also been reported. The most frequently reported reactions were anxiety, insomnia, nausea, pain, and sweating.

7.1 Opioids

Respiratory depression and sedation, sometimes resulting in death, have been reported following coadministration of gabapentin with opioids (e.g., morphine, hydrocodone, oxycodone, buprenorphine) [see Warnings and Precautions (5.7)].

Hydrocodone

Coadministration of NEURONTIN with hydrocodone decreases hydrocodone exposure [see Clinical Pharmacology (12.3)]. The potential for alteration in hydrocodone exposure and effect should be considered when NEURONTIN is started or discontinued in a patient taking hydrocodone.

Morphine

When gabapentin is administered with morphine, patients should be observed for signs of CNS depression, such as somnolence, sedation and respiratory depression [see Clinical Pharmacology (12.3)].

7.2 Other Antiepileptic Drugs

Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs [see Clinical Pharmacology (12.3)].

7.3 Maalox (aluminum hydroxide, magnesium hydroxide)

The mean bioavailability of gabapentin was reduced by about 20% with concomitant use of an antacid (Maalox) containing magnesium and aluminum hydroxides. It is recommended that gabapentin be taken at least 2 hours following Maalox administration [see Clinical Pharmacology (12.3)].

7.4 Drug / Laboratory Test Interactions

Because false positive readings were reported with the Ames N-Multistix SG dipstick test for urinary protein when gabapentin was added to other antiepileptic drugs, the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as NEURONTIN, during pregnancy. Encourage women who are taking NEURONTIN during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll free number 1-888-233-2334.

Risk Summary

There are no adequate data on the developmental risks associated with the use of NEURONTIN in pregnant women. In nonclinical studies in mice, rats, and rabbits, gabapentin was developmentally toxic (increased fetal skeletal and visceral abnormalities, and increased embryofetal mortality) when administered to pregnant animals at doses similar to or lower than those used clinically [see Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal data

When pregnant mice received oral doses of gabapentin (500, 1000, or 3000 mg/kg/day) during the period of organogenesis, embryofetal toxicity (increased incidences of skeletal variations) was observed at the two highest doses. The no-effect dose for embryofetal developmental toxicity in mice (500 mg/kg/day) is less than the maximum recommended human dose (MRHD) of 3600 mg on a body surface area (mg/m²) basis.

In studies in which rats received oral doses of gabapentin (500 to 2000 mg/kg/day) during pregnancy, adverse effect on offspring development (increased incidences of hydroureter and/or hydronephrosis) were observed at all doses. The lowest dose tested is similar to the MRHD on a mg/m² basis.

When pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryofetal mortality was observed at all doses tested (60, 300, or 1500 mg/kg). The lowest dose tested is less than the MRHD on a mg/m² basis.

In a published study, gabapentin (400 mg/kg/day) was administered by intraperitoneal injection to neonatal mice during the first postnatal week, a period of synaptogenesis in rodents (corresponding to the last trimester of pregnancy in humans). Gabapentin caused a marked decrease in neuronal synapse formation in brains of intact mice and abnormal neuronal synapse formation in a mouse model of synaptic repair. Gabapentin has been shown in vitro to interfere with activity of the α2δ subunit of voltage-activated calcium channels, a receptor involved in neuronal synaptogenesis. The clinical significance of these findings is unknown.

Risk Summary

Gabapentin is secreted in human milk following oral administration. The effects on the breastfed infant and on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NEURONTIN and any potential adverse effects on the breastfed infant from NEURONTIN or from the underlying maternal condition.

Safety and effectiveness of NEURONTIN in the management of postherpetic neuralgia in pediatric patients have not been established.

Safety and effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below the age of 3 years has not been established [see Clinical Studies (14.2)].

The total number of patients treated with NEURONTIN in controlled clinical trials in patients with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%) were 75 years of age and older. There was a larger treatment effect in patients 75 years of age and older compared to younger patients who received the same dosage. Since gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients ≥75 years may be a consequence of increased gabapentin exposure for a given dose that results from an age-related decrease in renal function. However, other factors cannot be excluded. The types and incidence of adverse reactions were similar across age groups except for peripheral edema and ataxia, which tended to increase in incidence with age.

Clinical studies of NEURONTIN in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and dose should be adjusted based on creatinine clearance values in these patients [see Dosage and Administration (2.4), Adverse Reactions (6), and Clinical Pharmacology (12.3)].

Dosage adjustment in adult patients with compromised renal function is necessary [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Pediatric patients with renal insufficiency have not been studied.

Dosage adjustment in patients undergoing hemodialysis is necessary [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Gabapentin is not a scheduled drug.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed.

Gabapentin does not exhibit affinity for benzodiazepine, opioid (mu, delta or kappa), or cannabinoid 1 receptor sites. Gabapentin misuse and abuse have been reported in the postmarketing setting and published literature. Most of the individuals described in these reports had a history of polysubstance abuse. Some of these individuals were taking higher than recommended doses of gabapentin for unapproved uses. When prescribing NEURONTIN, carefully evaluate patients for a history of drug abuse and observe them for signs and symptoms of gabapentin misuse or abuse (e.g., self-dose escalation and drug-seeking behavior). The abuse potential of gabapentin has not been evaluated in human studies.

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. There are rare postmarketing reports of individuals experiencing withdrawal symptoms shortly after discontinuing higher than recommended doses of gabapentin used to treat illnesses for which the drug is not approved. Such symptoms included agitation, disorientation and confusion after suddenly discontinuing gabapentin that resolved after restarting gabapentin. The dependence potential of gabapentin has not been evaluated in human studies.