Neurontin (gabapentin) Side Effects, Warnings, and Drug Interactions

Neurontin (gabapentin) is an anti-seizure (anti-convulsant) drug that is used for preventing seizures and for treating post-herpetic neuralgia, the pain that follows an episode of shingles. There are many non-FDA-approved uses for gabapentin, including alcohol withdrawal, cocaine withdrawal, hiccups, restless leg syndrome, excessive sweating (hyperhidrosis), headaches, diabetic neuropathy, hot flashes, and fibromyalgia.

Common side effects of Neurontin include dizziness, sleepiness, loss of coordination, fatigue, drowsiness, fluid retention (edema), hostility, nausea, vomiting, difficulty speaking, jerky movements, unusual eye movements, double vision, tremors, memory loss, and unsteadiness.

Serious side effects of Neurontin include weight gain, joint pain, motion sickness, blurred vision, and viral infection. Antiepileptic medications including gabapentin have been associated with an increased risk of suicidal thinking and behavior.

Drug interactions of Neurontin include antacids and morphine. The safety of gabapentin during pregnancy is unknown. Gabapentin is secreted in human breast milk. Breastfeeding while using gabapentin is not recommended.

The most common side effects of gabapentin are:

• Dizziness
• Sleepiness
• Ataxia
• Fatigue
• Drowsiness
• Fluid retention (edema)
• Hostility
• Nausea
• Vomiting
• Difficulty speaking
• Jerky movements
• Unusual eye movements
• Double vision
• Tremors
• Memory loss
• Unsteadiness

Other adverse effects and serious side effects associated with gabapentin include:

• Weight gain
• Joint pain
• Motion sickness
• Blurred vision
• Viral infection

Antiepileptic medications have been associated with an increased risk of suicidal thinking and behavior. Anyone considering the use of antiepileptic drugs must balance this risk of suicide with the clinical need. Patients who are started on therapy should be closely observed for clinical worsening, suicidal thoughts, or unusual changes in behavior.

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

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity
• Anaphylaxis and Angioedema
• Somnolence/Sedation and Dizziness
• Withdrawal Precipitated Seizure, Status Epilepticus
• Suicidal Behavior and Ideation
• Neuropsychiatric Adverse Reactions (Pediatric Patients 3–12 Years of Age)
• Sudden and Unexplained Death in Patients with Epilepsy

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

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.

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 hyperkinesias (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

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

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.

Postmarketing Experience

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, erythema multiforme, Stevens-Johnson syndrome.

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

Other Antiepileptic Drugs

Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs.

Opioids

Hydrocodone

Coadministration of Neurontin with hydrocodone decreases hydrocodone exposure. 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 central nervous system (CNS) depression, such as somnolence, sedation and respiratory depression.

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.

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.

Drug Abuse And Dependence

Controlled Substance

Gabapentin is not a scheduled drug.

Abuse

Gabapentin does not exhibit affinity for benzodiazepine, opiate (mu, delta or kappa), or cannabinoid 1 receptor sites. A small number of postmarketing cases report gabapentin misuse and abuse. These individuals were taking higher than recommended doses of gabapentin for unapproved uses. Most of the individuals described in these reports had a history of poly-substance abuse or used gabapentin to relieve symptoms of withdrawal from other substances. When prescribing gabapentin carefully evaluate patients for a history of drug abuse and observe them for signs and symptoms of gabapentin misuse or abuse (e.g., development of tolerance, self-dose escalation, and drug-seeking behavior).

Dependence

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. Most of these individuals had a history of poly-substance abuse or used gabapentin to relieve symptoms of withdrawal from other substances. The dependence and abuse potential of gabapentin has not been evaluated in human studies.