NEURONTIN: Indications and Usage
Postherpetic Neuralgia
Neurontin (gabapentin) is indicated for the management of postherpetic neuralgia in adults.
Epilepsy
Neurontin (gabapentin) is indicated as adjunctive therapy in the treatment of partial seizures with and without secondary generalization in patients over 12 years of age with epilepsy. Neurontin is also indicated as adjunctive therapy in the treatment of partial seizures in pediatric patients age 3 – 12 years.
NEURONTIN: Dosage & Administration
Neurontin is given orally with or without food. Patients should be informed that, should they break the scored 600 or 800 mg tablet in order to administer a half-tablet, they should take the unused half-tablet as the next dose. Half-tablets not used within several days of breaking the scored tablet should be discarded.
If Neurontin dose is reduced, discontinued or substituted with an alternative medication, this should be done gradually over a minimum of 1 week (a longer period may be needed at the discretion of the prescriber).
Postherpetic Neuralgia
In adults with postherpetic neuralgia, Neurontin therapy may be initiated as a single 300-mg dose on Day 1, 600 mg/day on Day 2 (divided BID), and 900 mg/day on Day 3 (divided TID). The dose can subsequently be titrated up as needed for pain relief to a daily dose of 1800 mg (divided TID). In clinical studies, efficacy was demonstrated over a range of doses from 1800 mg/day to 3600 mg/day with comparable effects across the dose range. Additional benefit of using doses greater than 1800 mg/day was not demonstrated.
Epilepsy
Neurontin is recommended for add-on therapy in patients 3 years of age and older. Effectiveness in pediatric patients below the age of 3 years has not been established.
Patients >12 years of age: The effective dose of Neurontin is 900 to 1800 mg/day and given in divided doses (three times a day) using 300 or 400 mg capsules, or 600 or 800 mg tablets. The starting dose is 300 mg three times a day. If necessary, the dose may be increased using 300 or 400 mg capsules, or 600 or 800 mg tablets three times a day up to 1800 mg/day. Dosages up to 2400 mg/day have been well tolerated in long-term clinical studies. Doses of 3600 mg/day have also been administered to a small number of patients for a relatively short duration, and have been well tolerated. The maximum time between doses in the TID schedule should not exceed 12 hours.
Pediatric Patients Age 3–12 years: The starting dose should range from 10–15 mg/kg/day in 3 divided doses, and the effective dose reached by upward titration over a period of approximately 3 days. The effective dose of Neurontin in patients 5 years of age and older is 25–35 mg/kg/day and given in divided doses (three times a day). The effective dose in pediatric patients ages 3 and 4 years is 40 mg/kg/day and given in divided doses (three times a day) (see CLINICAL PHARMACOLOGY, Pediatrics.) Neurontin may be administered as the oral solution, capsule, or tablet, or using combinations of these formulations. Dosages up to 50 mg/kg/day have been well-tolerated in a long-term clinical study. The maximum time interval between doses should not exceed 12 hours.
It is not necessary to monitor gabapentin plasma concentrations to optimize Neurontin therapy. Further, because there are no significant pharmacokinetic interactions among Neurontin and other commonly used antiepileptic drugs, the addition of Neurontin does not alter the plasma levels of these drugs appreciably.
If Neurontin is discontinued and/or an alternate anticonvulsant medication is added to the therapy, this should be done gradually over a minimum of 1 week.
Dosage in Renal Impairment
Creatinine clearance is difficult to measure in outpatients. In patients with stable renal function, creatinine clearance (CCr) can be reasonably well estimated using the equation of Cockcroft and Gault:
for females CCr=(0.85)(140-age)(weight)/[(72)(SCr)]
for males CCr=(140-age)(weight)/[(72)(SCr)]
where age is in years, weight is in kilograms and SCr is serum creatinine in mg/dL.
Dosage adjustment in patients ≥12 years of age with compromised renal function or undergoing hemodialysis is recommended as follows (see dosing recommendations above for effective doses in each indication).
| Renal Function Creatinine Clearance (mL/min) | Total Daily Dose Range (mg/day) | Dose Regimen (mg) | ||||
|---|---|---|---|---|---|---|
| ||||||
| ≥60 | 900–3600 | 300 TID | 400 TID | 600 TID | 800 TID | 1200 TID |
| >30–59 | 400–1400 | 200 BID | 300 BID | 400 BID | 500 BID | 700 BID |
| >15–29 | 200–700 | 200 QD | 300 QD | 400 QD | 500 QD | 700 QD |
| 15FOOTNOTE2X* | 100–300 | 100 QD | 125 QD | 150 QD | 200 QD | 300 QD |
| Post-Hemodialysis Supplemental Dose (mg)FOOTNOTE2X† | ||||||
| Hemodialysis | 125† | 150† | 200† | 250† | 350† | |
The use of Neurontin in patients <12 years of age with compromised renal function has not been studied.
NEURONTIN: Adverse Reactions
Postherpetic Neuralgia
The most commonly observed adverse events 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 studies 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 event. The adverse events that most frequently led to withdrawal in Neurontin-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 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. Adverse events were usually mild to moderate in intensity.
| Body System/ | Neurontin | Placebo |
|---|---|---|
| Preferred Term | N=336 % | N=227 % |
| ||
| Body as a Whole | ||
| Asthenia | 5.7 | 4.8 |
| Infection | 5.1 | 3.5 |
| Headache | 3.3 | 3.1 |
| Accidental injury | 3.3 | 1.3 |
| Abdominal pain | 2.7 | 2.6 |
| Digestive System | ||
| Diarrhea | 5.7 | 3.1 |
| Dry mouth | 4.8 | 1.3 |
| Constipation | 3.9 | 1.8 |
| Nausea | 3.9 | 3.1 |
| Vomiting | 3.3 | 1.8 |
| Flatulence | 2.1 | 1.8 |
| Metabolic and Nutritional Disorders | ||
| Peripheral edema | 8.3 | 2.2 |
| Weight gain | 1.8 | 0.0 |
| Hyperglycemia | 1.2 | 0.4 |
| Nervous System | ||
| Dizziness | 28.0 | 7.5 |
| Somnolence | 21.4 | 5.3 |
| Ataxia | 3.3 | 0.0 |
| Thinking abnormal | 2.7 | 0.0 |
| Abnormal gait | 1.5 | 0.0 |
| Incoordination | 1.5 | 0.0 |
| Amnesia | 1.2 | 0.9 |
| Hypesthesia | 1.2 | 0.9 |
| Respiratory System | ||
| Pharyngitis | 1.2 | 0.4 |
| Skin and Appendages | ||
| Rash | 1.2 | 0.9 |
| Special Senses | ||
| AmblyopiaFOOTNOTE2X* | 2.7 | 0.9 |
| Conjunctivitis | 1.2 | 0.0 |
| Diplopia | 1.2 | 0.0 |
| Otitis media | 1.2 | 0.0 |
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 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 commonly observed adverse events reported with the use of 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, 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 Neurontin 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 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. Adverse events were usually mild to moderate in intensity.
The prescriber should be aware that these figures, obtained when Neurontin 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.
| Body System/ | NeurontinFOOTNOTE2X* | Placebo* |
|---|---|---|
| Adverse Event | N=543 % | N=378 % |
| Body As A Whole | ||
| Fatigue | 11.0 | 5.0 |
| Weight Increase | 2.9 | 1.6 |
| Back Pain | 1.8 | 0.5 |
| Peripheral Edema | 1.7 | 0.5 |
| Cardiovascular | ||
| Vasodilatation | 1.1 | 0.3 |
| Digestive System | ||
| Dyspepsia | 2.2 | 0.5 |
| Mouth or Throat Dry | 1.7 | 0.5 |
| Constipation | 1.5 | 0.8 |
| Dental Abnormalities | 1.5 | 0.3 |
| Increased Appetite | 1.1 | 0.8 |
| Hematologic and Lymphatic Systems | ||
| Leukopenia | 1.1 | 0.5 |
| Musculoskeletal System | ||
| Myalgia | 2.0 | 1.9 |
| Fracture | 1.1 | 0.8 |
| Nervous System | ||
| Somnolence | 19.3 | 8.7 |
| Dizziness | 17.1 | 6.9 |
| Ataxia | 12.5 | 5.6 |
| Nystagmus | 8.3 | 4.0 |
| Tremor | 6.8 | 3.2 |
| Nervousness | 2.4 | 1.9 |
| Dysarthria | 2.4 | 0.5 |
| Amnesia | 2.2 | 0.0 |
| Depression | 1.8 | 1.1 |
| Thinking Abnormal | 1.7 | 1.3 |
| Twitching | 1.3 | 0.5 |
| Coordination Abnormal | 1.1 | 0.3 |
| Respiratory System | ||
| Rhinitis | 4.1 | 3.7 |
| Pharyngitis | 2.8 | 1.6 |
| Coughing | 1.8 | 1.3 |
| Skin and Appendages | ||
| Abrasion | 1.3 | 0.0 |
| Pruritus | 1.3 | 0.5 |
| Urogenital System | ||
| Impotence | 1.5 | 1.1 |
| Special Senses | ||
| Diplopia | 5.9 | 1.9 |
| AmblyopiaFOOTNOTE2X† | 4.2 | 1.1 |
| Laboratory Deviations | ||
| WBC Decreased | 1.1 | 0.5 |
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 Neurontin-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 Neurontin. The incidence of adverse events 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 events by race.
Table 5 lists treatment-emergent signs and symptoms 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 were numerically more common in the Neurontin group. Adverse events were usually mild to moderate in intensity.
| Body System/ | NeurontinFOOTNOTE2X* | Placebo* |
|---|---|---|
| Adverse Event | N=119 % | N=128 % |
| ||
| Body As A Whole | ||
| Viral Infection | 10.9 | 3.1 |
| Fever | 10.1 | 3.1 |
| Weight Increase | 3.4 | 0.8 |
| Fatigue | 3.4 | 1.6 |
| Digestive System | ||
| Nausea and/or Vomiting | 8.4 | 7.0 |
| Nervous System | ||
| Somnolence | 8.4 | 4.7 |
| Hostility | 7.6 | 2.3 |
| Emotional Lability | 4.2 | 1.6 |
| Dizziness | 2.5 | 1.6 |
| Hyperkinesia | 2.5 | 0.8 |
| Respiratory System | ||
| Bronchitis | 3.4 | 0.8 |
| Respiratory Infection | 2.5 | 0.8 |
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)
Neurontin 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 Neurontin who experienced an event of the type cited on at least one occasion while receiving Neurontin. 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.
Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Body As A Whole: Frequent: asthenia, malaise, face edema; Infrequent: allergy, generalized edema, weight decrease, chill; Rare: strange feelings, lassitude, alcohol intolerance, hangover effect.
Cardiovascular System: Frequent: hypertension; Infrequent: hypotension, angina pectoris, peripheral vascular disorder, palpitation, tachycardia, migraine, murmur; Rare: atrial fibrillation, heart failure, thrombophlebitis, deep thrombophlebitis, myocardial infarction, cerebrovascular accident, pulmonary thrombosis, ventricular extrasystoles, bradycardia, premature atrial contraction, pericardial rub, heart block, pulmonary embolus, hyperlipidemia, hypercholesterolemia, pericardial effusion, pericarditis.
Digestive System: Frequent: anorexia, flatulence, gingivitis; Infrequent: glossitis, gum hemorrhage, thirst, stomatitis, increased salivation, gastroenteritis, hemorrhoids, bloody stools, fecal incontinence, hepatomegaly; Rare: dysphagia, eructation, pancreatitis, peptic ulcer, colitis, blisters in mouth, tooth discolor, perlèche, salivary gland enlarged, lip hemorrhage, esophagitis, hiatal hernia, hematemesis, proctitis, irritable bowel syndrome, rectal hemorrhage, esophageal spasm.
Endocrine System: Rare: hyperthyroid, hypothyroid, goiter, hypoestrogen, ovarian failure, epididymitis, swollen testicle, cushingoid appearance.
Hematologic and Lymphatic System: Frequent: purpura most often described as bruises resulting from physical trauma; Infrequent: anemia, thrombocytopenia, lymphadenopathy; Rare: WBC count increased, lymphocytosis, non-Hodgkin's lymphoma, bleeding time increased.
Musculoskeletal System: Frequent: arthralgia; Infrequent: tendinitis, arthritis, joint stiffness, joint swelling, positive Romberg test; Rare: costochondritis, osteoporosis, bursitis, contracture.
Nervous System: Frequent: vertigo, hyperkinesia, paresthesia, decreased or absent reflexes, increased reflexes, anxiety, hostility; Infrequent: CNS tumors, syncope, dreaming abnormal, aphasia, hypesthesia, intracranial hemorrhage, hypotonia, dysesthesia, paresis, dystonia, hemiplegia, facial paralysis, stupor, cerebellar dysfunction, positive Babinski sign, decreased position sense, subdural hematoma, apathy, hallucination, decrease or loss of libido, agitation, paranoia, depersonalization, euphoria, feeling high, doped-up sensation, psychosis; Rare: choreoathetosis, orofacial dyskinesia, encephalopathy, nerve palsy, personality disorder, increased libido, subdued temperament, apraxia, fine motor control disorder, meningismus, local myoclonus, hyperesthesia, hypokinesia, mania, neurosis, hysteria, antisocial reaction.
Respiratory System: Frequent: pneumonia; Infrequent: epistaxis, dyspnea, apnea; Rare: mucositis, aspiration pneumonia, hyperventilation, hiccup, laryngitis, nasal obstruction, snoring, bronchospasm, hypoventilation, lung edema.
Dermatological: Infrequent: alopecia, eczema, dry skin, increased sweating, urticaria, hirsutism, seborrhea, cyst, herpes simplex; Rare: herpes zoster, skin discolor, skin papules, photosensitive reaction, leg ulcer, scalp seborrhea, psoriasis, desquamation, maceration, skin nodules, subcutaneous nodule, melanosis, skin necrosis, local swelling.
Urogenital System: Infrequent: hematuria, dysuria, urination frequency, cystitis, urinary retention, urinary incontinence, vaginal hemorrhage, amenorrhea, dysmenorrhea, menorrhagia, breast cancer, unable to climax, ejaculation abnormal; Rare: kidney pain, leukorrhea, pruritus genital, renal stone, acute renal failure, anuria, glycosuria, nephrosis, nocturia, pyuria, urination urgency, vaginal pain, breast pain, testicle pain.
Special Senses: Frequent: abnormal vision; Infrequent: cataract, conjunctivitis, eyes dry, eye pain, visual field defect, photophobia, bilateral or unilateral ptosis, eye hemorrhage, hordeolum, hearing loss, earache, tinnitus, inner ear infection, otitis, taste loss, unusual taste, eye twitching, ear fullness; Rare: eye itching, abnormal accommodation, perforated ear drum, sensitivity to noise, eye focusing problem, watery eyes, retinopathy, glaucoma, iritis, corneal disorders, lacrimal dysfunction, degenerative eye changes, blindness, retinal degeneration, miosis, chorioretinitis, strabismus, eustachian tube dysfunction, labyrinthitis, otitis externa, odd smell.
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.
Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Body as a Whole: Infrequent: chest pain, cellulitis, malaise, neck pain, face edema, allergic reaction, abscess, chills, chills and fever, mucous membrane disorder; Rare: body odor, cyst, fever, hernia, abnormal BUN value, lump in neck, pelvic pain, sepsis, viral infection.
Cardiovascular System: Infrequent: hypertension, syncope, palpitation, migraine, hypotension, peripheral vascular disorder, cardiovascular disorder, cerebrovascular accident, congestive heart failure, myocardial infarction, vasodilatation; Rare: angina pectoris, heart failure, increased capillary fragility, phlebitis, thrombophlebitis, varicose vein.
Digestive System: Infrequent: gastroenteritis, increased appetite, gastrointestinal disorder, oral moniliasis, gastritis, tongue disorder, thirst, tooth disorder, abnormal stools, anorexia, liver function tests abnormal, periodontal abscess; Rare: cholecystitis, cholelithiasis, duodenal ulcer, fecal incontinence, gamma glutamyl transpeptidase increased, gingivitis, intestinal obstruction, intestinal ulcer, melena, mouth ulceration, rectal disorder, rectal hemorrhage, stomatitis.
Endocrine System: Infrequent: diabetes mellitus.
Hemic and Lymphatic System: Infrequent: ecchymosis, anemia; Rare: lymphadenopathy, lymphoma-like reaction, prothrombin decreased.
Metabolic and Nutritional: Infrequent: edema, gout, hypoglycemia, weight loss; Rare: alkaline phosphatase increased, diabetic ketoacidosis, lactic dehydrogenase increased.
Musculoskeletal: Infrequent: arthritis, arthralgia, myalgia, arthrosis, leg cramps, myasthenia; Rare: shin bone pain, joint disorder, tendon disorder.
Nervous System: Frequent: confusion, depression; Infrequent: vertigo, nervousness, paresthesia, insomnia, neuropathy, libido decreased, anxiety, depersonalization, reflexes decreased, speech disorder, abnormal dreams, dysarthria, emotional lability, nystagmus, stupor, circumoral paresthesia, euphoria, hyperesthesia, hypokinesia; Rare: agitation, hypertonia, libido increased, movement disorder, myoclonus, vestibular disorder.
Respiratory System: Infrequent: cough increased, bronchitis, rhinitis, sinusitis, pneumonia, asthma, lung disorder, epistaxis; Rare: hemoptysis, voice alteration.
Skin and Appendages: Infrequent: pruritus, skin ulcer, dry skin, herpes zoster, skin disorder, fungal dermatitis, furunculosis, herpes simplex, psoriasis, sweating, urticaria, vesiculobullous rash; Rare: acne, hair disorder, maculopapular rash, nail disorder, skin carcinoma, skin discoloration, skin hypertrophy.
Special Senses: Infrequent: abnormal vision, ear pain, eye disorder, taste perversion, deafness; Rare: conjunctival hyperemia, diabetic retinopathy, eye pain, fundi with microhemorrhage, retinal vein thrombosis, taste loss.
Urogenital System: Infrequent: urinary tract infection, dysuria, impotence, urinary incontinence, vaginal moniliasis, breast pain, menstrual disorder, polyuria, urinary retention; Rare: cystitis, ejaculation abnormal, swollen penis, gynecomastia, nocturia, pyelonephritis, swollen scrotum, urinary frequency, urinary urgency, urine abnormality.
Postmarketing and Other Experience
In addition to the adverse experiences reported during clinical testing of Neurontin, the following adverse experiences have been reported in patients receiving marketed Neurontin. 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.
NEURONTIN: Contraindications
NEURONTIN: Warning
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 1000 Patients | Drug Patients with Events Per 1000 Patients | Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients | Risk Difference: Additional Drug Patients with Events Per 1000 Patients |
|---|---|---|---|---|
| Epilepsy | 1.0 | 3.4 | 3.5 | 2.4 |
| Psychiatric | 5.7 | 8.5 | 1.5 | 2.9 |
| Other | 1.0 | 1.8 | 1.9 | 0.9 |
| Total | 2.4 | 4.3 | 1.8 | 1.9 |
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.
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 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 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.
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 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.
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 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 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.
NEURONTIN: Over Dosage
A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation.
Acute oral overdoses of Neurontin up to 49 grams have been reported. In these cases, double vision, slurred speech, drowsiness, lethargy and diarrhea were observed. All patients recovered with supportive care.
Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient's clinical state or in patients with significant renal impairment.
NEURONTIN: How Supplied
Neurontin (gabapentin) capsules, tablets and oral solution are supplied as follows:
100 mg capsules;
White hard gelatin capsules printed with "PD" on one side and "Neurontin/100 mg" on the other; available in:
Bottles of 100: N 0071-0803-24
Unit dose 50's: N 0071-0803-40
300 mg capsules;
Yellow hard gelatin capsules printed with "PD" on one side and "Neurontin/300 mg" on the other; available in:
Bottles of 100: N 0071-0805-24
Unit dose 50's: N 0071-0805-40
400 mg capsules;
Orange hard gelatin capsules printed with "PD" on one side and "Neurontin/400 mg" on the other; available in:
Bottles of 100: N 0071-0806-24
Unit dose 50's: N 0071-0806-40
600 mg tablets;
White elliptical film-coated scored tablets debossed with "NT" and "16" on one side; available in:
Bottles of 100: N 0071-0513-24
800 mg tablets;
White elliptical film-coated scored tablets debossed with "NT" and "26" on one side; available in:
Bottles of 100: N 0071-0401-24
250 mg/5 mL oral solution;
Clear colorless to slightly yellow solution; each 5 mL of oral solution contains 250 mg of gabapentin; available in:
Bottles containing 470 mL: N0071-2012-23
Storage (Capsules)
Store at 25°C (77°F); excursions permitted to 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature].
Storage (Tablets)
Store at 25°C (77°F); excursions permitted to 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature].
Storage (Oral Solution)
Store refrigerated, 2°–8°C (36°–46°F)
Neurontin (gabapentin) capsules, tablets and oral solution are supplied as follows:
100 mg capsules;
White hard gelatin capsules printed with "PD" on one side and "Neurontin/100 mg" on the other; available in:
Bottles of 100: N 0071-0803-24
Unit dose 50's: N 0071-0803-40
300 mg capsules;
Yellow hard gelatin capsules printed with "PD" on one side and "Neurontin/300 mg" on the other; available in:
Bottles of 100: N 0071-0805-24
Unit dose 50's: N 0071-0805-40
400 mg capsules;
Orange hard gelatin capsules printed with "PD" on one side and "Neurontin/400 mg" on the other; available in:
Bottles of 100: N 0071-0806-24
Unit dose 50's: N 0071-0806-40
600 mg tablets;
White elliptical film-coated scored tablets debossed with "NT" and "16" on one side; available in:
Bottles of 100: N 0071-0513-24
800 mg tablets;
White elliptical film-coated scored tablets debossed with "NT" and "26" on one side; available in:
Bottles of 100: N 0071-0401-24
250 mg/5 mL oral solution;
Clear colorless to slightly yellow solution; each 5 mL of oral solution contains 250 mg of gabapentin; available in:
Bottles containing 470 mL: N0071-2012-23
Storage (Capsules)
Store at 25°C (77°F); excursions permitted to 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature].
Storage (Tablets)
Store at 25°C (77°F); excursions permitted to 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature].
Storage (Oral Solution)
Store refrigerated, 2°–8°C (36°–46°F)
NEURONTIN: Drug Interations
Drug Interactions
In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations. Only at the highest concentration tested (171 µg/mL; 1 mM) was a slight degree of inhibition (14%–30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 µg/mL (approximately 15 times the Cmax at 3600 mg/day).
Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs.
The drug interaction data described in this section were obtained from studies involving healthy adults and adult patients with epilepsy.
Phenytoin
In a single (400 mg) and multiple dose (400 mg TID) study of Neurontin in epileptic patients (N=8) maintained on phenytoin monotherapy for at least 2 months, gabapentin had no effect on the steady-state trough plasma concentrations of phenytoin and phenytoin had no effect on gabapentin pharmacokinetics.
Carbamazepine
Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide concentrations were not affected by concomitant gabapentin (400 mg TID; N=12) administration. Likewise, gabapentin pharmacokinetics were unaltered by carbamazepine administration.
Valproic Acid
The mean steady-state trough serum valproic acid concentrations prior to and during concomitant gabapentin administration (400 mg TID; N=17) were not different and neither were gabapentin pharmacokinetic parameters affected by valproic acid.
Phenobarbital
Estimates of steady-state pharmacokinetic parameters for phenobarbital or gabapentin (300 mg TID; N=12) are identical whether the drugs are administered alone or together.
Naproxen
Coadministration (N=18) of naproxen sodium capsules (250 mg) with Neurontin (125 mg) appears to increase the amount of gabapentin absorbed by 12% to 15%. Gabapentin had no effect on naproxen pharmacokinetic parameters. These doses are lower than the therapeutic doses for both drugs. The magnitude of interaction within the recommended dose ranges of either drug is not known.
Hydrocodone
Coadministration of Neurontin (125 to 500 mg; N=48) decreases hydrocodone (10 mg; N=50) Cmax and AUC values in a dose-dependent manner relative to administration of hydrocodone alone; Cmax and AUC values are 3% to 4% lower, respectively, after administration of 125 mg Neurontin and 21% to 22% lower, respectively, after administration of 500 mg Neurontin. The mechanism for this interaction is unknown. Hydrocodone increases gabapentin AUC values by 14%. The magnitude of interaction at other doses is not known.
Morphine
A literature article reported that when a 60-mg controlled-release morphine capsule was administered 2 hours prior to a 600-mg Neurontin capsule (N=12), mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine (see PRECAUTIONS). Morphine pharmacokinetic parameter values were not affected by administration of Neurontin 2 hours after morphine. The magnitude of interaction at other doses is not known.
Cimetidine
In the presence of cimetidine at 300 mg QID (N=12) the mean apparent oral clearance of gabapentin fell by 14% and creatinine clearance fell by 10%. Thus cimetidine appeared to alter the renal excretion of both gabapentin and creatinine, an endogenous marker of renal function. This small decrease in excretion of gabapentin by cimetidine is not expected to be of clinical importance. The effect of gabapentin on cimetidine was not evaluated.
Oral Contraceptive
Based on AUC and half-life, multiple-dose pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of tablets containing 2.5 mg of norethindrone acetate and 50 mcg of ethinyl estradiol were similar with and without coadministration of gabapentin (400 mg TID; N=13). The Cmax of norethindrone was 13% higher when it was coadministered with gabapentin; this interaction is not expected to be of clinical importance.
