Neurontin

Gabapentin comes as a capsule, a tablet, an extended-release (long-acting) tablet, and an oral solution (liquid) to take by mouth. Gabapentin capsules, tablets, and oral solution are usually taken with a full glass of water (8 ounces [240 milliliters]), with or without food, three times a day.

These medications should be taken at evenly spaced times throughout the day and night; no more than 12 hours should pass between doses. The extended-release tablet (Horizant) is taken with food once daily at about 5 PM. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take gabapentin exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Gabapentin extended-release tablets cannot be substituted for another type of gabapentin product. Be sure that you receive only the type of gabapentin that was prescribed by your doctor. Ask your pharmacist if you have any questions about the type of gabapentin you were given.

Swallow the extended-release tablets whole; do not cut, chew, or crush them.

If your doctor tells you to take one-half of a regular tablet as part of your dose, carefully split the tablet along the score mark. Use the other half-tablet as part of your next dose. Properly throw away any half-tablets that you have not used within several days of breaking them.

If you are taking gabapentin to control seizures or PHN, your doctor will probably start you on a low dose of gabapentin and gradually increase your dose as needed to treat your condition. If you are taking gabapentin to treat PHN, tell your doctor if your symptoms do not improve during your treatment.

Gabapentin may help to control your condition but will not cure it. Continue to take gabapentin even if you feel well. Do not stop taking gabapentin without talking to your doctor, even if you experience side effects such as unusual changes in behavior or mood. If you suddenly stop taking gabapentin tablets, capsules, or oral solution, you may experience withdrawal symptoms such as anxiety, difficulty falling asleep or staying asleep, nausea, pain, and sweating. If you are taking gabapentin to treat seizures and you suddenly stop taking the medication, you may experience seizures more often. Your doctor may decrease your dose gradually over at least a week.

Your doctor or pharmacist will give you the manufacturer's patient information sheet (Medication Guide) when you begin treatment with gabapentin and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs) or the manufacturer's website to obtain the Medication Guide.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Neurontin is a prescription medicine used to treat:

• Pain from damaged nerves (postherpetic pain) that follows healing of shingles (a painful rash that comes after a herpes zoster infection) in adults.
• Partial seizures when taken together with other medicines in adults and children 3 years of age and older.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

• Parke-Davis Div of Pfizer Inc

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Neurontin there are no specific foods that you must exclude from your diet when receiving Neurontin.

Tell your healthcare provider if you are breastfeeding or plan to breastfeed. Neurontin can pass into breast milk. You and your healthcare provider should decide how you will feed your baby while you take Neurontin.

Contraindications

• Gabapentin: Known hypersensitivity to gabapentin or any ingredient in the formulation.1 60

• Gabapentin enacarbil: Manufacturer states none known.61

Warnings/Precautions

Warnings

Increased risk of suicidality (suicidal ideation or behavior) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).1 55 56 57 60 61 Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.1 55 56 57 60 61 Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1 55 56 57 60 61

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.55 56 57 Anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality.55

Balance risk of suicidality with the risk of untreated illness.55 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.1 60 61 If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.1 60 61 (See Advice to Patients.)

Emotional lability (primarily behavioral problems), hostility (including aggressive behaviors), thought disorders (including concentration and school performance changes), and hyperkinesia (primarily restlessness and hyperactivity) associated with use in children 3–12 years of age with epilepsy.1

Risk of somnolence, sedation, and dizziness.1 60 61 (See Advice to Patients.) Avoid concomitant use of alcohol or other drugs that can potentiate these effects.1 60 61 (See Specific Drugs under Interactions.)

Risk of substantial driving impairment; may be related to somnolence or other CNS effects of the drug.1 61 72 (See Dizziness and Somnolence under Cautions.) Duration of such impairment not known.1 61

Patients should not drive (or operate other complex machinery) until they have gained sufficient experience with the drug.1 61

Abrupt withdrawal may result in increased seizure frequency and other withdrawal symptoms (e.g., anxiety, insomnia, nausea, pain); withdraw therapy gradually.1 60 61 (See Dosage under Dosage and Administration.)

Increased incidence of pancreatic acinar adenocarcinomas observed in rat carcinogenicity studies with gabapentin and gabapentin enacarbil.1 61 Clinical relevance of these findings to humans unknown.1 60 61 72

New tumors or worsening of preexisting tumors reported in some patients receiving gabapentin; however, causal relationship not established.60 61

Higher incidence of sudden and unexplained deaths than would be expected in a healthy (nonepileptic) population; however, incidence is within range of estimates for patients with epilepsy or refractory epilepsy.1

Different formulations of gabapentin (e.g., conventional [immediate-release] gabapentin preparations, gabapentin gastroretentive tablets, gabapentin enacarbil extended-release tablets) not interchangeable because of differences in pharmacokinetics that affect frequency of administration.60 61

Sensitivity Reactions

Multiorgan hypersensitivity reactions (also known as drug reaction with eosinophilia and systemic symptoms or DRESS) reported with anticonvulsants, including gabapentin; clinical presentation is variable but typically includes fever, rash, eosinophilia, and/or lymphadenopathy associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myositis, myocarditis).1 60 61 Potentially fatal or life-threatening.1 60 61

If manifestations of DRESS occur, evaluate patient immediately; discontinue gabapentin if an alternative etiology cannot be identified.1 60 61

Specific Populations

Category C.1

No adequate and well-controlled studies to date in pregnant women; developmental toxicity (e.g., skeletal abnormalities, hydroureter and hydronephrosis, increased embryofetal mortality) demonstrated in animals.1 16 60

North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 (for patients); NAAED registry information also available on the website .1

Distributed into milk; use only if potential benefits outweigh risks.1 60 The manufacturer of gabapentin enacarbil states to discontinue nursing or the drug.61

Safety and efficacy of conventional (immediate-release) gabapentin as adjunctive therapy for management of partial seizures not established in children <3 years of age.1

Safety and efficacy of conventional (immediate-release) gabapentin for management of PHN not established in children.1

Safety and efficacy of gabapentin gastroretentive tablets not established in children.60

Safety and efficacy of gabapentin enacarbil not established in children.61

Insufficient experience with conventional (immediate-release) gabapentin for the management of partial seizures in patients ≥65 years of age to determine whether they respond differently than younger adults.1 Select dosage carefully.1 (See Geriatric Patients under Dosage and Administration.)

Appeared to be more effective for the management of PHN in patients >75 years of age than in younger patients; apparent difference in efficacy may be related to decreased renal function in older patients.1 Adverse effects in older patients with PHN generally similar to those in younger adults; however, the incidence of peripheral edema and ataxia appears to increase with age.1

Adverse effects reported with gabapentin as gastroretentive tablets generally similar across all age groups except for peripheral edema, which tended to increase with age.60

Insufficient experience with gabapentin enacarbil in patients ≥65 years of age to determine whether they respond differently than younger patients.61 No overall differences in safety and efficacy observed between geriatric and younger patients receiving the drug.61

Geriatric patients may have decreased hepatic, renal, or cardiac function, with increased risk of adverse effects.1 16 60 61 Use with caution; dosage reductions may be necessary in those with renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Eliminated renally; dosage adjustments may be necessary in patients with renal impairment.1 60 61 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Children 3–12 years of age receiving conventional (immediate-release) gabapentin as adjunctive therapy for partial seizures: viral infection, fever, nausea and/or vomiting, somnolence, hostility.1

Adults and children >12 years of age receiving conventional (immediate-release) gabapentin as adjunctive therapy for partial seizures: somnolence, dizziness, ataxia, fatigue, nystagmus.1

Adults receiving conventional (immediate-release) gabapentin for management of PHN: dizziness, somnolence, peripheral edema.1

Adults receiving gabapentin gastroretentive tablets for PHN: dizziness.60

Adults receiving gabapentin enacarbil for PHN: dizziness, somnolence, headache.61

Adults receiving gabapentin enacarbil for restless legs syndrome: somnolence/sedation, dizziness.61

Absorption

Bioavailability

Conventional (immediate-release) gabapentin: Following oral administration, absorbed principally in the proximal small intestine via a saturable L-amino acid transport system; bioavailability is not dose proportional and decreases as dose increases.1 60 63 83 84 Bioavailability is 60 to 27% for doses ranging from 900 mg to 4.8 g daily.1

Gabapentin gastroretentive tablets: In healthy individuals, time to peak plasma concentrations is prolonged (about 4–6 hours longer), peak plasma concentrations are higher, and systemic exposure is lower relative to immediate-release formulations.60

Gabapentin enacarbil extended-release tablets: Absorbed by high-capacity transporters throughout the GI tract and not affected by saturable absorption; this improves bioavailability and allows for dose-proportional exposure.61 72 74 78 80 83 Mean bioavailability in the fed state is about 75% and in the fasted state is about 42–65%.61 Steady-state achieved in about 2 days with daily administration.61

Food

Conventional (immediate-release) gabapentin: Food does not substantially affect bioavailability.1 60 64

Gabapentin gastroretentive tablets: Food increases absorption of the drug formulation; tablets swell upon contact with gastric fluid to a size that promotes gastric retention for approximately 8–10 hours when taken with a meal.60 63 64 65

Gabapentin enacarbil extended-release tablets: Food increases systemic exposure.61 76

Distribution

Extent

Readily crosses the blood-brain barrier and concentrates in brain tissue.29 Distributed into breast milk.1 Not known whether gabapentin crosses the placenta.1

Plasma Protein Binding

<3%.1

Elimination

Metabolism

Gabapentin is not appreciably metabolized.1 61

Gabapentin enacarbil, the prodrug of gabapentin, is rapidly and efficiently converted to gabapentin by first-pass hydrolysis following oral administration.61 74

Elimination Route

Excreted renally as unchanged drug.1 61

Half-life

Approximately 5–7 hours.1 60 61

Special Populations

In children <5 years of age, clearance normalized for weight is higher than in adults and children ≥5 years of age.1

In patients with renal impairment, plasma clearance is decreased and half-life is prolonged.1 In patients with Clcr <30 mL/minute, half-life of 52 hours reported with conventional (immediate-release) gabapentin; in anuric patients, half-life reported to be 132 hours on nondialysis days and 3.8 hours during hemodialysis.1

In the U.S.

• FusePaq Fanatrex
• Gabarone
• Gralise
• Neurontin

Available Dosage Forms:

• Tablet
• Capsule
• Suspension
• Solution

Therapeutic Class: Anticonvulsant

Chemical Class: Gamma Aminobutyric Acid (class)

Neurontin® is indicated for:

• Management of postherpetic neuralgia in adults
• Adjunctive therapy in the treatment of partial onset seizures, with and without secondary generalization, in adults and pediatric patients 3 years and older with epilepsy

Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. In nonclinical studies in mice, rats, and rabbits, gabapentin was developmentally toxic when administered to pregnant animals at doses similar to or lower than those used clinically. Neurontin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When pregnant mice received oral doses of gabapentin (500, 1000, or 3000 mg/kg/day) during the period of organogenesis, embryo-fetal toxicity (increased incidences of skeletal variations) was observed at the two highest doses. The no-effect dose for embryo-fetal developmental toxicity in mice was 500 mg/kg/day or approximately ½ of the maximum recommended human dose (MRHD) of 3600 mg/kg 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 effect dose for developmental toxicity in rats is approximately equal to the MRHD on a mg/m2 basis.

When pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryo-fetal mortality was observed at all doses tested (60, 300, or 1500 mg/kg). The lowest effect dose for embryo-fetal developmental toxicity in rabbits 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.

To provide information regarding the effects of in utero exposure to Neurontin, physicians are advised to recommend that pregnant patients taking Neurontin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Nursing Mothers

Gabapentin is secreted into human milk following oral administration. A nursed infant could be exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on the nursing infant is unknown, Neurontin should be used in women who are nursing only if the benefits clearly outweigh the risks.

Pediatric Use

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

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)].

Geriatric Use

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 with 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)].

Renal Impairment

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)].

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. Coma, resolving with dialysis, has been reported in patients with chronic renal failure who were treated with Neurontin.

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.

If overexposure occurs, call your poison control center at 1-800-222-1222.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Gabapentin was administered orally to mice and rats in 2-year carcinogenicity studies. No evidence of drug-related carcinogenicity was observed in mice treated at doses up to 2000 mg/kg/day. At 2000 mg/kg, the plasma gabapentin exposure (AUC) in mice is approximately 2 times that in humans at the MRHD of 3600 mg/day. In rats, increases in the incidence of pancreatic acinar cell adenoma and carcinoma were found in male rats receiving the highest dose (2000 mg/kg), but not at doses of 250 or 1000 mg/kg/day. At 1000 mg/kg, the plasma gabapentin exposure (AUC) in rats is approximately 5 times that in humans at the MRHD.

Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known whether gabapentin has the ability to increase cell proliferation in other cell types or in other species, including humans.

Gabapentin did not demonstrate mutagenic or genotoxic potential in three in vitro and four in vivo assays. It was negative in the Ames test and the in vitro HGPRT forward mutation assay in Chinese hamster lung cells; it did not produce significant increases in chromosomal aberrations in the in vitro Chinese hamster lung cell assay; it was negative in the in vivo chromosomal aberration assay and in the in vivo micronucleus test in Chinese hamster bone marrow; it was negative in the in vivo mouse micronucleus assay; and it did not induce unscheduled DNA synthesis in hepatocytes from rats given gabapentin.

No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg. At 2000 mg/kg, the plasma gabapentin exposure (AUC) in rats is approximately 8 times that in humans at the MRHD.

ALWAYS DISPENSE WITH MEDICATION GUIDE

Pfizer
NDC 0071-0805-40

Neurontin®
(gabapentin)
capsules

300 mg

For in-institution use only

UNIT DOSE

50 Capsules
Rx only

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

Take Neurontin exactly as prescribed by your doctor. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Neurontin can be taken with or without food.

If you break a Neurontin tablet and take only half of it, take the other half at your next dose. Any tablet that has been broken should be used as soon as possible or within a few days.

Measure liquid medicine with the dosing syringe provided, or with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.

If your doctor changes your brand, strength, or type of gabapentin, your dosage needs may change. Ask your pharmacist if you have any questions about the new kind of gabapentin you receive at the pharmacy.

Do not stop using Neurontin suddenly, even if you feel fine. Stopping suddenly may cause increased seizures. Follow your doctor's instructions about tapering your dose.

Wear a medical alert tag or carry an ID card stating that you take Neurontin. Any medical care provider who treats you should know that you take seizure medication.

Neurontin can cause you to have a false positive urine protein screening test. If you provide a urine sample for testing, tell the laboratory staff that you are taking Neurontin.

Store Neurontin tablets and capsules at room temperature away from light and moisture.

Store the liquid medicine in the refrigerator. Do not freeze.

Take the missed dose as soon as you remember. Be sure to take the medicine with food. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Taking this medicine with other drugs that make you sleepy can worsen this effect. Ask your doctor before taking Neurontin with a sleeping pill, narcotic pain medicine, muscle relaxer, or medicine for anxiety, depression, or seizures.

Other drugs may interact with gabapentin, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.