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| Product NDC Code | 58151-282 | ||
|---|---|---|---|
| Drug Name | Neurontin |
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| Type | Brand | ||
| Pharm Class | Decreased Central Nervous System Disorganized Electrical Activity [PE] | ||
| Active Ingredients |
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| Route | ORAL | ||
| Dosage Form | CAPSULE | ||
| RxCUI drug identifier | 105028, 105029, 105030, 261280, 261281, 283523, 310430, 310431, 310432, 310433, 310434, 351973 |
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| Application Number | NDA020235 | ||
| Labeler Name | Viatris Specialty LLC | ||
| Check if available Online | Get Medication Prices online with Discount |
Abuse
Information about the types of abuse that can occur with the drug and adverse reactions pertinent to those types of abuse, primarily based on human data. May include descriptions of particularly susceptible patient populations.9.2 Abuse 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.
Controlled substance
Information about the schedule in which the drug is controlled by the Drug Enforcement Administration, if applicable.9.1 Controlled Substance Gabapentin is not a scheduled drug.
Dependence
Information about characteristic effects resulting from both psychological and physical dependence that occur with the drug, the quantity of drug over a period of time that may lead to tolerance or dependence, details of adverse effects related to chronic abuse and the effects of abrupt withdrawl, procedures necessary to diagnose the dependent state, and principles of treating the effects of abrupt withdrawal.9.3 Dependence 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.
Drug abuse and dependence
Information about whether the drug is a controlled substance, the types of abuse that can occur with the drug, and adverse reactions pertinent to those types of abuse.9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Gabapentin is not a scheduled drug. 9.2 Abuse 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. 9.3 Dependence 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.
Overdosage of Neurontin
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation. Acute oral overdoses of NEURONTIN have been reported. Symptoms have included double vision, tremor, slurred speech, drowsiness, altered mental status, dizziness, lethargy, and diarrhea. Fatal respiratory depression has been reported with NEURONTIN overdose, alone and in combination with other CNS depressants. Gabapentin can be removed by hemodialysis. If overexposure occurs, call your poison control center at 1-800-222-1222.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS 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) ] Most common adverse reactions (incidence ≥8% and at least twice that for placebo) were: • Postherpetic neuralgia: Dizziness, somnolence, and peripheral edema ( 6.1 ) • Epilepsy in patients >12 years of age: Somnolence, dizziness, ataxia, fatigue, and nystagmus ( 6.1 ) • Epilepsy in patients 3 to 12 years of age: Viral infection, fever, nausea and/or vomiting, somnolence, and hostility ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 NEURONTIN N=336 % Placebo N=227 % Body as a Whole Asthenia 6 5 Infection 5 4 Accidental injury 3 1 Digestive System Diarrhea 6 3 Dry mouth 5 1 Constipation 4 2 Nausea 4 3 Vomiting 3 2 Metabolic and Nutritional Disorders Peripheral edema 8 2 Weight gain 2 0 Hyperglycemia 1 0 Nervous System Dizziness 28 8 Somnolence 21 5 Ataxia 3 0 Abnormal thinking 3 0 Abnormal gait 2 0 Incoordination 2 0 Respiratory System Pharyngitis 1 0 Special Senses Amblyopia Reported as blurred vision 3 1 Conjunctivitis 1 0 Diplopia 1 0 Otitis media 1 0 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 NEURONTIN Plus background antiepileptic drug therapy N=543 % Placebo N=378 % Body as a Whole Fatigue 11 5 Increased weight 3 2 Back pain 2 1 Peripheral edema 2 1 Cardiovascular Vasodilatation 1 0 Digestive System Dyspepsia 2 1 Dry mouth or throat 2 1 Constipation 2 1 Dental abnormalities 2 0 Nervous System Somnolence 19 9 Dizziness 17 7 Ataxia 13 6 Nystagmus 8 4 Tremor 7 3 Dysarthria 2 1 Amnesia 2 0 Depression 2 1 Abnormal thinking 2 1 Abnormal coordination 1 0 Respiratory System Pharyngitis 3 2 Coughing 2 1 Skin and Appendages Abrasion 1 0 Urogenital System Impotence 2 1 Special Senses Diplopia 6 2 Amblyopia Amblyopia was often described as blurred vision. 4 1 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 NEURONTIN Plus background antiepileptic drug therapy N=119 % Placebo N=128 % Body as a Whole Viral infection 11 3 Fever 10 3 Increased weight 3 1 Fatigue 3 2 Digestive System Nausea and/or vomiting 8 7 Nervous System Somnolence 8 5 Hostility 8 2 Emotional lability 4 2 Dizziness 3 2 Hyperkinesia 3 1 Respiratory System Bronchitis 3 1 Respiratory infection 3 1 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. 6.2 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 [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.
Neurontin Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS Concentrations increased by morphine; may need dose adjustment ( 5.4 , 7.1 ) 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.
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanisms by which gabapentin produces its analgesic and antiepileptic actions are unknown. Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but has no effect on GABA binding, uptake, or degradation. In vitro studies have shown that gabapentin binds with high-affinity to the α2δ subunit of voltage-activated calcium channels; however, the relationship of this binding to the therapeutic effects of gabapentin is unknown. 12.3 Pharmacokinetics All pharmacological actions following gabapentin administration are due to the activity of the parent compound; gabapentin is not appreciably metabolized in humans. Oral Bioavailability Gabapentin bioavailability is not dose proportional; i.e., as dose is increased, bioavailability decreases. Bioavailability of gabapentin is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided doses, respectively. Food has only a slight effect on the rate and extent of absorption of gabapentin (14% increase in AUC and C max ). Distribution Less than 3% of gabapentin circulates bound to plasma protein. The apparent volume of distribution of gabapentin after 150 mg intravenous administration is 58±6 L (mean ±SD). In patients with epilepsy, steady-state predose (C min ) concentrations of gabapentin in cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations. Elimination Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug. Gabapentin is not appreciably metabolized in humans. Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance. In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin can be removed from plasma by hemodialysis. Specific Populations Age The effect of age was studied in subjects 20-80 years of age. Apparent oral clearance (CL/F) of gabapentin decreased as age increased, from about 225 mL/min in those under 30 years of age to about 125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr adjusted for body surface area also declined with age; however, the decline in the renal clearance of gabapentin with age can largely be explained by the decline in renal function. [see Dosage and Administration (2.4) and Use in Specific Populations (8.5) ] . Gender Although no formal study has been conducted to compare the pharmacokinetics of gabapentin in men and women, it appears that the pharmacokinetic parameters for males and females are similar and there are no significant gender differences. Race Pharmacokinetic differences due to race have not been studied. Because gabapentin is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected. Pediatric Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the ages of 1 month and 12 years following a dose of approximately 10 mg/kg. Peak plasma concentrations were similar across the entire age group and occurred 2 to 3 hours postdose. In general, pediatric subjects between 1 month and <5 years of age achieved approximately 30% lower exposure (AUC) than that observed in those 5 years of age and older. Accordingly, oral clearance normalized per body weight was higher in the younger children. Apparent oral clearance of gabapentin was directly proportional to creatinine clearance. Gabapentin elimination half-life averaged 4.7 hours and was similar across the age groups studied. A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month and 13 years of age. Patients received 10 to 65 mg/kg/day given three times a day. Apparent oral clearance (CL/F) was directly proportional to creatinine clearance and this relationship was similar following a single dose and at steady-state. Higher oral clearance values were observed in children <5 years of age compared to those observed in children 5 years of age and older, when normalized per body weight. The clearance was highly variable in infants <1 year of age. The normalized CL/F values observed in pediatric patients 5 years of age and older were consistent with values observed in adults after a single dose. The oral volume of distribution normalized per body weight was constant across the age range. These pharmacokinetic data indicate that the effective daily dose in pediatric patients with epilepsy ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations similar to those achieved in patients 5 years of age and older receiving gabapentin at 30 mg/kg/day [see Dosage and Administration (2.2) ] . Adult Patients with Renal Impairment Subjects (N=60) with renal impairment (mean creatinine clearance ranging from 13-114 mL/min) were administered single 400 mg oral doses of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours (patients with creatinine clearance >60 mL/min) to 52 hours (creatinine clearance <30 mL/min) and gabapentin renal clearance from about 90 mL/min (>60 mL/min group) to about 10 mL/min (<30 mL/min). Mean plasma clearance (CL/F) decreased from approximately 190 mL/min to 20 mL/min [see Dosage and Administration (2.3) and Use in Specific Populations (8.6) ] . Pediatric patients with renal insufficiency have not been studied. Hemodialysis In a study in anuric adult subjects (N=11), the apparent elimination half-life of gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin elimination in anuric subjects [see Dosage and Administration (2.3) and Use in Specific Populations (8.6) ] . Hepatic Disease Because gabapentin is not metabolized, no study was performed in patients with hepatic impairment. Drug Interactions • In Vitro Studies 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 mcg/mL; 1 mM) was a slight degree of inhibition (14% to 30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 mcg/mL (approximately 15 times the C max at 3600 mg/day). • In Vivo Studies 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 three times a day) 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 three times a day; 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 three times a day; 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 three times a day; 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) C max and AUC values in a dose-dependent manner relative to administration of hydrocodone alone; C max 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. 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 four times a day (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 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 three times a day; N=13). The C max of norethindrone was 13% higher when it was coadministered with gabapentin; this interaction is not expected to be of clinical importance. Antacid (Maalox ® ) (aluminum hydroxide, magnesium hydroxide) Antacid (Maalox ® ) containing magnesium and aluminum hydroxides reduced the mean bioavailability of gabapentin (N=16) by about 20%. This decrease in bioavailability was about 10% when gabapentin was administered 2 hours after Maalox. Probenecid Probenecid is a blocker of renal tubular secretion. Gabapentin pharmacokinetic parameters without and with probenecid were comparable. This indicates that gabapentin does not undergo renal tubular secretion by the pathway that is blocked by probenecid.
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action The precise mechanisms by which gabapentin produces its analgesic and antiepileptic actions are unknown. Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but has no effect on GABA binding, uptake, or degradation. In vitro studies have shown that gabapentin binds with high-affinity to the α2δ subunit of voltage-activated calcium channels; however, the relationship of this binding to the therapeutic effects of gabapentin is unknown.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics All pharmacological actions following gabapentin administration are due to the activity of the parent compound; gabapentin is not appreciably metabolized in humans. Oral Bioavailability Gabapentin bioavailability is not dose proportional; i.e., as dose is increased, bioavailability decreases. Bioavailability of gabapentin is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided doses, respectively. Food has only a slight effect on the rate and extent of absorption of gabapentin (14% increase in AUC and C max ). Distribution Less than 3% of gabapentin circulates bound to plasma protein. The apparent volume of distribution of gabapentin after 150 mg intravenous administration is 58±6 L (mean ±SD). In patients with epilepsy, steady-state predose (C min ) concentrations of gabapentin in cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations. Elimination Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug. Gabapentin is not appreciably metabolized in humans. Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance. In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin can be removed from plasma by hemodialysis. Specific Populations Age The effect of age was studied in subjects 20-80 years of age. Apparent oral clearance (CL/F) of gabapentin decreased as age increased, from about 225 mL/min in those under 30 years of age to about 125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr adjusted for body surface area also declined with age; however, the decline in the renal clearance of gabapentin with age can largely be explained by the decline in renal function. [see Dosage and Administration (2.4) and Use in Specific Populations (8.5) ] . Gender Although no formal study has been conducted to compare the pharmacokinetics of gabapentin in men and women, it appears that the pharmacokinetic parameters for males and females are similar and there are no significant gender differences. Race Pharmacokinetic differences due to race have not been studied. Because gabapentin is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected. Pediatric Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the ages of 1 month and 12 years following a dose of approximately 10 mg/kg. Peak plasma concentrations were similar across the entire age group and occurred 2 to 3 hours postdose. In general, pediatric subjects between 1 month and <5 years of age achieved approximately 30% lower exposure (AUC) than that observed in those 5 years of age and older. Accordingly, oral clearance normalized per body weight was higher in the younger children. Apparent oral clearance of gabapentin was directly proportional to creatinine clearance. Gabapentin elimination half-life averaged 4.7 hours and was similar across the age groups studied. A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month and 13 years of age. Patients received 10 to 65 mg/kg/day given three times a day. Apparent oral clearance (CL/F) was directly proportional to creatinine clearance and this relationship was similar following a single dose and at steady-state. Higher oral clearance values were observed in children <5 years of age compared to those observed in children 5 years of age and older, when normalized per body weight. The clearance was highly variable in infants <1 year of age. The normalized CL/F values observed in pediatric patients 5 years of age and older were consistent with values observed in adults after a single dose. The oral volume of distribution normalized per body weight was constant across the age range. These pharmacokinetic data indicate that the effective daily dose in pediatric patients with epilepsy ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations similar to those achieved in patients 5 years of age and older receiving gabapentin at 30 mg/kg/day [see Dosage and Administration (2.2) ] . Adult Patients with Renal Impairment Subjects (N=60) with renal impairment (mean creatinine clearance ranging from 13-114 mL/min) were administered single 400 mg oral doses of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours (patients with creatinine clearance >60 mL/min) to 52 hours (creatinine clearance <30 mL/min) and gabapentin renal clearance from about 90 mL/min (>60 mL/min group) to about 10 mL/min (<30 mL/min). Mean plasma clearance (CL/F) decreased from approximately 190 mL/min to 20 mL/min [see Dosage and Administration (2.3) and Use in Specific Populations (8.6) ] . Pediatric patients with renal insufficiency have not been studied. Hemodialysis In a study in anuric adult subjects (N=11), the apparent elimination half-life of gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin elimination in anuric subjects [see Dosage and Administration (2.3) and Use in Specific Populations (8.6) ] . Hepatic Disease Because gabapentin is not metabolized, no study was performed in patients with hepatic impairment. Drug Interactions • In Vitro Studies 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 mcg/mL; 1 mM) was a slight degree of inhibition (14% to 30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 mcg/mL (approximately 15 times the C max at 3600 mg/day). • In Vivo Studies 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 three times a day) 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 three times a day; 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 three times a day; 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 three times a day; 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) C max and AUC values in a dose-dependent manner relative to administration of hydrocodone alone; C max 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. 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 four times a day (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 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 three times a day; N=13). The C max of norethindrone was 13% higher when it was coadministered with gabapentin; this interaction is not expected to be of clinical importance. Antacid (Maalox ® ) (aluminum hydroxide, magnesium hydroxide) Antacid (Maalox ® ) containing magnesium and aluminum hydroxides reduced the mean bioavailability of gabapentin (N=16) by about 20%. This decrease in bioavailability was about 10% when gabapentin was administered 2 hours after Maalox. Probenecid Probenecid is a blocker of renal tubular secretion. Gabapentin pharmacokinetic parameters without and with probenecid were comparable. This indicates that gabapentin does not undergo renal tubular secretion by the pathway that is blocked by probenecid.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS NEURONTIN is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. Known hypersensitivity to gabapentin or its ingredients ( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION The active ingredient in NEURONTIN capsules, tablets, and oral solution is gabapentin, which has the chemical name 1-(aminomethyl)cyclohexaneacetic acid. The molecular formula of gabapentin is C 9 H 17 NO 2 and the molecular weight is 171.24. The structural formula of gabapentin is: Gabapentin is a white to off-white crystalline solid with a pK a1 of 3.7 and a pK a2 of 10.7. It is freely soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is -1.25. Each NEURONTIN capsule contains 100 mg, 300 mg, or 400 mg of gabapentin and the following inactive ingredients: cornstarch, FD&C Blue No. 2, gelatin, lactose, red iron oxide (400 mg only), talc, titanium dioxide, and yellow iron oxide (300 mg and 400 mg only). Each NEURONTIN tablet contains 600 mg or 800 mg of gabapentin and the following inactive ingredients: candelilla wax, copovidone, cornstarch, hydroxypropyl cellulose, magnesium stearate, poloxamer 407, and talc. NEURONTIN oral solution contains 250 mg of gabapentin per 5 mL (50 mg per mL) and the following inactive ingredients: artificial cool strawberry anise flavor, glycerin, purified water, and xylitol. Chemical Structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION • Postherpetic Neuralgia ( 2.1 ) o Dose can be titrated up as needed to a dose of 1800 mg/day o Day 1: Single 300 mg dose o Day 2: 600 mg/day (i.e., 300 mg two times a day) o Day 3: 900 mg/day (i.e., 300 mg three times a day) • Epilepsy with Partial Onset Seizures ( 2.2 ) o Patients 12 years of age and older: starting dose is 300 mg three times daily; may be titrated up to 600 mg three times daily o Patients 3 to 11 years of age: starting dose range is 10 to 15 mg/kg/day, given in three divided doses; recommended dose in patients 3 to 4 years of age is 40 mg/kg/day, given in three divided doses; the recommended dose in patients 5 to 11 years of age is 25 to 35 mg/kg/day, given in three divided doses. The recommended dose is reached by upward titration over a period of approximately 3 days • Dose should be adjusted in patients with reduced renal function ( 2.3 , 2.4 ) 2.1 Dosage for Postherpetic Neuralgia In adults with postherpetic neuralgia, NEURONTIN may be initiated on Day 1 as a single 300 mg dose, on Day 2 as 600 mg/day (300 mg two times a day), and on Day 3 as 900 mg/day (300 mg three times a day). The dose can subsequently be titrated up as needed for pain relief to a dose of 1800 mg/day (600 mg three times a day). 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; however, in these clinical studies, the additional benefit of using doses greater than 1800 mg/day was not demonstrated. 2.2 Dosage for Epilepsy with Partial Onset Seizures Patients 12 Years of Age and Above The starting dose is 300 mg three times a day. The recommended maintenance dose of NEURONTIN is 300 mg to 600 mg three times a day. Dosages up to 2400 mg/day have been administered 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. Administer NEURONTIN three times a day using 300 mg or 400 mg capsules, or 600 mg or 800 mg tablets. The maximum time between doses should not exceed 12 hours. Pediatric Patients Age 3 to 11 Years The starting dose range is 10 mg/kg/day to 15 mg/kg/day, given in three divided doses, and the recommended maintenance dose reached by upward titration over a period of approximately 3 days. The recommended maintenance dose of NEURONTIN in patients 3 to 4 years of age is 40 mg/kg/day, given in three divided doses. The recommended maintenance dose of NEURONTIN in patients 5 to 11 years of age is 25 mg/kg/day to 35 mg/kg/day, given in three divided doses. 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 administered in a long-term clinical study. The maximum time interval between doses should not exceed 12 hours. 2.3 Dosage Adjustment in Patients with Renal Impairment Dosage adjustment in patients 12 years of age and older with renal impairment or undergoing hemodialysis is recommended, as follows (see dosing recommendations above for effective doses in each indication): TABLE 1. NEURONTIN Dosage Based on Renal Function TID = Three times a day; BID = Two times a day; QD = Single daily dose Renal Function Creatinine Clearance (mL/min) Total Daily Dose Range (mg/day) Dose Regimen (mg) ≥ 60 900 to 3600 300 TID 400 TID 600 TID 800 TID 1200 TID >30 to 59 400 to 1400 200 BID 300 BID 400 BID 500 BID 700 BID >15 to 29 200 to 700 200 QD 300 QD 400 QD 500 QD 700 QD 15 For patients with creatinine clearance <15 mL/min, reduce daily dose in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients with a creatinine clearance of 15 mL/min receive). 100 to 300 100 QD 125 QD 150 QD 200 QD 300 QD Post-Hemodialysis Supplemental Dose (mg) Patients on hemodialysis should receive maintenance doses based on estimates of creatinine clearance as indicated in the upper portion of the table and a supplemental post-hemodialysis dose administered after each 4 hours of hemodialysis as indicated in the lower portion of the table. Hemodialysis 125 150 200 250 350 Creatinine clearance (CLCr) is difficult to measure in outpatients. In patients with stable renal function, creatinine clearance can be reasonably well estimated using the equation of Cockcroft and Gault: The use of NEURONTIN in patients less than 12 years of age with compromised renal function has not been studied. Equation 2.4 Dosage in Elderly 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. 2.5 Administration Information Administer NEURONTIN orally with or without food. NEURONTIN capsules should be swallowed whole with water. Inform patients that, should they divide the scored 600 mg or 800 mg NEURONTIN tablet in order to administer a half-tablet, they should take the unused half-tablet as the next dose. Half-tablets not used within 28 days of dividing the scored tablet should be discarded. If the 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).
| TID = Three times a day; BID = Two times a day; QD = Single daily dose | ||||||
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Capsules • 100 mg: white hard gelatin capsules printed with "VLE" on the body and "Neurontin/100 mg" on the cap • 300 mg: yellow hard gelatin capsules printed with "VLE" on the body and "Neurontin/300 mg" on the cap • 400 mg: orange hard gelatin capsules printed with "VLE" on the body and "Neurontin/400 mg" on the cap Tablets • 600 mg: white elliptical film-coated scored tablets debossed with "NT" and "16" on one side • 800 mg: white elliptical film-coated scored tablets debossed with "NT" and "26" on one side Oral Solution • 250 mg per 5 mL (50 mg per mL), clear colorless to slightly yellow solution • Capsules: 100 mg, 300 mg, and 400 mg ( 3 ) • Tablets: 600 mg, and 800 mg ( 3 ) • Oral Solution: 250 mg/5mL ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE 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 NEURONTIN is indicated for: • Postherpetic neuralgia in adults ( 1 ) • 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 ( 1 )
Spl product data elements
Usually a list of ingredients in a drug product.Neurontin gabapentin GABAPENTIN GABAPENTIN LACTOSE, UNSPECIFIED FORM STARCH, CORN TALC GELATIN, UNSPECIFIED TITANIUM DIOXIDE FD&C BLUE NO. 2 VLE;Neurontin;100;mg Neurontin gabapentin GABAPENTIN GABAPENTIN LACTOSE, UNSPECIFIED FORM STARCH, CORN TALC GELATIN, UNSPECIFIED TITANIUM DIOXIDE FERRIC OXIDE YELLOW FD&C BLUE NO. 2 VLE;Neurontin;300;mg Neurontin gabapentin GABAPENTIN GABAPENTIN LACTOSE, UNSPECIFIED FORM STARCH, CORN TALC GELATIN, UNSPECIFIED FERRIC OXIDE RED TITANIUM DIOXIDE FERRIC OXIDE YELLOW FD&C BLUE NO. 2 VLE;Neurontin;400;mg Neurontin gabapentin GABAPENTIN GABAPENTIN POLOXAMER 407 COPOVIDONE K25-31 STARCH, CORN MAGNESIUM STEARATE HYDROXYPROPYL CELLULOSE (1600000 WAMW) TALC CANDELILLA WAX WATER elliptical NT;16 Neurontin gabapentin GABAPENTIN GABAPENTIN POLOXAMER 407 COPOVIDONE K25-31 STARCH, CORN MAGNESIUM STEARATE HYDROXYPROPYL CELLULOSE (1600000 WAMW) TALC CANDELILLA WAX WATER elliptical NT;26 Neurontin gabapentin GABAPENTIN GABAPENTIN GLYCERIN XYLITOL WATER cool strawberry anise
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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 was 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 was 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. Mutagenesis Gabapentin did not demonstrate mutagenic or genotoxic potential in in vitro (Ames test, HGPRT forward mutation assay in Chinese hamster lung cells) and in vivo (chromosomal aberration and micronucleus test in Chinese hamster bone marrow, mouse micronucleus, unscheduled DNA synthesis in rat hepatocytes) assays. Impairment of Fertility 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.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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 was 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 was 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. Mutagenesis Gabapentin did not demonstrate mutagenic or genotoxic potential in in vitro (Ames test, HGPRT forward mutation assay in Chinese hamster lung cells) and in vivo (chromosomal aberration and micronucleus test in Chinese hamster bone marrow, mouse micronucleus, unscheduled DNA synthesis in rat hepatocytes) assays. Impairment of Fertility 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.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PRINCIPAL DISPLAY PANEL – 100 mg Capsules ALWAYS DISPENSE WITH MEDICATION GUIDE Neurontin ® (gabapentin) capsules 100 mg 100 Capsules Rx only Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in tight (USP), child-resistant containers. DOSAGE AND USE See package insert for full prescribing information. Each capsule contains 100 mg of gabapentin. Neurontin Capsules 100 mg Bottle Label
PRINCIPAL DISPLAY PANEL – 300 mg Capsules ALWAYS DISPENSE WITH MEDICATION GUIDE Neurontin ® (gabapentin) capsules 300 mg 100 Capsules Rx only Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in tight (USP), child-resistant containers. DOSAGE AND USE See package insert for full prescribing information. Each capsule contains 300 mg of gabapentin. Neurontin Capsules 300 mg Bottle Label
PRINCIPAL DISPLAY PANEL – 400 mg Capsules ALWAYS DISPENSE WITH MEDICATION GUIDE Neurontin ® (gabapentin) capsules 400 mg 100 Capsules Rx only Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in tight (USP), child-resistant containers. DOSAGE AND USE See package insert for full prescribing information. Each capsule contains 400 mg of gabapentin. Neurontin Capsules 400 mg Bottle Label
PRINCIPAL DISPLAY PANEL – 600 mg Tablets ALWAYS DISPENSE WITH MEDICATION GUIDE Neurontin ® (gabapentin) tablets 600 mg 100 Tablets Rx only Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in tight (USP), child-resistant containers. DOSAGE AND USE See package insert for full prescribing information. Each tablet contains 600 mg of gabapentin. Neurontin Tablets 600 mg Bottle Label
PRINCIPAL DISPLAY PANEL – 800 mg Tablets ALWAYS DISPENSE WITH MEDICATION GUIDE Neurontin ® (gabapentin) tablets 800 mg 100 Tablets Rx only Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in tight (USP), child-resistant containers. DOSAGE AND USE See package insert for full prescribing information. Each tablet contains 800 mg of gabapentin. Neurontin Tablets 800 mg Bottle Label
PRINCIPAL DISPLAY PANEL – 250 mg/5 mL Solution ALWAYS DISPENSE WITH MEDICATION GUIDE Neurontin ® (gabapentin) oral solution 250 mg per 5 mL 470 mL Rx only Store refrigerated, 2°C to 8°C (36°F to 46°F). DOSAGE AND USE See accompanying prescribing information. Keep this and all drugs out of the reach of children. Each 5 mL of oral solution contains 250 mg of gabapentin. Neurontin Oral Solution 250 mg per 5 mL Carton Label
Neurontin: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Administration Information Inform patients that NEURONTIN is taken orally with or without food. Inform patients that, should they divide the scored 600 mg or 800 mg tablet in order to administer a half-tablet, they should take the unused half-tablet as the next dose. Advise patients to discard half-tablets not used within 28 days of dividing the scored tablet. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Prior to initiation of treatment with NEURONTIN, instruct patients that a rash or other signs or symptoms of hypersensitivity (such as fever or lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately [see Warnings and Precautions (5.1) ] . Anaphylaxis and Angioedema Advise patients to discontinue NEURONTIN and seek medical care if they develop signs or symptoms of anaphylaxis or angioedema [ see Warnings and Precautions (5.2) ] . Dizziness and Somnolence and Effects on Driving and Operating Heavy Machinery Advise patients that NEURONTIN may cause dizziness, somnolence, and other symptoms and signs of CNS depression. Other drugs with sedative properties may increase these symptoms. Accordingly, although patients’ ability to determine their level of impairment can be unreliable, advise them neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on NEURONTIN to gauge whether or not it affects their mental and/or motor performance adversely. Inform patients that it is not known how long this effect lasts [see Warnings and Precautions (5.3) and Warnings and Precautions (5.4) ] . Suicidal Thinking and Behavior Counsel the patient, their caregivers, and families that AEDs, including NEURONTIN, may increase the risk of suicidal thoughts and behavior. Advise patients of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients to report behaviors of concern immediately to healthcare providers [see Warnings and Precautions (5.6) ] . Respiratory Depression Inform patients about the risk of respiratory depression. Include information that the risk is greatest for those using concomitant CNS depressants (such as opioid analgesics) or those with underlying respiratory impairment. Teach patients how to recognize respiratory depression and advise them to seek medical attention immediately if it occurs [see Warnings and Precautions (5.7) ] . Use in Pregnancy Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breast feeding or intend to breast feed during therapy [see Use in Specific Populations (8.1) and (8.2) ] . Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334 [see Use in Specific Populations (8.1) ] . Distributed by: Viatris Specialty LLC Morgantown, WV 26505 U.S.A. © 2024 Viatris Inc. NEURONTIN is a registered trademark of UPJOHN US 1 LLC, a Viatris Company. The brands listed are trademarks of their respective owners. UPJ:NRTNCTOS:RXC
Spl medguide
Information about the patient medication guide that accompanies the drug product. Certain drugs must be dispensed with an accompanying medication guide. This field may contain information about when to consult the medication guide and the contents of the medication guide.MEDICATION GUIDE NEURONTIN (neu-RON-tin) (gabapentin) capsules, for oral use NEURONTIN (neu-RON-tin) (gabapentin) tablets, for oral use NEURONTIN (neu-RON-tin) (gabapentin) oral solution What is the most important information I should know about NEURONTIN? Do not stop taking NEURONTIN without first talking to your healthcare provider. Stopping NEURONTIN suddenly can cause serious problems. NEURONTIN can cause serious side effects including: 1. Suicidal Thoughts. Like other antiepileptic drugs, NEURONTIN may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. • Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Do not stop taking NEURONTIN without first talking to a healthcare provider. • Stopping NEURONTIN suddenly can cause serious problems. Stopping a seizure medicine suddenly in a person who has epilepsy can cause seizures that will not stop (status epilepticus). • Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. 2. Changes in behavior and thinking. Using NEURONTIN in children 3 to 12 years of age can cause emotional changes, aggressive behavior, problems with concentration, changes in school performance, restlessness, and hyperactivity. 3. NEURONTIN may cause serious or life-threatening allergic reactions that may affect your skin or other parts of your body such as your liver or blood cells. This may cause you to be hospitalized or to stop NEURONTIN. You may or may not have a rash with an allergic reaction caused by NEURONTIN. Call a healthcare provider right away if you have any of the following symptoms: • skin rash • hives • difficulty breathing • fever • swollen glands that do not go away • swelling of your face, lips, throat, or tongue • yellowing of your skin or of the whites of the eyes • unusual bruising or bleeding • severe fatigue or weakness • unexpected muscle pain • frequent infections These symptoms may be the first signs of a serious reaction. A healthcare provider should examine you to decide if you should continue taking NEURONTIN. 4. Serious breathing problems. Serious breathing problems can happen when NEURONTIN is taken with other medicines (such as opioid pain medicines) that can cause severe sleepiness or decreased awareness, or when it is taken by someone who already has breathing problems. Call your healthcare provider or get medical help right away if you have any of the following symptoms: • feel short of breath • breathing slower than normal • feel very tired • confusion • dizziness • headache Be sure that your caregiver or family members know which symptoms may be serious so they can call your healthcare provider or get medical help if you are unable to seek treatment on your own. Your healthcare provider may lower your dose or stop your treatment with NEURONTIN if you have serious breathing problems. What is NEURONTIN? 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 with seizures. It is not known if NEURONTIN is safe and effective to treat: • children with pain from damaged nerves from a painful rash caused by the chicken pox virus. • partial seizures in children under 3 years of age. Do not take NEURONTIN if you: • are allergic to gabapentin or any of the other ingredients in NEURONTIN. See the end of this Medication Guide for a complete list of ingredients in NEURONTIN. Before taking NEURONTIN, tell your healthcare provider about all of your medical conditions including if you: • have or have had kidney problems or are on hemodialysis. • have or have had depression, mood problems, or suicidal thoughts or behavior. • have a history of drug abuse. • have diabetes. • have breathing problems. • are pregnant or plan to become pregnant. It is not known if NEURONTIN can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking NEURONTIN. You and your healthcare provider will decide if you should take NEURONTIN while you are pregnant. o Pregnancy Registry : If you become pregnant while taking NEURONTIN, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. You can enroll in this registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. • 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. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take: • any opioid pain medicine such as morphine, hydrocodone, oxycodone, or buprenorphine. • any medicines for anxiety (such as lorazepam) or insomnia (such as zolpidem), or any medicines that make you sleepy. You may have a higher chance for dizziness, sleepiness, or breathing problems if these medicines are taken with NEURONTIN. Taking NEURONTIN with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take NEURONTIN? • Take NEURONTIN exactly as prescribed. Your healthcare provider will tell you how much NEURONTIN to take. • Do not change your dose of NEURONTIN without talking to your healthcare provider. • NEURONTIN can be taken with or without food. • Swallow NEURONTIN capsules whole with water. • If you take NEURONTIN tablets and break a tablet in half, the unused half of the tablet should be taken at your next scheduled dose. Half tablets not used within 28 days of breaking should be thrown away. • If you take an antacid containing aluminum and magnesium, such as Maalox, Mylanta, Gelusil, Gaviscon, or Di-Gel, you should wait at least 2 hours before taking your next dose of NEURONTIN. • In case of overdose, get medical help or contact a live Poison Center expert right away at 1-800-222-1222. Advice is also available online at poisonhelp.org. What should I avoid while taking NEURONTIN? • Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking NEURONTIN without first talking with your healthcare provider. Taking NEURONTIN with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. • Do not drive, operate heavy machinery, or do other dangerous activities until you know how NEURONTIN affects you. NEURONTIN can slow your thinking and motor skills. What are the possible side effects of NEURONTIN? NEURONTIN may cause serious side effects, including: • See “What is the most important information I should know about NEURONTIN?” • problems driving while using NEURONTIN. See “What should I avoid while taking NEURONTIN?” • sleepiness and dizziness, which could increase your chance of having an accidental injury, including falls. The most common side effects of NEURONTIN include: • lack of coordination • viral infection • difficulty with speaking • tremor • swelling, usually of legs and feet • feeling tired • fever • feeling drowsy • nausea and vomiting • jerky movements • difficulty with coordination • double vision • unusual eye movement Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of NEURONTIN. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store NEURONTIN? • Store NEURONTIN capsules and tablets at room temperature between 68°F to 77°F (20°C to 25°C). • Store NEURONTIN oral solution in the refrigerator between 36°F to 46°F (2°C to 8°C). Keep NEURONTIN and all medicines out of the reach of children. General information about the safe and effective use of NEURONTIN. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NEURONTIN for a condition for which it was not prescribed. Do not give NEURONTIN to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about NEURONTIN that is written for health professionals. What are the ingredients in NEURONTIN? Active ingredient: gabapentin. Inactive ingredients in the capsules: cornstarch, FD&C Blue No. 2, gelatin, lactose, talc, and titanium dioxide. The 300-mg capsule shell also contains: yellow iron oxide. The 400-mg capsule shell also contains: red iron oxide and yellow iron oxide. Inactive ingredients in the tablets: candelilla wax, copovidone, cornstarch, hydroxypropyl cellulose, magnesium stearate, poloxamer 407, and talc. Inactive ingredients in the oral solution: artificial cool strawberry anise flavor, glycerin, purified water, and xylitol. Distributed by: Viatris Specialty LLC Morgantown, WV 26505 U.S.A. © 202# Viatris Inc. NEURONTIN is a registered trademark of UPJOHN US 1 LLC, a Viatris Company. The brands listed are trademarks of their respective owners. UPJ:MG:NRTNCTOS:RXB For more information, call Viatris at 1-877-446-3679 (1-877-4-INFO-RX). This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 7/2024
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Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES 14.1 Postherpetic Neuralgia NEURONTIN was evaluated for the management of postherpetic neuralgia (PHN) in two randomized, double-blind, placebo-controlled, multicenter studies. The intent-to-treat (ITT) population consisted of a total of 563 patients with pain for more than 3 months after healing of the herpes zoster skin rash (Table 6). TABLE 6. Controlled PHN Studies: Duration, Dosages, and Number of Patients Study Study Duration Gabapentin (mg/day) Given in 3 divided doses (TID) Target Dose Patients Receiving Gabapentin Patients Receiving Placebo 1 8 weeks 3600 113 116 2 7 weeks 1800, 2400 223 111 Total 336 227 Each study included a 7- or 8-week double-blind phase (3 or 4 weeks of titration and 4 weeks of fixed dose). Patients initiated treatment with titration to a maximum of 900 mg/day gabapentin over 3 days. Dosages were then to be titrated in 600 to 1200 mg/day increments at 3- to 7-day intervals to the target dose over 3 to 4 weeks. Patients recorded their pain in a daily diary using an 11-point numeric pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). A mean pain score during baseline of at least 4 was required for randomization. Analyses were conducted using the ITT population (all randomized patients who received at least one dose of study medication). Both studies demonstrated efficacy compared to placebo at all doses tested. The reduction in weekly mean pain scores was seen by Week 1 in both studies, and were maintained to the end of treatment. Comparable treatment effects were observed in all active treatment arms. Pharmacokinetic/pharmacodynamic modeling provided confirmatory evidence of efficacy across all doses. Figures 1 and 2 show pain intensity scores over time for Studies 1 and 2. Figure 1. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 1 Figure 2. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 2 The proportion of responders (those patients reporting at least 50% improvement in endpoint pain score compared to baseline) was calculated for each study (Figure 3). Figure 3. Proportion of Responders (patients with ≥50% reduction in pain score) at Endpoint: Controlled PHN Studies Figure 1. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 1 Figure 2. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 2 Figure 3. Proportion of Responders (patients with ≥50% reduction in pain score) at Endpoint: Controlled PHN Studies 14.2 Epilepsy for Partial Onset Seizures (Adjunctive Therapy) The effectiveness of NEURONTIN as adjunctive therapy (added to other antiepileptic drugs) was established in multicenter placebo-controlled, double-blind, parallel-group clinical trials in adult and pediatric patients (3 years and older) with refractory partial seizures. Evidence of effectiveness was obtained in three trials conducted in 705 patients (age 12 years and above) and one trial conducted in 247 pediatric patients (3 to 12 years of age). The patients enrolled had a history of at least 4 partial seizures per month in spite of receiving one or more antiepileptic drugs at therapeutic levels and were observed on their established antiepileptic drug regimen during a 12-week baseline period (6 weeks in the study of pediatric patients). In patients continuing to have at least 2 (or 4 in some studies) seizures per month, NEURONTIN or placebo was then added on to the existing therapy during a 12-week treatment period. Effectiveness was assessed primarily on the basis of the percent of patients with a 50% or greater reduction in seizure frequency from baseline to treatment (the “responder rate”) and a derived measure called response ratio, a measure of change defined as (T - B)/(T + B), in which B is the patient’s baseline seizure frequency and T is the patient’s seizure frequency during treatment. Response ratio is distributed within the range -1 to +1. A zero value indicates no change while complete elimination of seizures would give a value of -1; increased seizure rates would give positive values. A response ratio of -0.33 corresponds to a 50% reduction in seizure frequency. The results given below are for all partial seizures in the intent-to-treat (all patients who received any doses of treatment) population in each study, unless otherwise indicated. One study compared NEURONTIN 1200 mg/day, in three divided doses with placebo. Responder rate was 23% (14/61) in the NEURONTIN group and 9% (6/66) in the placebo group; the difference between groups was statistically significant. Response ratio was also better in the NEURONTIN group (-0.199) than in the placebo group (-0.044), a difference that also achieved statistical significance. A second study compared primarily NEURONTIN 1200 mg/day, in three divided doses (N=101), with placebo (N=98). Additional smaller NEURONTIN dosage groups (600 mg/day, N=53; 1800 mg/day, N=54) were also studied for information regarding dose response. Responder rate was higher in the NEURONTIN 1200 mg/day group (16%) than in the placebo group (8%), but the difference was not statistically significant. The responder rate at 600 mg (17%) was also not significantly higher than in the placebo, but the responder rate in the 1800 mg group (26%) was statistically significantly superior to the placebo rate. Response ratio was better in the NEURONTIN 1200 mg/day group (-0.103) than in the placebo group (-0.022); but this difference was also not statistically significant (p = 0.224). A better response was seen in the NEURONTIN 600 mg/day group (-0.105) and 1800 mg/day group (-0.222) than in the 1200 mg/day group, with the 1800 mg/day group achieving statistical significance compared to the placebo group. A third study compared NEURONTIN 900 mg/day, in three divided doses (N=111), and placebo (N=109). An additional NEURONTIN 1200 mg/day dosage group (N=52) provided dose-response data. A statistically significant difference in responder rate was seen in the NEURONTIN 900 mg/day group (22%) compared to that in the placebo group (10%). Response ratio was also statistically significantly superior in the NEURONTIN 900 mg/day group (-0.119) compared to that in the placebo group (-0.027), as was response ratio in 1200 mg/day NEURONTIN (-0.184) compared to placebo. Analyses were also performed in each study to examine the effect of NEURONTIN on preventing secondarily generalized tonic-clonic seizures. Patients who experienced a secondarily generalized tonic-clonic seizure in either the baseline or in the treatment period in all three placebo-controlled studies were included in these analyses. There were several response ratio comparisons that showed a statistically significant advantage for NEURONTIN compared to placebo and favorable trends for almost all comparisons. Analysis of responder rate using combined data from all three studies and all doses (N=162, NEURONTIN; N=89, placebo) also showed a significant advantage for NEURONTIN over placebo in reducing the frequency of secondarily generalized tonic-clonic seizures. In two of the three controlled studies, more than one dose of NEURONTIN was used. Within each study, the results did not show a consistently increased response to dose. However, looking across studies, a trend toward increasing efficacy with increasing dose is evident (see Figure 4). Figure 4. Responder Rate in Patients Receiving NEURONTIN Expressed as a Difference from Placebo by Dose and Study: Adjunctive Therapy Studies in Patients ≥12 Years of Age with Partial Seizures In the figure, treatment effect magnitude, measured on the Y axis in terms of the difference in the proportion of gabapentin and placebo-assigned patients attaining a 50% or greater reduction in seizure frequency from baseline, is plotted against the daily dose of gabapentin administered (X axis). Although no formal analysis by gender has been performed, estimates of response (Response Ratio) derived from clinical trials (398 men, 307 women) indicate no important gender differences exist. There was no consistent pattern indicating that age had any effect on the response to NEURONTIN. There were insufficient numbers of patients of races other than Caucasian to permit a comparison of efficacy among racial groups. A fourth study in pediatric patients age 3 to 12 years compared 25-35 mg/kg/day NEURONTIN (N=118) with placebo (N=127). For all partial seizures in the intent-to-treat population, the response ratio was statistically significantly better for the NEURONTIN group (-0.146) than for the placebo group (-0.079). For the same population, the responder rate for NEURONTIN (21%) was not significantly different from placebo (18%). A study in pediatric patients age 1 month to 3 years compared 40 mg/kg/day NEURONTIN (N=38) with placebo (N=38) in patients who were receiving at least one marketed antiepileptic drug and had at least one partial seizure during the screening period (within 2 weeks prior to baseline). Patients had up to 48 hours of baseline and up to 72 hours of double-blind video EEG monitoring to record and count the occurrence of seizures. There were no statistically significant differences between treatments in either the response ratio or responder rate. Figure 4. Responder Rate in Patients Receiving NEURONTIN Expressed as a Difference from Placebo by Dose and Study: Adjunctive Therapy Studies in Patients ≥12 Years of Age with Partial Seizures
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 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 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) ] .
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use 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) ] .
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy 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 or visiting http://www.aedpregnancyregistry.org/ . Risk Summary The totality of available data from published prospective and retrospective cohort studies pertaining to gabapentin use during pregnancy has not indicated an increased risk of major birth defects or miscarriage. There are important methodological limitations hindering interpretation of these studies [see Data ] . 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 ]. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. Data Human Data An observational study based on routinely collected data from administrative and medical registers in Denmark, Finland, Norway, and Sweden, compared the prevalence of major congenital malformations in approximately 1,500 pregnancies exposed to gabapentin monotherapy in the first trimester to pregnancies unexposed to antiepileptics (n=2,995,816) and pregnancies exposed to lamotrigine monotherapy in the first trimester (n=7,582). The adjusted prevalence ratios in a pooled analysis were 1.00 (95% CI: 0.80-1.24) compared to pregnancies unexposed to antiepileptics and 1.29 (95% CI: 1.00-1.67) compared to pregnancies exposed to lamotrigine monotherapy in the first trimester. Data from another observational study in the US based on Medicaid data, which compared the risk for major congenital malformations in more than 4,600 pregnancies exposed to gabapentin during the first trimester to unexposed pregnancies (n=1,753,865), estimated an adjusted relative risk of 1.07 (95% CI: 0.94-1.21). The data from these observational studies should be interpreted with caution due to the potential for exposure misclassification, outcome misclassification, and residual confounding, including by underlying disease. 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/m 2 ) 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/m 2 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/m 2 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.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) 8.1 Pregnancy 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 or visiting http://www.aedpregnancyregistry.org/ . Risk Summary The totality of available data from published prospective and retrospective cohort studies pertaining to gabapentin use during pregnancy has not indicated an increased risk of major birth defects or miscarriage. There are important methodological limitations hindering interpretation of these studies [see Data ] . 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 ]. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. Data Human Data An observational study based on routinely collected data from administrative and medical registers in Denmark, Finland, Norway, and Sweden, compared the prevalence of major congenital malformations in approximately 1,500 pregnancies exposed to gabapentin monotherapy in the first trimester to pregnancies unexposed to antiepileptics (n=2,995,816) and pregnancies exposed to lamotrigine monotherapy in the first trimester (n=7,582). The adjusted prevalence ratios in a pooled analysis were 1.00 (95% CI: 0.80-1.24) compared to pregnancies unexposed to antiepileptics and 1.29 (95% CI: 1.00-1.67) compared to pregnancies exposed to lamotrigine monotherapy in the first trimester. Data from another observational study in the US based on Medicaid data, which compared the risk for major congenital malformations in more than 4,600 pregnancies exposed to gabapentin during the first trimester to unexposed pregnancies (n=1,753,865), estimated an adjusted relative risk of 1.07 (95% CI: 0.94-1.21). The data from these observational studies should be interpreted with caution due to the potential for exposure misclassification, outcome misclassification, and residual confounding, including by underlying disease. 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/m 2 ) 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/m 2 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/m 2 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. 8.2 Lactation 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. 8.4 Pediatric Use 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) ] . 8.5 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 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) ] . 8.6 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) ] .
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING NEURONTIN (gabapentin) capsules, tablets, and oral solution are supplied as follows: 100 mg capsules: White hard gelatin capsules printed with “VLE” on the body and “Neurontin/100 mg” on the cap; available in: Bottles of 100: NDC 58151-281-01 300 mg capsules: Yellow hard gelatin capsules printed with “VLE” on the body and “Neurontin/300 mg” on the cap; available in: Bottles of 100: NDC 58151-282-01 400 mg capsules: Orange hard gelatin capsules printed with “VLE” on the body and “Neurontin/400 mg” on the cap; available in: Bottles of 100: NDC 58151-283-01 600 mg tablets: White elliptical film-coated scored tablets debossed with “NT” and “16” on one side; available in: Bottles of 100: NDC 58151-284-01 800 mg tablets: White elliptical film-coated scored tablets debossed with “NT” and “26” on one side; available in: Bottles of 100: NDC 58151-285-01 250 mg per 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: NDC 58151-290-35 Store NEURONTIN Tablets and Capsules at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store NEURONTIN Oral Solution refrigerated, 2°C to 8°C (36°F to 46°F).
Storage and handling
Information about safe storage and handling of the drug product.Store NEURONTIN Tablets and Capsules at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store NEURONTIN Oral Solution refrigerated, 2°C to 8°C (36°F to 46°F).
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API