Action And Clinical Pharmacology: Gabapentin exhibits antiseizure activity in mice and rats both in the maximal electroshock and in the pentylenetetrazol seizure models.
Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but does not interact with GABA receptors, it is not metabolized to GABA or to GABA agonists, and it is not an inhibitor of GABA uptake or degradation. Gabapentin at concentrations up to 100 M did not demonstrate affinity for other receptor sites such as benzodiazepine, glutamate, glycine or N-methyl-D-aspartate receptors nor does it interact with neuronal sodium channels or L-type calcium channels.
The mechanism of action of gabapentin has not yet been established; however, it is unlike that of the commonly used anticonvulsant drugs.
In vitro studies with radiolabeled gabapentin have revealed a gabapentin binding site in rat brain tissues including neocortex and hippocampus. The identity and function of this binding site remain to be elucidated.
Pharmacokinetics: Adults: Following oral administration of gabapentin, peak plasma concentrations are observed within 2 to 3 hours. Absolute bioavailability of a 300 mg dose of Neurontin capsules is approximately 59%. At doses of 300 and 400 mg, gabapentin bioavailability is unchanged following multiple dose administration. Gabapentin elimination from plasma is best described by linear pharmacokinetics. The elimination half-life of gabapentin is independent of dose and averages 5 to 7 hours in subjects with normal renal function.
Plasma gabapentin concentrations are dose-proportional at doses of 300 to 400 mg q8h, ranging between 1 g/mL and 10 Âµg/mL, but are less than dose-proportional above the clinical range (>600 mg q8h). There is no correlation between plasma levels and efficacy. Gabapentin pharmacokinetics are not affected by repeated administration, and steady-state plasma concentrations are predictable from single-dose data.
Gabapentin is not appreciably metabolized in humans, is eliminated solely by renal excretion, and can be removed from plasma by hemodialysis.
Gabapentin does not induce or inhibit hepatic mixed function oxidase enzymes responsible for drug metabolism, does not interfere with the metabolism of commonly coadministered antiepileptic drugs, and is minimally bound to plasma proteins.
Food has no effect on the rate or extent of absorption of gabapentin.
In patients with epilepsy, gabapentin concentrations in cerebrospinal fluid are approximately 20% of corresponding steady-state trough plasma concentrations.
Geriatrics: Apparent oral clearance (CL/F) of gabapentin decreased as age increased, from about 225 mL/min in subjects under 30 years of age to about 125 mL/min in subjects over 70 years of age. Renal clearance (CLr) of gabapentin also declined with age; however, this decrease can largely be explained by the decline in renal function. Reduction of gabapentin dose may be required in patients who have age-related compromised renal function (see Dosage).
Renal Impairment: In patients with impaired renal function, gabapentin clearance is markedly reduced and dosage adjustment is necessary.
Hemodialysis: In a study in anuric subjects (n=11), the apparent elimination half-life of gabapentin on nondialysis days was about 132 hours; dialysis 3 times a week (4 hours duration) lowered the apparent half-life of gabapentin by about 60%, from 132 hours to 51 hours. Hemodialysis thus has a significant effect on gabapentin elimination in anuric subjects.
Dosage adjustment in patients undergoing hemodialysis is necessary.
Children: There are no pharmacokinetic data available in children under 18 years of age.
Hepatic Impairment: Because gabapentin is not appreciably metabolized in humans, no study was performed in patients with hepatic impairment.
Clinical Trials: In placebo-controlled trials in patients not satisfactorily controlled with current antiepileptic drugs, gabapentin, when added to current antiepileptic therapy, was superior to placebo in reducing the frequency of both simple and complex partial seizures and secondarily generalized tonic-clonic seizures. Further analysis of data indicated a higher efficacy for complex partial seizures and secondarily generalized tonic-clonic seizures as compared to all seizure types. Doses ranged from 900 to 1 800 mg/day, with a median dose of 1 200 mg/day.
Long-term, open, uncontrolled studies in drug-resistant patients for periods of up to 18 months demonstrated that doses up to 2 400 mg/day did not result in anything unusual in the type or frequency of adverse events.
Indications And Clinical Uses: As adjunctive therapy for the management of patients with epilepsy who are not satisfactorily controlled by conventional therapy.
Contra-Indications: Patients who have demonstrated hypersensitivity to the drug or to any of the components of the formulation.
Precautions: General: Gabapentin is not considered effective in the treatment of absence seizures and should therefore be used with caution in patients who have mixed seizure disorders that include absence seizures.
Tumorigenic Potential: Gabapentin produced an increased incidence of acinar cell adenomas and carcinomas in the pancreas of male rates, but not female rats or in mice, in oncogenic studies with doses of 2 000 mg/kg which resulted in plasma concentrations 14 times higher than those occurring in humans at the maximum recommended dose of 2 400 mg/day. The relevance of these pancreatic acinar cell tumors in male rats to humans is unknown, particularly since tumors of ductal rather than acinar cell origin are the predominant form of human pancreatic cancer.
Drug Discontinuation: As with other anticonvulsant agents, abrupt withdrawal is not recommended because of the possibility of increased seizure frequency. When in the judgment of the clinician there is a need for dose reduction, discontinuation or substitution with alternative medication, this should be done gradually over a minimum of one week.
Occupational Hazards: Patients with uncontrolled epilepsy should not drive or handle potentially dangerous machinery. During clinical trials, the most common adverse reactions observed were somnolence, ataxia, fatigue and nystagmus. Patients should be advised to refrain from activities requiring mental alertness or physical coordination until they are sure that gabapentin does not affect them adversely.
Drug Interactions: Antiepileptic Agents: There is no interaction between gabapentin and phenytoin, valproic acid, carbamazepine, or phenobarbital. Consequently, Neurontin may be used in combination with other commonly used antiepileptic drugs without concern for alteration of the plasma concentrations of gabapentin or the other antiepileptic drugs.
Gabapentin steady-state pharmacokinetics are similar for healthy subjects and patients with epilepsy receiving antiepileptic agents.
Oral Contraceptives: Coadministration of gabapentin with the oral contraceptive NorlEstrin does not influence the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.
Antacids: Coadministration of gabapentin with an aluminum and magnesium-based antacid reduces gabapentin bioavailability by up to 24%. Although the clinical significance of this decrease is not known, coadministration of similar antacids and gabapentin is not recommended.
Probenecid: Renal excretion of gabapentin is unaltered by probenecid.
Cimetidine: A slight decrease in renal excretion of gabapentin observed when it is coadministered with cimetidine is not expected to be of clinical importance.
Pregnancy: No evidence of impaired fertility or harm to the fetus due to gabapentin administration was revealed in reproduction studies in mice at doses up to 62 times, and in rats and rabbits at doses up to 31 times the human dose of 2 400 mg/day.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the fetus.
Lactation: It is not known if gabapentin is excreted in human milk, and the effect on the nursing infant is unknown. However, because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from gabapentin, breast-feeding is only recommended if the potential benefit outweighs the potential risks.
Children: Systematic studies to establish safety and efficacy in children have not been performed. Data in 39 patients between the ages of 12 and 18 years included in the double-blind, placebo-controlled trials showed that gabapentin was superior to placebo in reducing seizure frequency. Safety data showed that the incidence of adverse events in this group of patients were similar to those observed in older individuals.
Geriatrics: Systematic studies in geriatric patients have not been conducted. Adverse clinical events reported among 59 patients over the age of 65 years treated with gabapentin did not differ from those reported for younger individuals. The small number of individuals evaluated and the limited duration of exposure limits the strength of any conclusions reached about the influence of age, if any, on the kind and incidence of adverse events associated with the use of gabapentin.
As gabapentin is eliminated primarily by renal excretion, dosage adjustment may be required in elderly patients because of declining renal function (see Dosage).
Renal Impairment: Gabapentin clearance is markedly reduced in this patient population and dosage reduction is necessary.
Laboratory Tests: Clinical trials data do not indicate that routine monitoring of clinical laboratory parameters is necessary for the safe use of gabapentin. Gabapentin may be used in combination with other commonly used antiepileptic drugs without concern for alteration of the blood concentrations of gabapentin or other antiepileptic drugs.
For urinary protein determination the sulfosalicylic acid precipitation procedure is recommended, as false positive readings were reported with the Ames N-Multistix SG dipstick test, when gabapentin or placebo was added to other anticonvulsant drugs.
Adverse Reactions: Incidence in Controlled Clinical Trials: Table II lists treatment-emergent signs and symptoms that occurred in at least 1% of patients with partial seizures participating in placebo-controlled studies. In these studies, either gabapentin (at doses of 600, 900, 1 200 or 1 800 mg/day) or placebo were added to the patient’s current antiepileptic drug therapy.
The most commonly observed adverse events associated with the use of gabapentin in combination with other antiepileptic drugs, not seen at an equivalent frequency in placebo-treated patients, were somnolence, dizziness, ataxia, fatigue, nystagmus and tremor.
Among the treatment-emergent adverse events occurring in gabapentin-treated patients, somnolence and ataxia appeared to exhibit a positive dose-response relationship. Patients treated with 1 800 mg/day (n=54, from one controlled study) experienced approximately a 2-fold increase, as compared to patients on lower doses of 600 to 1 200 mg/day (n=489, from several controlled studies), in the incidence of nystagmus (20.4%), tremor (14.8%), rhinitis (13%), peripheral edema (7.4%), abnormal coordination, depression and myalgia (all at 5.6%). Adverse events were usually mild to moderate in intensity, with a median time to resolution of 2 weeks.
Since gabapentin was administered most often in combination with other antiepileptic agents, it was not possible to determine which agent(s) was associated with adverse events.
Data from long-term, open, uncontrolled studies shows that gabapentin treatment does not result in any new or unusual adverse events.
Withdrawal from Treatment Due to Adverse Events: Approximately 6.4% of the 543 patients who received gabapentin in the placebo-controlled studies withdrew due to adverse events. In comparison, approximately 4.5% of the 378 placebo-controlled participants withdrew due to adverse events during these studies. The adverse events most commonly associated with withdrawal were somnolence (1.2%), ataxia (0.8%), fatigue, nausea and/or vomiting and dizziness (all at 0.6%).
Other Adverse Events Observed in All Clinical Trials: Adverse events that occurred in at least 1% of the 2 074 individuals who participated in all clinical trials are described below.
Body as a Whole: asthenia, malaise, facial edema.
Digestive: anorexia, flatulence, gingivitis.
Hematologic and Lymphatic: purpura; most often described as bruises resulting from physical trauma.
CNS: vertigo, hyperkinesia, paresthesia, anxiety, hostility, decreased or absent reflexes.
Special Senses: abnormal vision.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Acute, life-threatening toxicity has not been observed with gabapentin overdoses of up to 49 g ingested at one time. In these cases, double vision, slurred speech, drowsiness, lethargy and diarrhea were observed. All patients recovered with supportive care.
Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patients clinical state or in patients with significant renal impairment.
Reduced absorption of gabapentin at higher doses may limit drug absorption at the time of overdosing and, hence, reduce toxicity from overdoses.
An oral lethal dose of gabapentin was not identified in mice and rats given doses as high as 8 000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, hypoactivity, or excitation.
Dosage And Administration: Adults: The usual effective maintenance dose is 900 to 1 200 mg/day. Treatment should be initiated with 300 to 400 mg/day. Titration to an effective dose, in increments of 300 or 400 mg/day, can progress rapidly and can be accomplished over 3 days. Gabapentin is given orally with or without food.
Data from clinical trials suggest that doses higher than 1 200 mg/day may have increased efficacy in some patients; however, higher doses may also increase the incidence of adverse events (see Adverse Effects).
Daily maintenance doses should be given in 3 equally divided doses, and the maximum time between doses in a 3 times daily schedule should not exceed 12 hours. It is not necessary to monitor gabapentin plasma concentrations in order to optimize gabapentin therapy. Further, as there are no drug interactions with commonly used antiepileptic drugs, Neurontin may be used in combination with these drugs without concern for alteration of plasma concentrations of either gabapentin or other antiepileptic drugs.
Dosage adjustment in elderly patients due to declining renal function and in patients with renal impairment or undergoing hemodialysis is recommended.
Children over 12 years of age: The dosage used in a limited number of patients in this age group was 900 to 1 200 mg/day. Doses above 1 200 mg/day have not been investigated.
Availability And Storage: 100 mg: Each hard gelatin capsule, with white opaque body and cap printed with “PD” on one side and “Neurontin/100 mg” on the other, contains: gabapentin 100 mg. Nonmedicinal ingredients: cornstarch, lactose and talc; capsule shells may contain FD&C blue No. 2, gelatin, red iron oxide, silicon dioxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. Bottles of 100.
300 mg: Each hard gelatin capsule, with yellow opaque body and cap printed with “PD” on one side and “Neurontin/300 mg” on the other, contains: gabapentin 300 mg. Nonmedicinal ingredients: cornstarch, lactose and talc; capsule shells may contain FD&C blue No. 2, gelatin, red iron oxide, silicon dioxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. Bottles of 100.
400 mg: Each hard gelatin capsule, with orange opaque body and cap printed with “PD” on one side and “Neurontin/400 mg” on the other, contains: gabapentin 400 mg. Nonmedicinal ingredients: cornstarch, lactose and talc; capsule shells may contain FD&C blue No. 2, gelatin, red iron oxide, silicon dioxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. Bottles of 100.
Store at controlled room temperature 15 to 30°C.
NEURONTIN Parke-Davis Gabapentin Antiepileptic