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Apo-Gabapentin

Gabapentin 300mg and 400mg capsules

Anti-epileptic

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 (gammaaminobutyric 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 µM 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. The mechanism of the anticonvulsant action of gabapentin appears to be distinctly different from that of other antiepileptic drugs. Although structurally similar to GABA (gamma-aminobutyric acid), gabapentin at concentrations up to 1000 µM, did not bind to GABA receptors, it was not metabolized to GABA or a GABA agonist, and it did inhibit the uptake of GABA or its degradation by GABA-transaminase. Therefore, it does not appear to act through any known GABA mechanism, in contrast to the benzodiazepines, barbiturates, sodium valproate and other similar agents. Gabapentin (0.01 to 100 µM) did not interact with neuronal sodium channels or L-type calcium channels, in contrast to phenytoin, carbamazepine and sodium valproate which interact with these to promote the stability of excitable membranes. Finally, gabapentin (0.01 to 100 µM) did not interact with glutamate, glycine or N-methyl-D-aspartate (NMDA) receptors, in contrast to other drugs that have demonstrated anticonvulsant activity in animal models following interaction with these receptors. These neurophysiological findings indicate that gabapentin has a mechanism of action different from that of commonly used antiepileptic drugs.

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 gabapentin 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 and 10 µg/mL, but are less than doseproportional 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 co-administered antiepileptic drugs, and is minimally bound to plasma proteins.

Food has no effect on the rate or extent of absorption of gabapentin.

In patients of epilepsy, gabapentin concentrations in cerebrospinal fluid are approximately 20% of corresponding steady-state trough plasma concentrations.

Indications
Neuropathic Pain
Apo-Gabapentin is indicated for the treatment of neuropathic pain.

Epilepsy
Apo-Gabapentin is indicated as adjunctive therapy in the treatment of partial seizures with or without secondary generalization in adults with epilepsy.

Dosage and Administration

Neuropathic Pain

Titration to an effective dose can progress rapidly and can be accomplished over a few days by administering 300 mg once a day on day 1, 300 mg twice a day on day 2 and 300 mg three times a day on day 3. as described in Table 1.

Thereafter, the dose can be increased using increments of 300 mg per day given in three divided doses to a maximum of 1800 mg per day. It is not necessary to divide the doses equally when titrating Apo-Gabapentin.

The maximum time between doses in a three times daily schedule should not exceed 12 hours. Gabapentin may be given orally with or without food.

If Apo-Gabapentin is discontinued, or the dose reduced or substituted with an alternative medication, this should be done gradually over a minimum of one week.

Elderly
Elderly patients may require dosage adjustment because of declining renal function with age (see Table 2).

Epilepsy
Apo-Gabapentin is recommended for add-on therapy in patients > 12 years. The effective dosage range was 900 to 1800 mg/day given in divided doses (3 times a day) using 300 or 400 mg capsules. Therapy may be initiated by titrating the dose as described below (see Table 1). Thereafter, the dose can be increased in three equally divided doses up to a clinically effective and tolerated dose. The first dose on Day 1 may be administered at bedtime to minimize potential side effects, especially somnolence, ataxia, fatigue and dizziness. Doses up to 2400 mg/day have been well tolerated in long-term open-label clinical studies. Doses of 3600 mg/day have also been administered to a small number of patients for a relatively short duration and have been well tolerated. APO-GABAPENTIN (gabapentin) is given orally with or without food.

Table 1. Titration schedule

Daily maintenance doses should be given in three equally divided doses (see Table 2), and the maximum time between doses in a three times daily schedule should not exceed 12 hours. It is not necessary to monitor gabapentin plasma concentrations in order to optimize APO-GABAPENTIN therapy.

Further, as there are no drug interactions with commonly used antiepileptic drugs, APO-GABAPENTIN 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 as follows (see Table 2).

Table 2: Maintenance dosage of APO-GABAPENTIN in adults with reduced renal function

* Loading dose of 300 to 400 mg
** Maintenance dose of 200 to 300 mg APO-GABAPENTIN following each 4 hours of hemodialysis

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