INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
NEURONTIN 100, 300, 400

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

NEURONTIN 100, 300, 400

Neurontin 100 (capsule)
Neurontin 300 (capsule)
Neurontin 400 (capsule)

COMPOSITION:
Neurontin 100 - each capsule contains 100 mg gabapentin.
Neurontin 300 - each capsule contains 300 mg gabapentin.
Neurontin 400 - each capsule contains 400 mg gabapentin.

PHARMACOLOGICAL CLASSIFICATION:
A: 2.5 Central nervous system depressants - Anticonvulsants, including anti-epileptics.

PHARMACOLOGICAL ACTION:
Mechanism of Action:
Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid). In vitro animal studies with radiolabeled gabapentin have characterized a peptide binding site in brain tissues including neocortex and hippocampus that may relate to anticonvulsant activity of gabapentin and its structural derivatives. However the mechanism of action remains unclear.
Pharmacokinetics and Metabolism:
Following oral administration, peak plasma gabapentin concentrations are observed within 2 to 3 hours. Absolute bioavailability of 300 mg and 400 mg gabapentin capsules is approximately 55%. Food has no effect on gabapentin pharmacokinetics. Gabapentin elimination parameters are independent of dose. However, the extent of gabapentin absorption decreases with increasing dose. Following doses of 300 and 600 mg Neurontin, absolute bioavailability is 57% and 42%, respectively. In normal volunteers the elimination half-life of gabapentin is independent of dose and averages 5 to 7 hours. Although plasma gabapentin concentrations were generally between 2 micrograms/mL and 20 micrograms/mL in clinical studies, such concentrations were not predictive of safety or efficacy.
Gabapentin is not bound to plasma proteins and has an apparent volume of distribution of 57,7 litres. In patients with epilepsy, gabapentin concentrations in CSF ranged from 7 - 35% of corresponding steady-state trough plasma concentrations. Gabapentin is eliminated solely by renal excretion. Gabapentin does not induce hepatic mixed-function oxidase enzymes responsible for drug metabolism.
In elderly patients, age-related alterations in renal function decrease gabapentin plasma clearance and increase gabapentin elimination half-life. Gabapentin elimination-rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance.
Gabapentin is removed from plasma by haemodialysis.

INDICATIONS:
Neurontin is indicated as adjunctive therapy with standard anti-epileptic drugs in patients who have not achieved adequate seizure control with these agents used alone or in combination. Neurontin is indicated in controlling both simple and complex partial seizures with or without secondarily generalized tonic clonic seizures.

CONTRA-INDICATIONS:
Neurontin is contra-indicated in patients who are hypersensitive to gabapentin or the product'sexcipients.
Safety and efficacy have not been established in children, pregnancy and lactation.

DOSAGE AND DIRECTIONS FOR USE:

1.	Adults & children over 12 years:
	Usual effective dose: 900 - 1800 mg/day in three divided doses with not more than 12 hours between doses.
	Since titration to an effective dose can progress rapidly, this may be accomplished in as few as three days using one of the following approaches:

	Day 1	Day 2	Day 3
900 mg/day	1x100 mg, three times a day	2x100 mg, three times a day	1x300 mg, three times a day
or	1x300 mg, once a day	1x300 mg, twice a day	1x300 mg, three times a day
1200 mg/day	2x100 mg, three times a day	3x100 mg, three times a day	1x400 mg, three times a day
or	1x400 mg, once a day	1x400 mg, twice a day	1x400 mg, three times a day

2.	Paediatric use: Safety and effectiveness in children under 12 years have not been established.
3.	Elderly: No significant changes in the adverse event profile were found in the elderly (i.e. over 65 years of age); an increased incidence of certain adverse events cannot be excluded. However, only small numbers of patients have been studied. Elderly patients should be carefully monitored for adverse events. Elderly patients may require dosage adjustment because of declining renal function with age: Adjust according to Creatinine Clearance as in table under 4.
4.	Compromised renal function: The elimination of Neurontin is decreased in patients with impaired renal function. This patient population has not been fully examined but the following guidelines are based on information derived from single doses in non-epileptic patients. For patients with compromised renal function or those undergoing haemodialysis the following maintenance dosage is recommended.

Renal Function Creatinine Clearance (mL/min)	Total Daily Dose (mg/day)	Dose Regimen         (mg)
>60	1200	400 three times a day
30-60	600	300 twice a day
15-30	300	300 once a day
<15	150	300 every other day
Haemodialysisa	-	200-300b

^a Loading dose of 300 to 400 mg
^b Maintenance dose of 200 to 300 mg gabapentin following each 4 hours of haemodialysis

5.	It is unnecessary to monitor gabapentin plasma concentrations to optimise gabapentin therapy.
6.	Neurontin may be used in combination with phenobarbital, phenytoin, valproic acid and carbamazepine without concern for alteration of the plasma concentrations or serum concentrations of gabapentin or the other anti-epileptic agents.
7.	If Neurontin is discontinued and/or an alternate medication is added to the therapy this should be done gradually over a minimum of one week.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects:
The most frequent clinical adverse events occurring in all clinical studies were: somnolence, dizziness, ataxia, headache, nystagmus, tremor, fatigue, diplopia, nausea and/or vomiting and rhinitis.
From data drawn from placebo controlled studies, adverse events are listed in descending order of frequency both by bodily system and by associated adverse events:
Nervous system: Somnolence, dizziness, ataxia, nystagmus, tremor, dysarthria, amnesia, confusion, insomnia, twitching, abnormal co-ordination, paresthesia, vertigo.
Body as a whole: Fatigue, headache, weight increase, back pain, peripheral oedema, viral infection, fever.
Digestive System: Nausea and vomiting, dyspepsia, abdominal pain, dry mouth or throat, constipation, dental abnormalities, diarrhoea, increased appetite.
Special Senses: Diplopia, amblyopia.
Respiratory System: Rhinitis, pharyngitis, coughing, respiratory tract infection.
Skin and Appendages: Rash, pruritus, abrasion, acne, maculopapular rash.
Psychobiologic Function: Nervousness, depression, thinking abnormal, emotional lability.
Laboratory Deviations: White blood cells decreased.
Urogenital System: Impotence.
Musculoskeletal System: Myalgia, fracture.
Cardiovascular System: Vasodilation.
Haemic & Lymphatic System: Leucopenia, purpura.
Sudden and Unexplained Deaths:
During the course of premarketing development of Neurontin, 8 sudden and unexplained deaths were recorded among a cohort of 2203 patients treated (2103 patient-years of exposure).
Some of these could represent seizure-related deaths in which the seizure was not observed e.g. at night. This represents an incidence of 0,0038 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving Neurontin (ranging from 0.0005 for the general population of epileptics, to 0,003 for a clinical trial population similar to that in the Neurontin program, to 0,005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or raise further concern depends on comparability of the populations reported upon to the Neurontin cohort and the accuracy of the estimates provided.
Additional post-marketing adverse events reported include pancreatitis, erythema multiforme, Stevens-Johnson syndrome and elevated liver function tests (LFTS).
Interactions:
There is no interaction between gabapentin, phenobarbitone, phenytoin, valproic acid, carbamazepine or carbamazepine 10,11-epoxide. Gabapentin steady-state pharmacokinetics are similar for healthy subjects and patients with epilepsy receiving anti-epileptic agents.
Co-administration of gabapentin with oral contraceptives containing norethindrone and/or ethinyl estradiol, does not influence the steady-state pharmacokinetics of either component.
Co-administration of gabapentin with a magnesium-and aluminium-containing antacid reduces gabapentin bioavailability by approximately 24%. It is recommended that gabapentin be taken about two hours following antacid administration. Renal excretion of gabapentin is unaltered by probenecid. A slight decrease in renal excretion of gabapentin observed when it is co-administered with cimetidine is not expected to be of clinical importance.
False positive tests for proteinuria may occur with Ames Multistix-SG.
Special precautions:
General:
Although there is no evidence of rebound seizures with gabapentin, abrupt withdrawal of anticonvulsants in epileptic patients may precipitate status epilepticus. When in the judgement of the clinician there is a need for dose reduction, discontinuation, or substitution of alternative anticonvulsant medication, this should be done gradually over a minimum of one week.
Gabapentin is not generally considered effective in the treatment of absence seizures.
Special care should be taken by patients driving, operating machinery or performing any hazardous tasks.
Usage in Pregnancy:
Gabapentin did not increase the incidence of malformations, compared to controls, in the offspring of mice, rats, or rabbits at doses up to 50, 30 and 25 times, respectively, the daily human dose of 3600 mg, (four, five or eight times, respectively, the human daily dose of a mg/m² basis.) 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 be used during pregnancy only if the potentialbenefit to the patient justifies the potential risk to the foetus.
Usage in Nursing Mothers:
It is not known if gabapentin is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
No specific information is available on the treatment of overdose with Neurontin, although haemodialysis has been shown to be effective in eliminating gabapentin. Treatment is symptomatic and supportive, consistent with established medical care.
Overdoses of Neurontin up to 49 g ingested at one time have been reported in four people, all of whom recovered fully.
Symptoms of overdose included dizziness, double vision, slurred speech, drowsiness, lethargy and mild diarrhoea.
Reduced absorption of Neurontin at higher doses may limit drug absorption and hence minimise toxicity at the time of overdosing.
In patients with renal impairment haemodialysis may be indicated.

IDENTIFICATION:

NEURONTIN 100:	White, opaque hard gelatine capsules imprinted in blue ink with “Neurontin 100 mg”on the cap and “PD”on the body.
NEURONTIN 300:	Pale yellow, opaque hard gelatine capsules imprinted in grey ink with “Neurontin 300 mg” on the cap and “PD”on the body
NEURONTIN 400:	Orange, opaque hard gelatine capsules imprinted in grey ink with “Neurontin 400 mg”on the cap and “PD”on the body

PRESENTATION:
White Securitainers of 100.

STORAGE INSTRUCTIONS:
Store in a cool (below 25°C), dry place. Do not freeze.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS:

Neurontin 100:	27/2.5/0598
Neurontin 300:	27/2.5/0599
Neurontin 400:	27/2.5/0600

NAME OF ADDRESS OF APPLICANT:
Pfizer Laboratories (Pty) Ltd
102 Rivonia Rd
SANDTON 2196
Republic of South Africa

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
21 January 1994

Updated on this site: February 2005
Source: Pharmaceutical Industry
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