Manufactured by Pfizer
Uses: Complex partial, Tonic-clonic, Simple partial
Common side effects: Drowsiness, dizziness, fatigue, and lack of co-ordination
Remarks: Doesn't interact with other anticonvulsants
Product Info:
The information below has been provided by Pfizer "AS IS" WITHOUT WARRANTY OF ANY KIND, EITHER EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, OR NON-INFRINGEMENT.
Furthermore the information contained in this document is accurate as of 27th of April 2001 and may become out of date over time and thus should be considered current only as of the date stated. This information is not intended to be a substitute for the advice of a health care professional, or a recommendation for any particular treatment plan, and is not intended to supplement, modify or supercede the information provided in the product package insert with respect to the use of the product for medical purposes.
Gabapentin (Neurontin) is available in: 100mg/300mg/400mg capsules and 600mg/800mg tablets.
Please note that the information given below only deals with the administration of Neurontin as an anti-epileptic drug. For details regarding the use of Neurontin to treat neuropathic pain please contact Pfizer.
CLINICAL PARTICULARS
THERAPEUTIC INDICATIONS
Epilepsy
Adults and children over 12 years of age
Neurontin is an anti-epileptic drug indicated as add-on therapy for partial seizures and partial seizures with secondary generalisation in patients who have not achieved satisfactory control with or who are intolerant to standard anticonvulsants used alone or in combination.
Children 6-12 years of age
Neurontin may be used as add-on therapy for partial seizures and partial seizures with secondary generalisation, in children age between 6-12 years, who have not achieved satisfactory control with, or who are intolerant to, standard anticonvulsants used alone or in combination, if the benefit: risk is considered favourable. Neurontin should be initiated and supervised by a neurological specialist.
Children under 6 years of age
There are inadequate data in this age group and therefore the use of Neurontin is not recommended.
POSOLOGY AND METHOD OF ADMINISTRATION
Epilepsy
Adults and children over 12 years of age
The anti-epileptic effect of Neurontin generally occurs at 900 to 1200mg/day. It is not necessary to monitor Neurontin plasma concentrations to optimise Neurontin therapy.
Titration to an effective dose can progress rapidly and can be accomplished over a few days by administering 300mg once a day on day 1, 300mg twice a day on day2 and 300mg three times a day on day 3. Thereafter, the dose can be increased using increments of 300mg per day given in three equally divided doses to a maximum of 2400mg per day.
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 Neurontin is discontinued and/or an alternate anticonvulsant medication is added to the therapy, this should be done gradually over a minimum of one week.
Children 6-12 years of age
The recommended dose of Neurontin is 25 to 35mg/kg/day given in divided doses ( 3 times a day). Titration to an effective dose can take place over 3 days by giving 10mg/kg/day on Day 1, 20mg/kg/day on Day 2 and 25 to 35mg/kg/day on Day 3.
CONTRA-INDICATIONS
Neurontin is contra-indicated in patients who are hypersensitive to Neurontin or to the product's components.
SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE
Although there is no evidence of rebound seizures with Neurontin, abrupt withdrawl of anticonvulsant agents 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.
Neurontin is not generally considered effective in the treatment of absence seizures.
Patients taking Neurontin can be the subject of mood and behavioural disturbances. Such reports have been noted in patients on Neurontin although a causal link has not been established.
Caution is recommended in patients with a history of psychotic illness. On commencing Neurontin therapy, psychotic episodes have been reported in some patients with, and rarely without, a history of psychotic illness. Most of these events resolved when Neurontin was discontinued or the dosage was reduced.
INTERACTIONS WITH OTHER MEDICAMENTS AND OTHER FORMS OF INTERACTION
Neurontin may be used in combination with other anti-epileptic drugs without concern for alteration of the plasma concentrations of Neurontin or serum concentrations of other anti-epileptic drugs.
There is no interaction between Neurontin and phenytoin, valproic acid, carbamazepine or phenobarbitone. Neurontin steady-state pharmacokinetics are similar for healthy subjects and patients with epilepsy receiving anti-epileptic agents.
Co-administration of Neurontin with oral contraceptives including norethisterone and/or ethinyl oestradiol does not influence the steady-state of either component.
In a clinical study where Neurontin and an aluminium and magnesium containing antacid when given at the same time, Neurontin's bioavailability was reduced by up to 24%. It is recommended that Neurontin is taken about two hours following any such antacid administration. The slight decrease in renal excretion of Neurontin observed when co-administered with cimetidine is not expected to be of clinical importance.
Renal excretion of Neurontin is unaltered by probenecid.
Food has no effect on Neurontin pharmacokinetics.
Because false positive readings were reported with the Ames N-Multistix SG dipstick test when Neurontin was added to other anticonvulsant drugs, the more specific sulphosalicylic acid precipitation procedure is recommended to determine urinary protein.
PREGNANCY AND LACTATION
Safe use in human pregnancy has not been established. Reproduction studies in mice, rats or rabbits at doses up to 50, 30 and 25 times respectively, the daily human dose of 3600mg revealed no evidence of impaired fertility or harm to the foetus due to Neurontin administration. However, because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed.
Neurontin is excreted in human milk but the effect on the nursing infant is unknown. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Neurontin, 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.
EFFECTS ON THE ABILITY TO DRIVE AND USE MACHINES
Neurontin acts on the central nervous system and may produce drowsiness, dizziness, or other related symptoms. These otherwise mild or moderate adverse events could be potentially dangerous in patients driving or operating machinery, particularly until such time as the individual patient's experience with the drug is established.
UNDESIRABLE EFFECTS
Since Neurontin has most often been administered in combination with other anti-epileptic agents, it is not possible to determine which agents, if any, are associated with adverse events. However, based on placebo-controlled, double blind studies, the most frequent possible side effects are: somnolence, dizziness, ataxia, and fatigue.
Less frequent possible side effects are: nystagmus, tremor, diplopia, amblyopia, dysarthria, amnesia, asthenia, paraesthesia, arthralgia, purpura, leucopenia, dyspepsia, anxiety, weight increase, urinary tract infection and pharyngitis.
As with other AED's there have been rare reports of pancreatitis, elevated liver function tests, erythema multiforme and Stevens johnson Syndrome where a causal relationship to treatment has not been established. Rarely confusion, depression, emotional lability, hostility, abnormal thinking and psychoses/halluncinations have been reported. Blood glucose fluctuations in patients with diabetes, rhinitis, nervousness, myalgia, headache, nausea and/or vomiting have also been reported.
Children
In children aged 3-12 years in placebo controlled and long term trials, the most common (>10%) side effects were emotional lability, nervousness and thinking abnormally. All reports of these events were rated as mild or moderate and discontinuation or dose reduction were infrequent.
In children aged 3-12 years in controlled add-on, side effects that occured with an incidence of 2% or greater than placebo were: somnolence, fatigue, weight increase, hostility, emotional lability, dizziness, hyperkinesia, nausea/vomiting, viral infection, fever, bronchitis, respiratory infection. Some of these side effects could be attributed to common viral childhood illness.
OVERDOSE
Acute, life threatening toxicity has not been observed with Neurontin overdoses of up to 49g. Symptoms of the overdose included dizziness, double vision, slurred speech, drowsiness, lethargy and mild diarrhoea. All patients fully recovered with supportive care. Reduced absorption of Neurontin at higher doses may limit drug absorption at the time of overdosing and, hence, minimise toxicity from overdoses.
Although Neurontin can be removed by haemodialysis it is not usually required. However, in patients with renal impairment, haemodialysis may be indicated.
PHARMACOLOGICAL PROPERTIES
PHARMACODYNAMIC PROPERTIES
Neurontin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but its mechanism of action is different from that of several drugs that interact with GABA synapses. The identification and function of the gabapentin binding site remains to be elucidated and the relevance of its various actions to the anticonvulsant effect to be established. analgesic activity has been shown in animal models of inflammatory and neuropathic pain.
PHARMACOKINETIC PROPERTIES
Mean plasma gabapentin concentrations (Cmax) occured approximately 3 hours (Tmax) following a single oral doses of Neurontin regardless of dose size or formulation. Mean Tmax values following multiple dose administration were approximately 1 hour shorter than the values following single-dose administration.
Mean Cmax and AUC values increased with increasing dose; however, the increase was less than dose proportional. Deviation from linearity was very slight up to 600mg for both parameters and thus should be minimal at doses of 300mg to 400mg three times daily where the anti-epileptic effect generally occurs.
Following repeated Neurontin administration, steady state was achieved within 1 to 2 days after the start of multiple dosing and was maintained throughout the dosing regime.
Plasma gabapentin concentration-time profiles were similar between gabapentin solution and capsule formulations following single doses of 300 and 400mg. Absolute bioavailability of a 300mg oral dose of Neurontin was approximately 60%. At doses of 300mg and 400mg, Neurontin bioavailability was unchanged following multiple-dose administration.
Based on results of bioavailability studies performed with Neurontin Tablets, the 600 and 800mg tablets are bioequivalent to marketed Neurontin Capsules. the 600mg tablets were found to be bioequivalent to 2 X 300mg marketed capsules based on similar rate and extent of drug absorption. Likewise, 800mg tablets were found to be bioequivalent to 2 X 400mg marketed capsules based on a similar rate and extent of drug absorption.
The presence of food did not influence the bioavailability of Neurontin.
Gabapentin is not metabolised in humans and does not induce hepatic mixed function oxidase enzymes.
Gabapentin elimination from plasma following IV administration was best described by linear pharmacokinetics. elimination helf-lie (T1/2) of gabapentin ranged from 5 to 7 hours. Gabapentin elimination parameters, apparent plasma T 1/2 and renal clearance (CLr) were independent of dose and remained unchanged following repeated administration. Renal clearance was the sole elimination pathway for gabapentin. Since gabapentin is not metabolised in humans, the amount of the drug recovered in urine is indicative of gabapentin bioavailability. Following a single 200mg oral dose of (C14) gabapentin recovery of radioactivity was essentially complete with approximately 80% and 20% of the dose recovered in urine and faeces, respectively.
As renal function (as determined by creatinine clearance) decreases with increasing age, gabapentin oral clearance, renal clearance and elimination-rate constant decrease proportionally.
Gabapentin pharmacokinetics were determined in 24 healthy paediatric subjects between the ages of 4 and 12 years. In one single dose study, pharmacokinetic parameters were similar in children weighing 26-50kg, but not in children weighing 17-25kg. No multiple dose studies have been conducted in children.
PRECLINICAL SAFETY DATA
Gabapentin was given in the diet of mice at 200, 600, and 2000mg/kg/day and to rats at 250, 1000, and 2000mg/kg/day for two years. A statistically significant increase in the incidence of pancreatic acinar cell tumours was found only in male rats at the highest dose. Peak plasma drug concentrations and areas under the concentration time curve in rats at 2000mg/kg is 10 times higher than plasma concentrations in humans given 3600mg/day.
The pancreatic acinar cell tumours in male rats are low-grade malignancies, did not affect survival, did not metastasise or invade surrounding tissue, and were similar to those seen in concurrent controls. The relevance of these pancreatic acinar cell tumours in male rats to carcinogenic risk in humans is therefore of uncertain significance.
Gabapentin has no genotoxic potential. It was not mutagenic in the Ames bacterial plate incorporation assay or at the HGPRT locus in mammalian cells in the presence or absence of metabolic activation. Gabapentin did not induce structural chromosome aberrations in mammalian cells in vitro or in vivo, and did not induce micronucleus formation in the bone marrow of hamsters.
PHARMACEUTICAL PARTICULARS
For information regarding the list of excipients in this product, incompatibles, shelf life, special precautions for storage please contact Pfizer.
Date of preparation May 2001
FURTHER READING
1. GUIDELINE FOR TREATING EPILEPSY IN THE AGE OF FELBAMATE, VIGABATRIN, LAMOTRIGINE AND GABAPENTIN - Laxer KD, West.J.Med., 1994, 161, 309-314
2. CLINICAL PHARMACOKINETICS OF NEWER ANTIEPILEPTIC DRUGS: LAMOTRIGINE, VIGABATRIN, GABAPENTIN AND OXCARABAZEPINE - Elwes RDC et al., Clin.Pharmacokinet.,1996,30(6), June,403-415
3. GABAPENTIN IN PARTIAL EPILEPSY - U.K Gabapentin Study Group, Lancet, 335:1114-1117 1990
4. GABAPENTIN TOXICITY IN CHILDREN MANIFESTING BEHAVIORAL CHANGES - S.M Wolf et al., Epilepsia, 36:1203-1205 1996
5. EFFICACY AND SAFETY OF GABAPENTIN - T.R Brown et al., In: New Trends in Epilepsy Mangement: The Role of Gabapentin edited by D. Chadwick Royal Society of Medicine, 47-57 1993
6. GABAPENTIN - M.J McLean, Epilepsia, 36 (suppl.2):S73-S86 1995
7. TWO OPEN-LABEL, MULTICENTER STUDIES OF THE SAFETY AND EFFICACY OF GABAPENTIN IN PATIENTS WITH REFRACTORY EPILEPSY - B. Abou-Khalil et al., Epilepsia, 33 (suppl 3):77 1991
8. GABAPENTIN (NEURONTIN) AS ADD-ON THERAPY IN PATIENTS WITH PARTIAL SEIZURES: A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY - H. Anhut et al., Epilepsia, 35:795-801 1994
9. LACK OF SERIOUS TOXICITY FOLLOWING GABAPENTIN OVERDOSE - J.H Fischer et al., Neurology, 44:982-983 1994
10. GABAPENTIN (NEURONTIN) ADD-ON THERAPY IN PATIENTS WITH GENERALIZED EPILEPSY - E. Garofalo et al., Epilepsia, 35 (suppl 7):61 1994
11. GABAPENTIN: A REVIEW OF ITS PHARMACOLOGICAL PROPERTIES AND CLINICAL POTENTIAL IN EPILEPSY - K.L Goa et al., Drugs, 46:409-427 1993
12. PHARMACOKINETICS OF GABAPENTIN IN PATIENTS TREATED WITH PHENYTOIN - N.M Graves et al., Pharmacotherapy, 9:196 1989
13. EFFECT OF GABAPENTIN ON CARBAMAZEPINE LEVELS - N.M Graves et al., Epilepsia, 31:644-645 1990
14. AN OPEN-LABEL MULTICENTER STUDY OF GABAPENTIN (NEURONTIN). MONOTHERAY AND SAFETY IN MEDICALLY REFRACTORY PATIENTS WITH PARTIAL SEIZURES - A. Hayes et al., Neurology, 44 (suppl 2):A204 1994
15. LACK OF A PHARMACOKINETIC INTERACTION BETWEEN PHENOBARBITONE AND GABAPENTIN - W.D Hooper et al., Br. J. Clin. Pharmacol, 31:171-174 1991
16. CLINICAL PHARMACOKINETICS OF GABAPENTIN - M.J McLean, Neurology, 44 (suppl):S17-22 1994
17. GABAPENTIN CONCENTRATIONS IN THE HUMAN BRAIN - L.M Ojemann et al., Epilepsia, 29:694 1988
18. LONG TERM TREATMENT WITH GABAPENTIN FOR PARTIAL EPILEPSY - L.M Ojemann et al., Epilepsy Res, 13:159-165 1992
19. LACK OF INTERACTION OF GABAPENTIN WITH CARBAMAZEPINE AND VALPROATE - L.L Radulovic et al., Epilepsia, 35:155-161 1994
20. CLINICAL EFFICACY AND SAFETY OF GABAPENTIN - R.E Ramsay., Neurology, 44 (suppl 5):S23-S30 1994
21. GABAPENTIN - D. Chadwick., In: Recent Advances in Epilepsy 5 edited by T.A Pedley et al., Churchill Livingstone 1992
22. COGNITIVE EFFECTS OF TOPIRAMATE, GABAPENTIN, AND LAMOTRIGINE IN HEATHY YOUNG ADULTS - R. Martin et al., Neurology 1999 52: 321
23. GABAPENTIN IN GENERALIZED SEIZURES - D. Chadwick et al., Epilepsy Res., 25:191-197 1996
24. GABAPENTIN FOR TREATMENT OF EPILEPSY IN CHILDREN - G.L Holmes., Sem Pediatr Neurol., 4:244-250 1997
25. GABAPENTIN: A NEW AGENT FOR THE MANAGEMENT OF EPILEPSY - C.O Andrews et al., Ann Pharmacother., 28:1188-1196 1994
26. GABAPENTIN ASSOCIATED WITH AGRESSIVE BEHAVIOR IN PEDIATRIC PATIENTS WITH SEIZURES - K.B Tallian et al., Epilepsia., 37:501-502 1996
© 2001-2007 Epiweb.org