Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2021 Publisher: Pharmacor Pty Ltd., Suite 803, Level 8, Tower A, The Zenith, 821 Pacific Highway, Chatswood, NSW, 2067, Australia, www.pharmacor.com.au
The mechanism by which gabapentin exerts its anticonvulsant action is unknown. Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but its mechanism of action is different from that of several other drugs that interact with GABA synapses including valproate, barbiturates, benzodiazepines, GABA transaminase inhibitors, GABA uptake inhibitors, GABA agonists, and GABA prodrugs. In vitro studies with radiolabelled gabapentin have characterised a novel peptide binding site in rat brain tissues including neocortex and hippocampus that may relate to anticonvulsant activity of gabapentin and its structural derivatives. However, the identification and function of the gabapentin binding site remains to be elucidated. Gabapentin at relevant clinical concentrations does not bind to other common drug or neurotransmitter receptors of the brain including GABAA, GABAB, benzodiazepine, glutamate, glycine or N-methyl-d-aspartate receptors.
Gabapentin does not interact with sodium channels in vitro and so differs from phenytoin and carbamazepine. Several test systems ordinarily used to assess activity at the NMDA receptor complex have been examined. Results are contradictory. Accordingly no general statement about the effects, if any, of gabapentin at the NMDA receptor can be made. Gabapentin slightly reduces the release of monoamine neurotransmitters in vitro. Gabapentin administration to rats increases GABA turnover in several brain regions in a manner similar to valproate sodium, although in different regions of brain. The relevance of these various actions of gabapentin to the anticonvulsant effects remains to be established. In animals, gabapentin readily enters the brain and shows efficacy in some, but not all, seizure models. These animal models included genetic models of seizures, and seizures induced by maximal electroshock, from chemical convulsants including inhibitors of GABA synthesis.
The effectiveness of gabapentin as adjunctive therapy was established in three multi-centre, placebo-controlled, double-blind, parallel-group clinical trials in 705 adults with refractory partial seizures. The patients enrolled had a history of at least 4 partial seizures per month in spite of receiving one or more anti-epileptic drugs at therapeutic levels and were observed on their established anti-epileptic drug regimen during a 12-week baseline period. In patients continuing to have at least 2 (or 4 in some studies) seizures per month, gabapentin 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), where 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 gabapentin 1200 mg/day, given as three divided doses (divided TID) with placebo. Responder rate was 23% (14/61) in the gabapentin group and 9% (6/66) in the placebo group; the difference between groups was statistically significant. Response ratio was also better in the gabapentin group (-0.199) than in the placebo group (-0.044), a difference that also achieved statistical significance.
A second study compared primarily 1200 mg/day gabapentin (N = 101), given as three divided doses, with placebo (N = 98). Additional smaller gabapentin 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 gabapentin 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 gabapentin 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 gabapentin 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 gabapentin 900 mg/day, given as three divided doses (N = 111) and placebo (N = 109). An additional gabapentin 1200 mg/day dosage group (N = 52) provided dose-response data. A statistically significant difference in responder rate was seen in the gabapentin 900 mg/day group (22%) compared to that in the placebo group (10%). Response ratio was also statistically significantly superior in the gabapentin 900 mg/day group(-0.119) compared to that in the placebo group (-0.027), as was response ratio in 1200 mg/day gabapentin (-0.184) compared to placebo.
A one week, prospective, multi-centre, randomised, double-blind, placebo lead-in, parallel-group study compared the tolerability of gabapentin administered as an initial dosage of 900 mg/day versus a dosage titrated to 900 mg/day over three days (i.e. 300 mg on Day 1, 600 mg on Day 2, 900 mg on Day 3). 781 patients (titrated = 383, non-titrated = 388) involved in the study had partial seizures which were not adequately controlled with one or two other anti-epileptic drugs. For the MITT population, on both the first day of active medication, and all 5 days of active medication, there were no clinically meaningful treatment group differences in the incidences of fatigue, ataxia, and somnolence (i.e. the upper 95% confidence limit for the difference <7.5%). Only the difference in dizziness exceeded this upper confidence limit (upper confidence limit = 10.7% for the first day and 11.3% for all 5 days), with the non-titrated group reporting the higher incidence, however, it did not lead to increased discontinuation in this group.
The safety and efficacy of gabapentin administered as adjunctive therapy for the treatment of partial seizures in paediatric patients aged 3 to 12 years were assessed in two randomised, double-blind, parallel-group, placebo-controlled, multicentre clinical studies. The studies were conducted in 247 children who had refractory partial seizures and were receiving 1 to 3 standard anti-epileptic drugs. After a 6-week baseline phase, during which patients received their prescribed anti-epileptic drugs, there was a 12-week double-blind treatment phase. Patients who had experienced a minimum of 4 seizures during baseline were randomised and had either gabapentin (25 to 35 mg/kg/day) or placebo added to their baseline AEDs. The primary analysis of RRatio (MITT population) demonstrated that gabapentin was significantly better than placebo in controlling partial seizures (p = 0.04). Results for the ITT population did not show a significant difference in RRatio between the treatment groups. Further analysis using ranktransformed data was performed as the data showed evidence of non-normality of distribution. Results of this analysis showed that mean RRatio was significantly lower (better) for the gabapentin treatment group than for the placebo group in both the MITT (p = 0.01) and ITT (p = 0.03) populations.
The efficacy and safety of gabapentin for the treatment of neuropathic pain in adults older than 18 years of age were assessed in two randomised, double-blind, parallel-group, placebocontrolled, multicentre studies. One study examined the efficacy and safety of gabapentin in the treatment of painful diabetic peripheral neuropathy and the other study was conducted in patients with post-herpetic neuralgia. The studies were of a similar design. Following a baseline screening week and randomisation, gabapentin was titrated from 900 mg/day to 1800 mg/day, 2400 mg/day and 3600 mg/day divided into three times a day dosing consecutively over the first four weeks of the study. Patients were then maintained at the maximum dose that was tolerated for the remaining four weeks. The primary efficacy measure used in both studies was change from baseline to the final week in mean pain score obtained from daily pain diaries (pain was measured using an 11-point Likert scale). Several secondary outcomes were also assessed including: the Short-Form McGill Pain Questionnaire (SF-MPQ) (sensory, affective and total pain scores), SF-MPQ visual analogue scale (VAS) and present pain intensity scale (PPI), mean sleep interference score, Patient and Clinical Global Impression of Change (PGIC and CGIC), and the quality of life measures SF-36 Quality of Life Questionnaire (QOL) and Profile of Mood States (POMS).
Results from both studies demonstrated that gabapentin provided statistically significantly greater improvement in relief of neuropathic pain than placebo. In patients with painful diabetic peripheral neuropathy, mean pain score decreased by 2.6 in patients receiving gabapentin and 1.4 in patients receiving placebo (p <0.001). In the post-herpetic neuralgia study, mean pain score decreased by 2.1 in patients receiving gabapentin and 0.5 in patients receiving placebo (p <0.001). Gabapentin was significantly better than placebo in controlling pain from week two of both studies (p <0.001). Sleep interference scores, Short-Form McGill sensory, affective and total pain scores, VAS and PPI scale as well as PGIC, CGIC and some of the quality of life measures showed significant differences in favour of gabapentin.
Gabapentin bioavailability is not dose proportional, i.e. as dose is increased, bioavailability decreases. A 400 mg dose, for example, is about 25% less bioavailable than a 100 mg dose. Over the recommended dose range of 300 mg to 600 mg three times a day, however, the differences in bioavailability are not large, and bioavailability is about 60%. The bioavailability of the 800 mg dose was found to be approximately 35% in single and multiple dose studies. The absolute bioavailability of gabapentin following daily doses of 1200 mg/day, 2400 mg/day, 3600 mg/day, and 4800 mg/day averaged 47%, 34%, 33%, and 27% respectively. Food has no effect on the rate and extent of absorption of gabapentin.
Gabapentin circulates largely unbound (<3%) to plasma proteins. The apparent volume of distribution of gabapentin after 150 mg intravenous administration is 58 ± 6 L (Mean ± SD). In patients with epilepsy, steady-state pre-dose (Cmin) concentrations of gabapentin in the cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations.
Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug. Gabapentin is not appreciably metabolised in humans.
The elimination half-life of gabapentin 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 by haemodialysis.
Dose adjustment in patients with compromised renal function or in those undergoing haemodialysis is recommended (see Section 4.2 Dose and method of administration).
Subjects with renal insufficiency (mean creatinine clearance ranging from 13 mL/min to 114 mL/min) were administered 400 mg oral dose of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours (patients with creatinine clearance (CLcr) >60 mL/min) to 52 hours (CLcr <30 mL/min) and gabapentin renal clearance ranged from about 90 mL/min (CLcr >60 mL/min) to about 10 mL/min (CLcr <30 mL/min). Gabapentin dosage should be adjusted in patients with compromised renal function (see Section 4.2 Dose and method of administration).
In a study in anuric patients, the elimination half-life of gabapentin on non-dialysis day was about 132 hours; dialysis three times a week (4 hour duration) lowered the apparent half-life of gabapentin by about 60%, from 132 hours to 51 hours. Gabapentin dosage should be adjusted in patients undergoing haemodialysis (see Section 4.2 Dose and method of administration).
In a study examining the effect of age on the elimination of gabapentin, apparent oral clearance (CL/F) of gabapentin decreased as age increased, from about 225 mL/min in those younger than 30 years of age to about 125 mL/min in those older than 70 years of age. Renal clearance also declined with age; however, the decline in the renal clearance of gabapentin can largely be explained by the decline in renal function. Reduction of gabapentin dose may be required in patients who have aged – related compromised renal function.
Gabapentin pharmacokinetics were determined in 24 healthy paediatric subjects between the ages of 4 and 12 years. In general, plasma gabapentin concentrations in these children are similar to those in adults.
There is no evidence that gabapentin has genotoxic potential. It was not mutagenic in vitro in standard assays using bacterial or mammalian cells. 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.
Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250, 1000 and 2000 mg/kg/day for two years. A statistically significant increase in the incidence of pancreatic acinar cell adenoma and carcinoma was found only in male rats at the highest dose. Peak plasma gabapentin concentrations and areas under the concentration time curve in rats at 2000 mg/kg/day were 14 times higher than plasma concentrations in humans given the recommended maximum tolerated dose of 2400 mg/day. The pancreatic acinar cell tumours in male rats were low grade malignancies, which 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 human is unclear.
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