Data Sheet
Arrow - Gabapentin
Gabapentin 100 mg, 300 mg and 400 mg capsules
Presentation
Arrow - Gabapentin 100 mg White opaque capsule marked in blue ink
with "
"
on the body and "GA 100" on the cap
Arrow - Gabapentin 300 mg Yellow opaque capsule marked in blue ink
with ""
on the body and "GA 300" on the cap
Arrow - Gabapentin 400 mg Orange opaque capsule marked in blue ink
with ""
on the body and "GA 400" on the cap
Uses
Actions
The mechanism by which gabapentin exerts its anticonvulsant action is unknown. Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) 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 (NMDA) 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.
Pharmacodynamics
Clinical studies
EPILEPSY
The effectiveness of gabapentin as adjunctive therapy was established in three multicentre, 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 of more anti-epileptic drugs (AEDs) at therapeutic levels and were observed on their established AED 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 1,200 mg/day (in 3 divided doses) 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 1,200 mg/day (in 3 divided doses) gabapentin (N = 101) with placebo (N = 98). Additional smaller gabapentin dosage groups (600 mg/day, N = 53; 1,800 mg/day, N = 54) were also studied for information regarding dose response. Responder rate was higher in the gabapentin 1,200 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 1,800 mg group (26%) was statistically significantly superior to the placebo rate. Response ratio was better in the gabapentin 1,200 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 1,800 mg/day group (-0.222) than in the 1,200 mg/day group, with the 1,800 mg/day group achieving statistical significance compared to the placebo group.
A third study compared gabapentin 900 mg/day (in 3 divided doses) (N = 111) and placebo (N = 109). An additional gabapentin 1,200 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 1,200 mg/day gabapentin (-0.184) compared to placebo.
A 1-week, prospective, multicentre, 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 3 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 AEDs. For the modified intention-to-treat (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 AEDs. After a 6-week baseline phase, during which patients received their prescribed AEDs, 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 response ratio in 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 response ratio between the treatment groups. Further analysis using rank-transformed data was performed, as the data showed evidence of non-normality of distribution. Results of this analysis showed that mean response ratio 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.
NEUROPATHIC PAIN
The efficacy and safety of gabapentin for the treatment of neuropathic pain in adults over 18 years of age were assessed in two randomised, double-blind, parallel-group, placebo-controlled, 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 1,800 mg, 2,400 mg and 3,600 mg/day (in three divided doses) consecutively over the first 4 weeks of the study. Patients were then maintained at the maximum dose that was tolerated for the remaining 4 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.
Pharmacokinetics
All pharmacological actions following gabapentin administration are due to the activity of the parent compound.
Absorption
Gabapentin bioavailability is not dose proportional, i.e., as dose is increased, bioavailability is decreased. A 400 mg dose, for example, is about 25% less bioavailable than a 100 mg dose. Over the recommended dose range of 300 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 1,200, 2,400, 3,600 and 4,800 mg/day averaged 47%, 34%, 33% and 27%, respectively. Food has no effect on the rate and extent of absorption of gabapentin.
Distribution
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 cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations.
Metabolism
Gabapentin is not appreciably metabolised in humans.
Elimination
Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug.
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.
Dosage adjustment in patients with compromised renal function or undergoing haemodialysis is recommended (see Dosage and Administration).
Special populations
Patients with renal insufficiency
Subjects with renal insufficiency [mean creatinine clearance (Clcr) ranging from 13 - 114 mL/minute (min)] were administered a 400 mg oral dose of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours (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 Dosage and Administration).
Patients on haemodialysis
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 Dosage and Administration).
Elderly patients
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 under 30 years of age to about 125 mL/min in those over 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.
Paediatric patients
Gabapentin pharmacokinetics was 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.
Indications
EPILEPSY
Adults and children aged 3 years and over
Gabapentin is indicated as an add-on therapy for the treatment of partial seizures, with or without secondary generalised tonic-clonic seizures, in adults and children aged 3 years and above who have not achieved adequate control with standard anti-epileptic drugs (AEDs).
NEUROPATHIC PAIN
Gabapentin is indicated for the treatment of neuropathic pain in adults over 18 years of age.
Dosage and Administration
Arrow - Gabapentin Capsules should be swallowed whole with water, with or without food.
EPILEPSY
Initiation of treatment should be as add-on therapy.
Adults and children over 12 years of age
In controlled clinical trials, the effective dose range was 900 to 1,800 mg/day given in three divided doses.
Therapy may be initiated by administering 300 mg capsules three times a day on Day 1 or by titrating the dose. Titration to an effective dose can take place rapidly, over a few days, giving 300 mg capsules on Day 1, 300 mg capsules twice a day on Day 2, 300 mg capsules three times a day on Day 3. Titration may be preferable for patients with renal impairment, patients with encephalopathy, patients on more than 2 other AEDs and patients with multiple other medical problems.
To minimise potential side effects, especially somnolence, dizziness, fatigue and ataxia, the first dose on Day 1 may be administered at bedtime. If necessary, the dose may be increased using 300 or 400 mg capsules three times a day up to 2,400 mg/day. Dosages up to 2,400 mg/day have been well tolerated in long-term open label clinical studies. The maximum time between doses in the three times daily schedule should not exceed 12 hours to prevent breakthrough convulsions.
Children aged 3 to 12 years of age
The effective dose of gabapentin is 25 to 35 mg/kg/day given in equally divided doses (3 times a day) as described in the following table. Initial titration to an effective dose can take place over 3 days by giving 10 mg/kg/day on Day 1, 20 mg/kg/day on Day 2, and 30 mg/kg/day on Day 3. Thereafter, the dose can be increased in three equally divided doses up to a maximum dose of 35 mg/kg/day. Dosages up to 40 to 50 mg/kg/day have been well tolerated in a long-term clinical study. Doses of 60 mg/kg/day have also been administered to a small number of children.
Table 1 Dosage of gabapentin in pediatric patients aged 3 to 12 years
| Weight range (kg) | Daily dose (mg/day) |
|---|---|
| 17 - 25 | 600 |
| 26 - 36 | 900 |
| 37 - 50 | 1200 |
| 51 - 72 | 1800 |
NEUROPATHIC PAIN
Adults over 18 years of age
The starting dose is 900 mg/day given in three divided doses, and titrated if necessary, based on response, up to a maximum dose of 3,600 mg/day.
General dosing recommendations in epilepsy and neuropathic pain
Impaired renal function
Dosage adjustment is recommended in patients with compromised renal function as described in the following table and/or those undergoing haemodialysis.
Table 2 Dosage of gabapentin in adults based on renal function
| Creatinine clearance (mL/minute) | Total daily dosea (mg/day) |
|---|---|
| ≥ 80 | 900 - 3,600 |
| 50 - 79 | 600 - 1,800 |
| 30 - 49 | 300 - 900 |
| 15 - 29 | 150b - 600 |
| < 15 | 150b - 300 |
a Total daily dose should be administered as a three times daily regimen. Doses used to treat patients with normal renal function (creatinine clearance > 80 mL/minute) range from 900 to 3,600 mg/day. Reduced dosages are for patients with renal impairment (creatinine clearance < 79 mL/minute).
b To be administered as 300 mg every other day
Patients undergoing haemodialysis
For patients undergoing haemodialysis who have never received gabapentin, a loading dose of 300 to 400 mg is recommended, then 200 to 300 mg of gabapentin following each 4 hours of haemodialysis.
Serum monitoring
Unlike other agents in this class, it is not necessary to monitor gabapentin plasma concentrations to optimise gabapentin therapy. Further, gabapentin may be used in combination with other AEDs without concern for alteration of the plasma concentrations of gabapentin or serum concentrations of other AEDs.
Discontinuation
If gabapentin is discontinued and/or an alternate anticonvulsant medication is added to the therapy, this should be done gradually over a minimum of one week.
Contraindications
Arrow - Gabapentin is contraindicated in patients with known hypersensitivity to gabapentin or any component of this preparation (see Further Information).
Warnings and 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 that there is a need for dose reduction, discontinuation, or substitution of alternative anticonvulsant medication, this should be done gradually over a minimum of 1 week.
Gabapentin is not generally considered effective in the treatment of absence seizures and may exacerbate these seizures in some patients. Consequently, gabapentin should be used with caution in patients who have mixed seizure disorders that include absence seizures.
Patients who require concomitant treatment with morphine may experience increases in gabapentin concentrations. Patients should be carefully observed for signs of depression of central nervous system, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately (see Interactions).
Information for patients
To assure safe and effective use of gabapentin, the following information and instructions should be given to patients:
- Inform your physician about any prescription or non-prescription medications, alcohol, or drugs you are now taking or plan to take during your treatment with gabapentin.
- No teratogenic effects have been found in animals. However, the risk to the human foetus cannot be dismissed. So, you should inform your physician if you are pregnant, or if you are planning to become pregnant, or if you become pregnant while you are taking gabapentin.
- Gabapentin is excreted in human milk, and the effect on the nursing infant is unknown. You should inform your physician if you are breastfeeding an infant.
- Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery.
- You should not allow more than 12 hours between gabapentin doses. If you have missed a dose by not more than 4 hours, take the dose as soon as you remember. However, if you have missed a dose by more than 4 hours, you should skip the dose and continue taking following doses as usual.
Risk of suicidality
An analysis of reports of suicidality (suicidal behaviour or ideation) from placebo-controlled clinical studies of eleven medicines used to treat epilepsy, as well as psychiatric disorders and other conditions, revealed that patients receiving AEDs had approximately twice the risk of suicidal behaviour or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behaviour and/or ideation was observed as early as 1 week after starting the AED and continued through 24 weeks. The results were generally consistent among the eleven medicines. Patients who were treated for epilepsy, psychiatric disorders and other conditions were all at increased risk for suicidality when compared to placebo, and there did not appear to be a specific demographic subgroup of patients to which the increased risk could be attributed. Such risk is considered to be a class effect of AEDs. The relative risk for suicidality was higher in the patients with epilepsy compared to patients who were given one of the medicines in the class for psychiatric or other conditions.
All patients who are currently taking or starting on any AEDs should be closely monitored for notable changes in behaviour that could indicate the emergence or worsening of suicidal thoughts or behaviour, or depression, especially if these symptoms are severe, abrupt in onset, or were not part of the patients' presenting symptoms. Certain patients, such as those with a history of suicidal behaviour or thoughts, young adults, and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, may be at a greater risk of suicidal thoughts or suicide attempts.
Health care professionals should inform patients, their families and caregivers of the potential for an increase in the risk of suicidality. Prescribers should advise patients to seek medical advice immediately if they develop any symptoms suggestive of suicidality.
Renal impairment
The dosage of gabapentin should be adjusted in patients with decreased renal function or on haemodialysis (see Pharmacokinetics and Dosage and Administration).
Elderly patients
The dosage of gabapentin should be adjusted in elderly patients with age-related reduction in renal function (see Pharmacokinetics and Dosage and Administration).
Use in children
The safety and effectiveness of gabapentin in children with epilepsy below the age of 3 years have not been established. Gabapentin is not recommended for treatment of neuropathic pain in children below the age of 18 years as the safety and effectiveness in this population have not been established.
Carcinogenesis, mutagenesis, impairment of fertility
Gabapentin was given in the diet to mice at 200, 600, and 2,000 mg/kg/day and to rats at 250, 1,000, and 2,000 mg/kg/day for 2 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 drug concentrations and areas under the concentration time curve in rats at 2,000 mg/kg/day are 14 times higher than plasma concentrations in humans given the recommended maximum tolerated dose of 2,400 mg/day. The pancreatic acinar cell tumours in male rats are low grade malignancies, 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.
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.
No adverse effects on fertility or reproduction were observed in rats at doses up to 2,000 mg/kg/day.
Use in pregnancy (Category B1)
The risk of having an abnormal child as a result of AEDs is far outweighed by the dangers to the mother and foetus of uncontrolled epilepsy.
It is recommended that:
- women on AEDs receive pre-pregnancy counselling with regard to the risk of foetal abnormalities;
- AEDs should be continued during pregnancy and monotherapy should be used if possible at the lowest effective dose as risk of abnormality is greater in women taking combined medication;
- folic acid supplementation (5 mg) should be commenced 4 weeks prior to and continue for 12 weeks after conception;
- specialist pre-natal diagnosis including detailed mid-trimester ultrasound should be offered.
Reproduction studies in mice at doses up to 3,000 mg/kg/day and in rats at doses up to 2,000 mg/kg/day revealed no evidence of impaired fertility or harm to the foetus due to gabapentin administration. In these studies, exposure to gabapentin (based on areas under the concentration time curve) was up to 5 times higher in the mouse, and up to 14 times higher in the rat, than in humans at the recommended maximum tolerated dose of 2,400 mg/day. In rabbits given 60, 300 or 1,500 mg/kg/day gabapentin during the period of organogenesis, maternal toxicity and abortion were observed at the high dose, but at the low and mid doses, no evidence of impaired fertility or harm to the foetus was observed. There are, however, no adequate or well-controlled studies in pregnant women. Therefore, this drug should be used during pregnancy only if clearly needed.
Use in lactation
Gabapentin is excreted in human milk. In a peri- and post-natal study in rats at doses of 500, 1,000 and 2,000 mg/kg/day, there was a dose related increase in the incidence of hydroureter in 21-day old pups. Because of the unknown effect of gabapentin and the potential for its serious adverse reactions in nursing infants, 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. Gabapentin should be used in nursing mothers only if the benefits clearly outweigh the risks.
Effect on ability to drive and use machines
Patients should be advised not to drive a car or operate potentially dangerous machinery until it is known that this medication does not affect their ability to engage in these activities.
Adverse Effects
EPILEPSY
Adults and children over 12 years of age
Gabapentin has been evaluated for safety in approximately 2,000 subjects and patients, and was well tolerated. Of these, 543 patients participated in controlled clinical trials.
The most commonly observed adverse events associated with the use of gabapentin in combination with other AEDs, not seen in an equivalent frequency among placebo-treated patients, were somnolence, dizziness, ataxia, fatigue and nystagmus.
Approximately 7% of the 2,074 individuals who received gabapentin in the pre-marketing clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal were somnolence, ataxia, fatigue, nausea and/or vomiting, and dizziness.
Incidence in controlled clinical trials
The following table lists the treatment-emergent signs and symptoms that occurred in at least 1% of gabapentin treated patients with epilepsy participating in gabapentin placebo-controlled trials. In these studies, either gabapentin or placebo was added to the patient's current AED therapy. Adverse events were usually mild to moderate in intensity.
Table 3 Adverse events reported in at least 1% of participants in gabapentin placebo-controlled trials
| COSTART Body system and adverse event |
Gabapentina N = 543 |
Placeboa N = 378 |
||
|---|---|---|---|---|
| No of patients | % | No of patients | % | |
| Body as a whole | ||||
| Abdominal pain | 10 | 1.8 | 9 | 2.4 |
| Back pain | 10 | 1.8 | 2 | 0.5 |
| Fatigue | 60 | 11.0 | 19 | 5.0 |
| Fever | 7 | 1.3 | 5 | 1.3 |
| Headache | 44 | 8.1 | 34 | 9.0 |
| Viral infection | 7 | 1.3 | 8 | 2.1 |
| Cardiovascular | ||||
| Vasodilation | 6 | 1.1 | 1 | 0.3 |
| Digestive system | ||||
| Constipation | 8 | 1.5 | 3 | 0.8 |
| Dental abnormalities | 8 | 1.5 | 1 | 0.3 |
| Diarrhoea | 7 | 1.3 | 8 | 2.1 |
| Dyspepsia | 12 | 2.2 | 2 | 0.5 |
| Increased appetite | 6 | 1.1 | 3 | 0.8 |
| Mouth or throat dry | 9 | 1.7 | 2 | 0.5 |
| Nausea and/or vomiting | 33 | 6.1 | 27 | 7.1 |
| Haematologic and lymphatic | ||||
| Leukopenia | 6 | 1.1 | 2 | 0.5 |
| WBC decreased | 6 | 1.1 | 2 | 0.5 |
| Metabolic and nutritional | ||||
| Peripheral oedema | 9 | 1.7 | 2 | 0.5 |
| Weight increase | 16 | 2.9 | 6 | 1.6 |
| Musculoskeletal system | ||||
| Fracture | 6 | 1.1 | 3 | 0.8 |
| Myalgia | 11 | 2.0 | 7 | 1.9 |
| Nervous system | ||||
| Amnesia | 12 | 2.2 | 0 | 0.0 |
| Ataxia | 68 | 12.5 | 21 | 5.6 |
| Confusion | 9 | 1.7 | 7 | 1.9 |
| Co-ordination abnormal | 6 | 1.1 | 1 | 0.3 |
| Depression | 10 | 1.8 | 7 | 1.8 |
| Dizziness | 93 | 17.1 | 26 | 6.9 |
| Dysarthria | 13 | 2.4 | 2 | 0.5 |
| Emotional lability | 6 | 1.1 | 5 | 1.3 |
| Insomnia | 6 | 1.1 | 7 | 1.9 |
| Nervousness | 13 | 2.4 | 7 | 1.9 |
| Nystagmus | 45 | 8.3 | 15 | 4.0 |
| Somnolence | 105 | 19.3 | 33 | 8.7 |
| Thinking abnormal | 9 | 1.7 | 5 | 1.3 |
| Tremor | 37 | 6.8 | 12 | 3.2 |
| Twitching | 7 | 1.3 | 2 | 0.5 |
| Respiratory system | ||||
| Coughing | 10 | 1.8 | 5 | 1.3 |
| Pharyngitis | 15 | 2.8 | 6 | 1.6 |
| Rhinitis | 22 | 4.1 | 14 | 3.7 |
| Skin and appendages | ||||
| Abrasion | 7 | 1.3 | 0 | 0.0 |
| Acne | 6 | 1.1 | 5 | 1.3 |
| Pruritus | 7 | 1.3 | 2 | 0.5 |
| Rash | 8 | 1.5 | 6 | 1.6 |
| Special senses | ||||
| Amblyopia | 23 | 4.2 | 4 | 1.1 |
| Diplopia | 32 | 5.9 | 7 | 1.9 |
| Urogenital system | ||||
| Impotence | 8 | 1.5 | 4 | 1.1 |
a Includes concomitant anti-epileptic drug therapy
Other adverse events observed during all clinical studies
Those events that occurred in at least 1% of the study participants with epilepsy who received gabapentin as adjunctive therapy in any clinical study and that are not described in the previous section as frequently occurring treatment-emergent signs and symptoms during placebo-controlled studies are summarized below.
Body as a whole: asthenia, malaise, facial oedema
Cardiovascular system: hypertension
Digestive system: flatulence, anorexia, gingivitis
Haemic and lymphatic systems: purpura most often described as bruises resulting from physical trauma
Musculoskeletal system: arthralgia
Nervous system: vertigo, hyperkinesia, increased, decreased or absent reflexes, paraesthesia, anxiety, hostility
Respiratory system: pneumonia
Urogenital system: urinary tract infection
Special senses: abnormal vision
Children from 3 to 12 years of age
The most commonly observed adverse events reported with the use of gabapentin in combination with other AEDs in children 3 to 12 years of age, not seen in equal frequency among placebo-treated patients, were viral infection, fever, nausea and/or vomiting, and somnolence.
Approximately 8% of the 292 children aged 3 to 12 years who received gabapentin in pre-approval clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal in children were somnolence (1.4%), hyperkinesia (1.0%) and hostility (1.0%).
Table 4 Treatment-emergent adverse event incidence in children aged 3 to 12 years in controlled add-on trials (events in at least 2% of gabapentin patients and numerically more frequent than in the placebo group)
| Body system and adverse event | Gabapentina % (N = 119) |
Placeboa % (N = 128) |
|---|---|---|
| Body as a whole | ||
| Viral infection | 10.9 | 3.1 |
| Fever | 10.1 | 3.1 |
| Weight increase | 3.4 | 0.8 |
| Fatigue | 3.4 | 1.6 |
| Digestive system | ||
| Nausea and/or vomiting | 8.4 | 7.0 |
| Nervous system | ||
| Somnolence | 8.4 | 4.7 |
| Hostility | 7.6 | 2.3 |
| Emotional lability | 4.2 | 1.6 |
| Dizziness | 2.5 | 1.6 |
| Hyperkinesia | 2.5 | 0.8 |
| Respiratory system | ||
| Bronchitis | 3.4 | 0.8 |
| Respiratory infection | 2.5 | 0.8 |
a Including concomitant anti-epileptic drug therapy
Other adverse events observed during clinical studies
Other events in more than 2% of children but equally or more frequent in the placebo group included: pharyngitis, upper respiratory infection, headache, rhinitis, convulsions, diarrhoea, anorexia, coughing and otitis media.
Adverse events occurring during clinical trials in children treated with gabapentin that were not reported in adjunctive therapy trials in adults are:
Body as a whole: dehydration, infectious mononucleosis
Digestive system: hepatitis, oral moniliasis
Haemic and lymphatic system: coagulation defect
Nervous system: aura disappeared, occipital neuralgia
Psychobiologic function: sleepwalking
Respiratory system: pseudo-croup, hoarseness
NEUROPATHIC PAIN
Adults over 18 years of age
The most commonly observed adverse events reported with the use of gabapentin in adults over 18 years of age with neuropathic pain, seen in at least twice the frequency among placebo-treated patients, were dry mouth, peripheral oedema, weight gain, abnormal gait, amnesia, ataxia, confusion, dizziness, hypoaesthesia, somnolence, abnormal thinking, vertigo, rash and amblyopia.
Of the 821 adults who received gabapentin in the painful diabetic peripheral neuropathy and post-herpetic neuralgia trial, 13.2% discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal were dizziness (4.4%), somnolence (2.9%), ataxia (1.0%) and nausea (1.3%).
Of the two treatment groups, gabapentin and placebo, the only adverse event observed in both groups with an equal percentage greater than 2% was flu syndrome.
Table 5 Summary of treatment-emergent signs and symptoms in 1% of gabapentin treated patients in neuropathic pain placebo-controlled studies
| COSTART Body system and adverse event |
Gabapentina N = 821 |
Placeboa N = 537 |
||
|---|---|---|---|---|
| No of patients | % | No of patients | % | |
| Body as a whole | ||||
| Abdominal pain | 23 | 2.8 | 17 | 3.2 |
| Accidental injury | 32 | 3.9 | 17 | 3.2 |
| Asthenia | 41 | 5.0 | 25 | 4.7 |
| Back pain | 19 | 2.3 | 8 | 1.5 |
| Flu syndrome | 21 | 2.6 | 14 | 2.6 |
| Headache | 45 | 5.5 | 33 | 6.1 |
| Infection | 38 | 4.6 | 40 | 7.4 |
| Pain | 30 | 3.7 | 36 | 6.7 |
| Digestive system | ||||
| Constipation | 19 | 2.3 | 9 | 1.7 |
| Diarrhoea | 46 | 5.6 | 24 | 4.5 |
| Dry mouth | 27 | 3.3 | 5 | 0.9 |
| Dyspepsia | 16 | 1.9 | 10 | 1.9 |
| Flatulence | 14 | 1.7 | 6 | 1.1 |
| Nausea | 45 | 5.5 | 29 | 5.4 |
| Vomiting | 16 | 1.9 | 13 | 2.4 |
| Metabolic and nutritional | ||||
| Peripheral oedema | 44 | 5.4 | 14 | 2.6 |
| Weight gain | 14 | 1.7 | 0 | 0.0 |
| Nervous system | ||||
| Abnormal gait | 9 | 1.1 | 0 | 0.0 |
| Amnesia | 15 | 1.8 | 3 | 0.6 |
| Ataxia | 19 | 2.3 | 0 | 0.0 |
| Confusion | 15 | 1.8 | 5 | 0.9 |
| Dizziness | 173 | 21.1 | 35 | 6.5 |
| Hypesthesia | 11 | 1.3 | 3 | 0.6 |
| Somnolence | 132 | 16.1 | 27 | 5.0 |
| Thinking abnormal | 12 | 1.5 | 0 | 0.0 |
| Tremor | 9 | 1.1 | 6 | 1.1 |
| Vertigo | 8 | 1.0 | 2 | 0.4 |
| Respiratory system | ||||
| Dyspnoea | 9 | 1.1 | 3 | 0.6 |
| Pharyngitis | 15 | 1.8 | 7 | 1.3 |
| Skin and appendages | ||||
| Rash | 14 | 1.7 | 4 | 0.7 |
| Special senses | ||||
| Amblyopia | 15 | 1.8 | 2 | 0.4 |
Post-marketing experience
The following adverse events have been reported in patients receiving gabapentin post-marketing. However, the data is insufficient to support an estimate of their incidence or to establish causation.
Sudden, unexplained deaths have been reported where a causal relationship to treatment with gabapentin has not been established. Additional post-marketing adverse events reported include abnormal liver function, acute kidney failure, allergic reaction including urticaria, alopecia, anaemia, angioedema, blood glucose fluctuations in patients with diabetes, cardiac arrest, chest pain, convulsions, depersonalisation, erythema multiforme, movement disorders such as choreoathetosis, dyskinesia and dystonia, palpitation, pancreatitis, renal impairment, speech disorder, sexual dysfunction, Stevens-Johnson syndrome, tachycardia, thrombocytopenia, tinnitus, urinary incontinence, and symptoms of psychosis such as delusions, hallucinations and abnormal thinking.
Generalised oedema, hepatitis, hypotension, neuropathy, peripheral neuropathy and syncope have been rarely reported.
Adverse events following the abrupt discontinuation of gabapentin have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain and sweating.
Sensory neuropathy has also been reported in a single patient being treated with gabapentin.
Some cases of hypomania have been reported after commencement of gabapentin. In each case, other anticonvulsants had been used concurrently, and symptoms of hypomania resolved following a reduction in dosage or cessation of the drug.
Risk of suicidality
From the analysis of reports of suicidality from placebo-controlled studies of AEDs, a two-fold increase in the risk of suicidality (0.43%) compared with patients receiving placebo (0.22%) was revealed. This adverse reaction is considered to be a class effect of AEDs. Physicians, patients and their families, and caregivers should be aware of the signs and symptoms of suicidal behaviour, suicidal ideation and emergence or worsening of existing depression (see Warnings and Precautions).
Interactions
Anti-epileptic drugs
In pharmacokinetic studies, no interactions were observed between gabapentin and phenobarbital (number of subjects, N = 12), phenytoin (N = 8), valproic acid (N = 17), or carbamazepine (N = 12).
Oral contraceptives
Gabapentin did not influence the steady-state pharmacokinetics of norethindrone and ethinyl oestradiol when administered concomitantly with an oral contraceptive containing these two drugs (N = 13).
Antacid and cimetidine
Co-administration of gabapentin with antacid reduced gabapentin bioavailability by about 20% (N = 16).
In the presence of cimetidine at 300 mg four times daily, the mean apparent oral clearance of gabapentin fell by 14% and creatinine clearance by 10% (N = 12). Thus, cimetidine appeared to alter the renal excretion of both gabapentin and creatinine, an endogenous marker of renal function. Renal excretion of gabapentin was unaltered by probenecid, a blocker of renal tubular secretion.
Morphine
A literature article reported that when a 60 mg controlled-release morphine capsule was administered 2 hours prior to a 600 mg gabapentin capsule (N = 12), mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine (see Warnings and Precautions). Morphine pharmacokinetic parameter values were not affected by administration of gabapentin 2 hours after morphine. The magnitude of interaction at other doses is not known.
Laboratory tests
False positive readings were reported with the Ames N-Multistix SG® dipstick test when gabapentin was added to other anticonvulsant drugs. To determine urinary protein, the more specific sulfosalicylic acid precipitation procedure is recommended.
Overdosage
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, laboured breathing, ptosis, and hypoactivity or excitation. No deaths or drug-related toxic effects were seen in monkeys, which received gabapentin doses up to 1,250 mg/kg orally.
Symptoms
Acute, life-threatening toxicity has not been observed in humans with gabapentin overdoses of up to 49 g. In these cases, double vision, slurred speech, drowsiness, lethargy and diarrhoea were observed. All patients recovered with supportive care.
Treatment
General principles of first-aid treatment should be followed. The patient should be monitored closely and given supportive care where necessary to maintain vital functions.
It is not known whether the use of activated charcoal is effective in delaying the absorption of gabapentin.
Gabapentin can be removed by haemodialysis. Although haemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient's clinical state or in patients with significant renal impairment.
Pharmaceutical Precautions
Storage
Store below 25°C
Shelf-life
18 months for 100 mg capsules; 24 months for 300 mg and 400 mg capsules
Medicines Classification
Prescription Medicine
Package Quantities
Blister packs of 100 capsules
Further Information
Gabapentin is a white to off-white crystalline solid, freely soluble in water and in both basic and acidic aqueous solutions. The chemical name of gabapentin is 1-(aminomethyl) cyclohexaneacetic acid. Its structural formula is:
C9H17NO2 Molecular weight: 171.24 CAS: 60142-96-3
Arrow - Gabapentin Capsules contain the following excipients: lactose, maize starch, purified talc, gelatin, titanium dioxide, iron oxide yellow (300 mg and 400 mg capsules only), iron oxide red (400 mg capsules only) and Opacode A-R-10561FD blue printing ink.
Name and Address
Arrow Pharmaceuticals (NZ) Limited
Mount Eden Central Business Park
33a Normanby Road, Mt. Eden
Auckland, New Zealand
Date of Preparation
14 February 2008
ARROW - GABAPENTIN/022008/PI/2