- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- 11. Dosimetry
- 12 Instructions for preparation of radiopharmaceuticals
EpilepsyGabapentin is indicated as adjunctive therapy in the treatment of partial seizures with and without secondary generalization in adults and children aged 6 years and above (see section 5.1).Gabapentin is indicated as monotherapy in the treatment of partial seizures with and without secondary generalization in adults and adolescents aged 12 years and above.
Treatment of peripheral neuropathic painGabapentin is indicated for the treatment of peripheral neuropathic pain such as painful diabetic neuropathy and post-herpetic neuralgia in adults.
|DOSING CHART INITIAL TITRATION|
|Day 1||Day 2||Day 3|
|300 mg once a day||300 mg two times a day||300 mg three times a day|
Discontinuation of gabapentinIn accordance with current clinical practice, if gabapentin has to be discontinued it is recommended this should be done gradually over a minimum of 1 week independent of the indication.
EpilepsyEpilepsy typically requires long-term therapy. Dosage is determined by the treating physician according to individual tolerance and efficacy.
Adults and adolescents:In clinical trials, the effective dosing range was 900 to 3600 mg/day. Therapy may be initiated by titrating the dose as described in Table 1 or by administering 300 mg three times a day (TID) on Day 1. Thereafter, based on individual patient response and tolerability, the dose can be further increased in 300 mg/day increments every 2-3 days up to a maximum dose of 3600 mg/day. Slower titration of gabapentin dosage may be appropriate for individual patients. The minimum time to reach a dose of 1800 mg/day is one week, to reach 2400 mg/day is a total of 2 weeks, and to reach 3600 mg/day is a total of 3 weeks. Dosages up to 4800 mg/day have been well tolerated in long-term open-label clinical studies. The total daily dose should be divided in three single doses, the maximum time interval between the doses should not exceed 12 hours to prevent breakthrough convulsions.
Children aged 6 years and above:The starting dose should range from 10 to 15 mg/kg/day and the effective dose is reached by upward titration over a period of approximately three days. The effective dose of gabapentin in children aged 6 years and older is 25 to 35 mg/kg/day. Dosages up to 50 mg/kg/day have been well tolerated in a long-term clinical study. The total daily dose should be divided in three single doses, the maximum time interval between doses should not exceed 12 hours.It is not necessary to monitor gabapentin plasma concentrations to optimize gabapentin therapy. Further, gabapentin may be used in combination with other antiepileptic medicinal products without concern for alteration of the plasma concentrations of gabapentin or serum concentrations of other antiepileptic medicinal products.
Peripheral neuropathic pain
AdultsThe therapy may be initiated by titrating the dose as described in Table 1. Alternatively, the starting dose is 900 mg/day given as three equally divided doses. Thereafter, based on individual patient response and tolerability, the dose can be further increased in 300 mg/day increments every 2-3 days up to a maximum dose of 3600 mg/day. Slower titration of gabapentin dosage may be appropriate for individual patients. The minimum time to reach a dose of 1800 mg/day is one week, to reach 2400 mg/day is a total of 2 weeks, and to reach 3600 mg/day is a total of 3 weeks.In the treatment of peripheral neuropathic pain such as painful diabetic neuropathy and post-herpetic neuralgia, efficacy and safety have not been examined in clinical studies for treatment periods longer than 5 months. If a patient requires dosing longer than 5 months for the treatment of peripheral neuropathic pain, the treating physician should assess the patient's clinical status and determine the need for additional therapy.
Instruction for all areas of indicationIn patients with poor general health, i.e., low body weight, after organ transplantation etc., the dose should be titrated more slowly, either by using smaller dosage strengths or longer intervals between dosage increases.
Use in elderly patients (over 65 years of age)Elderly patients may require dosage adjustment because of declining renal function with age (see Table 2). Somnolence, peripheral oedema and asthenia may be more frequent in elderly patients.
Use in patients with renal impairmentDosage adjustment is recommended in patients with compromised renal function as described in Table 2 and/or those undergoing haemodialysis. Gabapentin 100 mg capsules can be used to follow dosing recommendations for patients with renal insufficiency.
|DOSAGE OF GABAPENTIN IN ADULTS BASED ON RENAL FUNCTION|
|Creatinine Clearance (ml/min)||Total Daily Dosea (mg/day)|
Use in patients undergoing haemodialysisFor anuric patients undergoing haemodialysis who have never received gabapentin, a loading dose of 300 to 400 mg, then 200 to 300 mg of gabapentin following each 4 hours of haemodialysis, is recommended. On dialysis-free days, there should be no treatment with gabapentin.For renally impaired patients undergoing haemodialysis, the maintenance dose of gabapentin should be based on the dosing recommendations found in Table 2. In addition to the maintenance dose, an additional 200 to 300 mg dose following each 4-hour haemodialysis treatment is recommended.
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)Severe, life-threatening, systemic hypersensitivity reactions such as Drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking antiepileptic drugs including gabapentin (see section 4.8). It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Gabapentin should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Laboratory testsFalse positive readings may be obtained in the semi-quantitative determination of total urine protein by dipstick tests. It is therefore recommended to verify such a positive dipstick test result by methods based on a different analytical principle such as the Biuret method, turbidimetric or dye-binding methods, or to use these alternative methods from the beginning.Neurontin hard capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine
Risk related to epilepsy and antiepileptic medicinal products in generalThe risk of birth defects is increased by a factor of 2 3 in the offspring of mothers treated with an antiepileptic medicinal product. Most frequently reported are cleft lip, cardiovascular malformations and neural tube defects. Multiple antiepileptic drug therapy may be associated with a higher risk of congenital malformations than monotherapy, therefore it is important that monotherapy is practised whenever possible. Specialist advice should be given to women who are likely to become pregnant or who are of childbearing potential and the need for antiepileptic treatment should be reviewed when a woman is planning to become pregnant. No sudden discontinuation of antiepileptic therapy should be undertaken as this may lead to breakthrough seizures, which could have serious consequences for both mother and child. Developmental delay in children of mothers with epilepsy has been observed rarely. It is not possible to differentiate if the developmental delay is caused by genetic, social factors, maternal epilepsy or the antiepileptic therapy.
Risk related to gabapentinThere are no adequate data from the use of gabapentin in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Gabapentin should not be used during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the foetus.No definite conclusion can be made as to whether gabapentin is associated with an increased risk of congenital malformations when taken during pregnancy, because of epilepsy itself and the presence of concomitant antiepileptic medicinal products during each reported pregnancy.Gabapentin is excreted in human milk. Because the effect on the breast-fed infant is unknown, caution should be exercised when gabapentin is administered to a breast-feeding mother. Gabapentin should be used in breast-feeding mothers only if the benefits clearly outweigh the risks.
|Body System||Adverse drug reactions|
|Infections and infestations|
|Very Common||Viral infection|
|Common||Pneumonia, respiratory infection, urinary tract infection, infection, otitis media|
|Blood and the lymphatic system disorders|
|Immune system disorders|
|Uncommon||allergic reactions (e.g. urticaria)|
|Not known||hypersensitivity syndrome, a systemic reaction with a variable presentation that can include fever, rash, hepatitis, lymphadenopathy, eosinophilia, and sometimes other signs and symptoms.|
|Metabolism and Nutrition Disorders|
|Common||anorexia, increased appetite|
|Common||hostility, confusion and emotional lability, depression, anxiety, nervousness, thinking abnormal|
|Nervous system disorders|
|Very Common||somnolence, dizziness, ataxia|
|Common||convulsions, hyperkinesias, dysarthria, amnesia, tremor, insomnia, headache, sensations such as paresthesia, hypaesthesia, coordination abnormal, nystagmus, increased, decreased, or absent reflexes|
|Not known||other movement disorders (e.g. choreoathetosis, dyskinesia, dystonia)|
|Common||visual disturbances such as amblyopia, diplopia|
|Ear and Labyrinth disorders|
|Respiratory, thoracic and mediastinal disorders|
|Common||dyspnoea, bronchitis, pharyngitis, cough, rhinitis|
|Common||vomiting, nausea, dental abnormalities, gingivitis, diarrhea, abdominal pain, dyspepsia, constipation, dry mouth or throat, flatulence|
|Not known||hepatitis, jaundice|
|Skin and subcutaneous tissue disorders|
|Common||facial oedema, purpura most often described as bruises resulting from physical trauma, rash, pruritus, acne|
|Not known||Stevens-Johnson syndrome, angioedema, erythema multiforme, alopecia, drug rash with eosinophilia and systemic symptoms (see section 4.4)|
|Musculoskeletal, connective tissue and bone disorders|
|Common||arthralgia, myalgia, back pain, twitching|
|Not known||rhabdomyolysis, myoclonus|
|Renal and urinary disorder|
|Not known||acute renal failure, incontinence|
|Reproductive system and breast disorders|
|Not known||breast hypertrophy, gynaecomastia|
|General disorders and administration site conditions|
|Very Common||fatigue, fever|
|Common||peripheral oedema, abnormal gait, asthenia, pain, malaise, flu syndrome|
|Not known||withdrawal reactions (mostly anxiety, insomnia, nausea, pains, sweating), chest pain. Sudden unexplained deaths have been reported where a causal relationship to treatment with gabapentin has not been established.|
|Common||WBC (white blood cell count) decreased, weight gain|
|Uncommon||elevated liver function tests SGOT (AST), SGPT (ALT) and bilirubin|
|Not known||blood glucose fluctuations in patients with diabetes, blood creatine phosphokinase increased|
|Injury and poisoning|
|Common||accidental injury, fracture, abrasion|
|Response (≥ 50% Improved) by Treatment and Age MITT* Population|
|< 6 Years Old||4/21 (19.0%)||4/17 (23.5%)||0.7362|
|6 to 12 Years Old||17/99 (17.2%)||20/96 (20.8%)||0.5144|
AbsorptionFollowing oral administration, peak plasma gabapentin concentrations are observed within 2 to 3 hours. Gabapentin bioavailability (fraction of dose absorbed) tends to decrease with increasing dose. Absolute bioavailability of a 300 mg capsule is approximately 60%. Food, including a high-fat diet, has no clinically significant effect on gabapentin pharmacokinetics.Gabapentin pharmacokinetics are not affected by repeated administration. Although plasma gabapentin concentrations were generally between 2 μg/ml and 20 μg/ml in clinical studies, such concentrations were not predictive of safety or efficacy. Pharmacokinetic parameters are given in Table 3.Table 3Summary of gabapentin mean (%CV) steady-state pharmacokinetic parameters following every eight hours administration
|Pharmacokinetic parameter||300 mg (N = 7)||400 mg (N = 14)||800 mg (N=14)|
|AUC (0-8) μg•hr/ml)||24.8||(24)||34.5||(34)||51.4||(27)|
|Cmax = Maximum steady state plasma concentration tmax = Time for CmaxT1/2 = Elimination half-life AUC(0-8) = Steady state area under plasma concentration-time curve from time 0 to 8 hours postdose Ae% = Percent of dose excreted unchanged into the urine from time 0 to 8 hours postdose NA = Not available|
DistributionGabapentin is not bound to plasma proteins and has a volume of distribution equal to 57.7 litres. In patients with epilepsy, gabapentin concentrations in cerebrospinal fluid (CSF) are approximately 20% of corresponding steady-state trough plasma concentrations. Gabapentin is present in the breast milk of breast-feeding women.
MetabolismThere is no evidence of gabapentin metabolism in humans. Gabapentin does not induce hepatic mixed function oxidase enzymes responsible for drug metabolism.
EliminationGabapentin is eliminated unchanged solely by renal excretion. The elimination half-life of gabapentin is independent of dose and averages 5 to 7 hours.In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin elimination-rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance.Gabapentin is removed from plasma by haemodialysis. Dosage adjustment in patients with compromised renal function or undergoing haemodialysis is recommended (see section 4.2).Gabapentin pharmacokinetics in children were determined in 50 healthy subjects between the ages of 1 month and 12 years. In general, plasma gabapentin concentrations in children > 5 years of age are similar to those in adults when dosed on a mg/kg basis.In a pharmacokinetic study in 24 healthy paediatric subjects aged between 1 month and 48 months, an approximately 30% lower exposure (AUC), lower Cmax and higher clearance per body weight have been observed in comparison to available reported data in children older than 5 years.
Linearity/Non-linearityGabapentin bioavailability (fraction of dose absorbed) decreases with increasing dose which imparts non-linearity to pharmacokinetic parameters which include the bioavailability parameter (F) e.g. Ae%, CL/F, Vd/F. Elimination pharmacokinetics (pharmacokinetic parameters which do not include F such as CLr and T1/2), are best described by linear pharmacokinetics. Steady state plasma gabapentin concentrations are predictable from single-dose data.
CarcinogenesisGabapentin 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 tumours was found only in male rats at the highest dose. Peak plasma drug concentrations in rats at 2000 mg/kg are 10 times higher than plasma concentrations in humans given 3600 mg/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 unclear.
MutagenesisGabapentin demonstrated no 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.
Impairment of FertilityNo adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately five times the maximum daily human dose on a mg/m2 of body surface area basis).
TeratogenesisGabapentin 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 on a mg/m2 basis). Gabapentin induced delayed ossification in the skull, vertebrae, forelimbs, and hindlimbs in rodents, indicative of fetal growth retardation. These effects occurred when pregnant mice received oral doses of 1000 or 3000 mg/kg/day during organogenesis and in rats given 500, 1000, or 2000 mg/kg prior to and during mating and throughout gestation. These doses are approximately 1 to 5 times the human dose of 3600 mg on a mg/m2 basis.No effects were observed in pregnant mice given 500 mg/kg/day (approximately 1/2 of the daily human dose on a mg/m2 basis).An increased incidence of hydroureter and/or hydronephrosis was observed in rats given 2000 mg/kg/day in a fertility and general reproduction study, 1500 mg/kg/day in a teratology study, and 500, 1000, and 2000 mg/kg/day in a perinatal and postnatal study. The significance of these findings is unknown, but they have been associated with delayed development. These doses are also approximately 1 to 5 times the human dose of 3600 mg on a mg/m2 basis.In a teratology study in rabbits, an increased incidence of post-implantation fetal loss, occurred in doses given 60, 300, and 1500 mg/kg/day during organogenesis. These doses are approximately 1/4 to 8 times the daily human dose of 3600 mg on a mg/m2 basis.
Capsules, hardEach hard capsule contains the following excipients: lactose monohydrate, maize starch and talc.Capsule shell: gelatin, purified water and sodium lauryl sulphate. The 100 mg hard capsules contain the colouring E171 (titanium dioxide). The printing ink used on all hard capsules contains shellac, E171 (titanium dioxide) and E132 (indigocarmine).
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