Drug Class Description

Generic Name

Drug Description

Presentation

Indications

Epilepsy

Gabapentin is indicated as adjunctive therapy in the treatment of partial seizures with and without secondary generalisation in adults and children aged 6 years and above.

Gabapentin is indicated as monotherapy in the treatment of partial seizures with and without secondary generalisation in adults and adolescents aged 12 years and above.

Treatment of peripheral neuropathic pain

Gabapentin is indicated for the treatment of peripheral neuropathic pain such as painful diabetic neuropathy and post-herpetic neuralgia in adults

Adult Dosage

For oral use.

Gabapentin can be given with or without food and should be swallowed whole with sufficient fluid intake (e.g. a glass of water).

For all indications a titration scheme for the initiation of therapy is described in Table 1, which is recommended for adults and adolescents aged 12 years and above. Dosing instructions for children under 12 years of age are provided under a separate sub-heading later in this section.

Epilepsy

Epilepsy typically requires long-term therapy. Dosage is determined by the treating physician according to individual tolerance and efficacy. When in the judgment of the clinician there is a need for dose reduction, discontinuation, or substitution with an alternative medication, this should be done gradually over a minimum of one week.

Adults and adolescents:

In clinical trials, the effective dosing range was 900 to 3600mg/day. Therapy may be initiated by titrating the dose as described in Table 1 or by administering 300mg three times a day (TID) on Day 1. Thereafter, based on individual patient response and tolerability, the dose can be further increased in 300mg/day increments every 2-3 days up to a maximum dose of 3600mg/day. Slower titration of gabapentin dosage may be appropriate for individual patients. The minimum time to reach a dose of 1800mg/day is one week, to reach 2400mg/day is a total of 2 weeks, and to reach 3600mg/day is a total of 3 weeks.

Dosages up to 4800mg/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 15mg/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 35mg/kg/day. Dosages up to 50mg/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

Adults

The therapy may be initiated by titrating the dose as described in Table 1. Alternatively, the starting dose is 900mg/day given as three equally divided doses. Thereafter, based on individual patient response and tolerability, the dose can be further increased in 300mg/day increments every 2-3 days up to a maximum dose of 3600mg/day. Slower titration of gabapentin dosage may be appropriate for individual patients. The minimum time to reach a dose of 1800mg/day is one week, to reach 2400mg/day is a total of 2 weeks, and to reach 3600mg/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 indication

In 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 impairment Dosage adjustment is recommended in patients with compromised renal function as described in Table 2 and/or those undergoing haemodialysis. Gabapentin 100mg capsules can be used to follow dosing recommendations for patients with renal insufficiency.

^a Total daily dose should be administered as three divided doses. Reduced dosages are for patients with renal impairment (creatinine clearance < 79ml/min).

^b To be administered as 300mg every other day.

^c For patients with creatinine clearance <15ml/min, the daily dose should be reduced in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5ml/min should receive one-half the daily dose that patients with a creatinine clearance of 15ml/min receive).

Use in patients undergoing haemodialysis

For anuric patients undergoing haemodialysis who have never received gabapentin, a loading dose of 300 to 400mg, then 200 to 300mg 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 300mg dose following each 4-hour haemodialysis treatment is recommended.

Contra Indications

Hypersensitivity to the active substance or to any of the excipients.

Special Precautions

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Gabapentin.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

If a patient develops acute pancreatitis under treatment with gabapentin, discontinuation of gabapentin should be considered.

Although there is no evidence of rebound seizures with gabapentin, abrupt withdrawal of anticonvulsants in epileptic patients may precipitate status epilepticus.

As with other antiepileptic medicinal products, some patients may experience an increase in seizure frequency or the onset of new types of seizures with gabapentin.

As with other anti-epileptics, attempts to withdraw concomitant anti-epileptics in treatment refractory patients on more than one anti-epileptic, in order to reach gabapentin monotherapy have a low success rate.

Gabapentin is not considered effective against primary generalized seizures such as absences and may aggravate these seizures in some patients. Therefore, gabapentin should be used with caution in patients with mixed seizures including absences.

No systematic studies in patients 65 years or older have been conducted with gabapentin. In one double blind study in patients with neuropathic pain, somnolence, peripheral oedema and asthenia occurred in a somewhat higher percentage in patients aged 65 years or above, than in younger patients. Apart from these findings, clinical investigations in this age group do not indicate an adverse event profile different from that observed in younger patients.

The effects of long-term (greater than 36 weeks) gabapentin therapy on learning, intelligence, and development in children and adolescents have not been adequately studied. The benefits of prolonged therapy must therefore be weighed against the potential risks of such therapy.

Laboratory tests

False 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.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine.

Interactions

In a study involving healthy volunteers (N=12), when a 60mg controlled-release morphine capsule was administered 2 hours prior to a 600mg gabapentin capsule, mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine. Therefore, patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately.

No interaction between gabapentin and phenobarbital, phenytoin, valproic acid, or carbamazepine has been observed.

Gabapentin steady-state pharmacokinetics are similar for healthy subjects and patients with epilepsy receiving these antiepileptic agents.

Coadministration of gabapentin with oral contraceptives containing norethindrone and/or ethinyl estradiol, does not influence the steady-state pharmacokinetics of either component.

Coadministration of gabapentin with antacids containing aluminium and magnesium, reduces gabapentin bioavailability up to 24%. It is recommended that gabapentin be taken at the earliest two hours following antacid administration.

Renal excretion of gabapentin is unaltered by probenecid.

A slight decrease in renal excretion of gabapentin that is observed when it is coadministered with cimetidine is not expected to be of clinical importance.

Adverse Reactions

The adverse reactions observed during clinical studies conducted in epilepsy (adjunctive and monotherapy) and neuropathic pain have been provided in a single list below by class and frequency (very common (> 1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100) and rare (>1/10,000; <1/1,000). Additional reactions reported from the post-marketing experience are included as frequency 'not known' (cannot be estimated from the available data). Where an adverse reaction was seen at different frequencies in clinical studies, it was assigned to the highest frequency reported.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations

Very Common: Viral infection

Common: Pneumonia, respiratory infection, urinary tract infection, infection, otitis media

Blood and the lymphatic system disorders

Common: leucopenia

Rare: thrombocytopenia

Immune system disorders

Rare: allergic reactions (e.g. urticaria)

Not known: Hypersensitive 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

Psychiatric disorders

Common: hostility, confusion and emotional lability, depression, anxiety, nervousness, thinking abnormal

Rare: hallucinations

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

Uncommon: hypokinesia

Rare: movement disorders (e.g. choreoathetosis, dyskinesia, dystonia)

Not Known: myoclonus, syncope

Eye disorders

Common: visual disturbances such as amblyopia, diplopia

Ear and Labyrinth disorders

Common: vertigo

Rare: tinnitus

Cardiac disorders

Rare: palpitations

Vascular disorder

Common: hypertension, vasodilatation

Respiratory, thoracic and mediastinal disorders

Common: dyspnoea, bronchitis, pharyngitis, cough, rhinitis

Gastrointestinal disorders

Common: vomiting, nausea, dental abnormalities, gingivitis, diarrhoea, abdominal pain, dyspepsia, constipation, dry mouth or throat, flatulence

Rare: pancreatitis

Hepatobiliary disorders

Rare: hepatitis, jaundice

Skin and subcutaneous tissue disorders

Common: facial oedema, purpura most often described as bruises resulting from physical trauma, rash, pruritus, acne

Rare: Stevens-Johnson syndrome, angioedema, erythema multiforme, alopecia

Musculoskeletal, connective tissue and bone disorders

Common: arthralgia, myalgia, back pain, twitching

Renal and urinary disorders

Common: incontinence

Rare: acute renal failure

Reproductive system and breast disorders

Common: impotence

Not known: breast hypertrophy, gynaecomastia

General disorders and administration site conditions

Very Common: fatigue, fever

Common: peripheral or generalized oedema, abnormal gait, asthenia, pain, malaise, flu syndrome

Rare: 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.

Investigations

Common: WBC (white blood cell count) decreased, weight gain

Rare: Blood glucose fluctuations in patients with diabetes, elevated liver function tests SGOT (AST), SGPT (ALT) and bilirubin

Injury and poisoning

Common: accidental injury, fracture, abrasion

Under treatment with gabapentin cases of acute pancreatitis were reported. Causality with gabapentin is unclear.

Respiratory tract infections, otitis media, convulsions and bronchitis were reported only in clinical studies in children. Additionally, in clinical studies in children, aggressive behaviour and hyperkinesias were reported commonly.

In patients on haemodialysis due to end-stage renal failure, myopathy with elevated creatine kinase levels has been reported.

Manufacturer

Drug Availability

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