Gabapentin

Dosage adjustment is recommended in patients with compromised renal function as described in table below and/or those undergoing haemodialysis. Gabapentin can be used to follow dosing recommendations for patients with renal insufficiency.

Dosage of gabapentin in adults based on renal function:

^a Total daily dose should be administered as three divided doses. Reduced dosages are for patients with renal impairment (creatinine clearance <79 mL/min).
^b The 150 mg daily dose to be administered as 300 mg every other day.
^c For patients with creatinine clearance <15 mL/min, the daily dose should be reduced in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients with a creatinine clearance of 15 mL/min receive).

Use in patients undergoing haemodialysis

For 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 the table above. In addition to the maintenance dose, an additional 200 to 300 mg dose following each 4-hour haemodialysis treatment is recommended.

Co-administration 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.

There are spontaneous and literature case reports of respiratory depression and/or sedation associated with gabapentin and opioid use. In some of these reports, the authors considered this a particular concern with the combination of gabapentin and opioids, especially in elderly patients.

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

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

Renal excretion of gabapentin is unaltered by probenecid.

Risk related to epilepsy and antiepileptic medicinal products in general

The 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 gabapentin

Gabapentin crosses the human placenta.

There are no or limited amount of data from the use of gabapentin in pregnant women.

Studies in animals have shown reproductive toxicity. 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 causally 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.

Fertility

There is no effect on fertility in animal studies.

Gabapentin may have minor or moderate influence on the ability to drive and use machines. Gabapentin acts on the central nervous system and may cause drowsiness, dizziness or other related symptoms. Even, if they were only of mild or moderate degree, these undesirable effects could be potentially dangerous in patients driving or operating machinery. This is especially true at the beginning of the treatment and after increase in dose.

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 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Where an adverse reaction was seen at different frequencies in clinical studies, it was assigned to the highest frequency reported.

Additional reactions reported from post-marketing experience are included as frequency Not known (cannot be estimated from the available data) in italics in the list below.

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

Not known: Thrombocytopenia

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), anaphylaxis

Metabolism and nutrition disorders

Common: anorexia, increased appetite

Uncommon: hyperglycaemia (most often observed in patients with diabetes)

Rare: hypoglycaemia (most often observed in patients with diabetes)

Not known: hyponatraemia

Psychiatric disorders

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

Uncommon: agitation

Not known: 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, mental impairment

Rare: loss of consciousness

Not known: other movement disorders (e.g. choreoathetosis, dysk inesia, dystonia)

Eye disorders

Common: visual disturbances such as amblyopia, diplopia

Ear and labyrinth disorders

Common: vertigo

Not known: tinnitus

Cardiac disorders

Uncommon: palpitations

Vascular disorders

Common: hypertension, vasodilatation

Respiratory, thoracic and mediastinal disorders

Common: dyspnoea, bronchitis, pharyngitis, cough, rhinitis

Rare: respiratory depression

Gastrointestinal disorders

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

Not known: pancreatitis

Hepatobiliary disorders

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

Musculoskeletal and connective tissue 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

Common: impotence

Not known: breast hypertrophy, gynaecomastia, sexual dysfunction (including changes in libido, ejaculation disorders and anorgasmia)

General disorders and administration site conditions

__Very Common:___ fatigue, fever

__Common:___ peripheral oedema, abnormal gait, asthenia, pain, malaise, flu syndrome

__Uncommon:___ generalized oedema

__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.

Investigations

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

__Uncommon:___ elevated liver function tests SGOT (AST), SGPT (ALT) and bilirubin

__Not known:___ blood creatine phosphok inase increased

Injury, poisoning and procedural complications

__Common:___ accidental injury, fracture, abrasion

__Uncommon:___ fall

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

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

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.