GABACOR Capsule, hard Ref.[50338] Active ingredients: Gabapentin

Abuse Potential or Dependence

Gabapentin is a potential drug of abuse and dependence. Gabapentin poses risks of abuse and dependence which can lead to overdose and death especially when used concomitantly with opioids and other CNS depressants. Assess the patient’s risk of abuse or dependence before prescribing and monitor the patient regularly during treatment, particularly amongst patients with current or past abuse or dependence of opioids and/or benzodiazepines (see Section 4.4 Special warnings and precautions for use).

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 there is a need for dose reduction, discontinuation, or substitution of alternative anti-convulsant medication, this should be done gradually over a minimum of one week.

Gabapentin is generally not 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.

Gabapentin treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall). There have also been post-marketing reports of confusion, loss of consciousness and mental impairment. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication.

Central Nervous System Depression

Respiratory Depression

Gabapentin has been associated with central nervous system (CNS) depression including sedation, somnolence, loss of consciousness as well as serious cases of respiratory depression. This may occur without concomitant opioid use. Patients with compromised respiratory function, respiratory or neurological disease, renal impairment and the elderly are at higher risk of experiencing these severe adverse effects. Concomitant use of CNS depressants including opioids with gabapentin increases the risk of respiratory depression.

Concomitant Use with Opioids and Other CNS Depressants

Patients who require concomitant treatment with opioids may experience increases in gabapentin concentrations. Concomitant use of opioids may result in severe sedation, respiratory depression, coma, and death. Limit dosages and durations of gabapentin to the minimum required to achieve desired therapeutic effect. Patients who require concomitant treatment with CNS depressants, including opioids should be carefully observed for signs of CNS depression, such as somnolence, sedation and respiratory depression; and the dose of gabapentin or concomitant treatment with CNS depressants including opioids should be reduced appropriately (see Section 4.5 Interactions with other medicines and other forms of interactions: Concomitant Use with Opioids).

Caution is advised when prescribing gabapentin concomitantly with opioids due to risk of CNS depression. In a population-based, observational, nested case-control study of opioid users, coprescription of opioids and gabapentin was associated with an increased risk for opioid-related death compared to opioid prescription use alone (adjusted odds ratio [aOR], 1.49 [95% CI, 1.18 to 1.88, p <0.001]).

Suicidal Behaviour and Ideation

Anti-epileptic drugs (AED), including gabapentin, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviour, and/or any unusual changes in mood or behaviour.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomised to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behaviour compared to patients randomised to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behaviour or ideation among 27,863 AEDtreated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behaviour for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behaviour with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behaviour beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behaviour was generally consistent among drugs in the data analysed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.

The risk did not vary substantially by age (5-100 years) in the clinical trials analysed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

Table 2. Risk by Indication for Anti-epileptic Drugs in the Pooled Analysis:

The relative risk for suicidal thoughts or behaviour was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing gabapentin or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behaviour. Should suicidal thoughts and behaviour emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behaviour and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behaviour, or the emergence of suicidal thoughts, behaviour, or thoughts about self-harm. Behaviours of concern should be reported immediately to the treating doctor.

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 anti-epileptic drugs including gabapentin.

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 aetiology for the signs or symptoms cannot be established.

Anaphylaxis

Gabapentin can cause anaphylaxis. Signs and symptoms in reported cases have included difficulty breathing, swelling of the lips, throat, and tongue, and hypotension requiring emergency treatment. Patients should be instructed to discontinue gabapentin and seek immediate medical care should they experience signs or symptoms of anaphylaxis.

Abuse Potential or Dependence

Gabapentin is a potential drug of abuse and dependence.

There have been post market reports of overdose and deaths among users of gabapentin, particularly with concomitant use of other sedating medicines, such as opioids and/or benzodiazepines.

The risk of abuse of gabapentin should particularly be monitored among current or past opioid and/or benzodiazepine users.

Patients should be carefully evaluated for a history of substance abuse prior to being prescribed gabapentin and observed for signs of gabapentin abuse (e.g., development of tolerance, increase in dose, drug seeking behaviour).

Discontinuation

Withdrawal symptoms have been observed in some patients after discontinuation of gabapentin, including severe symptoms in patients taking high doses. Withdrawal symptoms after discontinuation of both short-term and long-term treatment with gabapentin have been observed in some patients. The following events have been mentioned: insomnia, headache, nausea, anxiety, hyperhidrosis and diarrhoea. Discontinuation should be done gradually over a minimum of one week (see Section 4.2 Dose and method of administration: Discontinuation of gabapentin).

Information for Patients

To assure safe and effective use of gabapentin, the following information and instructions should be given to patients:

1. You should inform your physician about any prescription or non-prescription medications, alcohol, or drugs you are now taking or are planning to take during your treatment with gabapentin.
2. No teratogenic effects have been found in animals. However, the risk to the human foetus cannot be dismissed. Therefore 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.
3. Gabapentin is excreted in human milk, and the effect on the nursing infant is unknown. You should inform your physician if you are breast-feeding an infant.
4. Gabapentin may impair your ability to drive a car or operate potentially dangerous machinery. Until it is known that this medication does not affect your ability to engage in these activities, do not drive a car or operate potentially dangerous machinery.
5. 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.
6. Prior to initiation of treatment with gabapentin, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity such as fever or lymphadenopathy may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.

Use in Renal Impairment

See Section 5.2 Pharmacokinetic properties, Section 4.2 Dose and method of administration, and Section 4.4 Special warnings and precautions for use: Central Nervous System Depression.

Use in the Elderly

See Section 5.2 Pharmacokinetic properties, and Section 4.4 Special warnings and precautions for use: Central Nervous System Depression

Paediatric Use

Epilepsy

Safety and effectiveness in children below the age of 3 years have not been established.

Neuropathic Pain

Safety and effectiveness in children below the age of 18 years have not been established.

Effects on 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.

There are spontaneous and literature case reports of respiratory depression, sedation, and death associated with gabapentin when co-administered with CNS depressants, including opioids. In some of these reports, the authors considered the combination of gabapentin with opioids to be a particular concern in frail patients, in the elderly, in patients with serious underlying respiratory disease, with polypharmacy, and in those patients with substance abuse disorders.

Anti-convulsants

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 estradiol when administered concomitantly with an oral contraceptive containing these two drugs (N = 13).

Antacid

Co-administration of gabapentin with large dose antacid (aluminium hydroxide 3600 mg, magnesium hydroxide 1800 mg) reduced gabapentin bioavailability (AUC) by about 20% (N = 16). Although the difference was not expected to be clinically significant, it is recommended that gabapentin should be taken about 2 hours following antacid administration, when the interaction has been shown to be diminished.

Cimetidine

In the presence of cimetidine at 300 mg four times a day (QID), 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.

Probenecid

Renal excretion of gabapentin was unaltered by probenecid, a blocker of renal tubular secretion.

Concomitant Use with Opioids

In post-marketing experience, there are reports of respiratory failure, coma and deaths in patients taking gabapentin and other CNS depressant medications including opioids, and in patients who have a history of substance abuse (see Section 4.4 Special warnings and precautions for use: Concomitant Use with Opioids and Other CNS Depressants).

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 section 4.4 Special warnings and precautions for use). 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.

Effects on fertility

No adverse effect on fertility or reproduction were observed in rats at doses up to 2000 mg/kg/day administered in the diet, with estimated exposure (plasma AUC) 14 times clinical exposure at the MRHD of 2400 mg/day.

Use in pregnancy

Pregnancy Category B3.

Gabapentin crosses the human placenta.

Congenital malformations and adverse pregnancy outcomes have been reported with gabapentin use, however there are no adequate and well-controlled studies in pregnant women and no definite conclusions can be made as to whether gabapentin is causally associated with an increased risk of congenital malformations or other adverse developmental outcomes when taken during pregnancy. The risk of birth defects is increased by a factor of 2-3 in the offspring of mothers treated with an anti-epileptic medicinal product.

Gabapentin should be used during pregnancy only if the potential benefit to the mother clearly outweighs the potential risk to the fetus.

The risk of having a child with a congenital defect as a result of anti-epileptic medication is far outweighed by the dangers to the mother and foetus of uncontrolled epilepsy.

It is recommended that:

• women on anti-epileptic drugs (AEDs) receive pre-pregnancy counselling with regard to the risk of fetal 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 four weeks prior to and continue for twelve weeks after conception;
• specialist prenatal diagnosis including detailed mid-trimester ultrasound should be offered.

Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.

Embryofetal development studies with gabapentin in mice at oral doses up to 3000 mg/kg/day and in rats at oral doses up to 1500 mg/kg/day revealed no evidence of fetal malformations. Delayed ossification in the skull, vertebrae and limbs, indicative of fetal growth retardation, was reported in the offspring of mice administered gabapentin at oral doses of 1000 and 3000 mg/kg/day during organogenesis, and rats administered gabapentin 2000 mg/kg/day in the diet during mating and throughout gestation. An increased incidence of hydroureter and/or hydronephrosis was observed in rats treated with dietary gabapentin from late gestation to weaning Section 4.6 Fertility, pregnancy and lactation: Use in Lactation). 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 dose of 2400 mg/day.

In female rabbits given 60, 300 or 1500 mg/kg/day gabapentin orally 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 harm to the fetus was observed.

Use in lactation

Gabapentin is excreted in human milk.

In a peri-postnatal study in rats administered gabapentin in the diet at doses of 500, 1000 and 2000 mg/kg/day from late gestation to weaning, there was a dose related reversible increase in the incidence of hydroureter and hydronephrosis in 21 day-old pups.

Because the effect on the nursing infant is unknown, and because of the potential for serious adverse reactions in nursing infants from gabapentin, 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.

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.

Adults and Children Over 12 Years of Age with Epilepsy

Gabapentin has been evaluated for safety in approximately 2000 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 anti-epileptic drugs, not seen in an equivalent frequency among placebotreated patients, were somnolence, dizziness, ataxia, fatigue, and nystagmus.

Approximately 7% of the 2074 individuals who received gabapentin in the premarketing 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 epilepsy 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 anti-epileptic drug therapy. Adverse events were usually mild to moderate in intensity.

Table 3. Adverse Events Reported in At Least 1% of Participants in Gabapentin PlaceboControlled Trials:

^a Plus background anti-epileptic drug therapy
^b Amblyopia was often described as blurred vision.

Other Adverse Events Observed During All Epilepsy 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 placebocontrolled studies are summarised below.

Body as a Whole: Asthenia, malaise, facial oedema.
Cardiovascular System: Hypertension.
Digestive System: Flatulence, anorexia, gingivitis.
Haematologic 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, most often described as a visual disturbance.

Children from 3 to 12 Years of Age with Epilepsy

The most commonly observed adverse events reported with the use of gabapentin in combination with other anti-epileptic drugs 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 preapproval 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 Age 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):

^a Plus background anti-epileptic drug therapy

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.
Haematologic and Lymphatic Systems: Coagulation defect.
Nervous System: Aura disappeared, occipital neuralgia.
Psychobiologic Function: Sleepwalking.
Respiratory System: Pseudo-croup, hoarseness.

Adults Over 18 Years of Age with Neuropathic Pain

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, thinking abnormal, vertigo, rash and amblyopia.

Of the 821 adults who received gabapentin in the painful diabetic peripheral neuropathy and post-herpetic neuralgia trials, 13.2% discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal were dizziness (4.4%), somnolence (2.9%), and nausea (1.3%).

Table 5. Summary of Treatment-Emergent Signs and Symptoms in ≥1% of Gabapentin- Treated Patients in Neuropathic Pain Placebo-Controlled Studies:

Post-Marketing Experience

The following adverse events have been reported in patients receiving gabapentin postmarketing, however, the data are 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 blood creatine phosphokinase increased, rhabdomyolysis, abnormal liver function, acute kidney failure, agitation, allergic reaction including urticaria, alopecia, anaphylaxis, anaemia, angioedema, hyperglycemia and hypoglycemia (most often observed in patients with diabetes), breast hypertrophy, gynaecomastia, cardiac arrest, chest pain, convulsions, depersonalisation, drug rash with eosinophilia and systemic symptoms, erythema multiforme, fall, hypersensitivity including systemic reactions, hyponatraemia, jaundice, loss of consciousness, movement disorders such as choreoathetosis, dyskinesia and dystonia, myoclonus, palpitation, pancreatitis, renal impairment, speech disorder, sexual dysfunction (including changes in libido, ejaculation disorders and anorgasmia), Stevens- Johnson syndrome, tachycardia, thrombocytopenia, tinnitus, urinary incontinence and symptoms of psychosis such as delusions, hallucinations, and thinking abnormal.

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.

Some cases of hypomania have been reported after commencement of gabapentin. In each case, other anti-convulsants had been used concurrently, and symptoms of hypomania resolved following a reduction in dosage or cessation of the drug.

Reporting suspected Adverse Effects

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reportingproblems.

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.