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General: pms-GABAPENTIN (gabapentin) is not considered effective in the treatment of absence seizures and should therefore be used with caution in patients who have mixed seizure disorders that include absence seizures.
Discontinuation of Treatment with pms-GABAPENTIN: As with other anticonvulsant agents, abrupt withdrawal is not recommended because of the possibility of increased seizure frequency. There have been post-marketing reports of adverse events such as anxiety, insomnia, nausea, pain and sweating following abrupt discontinuation of treatment (see Post-Market Adverse Drug Reactions under ADVERSE REACTIONS). When in the judgement 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 1 week (a longer period may be needed at the discretion of the prescriber).
Neurologic: 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 agitation, 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 (see Dosing Considerations and Special Patient Populations under DOSAGE & ADMINISTRATION).
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. 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 with gabapentin is also a contributing factor.
Concomitant Use with Opioids: Concomitant use of opioids with gabapentin potentiates the risk of respiratory depression, profound sedation, syncope, and death. Gabapentin concentrations may also increase in patients receiving concomitant opioid (see INTERACTIONS).
Patients who require concurrent treatment with opioids or other CNS depressants should be observed carefully for signs and symptoms of CNS depression, and the dose of gabapentin or opioid should be reduced accordingly.
Psychomotor Impairment: Patients with uncontrolled epilepsy should not drive or handle potentially dangerous machinery. Patients taking pms-GABAPENTIN should not drive until they have gained sufficient experience to assess whether pms-GABAPENTIN impairs the ability to drive. During clinical trials, the most common adverse reactions observed were somnolence, ataxia, fatigue, and nystagmus. Patients should be advised to refrain from activities requiring mental alertness or physical coordination until they are sure that pms-GABAPENTIN does not affect them adversely.
Carcinogenesis and Mutagenesis: Gabapentin produced an increased incidence of acinar cell adenomas and carcinomas in the pancreas of male rats, but not female rats or in mice, in oncogenic studies with doses of 2,000 mg/kg which resulted in plasma concentrations 14 times higher than those occurring in humans at a dose of 2400 mg/day. The relevance of these pancreatic acinar cell tumours in male rats to humans is unknown, particularly since tumours of ductal rather than acinar cell origin are the predominant form of human pancreatic cancer (see PHARMACOLOGY: TOXICOLOGY: Carcinogenesis and Mutagenesis under ACTIONS).
Dependence/Tolerance: The abuse and dependence potential of gabapentin has not been evaluated in human studies. Cases of abuse and dependence have been reported in the post-marketing database. These individuals were taking higher than recommended doses of gabapentin for unapproved uses. Most of the individuals described in these reports had a history of polysubstance abuse or used gabapentin to relieve symptoms of withdrawal from other substances. As with any CNS active drug, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of abuse or misuse of pms-GABAPENTIN (e.g., development of tolerance, self-dose escalation, and drug-seeking behavior).
There are rare post-marketing reports of individuals experiencing withdrawal symptoms shortly after discontinuing higher than recommended doses of gabapentin used to treat illnesses for which the drug is not indicated. Such symptoms included agitation, disorientation and confusion after suddenly discontinuing gabapentin that resolved after restarting gabapentin. Most of these individuals had a history of poly-substance abuse or used gabapentin to relieve symptoms of withdrawal from other substances.
Hypersensitivity: Serious Dermatological Reactions: There have been post-marketing reports of Stevens-Johnson syndrome (SJS) and Erythema multiforme (EM) in patients during treatment with gabapentin. Should signs and symptoms suggest SJS or ER, gabapentin should be discontinued immediately (see Post-Market Adverse Drug Reactions under ADVERSE REACTIONS).
There have been reports in the post-marketing experience of hypersensitivity including systemic reactions and cases of urticaria and angioedema (see Post-Market Adverse Drug Reactions under ADVERSE REACTIONS).
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Severe, life-threatening, systemic hypersensitivity reactions such as Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported in patients taking antiepileptic 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 etiology for the signs or symptoms cannot be established.
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
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.
Psychiatric: Suicidal Ideation and Behaviour: Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications.
All patients treated with antiepileptic drugs, irrespective of indication, should be monitored for signs of suicidal ideation and behaviour 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.
An FDA meta-analysis of randomized placebo controlled trials, in which antiepileptic drugs were used for various indications, has shown a small increased risk of suicidal ideation and behaviour in patients treated with these drugs. The mechanism of this risk is not known.
There were 43,892 patients treated in the placebo controlled clinical trials that were included in the meta-analysis. Approximately 75% of patients in these clinical trials were treated for indications other than epilepsy and, for the majority of non-epilepsy indications the treatment (antiepileptic drug or placebo) was administered as monotherapy. Patients with epilepsy represented approximately 25% of the total number of patients treated in the placebo controlled clinical trials and, for the majority of epilepsy patients, treatment (antiepileptic drug or placebo) was administered as adjunct to other antiepileptic agents (i.e., patients in both treatment arms were being treated with one or more antiepileptic drug). Therefore, the small increased risk of suicidal ideation and behaviour reported from the meta-analysis (0.43% for patients on antiepileptic drugs compared to 0.24% for patients on placebo) is based largely on patients that received monotherapy treatment (antiepileptic drug or placebo) for non-epilepsy indications. The study design does not allow an estimation of the risk of suicidal ideation and behaviour for patients with epilepsy that are taking antiepileptic drugs, due both to this population being the minority in the study, and the drug-placebo comparison in this population being confounded by the presence of adjunct antiepileptic drug treatment in both arms.
Monitoring and Laboratory Tests: Clinical trials data do not indicate that routine monitoring of clinical laboratory parameters is necessary for the safe use of gabapentin. Gabapentin may be used in combination with other commonly used antiepileptic drugs without concern for alteration of the blood concentrations of gabapentin or other antiepileptic drugs.
Use in Pregnancy: Based on animal data, gabapentin may cause fetal harm (see PHARMACOLOGY: TOXICOLOGY: Reproduction Studies under ACTIONS). In non-clinical studies in mice, rats and rabbits, gabapentin was developmentally toxic (e.g., increased fetal skeletal and visceral abnormalities, and increased embryofetal mortality) when administered to pregnant animals at doses lower than the maximum recommended human dose (MRHD) of 3,600 mg/day on a body surface area (mg/m2) basis.
Teratogenic Potential: Gabapentin crosses the human placental barrier. Although there are no adequate and well-controlled studies in pregnant women, congenital malformations and adverse pregnancy outcomes have been reported with gabapentin use; both, from literature and Pregnancy Registries. Since the potential risk for humans is uncertain, gabapentin should only be used during pregnancy if the potential benefit to the mother outweighs the potential risk to the fetus. If women decide to become pregnant while taking pms-GABAPENTIN, the use of this product should be carefully re-evaluated.
Pregnancy Registry: Physicians are advised to recommend that pregnant patients taking pms-GABAPENTIN enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the following website: http://aedpregnancyregistry.org/.
Use in Lactation: Gabapentin is excreted in human milk. There are no controlled studies on the effects of gabapentin on breast-fed infants. Because of the potential for serious adverse reactions in nursing infants, a decision should be made as to whether to discontinue nursing or to discontinue pms-GABAPENTIN, taking into account the benefit of the drug to the mother.
Use in Children (< 18 years of age): The safety and efficacy in patients under the age of 18 have not been established.
Safety data in 39 patients between the ages of 12 and 18 years included in the double-blind, placebo-controlled trials showed that, at doses of 900 to 1,200 mg/day, the incidence of adverse events in this group of patients was similar to that observed in older individuals.
In controlled clinical trials involving patients, 3 to 12 years of age (N = 323), psychiatric adverse events such as emotional lability, hostility, hyperkinesia and thought disorder were reported at a higher frequency in patients treated with gabapentin compared to placebo.
Use in the Elderly (> 65 years of age): Systematic studies in geriatric patients have not been conducted. Adverse clinical events reported among 59 patients over the age of 65 years treated with gabapentin did not differ from those reported for younger individuals. The small number of individuals evaluated and the limited duration of exposure limits the strength of any conclusions reached about the influence of age, if any, on the kind and incidence of adverse events associated with the use of gabapentin. As gabapentin is eliminated primarily by renal excretion, dosage adjustment may be required in elderly patients because of declining renal function (see Dosing Considerations under DOSAGE & ADMINISTRATION; PHARMACOLOGY: PHARMACOKINETICS: Special Populations and Conditions under ACTIONS).
