Gabapentin

Gabapentin capsules are contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. Known hypersensitivity to gabapentin or its ingredients (4)

• Drug Reaction with Eosinophilia and Systemic Symptoms (Multiorgan hypersensitivity):
• Discontinue if alternative etiology is not established (5.1) Anaphylaxis and Angioedema:
• Discontinue and evaluate patient immediately (5.2) Driving Impairment;
• Warn patients not to drive until they have gained sufficient experience to assess whether their ability to drive or operate heavy machinery will be impaired (5.3, 5.4) Increased seizure frequency may occur in patients with seizure disorders if gabapentin is abruptly discontinued (5.5) Suicidal Behavior and Ideation:
• Monitor for suicidal thoughts/behavior (5.6) Respiratory Depression:
• May occur with gabapentin when used with concomitant central nervous system (CNS) depressants, including opioids, or in the setting of underlying respiratory impairment.
• Monitor patients and adjust dosage as appropriate ( 5.7 ) Neuropsychiatric Adverse Reactions in
• Children 3 to 12 Years of Age:
• Monitor for such events ( 5.8 )
• 5.1 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with gabapentin.
• Some of these reactions have been fatal or life-threatening.
• DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection.
• Eosinophilia is often present.
• This disorder is variable in its expression, and other organ systems not noted here may be involved.
• 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.
• 5.2 Anaphylaxis and Angioedema Gabapentin can cause anaphylaxis and angioedema after the first dose or at any time during treatment.
• 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 or angioedema.
• 5.3 Effects on Driving and Operating Heavy Machinery Patients taking gabapentin should not drive until they have gained sufficient experience to assess whether gabapentin impairs their ability to drive.
• Driving performance studies conducted with a prodrug of gabapentin (gabapentin enacarbil tablet, extended-release) indicate that gabapentin may cause significant driving impairment.
• Prescribers and patients should be aware that patients’ ability to assess their own driving competence, as well as their ability to assess the degree of somnolence caused by gabapentin, can be imperfect.
• The duration of driving impairment after starting therapy with gabapentin is unknown.
• Whether the impairment is related to somnolence [see Warnings and Precautions (5.4) ] or other effects of gabapentin is unknown.
• Moreover, because gabapentin causes somnolence and dizziness [see Warnings and Precautions (5.4) ] , patients should be advised not to operate complex machinery until they have gained sufficient experience on gabapentin to assess whether gabapentin impairs their ability to perform such tasks.
• 5.4 Somnolence/Sedation and Dizziness During the controlled epilepsy trials in patients older than 12 years of age receiving doses of gabapentin up to 1,800 mg daily, somnolence, dizziness, and ataxia were reported at a greater rate in patients receiving gabapentin compared to placebo:
• i.e., 19% in drug versus 9% in placebo for somnolence, 17% in drug versus 7% in placebo for dizziness, and 13% in drug versus 6% in placebo for ataxia.
• In these trials somnolence, ataxia and fatigue were common adverse reactions leading to discontinuation of gabapentin in patients older than 12 years of age, with 1.2%, 0.8% and 0.6% discontinuing for these events, respectively.
• During the controlled trials in patients with post-herpetic neuralgia, somnolence, and dizziness were reported at a greater rate compared to placebo in patients receiving gabapentin, in dosages up to 3,600 mg per day:
• i.e., 21% in gabapentin-treated patients versus 5% in placebo-treated patients for somnolence and 28% in gabapentin-treated patients versus 8% in placebo-treated patients for dizziness.
• Dizziness and somnolence were among the most common adverse reactions leading to discontinuation of gabapentin.
• Patients should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence and sedation, when gabapentin is used with other drugs with sedative properties because of potential synergy.
• In addition, patients who require concomitant treatment with morphine may experience increases in gabapentin concentrations and may require dose adjustment [see Drug Interactions (7.1) ].
• 5.5 Withdrawal Precipitated Seizure, Status Epilepticus Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency.
• In the placebo-controlled epilepsy studies in patients > 12 years of age, the incidence of status epilepticus in patients receiving gabapentin was 0.6% (3 of 543) versus 0.5% in patients receiving placebo (2 of 378).
• Among the 2,074 patients > 12 years of age treated with gabapentin across all epilepsy studies (controlled and uncontrolled), 31 (1.5%) had status epilepticus.
• Of these, 14 patients had no prior history of status epilepticus either before treatment or while on other medications.
• Because adequate historical data are not available, it is impossible to say whether or not treatment with gabapentin is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with gabapentin.
• 5.6 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, increase the risk of suicidal thoughts or behavior 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 behavior, and/or any unusual changes in mood or behavior.
• Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized 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 behavior compared to patients randomized to placebo.
• In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated 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 behavior 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 behavior 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 behavior beyond 24 weeks could not be assessed.
• The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
• 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 to 100 years) in the clinical trials analyzed.
• Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
• TABLE 2.
• Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk:
• Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference:
• Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1 3.4 3.5
• 2.4 Psychiatric 5.7 8.5 1.5
• 2.9 Other 1 1.8 1.9
• 0.9 Total 2.4 4.3 1.8
• 1.9 The relative risk for suicidal thoughts or behavior 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 the risk of suicidal thoughts or behavior 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 behavior.
• Should suicidal thoughts and behavior 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 behavior 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 behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
• Behaviors of concern should be reported immediately to healthcare providers.
• 5.7 Respiratory Depression There is evidence from case reports, human studies, and animal studies associating gabapentin with serious, life-threatening, or fatal respiratory depression when co-administered with CNS depressants, including opioids, or in the setting of underlying respiratory impairment.
• When the decision is made to co-prescribe gabapentin with another CNS depressant, particularly an opioid, or to prescribe gabapentin to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating gabapentin at a low dose.
• The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including gabapentin).
• 5.8 Neuropsychiatric Adverse Reactions (Pediatric Patients 3 to 12 Years of Age) Gabapentin use in pediatric patients with epilepsy 3 to 12 years of age is associated with the occurrence of CNS related adverse reactions.
• The most significant of these can be classified into the following categories:
• 1) emotional lability (primarily behavioral problems), 2) hostility, including aggressive behaviors, 3) thought disorder, including concentration problems and change in school performance, and 4) hyperkinesia (primarily restlessness and hyperactivity).
• Among the gabapentin-treated patients, most of the reactions were mild to moderate in intensity.
• In controlled clinical epilepsy trials in pediatric patients 3 to 12 years of age, the incidence of these adverse reactions was:
• emotional lability 6% (gabapentin-treated patients) versus 1.3% (placebo-treated patients); hostility 5.2% versus 1.3%; hyperkinesia 4.7% versus 2.9%; and thought disorder 1.7% versus 0%.
• One of these reactions, a report of hostility, was considered serious.
• Discontinuation of gabapentin treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of gabapentin-treated patients reporting hostility and thought disorder.
• One placebo-treated patient (0.4%) withdrew due to emotional lability.
• 5.9 Tumorigenic Potential In an oral carcinogenicity study, gabapentin increased the incidence of pancreatic acinar cell tumors in rats [see Nonclinical Toxicology (13.1) ] .
• The clinical significance of this finding is unknown.
• Clinical experience during gabapentin’s premarketing development provides no direct means to assess its potential for inducing tumors in humans.
• In clinical studies in adjunctive therapy in epilepsy comprising 2,085 patient-years of exposure in patients > 12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ ), and preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of gabapentin.
• Without knowledge of the background incidence and recurrence in a similar population not treated with gabapentin, it is impossible to know whether the incidence seen in this cohort is or is not affected by treatment.
• 5.10 Sudden and Unexplained Death in Patients with Epilepsy During the course of premarketing development of gabapentin, 8 sudden and unexplained deaths were recorded among a cohort of 2,203 epilepsy patients treated (2,103 patient-years of exposure) with gabapentin.
• Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night.
• This represents an incidence of 0.0038 deaths per patient-year.
• Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving gabapentin (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical trial population similar to that in the gabapentin program, to 0.005 for patients with refractory epilepsy).
• Consequently, whether these figures are reassuring or raise further concern depends on comparability of the populations reported upon to the gabapentin cohort and the accuracy of the estimates provided.

• Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as gabapentin, during pregnancy.
• Encourage women who are taking gabapentin during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/ .
• Risk Summary There are no adequate data on the developmental risks associated with the use of gabapentin in pregnant women.
• In nonclinical studies in mice, rats, and rabbits, gabapentin was developmentally toxic (increased fetal skeletal and visceral abnormalities, and increased embryofetal mortality) when administered to pregnant animals at doses similar to or lower than those used clinically [see Data].
• In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 % to 4% and 15% to 20%, respectively.
• The background risk of major birth defects and miscarriage for the indicated population is unknown.
• Data Animal data When pregnant mice received oral doses of gabapentin (500 mg, 1,000 mg, or 3,000 mg/kg/day) during the period of organogenesis, embryofetal toxicity (increased incidences of skeletal variations) was observed at the two highest doses.
• The no-effect dose for embryofetal developmental toxicity in mice (500 mg/kg/day) is less than the maximum recommended human dose (MRHD) of 3,600 mg on a body surface area (mg/m 2 ) basis.
• In studies in which rats received oral doses of gabapentin (500 mg to 2,000 mg/kg/day) during pregnancy, adverse effect on offspring development (increased incidences of hydroureter and/or hydronephrosis) were observed at all doses.
• The lowest dose tested is similar to the MRHD on a mg/m 2 basis.
• When pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryo-fetal mortality was observed at all doses tested (60 mg, 300 mg, or 1,500 mg/kg).
• The lowest dose tested is less than the MRHD on a mg/m 2 basis.
• In a published study, gabapentin (400 mg/kg/day) was administered by intraperitoneal injection to neonatal mice during the first postnatal week, a period of synaptogenesis in rodents (corresponding to the last trimester of pregnancy in humans).
• Gabapentin caused a marked decrease in neuronal synapse formation in brains of intact mice and abnormal neuronal synapse formation in a mouse model of synaptic repair.
• Gabapentin has been shown in vitro to interfere with activity of the α2δ subunit of voltage-activated calcium channels, a receptor involved in neuronal synaptogenesis.
• The clinical significance of these findings is unknown.
• Risk Summary Gabapentin is secreted in human milk following oral administration.
• The effects on the breastfed infant and on milk production are unknown.
• The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for gabapentin and any potential adverse effects on the breastfed infant from gabapentin or from the underlying maternal condition.
• IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1)
• 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as gabapentin, during pregnancy.
• Encourage women who are taking gabapentin during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/ .
• Risk Summary There are no adequate data on the developmental risks associated with the use of gabapentin in pregnant women.
• In nonclinical studies in mice, rats, and rabbits, gabapentin was developmentally toxic (increased fetal skeletal and visceral abnormalities, and increased embryofetal mortality) when administered to pregnant animals at doses similar to or lower than those used clinically [see Data].
• In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 % to 4% and 15% to 20%, respectively.
• The background risk of major birth defects and miscarriage for the indicated population is unknown.
• Data Animal data When pregnant mice received oral doses of gabapentin (500 mg, 1,000 mg, or 3,000 mg/kg/day) during the period of organogenesis, embryofetal toxicity (increased incidences of skeletal variations) was observed at the two highest doses.
• The no-effect dose for embryofetal developmental toxicity in mice (500 mg/kg/day) is less than the maximum recommended human dose (MRHD) of 3,600 mg on a body surface area (mg/m 2 ) basis.
• In studies in which rats received oral doses of gabapentin (500 mg to 2,000 mg/kg/day) during pregnancy, adverse effect on offspring development (increased incidences of hydroureter and/or hydronephrosis) were observed at all doses.
• The lowest dose tested is similar to the MRHD on a mg/m 2 basis.
• When pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryo-fetal mortality was observed at all doses tested (60 mg, 300 mg, or 1,500 mg/kg).
• The lowest dose tested is less than the MRHD on a mg/m 2 basis.
• In a published study, gabapentin (400 mg/kg/day) was administered by intraperitoneal injection to neonatal mice during the first postnatal week, a period of synaptogenesis in rodents (corresponding to the last trimester of pregnancy in humans).
• Gabapentin caused a marked decrease in neuronal synapse formation in brains of intact mice and abnormal neuronal synapse formation in a mouse model of synaptic repair.
• Gabapentin has been shown in vitro to interfere with activity of the α2δ subunit of voltage-activated calcium channels, a receptor involved in neuronal synaptogenesis.
• The clinical significance of these findings is unknown.
• 8.2 Lactation Risk Summary Gabapentin is secreted in human milk following oral administration.
• The effects on the breastfed infant and on milk production are unknown.
• The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for gabapentin and any potential adverse effects on the breastfed infant from gabapentin or from the underlying maternal condition.
• 8.4 Pediatric Use Safety and effectiveness of gabapentin in the management of postherpetic neuralgia in pediatric patients have not been established.
• Safety and effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below the age of 3 years has not been established [see Clinical Studies (14.2) ].
• 8.5 Geriatric Use The total number of patients treated with gabapentin in controlled clinical trials in patients with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%) were 75 years of age and older.
• There was a larger treatment effect in patients 75 years of age and older compared to younger patients who received the same dosage.
• Since gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients ≥ 75 years may be a consequence of increased gabapentin exposure for a given dose that results from an age-related decrease in renal function.
• However, other factors cannot be excluded.
• The types and incidence of adverse reactions were similar across age groups except for peripheral edema and ataxia, which tended to increase in incidence with age.
• Clinical studies of gabapentin in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects.
• Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
• In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
• This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.
• Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and dose should be adjusted based on creatinine clearance values in these patients [see Dosage and Administration (2.4) , Adverse Reactions (6) , and Clinical Pharmacology (12.3) ].
• 8.6 Renal Impairment Dosage adjustment in adult patients with compromised renal function is necessary [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ].
• Pediatric patients with renal insufficiency have not been studied.
• Dosage adjustment in patients undergoing hemodialysis is necessary [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ].

• Concentrations increased by morphine; may need dose adjustment ( 5.4 , 7.1 )
• 7.1 Opioids Respiratory depression and sedation, sometimes resulting in death, have been reported following co-administration of gabapentin with opioids (e.g., morphine, hydrocodone, oxycodone, buprenorphine) [see Warnings and Precautions (5.7) ] .
• Hydrocodone Co-administration of gabapentin with hydrocodone decreases hydrocodone exposure [see Clinical Pharmacology (12.3) ] .
• The potential for alteration in hydrocodone exposure and effect should be considered when gabapentin is started or discontinued in a patient taking hydrocodone.
• Morphine When gabapentin is administered with morphine, patients should be observed for signs of CNS depression, such as somnolence, sedation and respiratory depression [see Clinical Pharmacology (12.3) ].
• 7.2 Other Antiepileptic Drugs Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly co-administered antiepileptic drugs [see Clinical Pharmacology (12.3) ] .
• 7.3 Maalox ® (aluminum hydroxide, magnesium hydroxide) The mean bioavailability of gabapentin was reduced by about 20% with concomitant use of an antacid (Maalox ® ) containing magnesium and aluminum hydroxides.
• It is recommended that gabapentin be taken at least 2 hours following Maalox administration [see Clinical Pharmacology (12.3) ].
• 7.4 Drug/Laboratory Test Interactions Because false positive readings were reported with the Ames N-Multistix SG ® dipstick test for urinary protein when gabapentin was added to other antiepileptic drugs, the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein.

• Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation.
• Acute oral overdoses of gabapentin have been reported.
• Symptoms have included double vision, tremor, slurred speech, drowsiness, altered mental status, dizziness, lethargy, and diarrhea.
• Fatal respiratory depression has been reported with gabapentin overdose, alone and in combination with other CNS depressants.
• Gabapentin can be removed by hemodialysis.
• If overexposure occurs, call your poison control center at 1-800-222-1222.

• 9.1 Controlled Substance Gabapentin is not a scheduled drug.
• 9.2 Abuse Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.
• Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed.
• Gabapentin does not exhibit affinity for benzodiazepine, opioid (mu, delta or kappa), or cannabinoid 1 receptor sites.
• Gabapentin misuse and abuse have been reported in the postmarketing setting and published literature.
• Most of the individuals described in these reports had a history of polysubstance abuse.
• Some of these individuals were taking higher than recommended doses of gabapentin for unapproved uses.
• When prescribing gabapentin carefully evaluate patients for a history of drug abuse and observe them for signs and symptoms of gabapentin misuse or abuse (e.g., self-dose escalation and drug-seeking behavior).
• The abuse potential of gabapentin has not been evaluated in human studies.
• 9.3 Dependence Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.
• There are rare postmarketing 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 approved.
• Such symptoms included agitation, disorientation and confusion after suddenly discontinuing gabapentin that resolved after restarting gabapentin.
• The dependence potential of gabapentin has not been evaluated in human studies.
• Gabapentin is not a scheduled drug.