Gabapentin (Page 4 of 8)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of gabapentin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hepatobiliary disorders: jaundice Investigations: elevated creatine kinase, elevated liver function tests Metabolism and nutrition disorders: hyponatremia

Musculoskeletal and connective tissue disorder: rhabdomyolysis

Nervous system disorders: movement disorder Reproductive system and breast disorders: breast enlargement, changes in libido, ejaculation disorders and anorgasmia

Skin and subcutaneous tissue disorders: angioedema [see Warnings and Precautions (5.2)], erythema multiforme, Stevens-Johnson syndrome.

Adverse reactions following the abrupt discontinuation of gabapentin have also been reported. The most frequently reported reactions were anxiety, insomnia, nausea, pain, and sweating.

7 DRUG INTERACTIONS

7.1 Other Antiepileptic Drugs

Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs [see Clinical Pharmacology (12.3)].

7.2 Opioids

Hydrocodone

Coadministration 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 central nervous system (CNS) depression, such as somnolence, sedation and respiratory depression [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 withthe Ames N-Multistix SG® dipstick test for urinary protein whengabapentin was added to other antiepileptic drugs, the more specificsulfosalicylic acid precipitation procedure is recommended to determine thepresence of urine protein.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

PregnancyCategory C: There are noadequate and well-controlled studies in pregnant women. In nonclinical studiesin mice, rats, and rabbits, gabapentin was developmentally toxic whenadministered to pregnant animals at doses similar to or lower than those usedclinically. Gabapentin should be used during pregnancy only if the potentialbenefit justifies the potential risk to the fetus.

When pregnantmice received oral doses of gabapentin (500, 1000, or 3000 mg/kg/day) duringthe period of organogenesis, embryo-fetal toxicity (increased incidences ofskeletal variations) was observed at the two highest doses. The no-effect dosefor embryo-fetal developmental toxicity in mice was 500 mg/kg/day orapproximately ½ of the maximum recommended human dose (MRHD) of 3600 mg/kg on abody surface area (mg/m2) basis.

In studies in which rats received oral doses of gabapentin (500 to 2000 mg/Kg/day) during pregnancy,adverse effect on offspring development (increased incidences of hydroureterand/or hydronephrosis) were observed at all doses. The lowest effect dose fordevelopmental toxicity in rats is approximately equal to the MRHD on a mg/m2 basis.

When pregnantrabbits were treated with gabapentin during the period of organogenesis, anincrease in embryo-fetal mortality was observed at all doses tested (60, 300,or 1500 mg/kg). The lowest effect dose for embryo-fetal developmental toxicityin rabbits is less than the MRHD on a mg/m2 basis.

In a publishedstudy, gabapentin (400 mg/kg/day) was administered by intraperitoneal injectionto neonatal mice during the first postnatal week, a period of synaptogenesis inrodents (corresponding to the last trimester of pregnancy in humans).Gabapentin caused a marked decrease in neuronal synapse formation in brains ofintact mice and abnormal neuronal synapse formation in a mouse model ofsynaptic repair. Gabapentin has been shown in vitro to interfere withactivity of the α2δ subunit of voltage-activated calcium channels, a receptorinvolved in neuronal synaptogenesis. The clinical significance of thesefindings is unknown.

To provide information regarding the effects of in utero exposureto gabapentin, physicians are advised to recommend that pregnant patientstaking gabapentin enroll in the North American Antiepileptic Drug (NAAED)Pregnancy Registry. This can be done by calling the toll free number1-888-233-2334, and must be done by patients themselves. Information on theregistry can also be found at the website http://www.aedpregnancyregistry.org/.

8.3 Nursing Mothers

Gabapentin is secreted into human milk following oral administration. A nursed infant could be exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on the nursing infant is unknown, gabapentin should be used in women who are nursing only if the benefits clearly outweigh the risks.

8.4 Pediatric Use

Safety and effectiveness of gabapentin in the management of postherpetic neuralgia in pediatric patients have not been established.

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 with 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)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Gabapentin is not a scheduled drug.

9.2 Abuse

Gabapentin does not exhibit affinity for benzodiazepine, opiate (mu, delta or kappa), or cannabinoid 1 receptor sites. A small number of postmarketing cases report gabapentin misuse and abuse. 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 poly-substance abuse or used gabapentin to relieve symptoms of withdrawal from other substances. 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. development of tolerance, self-dose escalation, and drug-seeking behavior).

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