Gabapentin: Package Insert and Label Information (Page 3 of 4)

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

Psychiatric disorders: agitation

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)], bullous pemphigoid , erythema multiforme, Stevens-Johnson syndrome.

There are postmarketing reports of life-threatening or fatal respiratory depression in patients taking gabapentin with opioids or other CNS depressants, or in the setting of underlying respiratory impairment [see Warnings and Precautions ( 5.7)].

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 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 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.

8 USE IN SPECIFIC POPULATIONS

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, 1000, or 3000 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 3600 mg on a body surface area (mg/m 2) 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 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 embryofetal mortality was observed at all doses tested (60, 300, or 1500 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)] .

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).

9.3 Dependence

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. Most of these individuals had a history of poly-substance abuse or used gabapentin to relieve symptoms of withdrawal from other substances. The dependence and abuse potential of gabapentin has not been evaluated in human studies.

10 OVERDOSAGE

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.

11 DESCRIPTION

The active ingredient in gabapentin capsules is gabapentin, which has the chemical name 1-(aminomethyl) cyclohexaneacetic acid. The molecular formula of gabapentin is C9H17NO2 and the molecular weight is 171.24. The structural formula of gabapentin is:
gabapentin-struc

Gabapentin is a white to off-white crystalline solid with a pKa1 of 3.7 and a pKa2 of 10.7. It is freely soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is –1.25

Each gabapentin capsule contains 100 mg, 300 mg, or 400 mg of gabapentin and the following inactive ingredients: anhydrous lactose, cornstarch, and talc. The 100 mg capsule shell contains gelatin, sodium lauryl sulfate, and titanium dioxide. The 300 mg capsule shell contains gelatin, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide. The 400 mg capsule shell contains gelatin, sodium lauryl sulfate, red iron oxide, titanium dioxide, and yellow iron oxide. The imprinting ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propyl glycol, strong ammonia solution, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The precise mechanisms by which gabapentin produces its analgesic and antiepileptic actions are unknown. Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but has no effect on GABA binding, uptake, or degradation. In vitro studies have shown that gabapentin binds with high-affinity to the α2δ subunit of voltage-activated calcium channels; however, the relationship of this binding to the therapeutic effects of gabapentin is unknown.

12.3 Pharmacokinetics

All pharmacological actions following gabapentin administration are due to the activity of the parent compound; gabapentin is not appreciably metabolized in humans.

Oral Bioavailability

Gabapentin bioavailability is not dose proportional; i.e., as dose is increased, bioavailability decreases. Bioavailability of gabapentin is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided doses, respectively. Food has only a slight effect on the rate and extent of absorption of gabapentin (14% increase in AUC and C max ).

Distribution

Less than 3% of gabapentin circulates bound to plasma protein. The apparent volume of distribution of gabapentin after 150 mg intravenous administration is 58±6 L (mean ±SD). In patients with epilepsy, steady-state predose (Cmin) concentrations of gabapentin in cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations.

Elimination

Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug. Gabapentin is not appreciably metabolized in humans.

Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance. In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin can be removed from plasma by hemodialysis.

Specific Populations

Age

The effect of age was studied in subjects 20-80 years of age. Apparent oral clearance (CL/F) of gabapentin decreased as age increased, from about 225 mL/min in those under 30 years of age to about 125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr adjusted for body surface area also declined with age; however, the decline in the renal clearance of gabapentin with age can largely be explained by the decline in renal function. [see Dosage and Administration (2.4) and Use in Specific Populations (8.5)] .

Gender

Although no formal study has been conducted to compare the pharmacokinetics of gabapentin in men and women, it appears that the pharmacokinetic parameters for males and females are similar and there are no significant gender differences.

Race

Pharmacokinetic differences due to race have not been studied. Because gabapentin is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected.

Pediatric

Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the ages of 1 month and 12 years following a dose of approximately 10 mg/kg. Peak plasma concentrations were similar across the entire age group and occurred 2 to 3 hours postdose. In general, pediatric subjects between 1 month and <5 years of age achieved approximately 30% lower exposure (AUC) than that observed in those 5 years of age and older. Accordingly, oral clearance normalized per body weight was higher in the younger children. Apparent oral clearance of gabapentin was directly proportional to creatinine clearance. Gabapentin elimination half-life averaged 4.7 hours and was similar across the age groups studied.

A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month and 13 years of age. Patients received 10 to 65 mg/kg/day given three times a day. Apparent oral clearance (CL/F) was directly proportional to creatinine clearance and this relationship was similar following a single dose and at steady-state. Higher oral clearance values were observed in children <5 years of age compared to those observed in children 5 years of age and older, when normalized per body weight. The clearance was highly variable in infants <1 year of age. The normalized CL/F values observed in pediatric patients 5 years of age and older were consistent with values observed in adults after a single dose. The oral volume of distribution normalized per body weight was constant across the age range.

These pharmacokinetic data indicate that the effective daily dose in pediatric patients with epilepsy ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations similar to those achieved in patients 5 years of age and older receiving gabapentin at 30 mg/kg/day [see Dosage and Administration (2.2)].

Adult Patients with Renal Impairment

Subjects (N=60) with renal impairment (mean creatinine clearance ranging from 13-114 mL/min) were administered single 400 mg oral doses of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours (patients with creatinine clearance >60 mL/min) to 52 hours (creatinine clearance <30 mL/min) and gabapentin renal clearance from about 90 mL/min (>60 mL/min group) to about 10 mL/min (<30 mL/min). Mean plasma clearance (CL/F) decreased from approximately 190 mL/min to 20 mL/min [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)] . Pediatric patients with renal insufficiency have not been studied.

Hemodialysis

In a study in anuric adult subjects (N=11), the apparent elimination half-life of gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin elimination in anuric subjects [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)] .

Hepatic Disease

Because gabapentin is not metabolized, no study was performed in patients with hepatic impairment.

Drug Interactions

In Vitro Studies

In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations. Only at the highest concentration tested (171 mcg/mL; 1 mM) was a slight degree of inhibition (14% to 30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 mcg/mL (approximately 15 times the C max at 3600 mg/day).

· In Vivo Studies

The drug interaction data described in this section were obtained from studies involving healthy adults and adult patients with epilepsy.

Phenytoin

In a single (400 mg) and multiple dose (400 mg three times a day) study of gabapentin in epileptic patients (N=8) maintained on phenytoin monotherapy for at least 2 months, gabapentin had no effect on the steady-state trough plasma concentrations of phenytoin and phenytoin had no effect on gabapentin pharmacokinetics.

Carbamazepine

Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide concentrations were not affected by concomitant gabapentin (400 mg three times a day; N=12) administration. Likewise, gabapentin pharmacokinetics were unaltered by carbamazepine administration.

Valproic Acid

The mean steady-state trough serum valproic acid concentrations prior to and during concomitant gabapentin administration (400 mg three times a day; N=17) were not different and neither were gabapentin pharmacokinetic parameters affected by valproic acid.

Phenobarbital

Estimates of steady-state pharmacokinetic parameters for phenobarbital or gabapentin (300 mg three times a day; N=12) are identical whether the drugs are administered alone or together.

Naproxen

Coadministration (N=18) of naproxen sodium capsules (250 mg) with gabapentin (125 mg) appears to increase the amount of gabapentin absorbed by 12% to 15%. Gabapentin had no effect on naproxen pharmacokinetic parameters. These doses are lower than the therapeutic doses for both drugs. The magnitude of interaction within the recommended dose ranges of either drug is not known.

Hydrocodone

Coadministration of gabapentin (125 to 500 mg; N=48) decreases hydrocodone (10 mg; N=50) C max and AUC values in a dose-dependent manner relative to administration of hydrocodone alone; C max and AUC values are 3% to 4% lower, respectively, after administration of 125 mg gabapentin and 21% to 22% lower, respectively, after administration of 500 mg gabapentin. The mechanism for this interaction is unknown. Hydrocodone increases gabapentin AUC values by 14%. The magnitude of interaction at other doses is not known.

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. 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.

Cimetidine

In the presence of cimetidine at 300 mg four times a day(N=12), the mean apparent oral clearance of gabapentin fell by 14% and creatinine clearance fell by 10%. Thus, cimetidine appeared to alter the renal excretion of both gabapentin and creatinine, an endogenous marker of renal function. This small decrease in excretion of gabapentin by cimetidine is not expected to be of clinical importance. The effect of gabapentin on cimetidine was not evaluated.

Oral Contraceptive

Based on AUC and half-life, multiple-dose pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of tablets containing 2.5 mg of norethindrone acetate and 50 mcg of ethinyl estradiol were similar with and without coadministration of gabapentin (400 mg three times a day; N=13). The C max of norethindrone was 13% higher when it was coadministered with gabapentin; this interaction is not expected to be of clinical importance.

Antacid (Maalox ®) (aluminum hydroxide, magnesium hydroxide)

Antacid (Maalox ® ) containing magnesium and aluminum hydroxides reduced the mean bioavailability of gabapentin (N=16) by about 20%. This decrease in bioavailability was about 10% when gabapentin was administered 2 hours after Maalox.

Probenecid

Probenecid is a blocker of renal tubular secretion. Gabapentin pharmacokinetic parameters without and with probenecid were comparable. This indicates that gabapentin does not undergo renal tubular secretion by the pathway that is blocked by probenecid.

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