GABAPENTIN tablet film coated

United States - English - NLM (National Library of Medicine)

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Active ingredient:
GABAPENTIN (UNII: 6CW7F3G59X) (GABAPENTIN - UNII:6CW7F3G59X)
Available from:
St Marys Medical Park Pharmacy
INN (International Name):
GABAPENTIN
Composition:
GABAPENTIN 800 mg
Prescription type:
PRESCRIPTION DRUG
Authorization status:
Abbreviated New Drug Application

GABAPENTIN- gabapentin tablet, film coated

St Marys Medical Park Pharmacy

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GABAPENTIN TABLETS, USP

DESCRIPTION

Gabapentin Tablets, USP are supplied as elliptical film-coated tablets containing 600 mg and 800 mg of

gabapentin.

The inactive ingredients are: calcium stearate, crospovidone, hydroxypropyl cellulose, hypromellose,

polyethylene glycol and titanium dioxide. The 600 mg tablet also contains FD&C blue #2 aluminum lake

and synthetic yellow iron oxide. The 800 mg tablet also contains synthetic black iron oxide.

Gabapentin is described as 1-(aminomethyl) cyclohexane-acetic acid with a molecular formula of C

and a molecular weight of 171.24. The structural formula of gabapentin is:

Gabapentin is a white to off-white crystalline solid with a pKa

of 3.7 and a pKa

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.

CLINICAL PHARMACOLOGY

Mechanism Of Action

The mechanism by which gabapentin exerts its analgesic action is unknown, but in animal models of

analgesia, gabapentin prevents allodynia (pain-related behavior in response to a normally innocuous

stimulus) and hyperalgesia (exaggerated response to painful stimuli). In particular, gabapentin prevents

pain-related responses in several models of neuropathic pain in rats or mice (e.g. spinal nerve ligation

models, streptozocin-induced diabetes model, spinal cord injury model, acute herpes zoster infection

model). Gabapentin also decreases pain-related responses after peripheral inflammation (carrageenan

footpad test, late phase of formalin test). Gabapentin did not alter immediate pain-related behaviors (rat

tail flick test, formalin footpad acute phase, acetic acid abdominal constriction test, footpad heat

irradiation test). The relevance of these models to human pain is not known.

The mechanism by which gabapentin exerts its anticonvulsant action is unknown, but in animal test

systems designed to detect anticonvulsant activity, gabapentin prevents seizures as do other marketed

anticonvulsants. Gabapentin exhibits antiseizure activity in mice and rats in both the maximal

electroshock and pentylenetetrazole seizure models and other preclinical models (e.g., strains with

genetic epilepsy, etc.). The relevance of these models to human epilepsy is not known.

Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but it does

not modify GABA

or GABA

radioligand binding, it is not converted metabolically into GABA or a

GABA agonist, and it is not an inhibitor of GABA uptake or degradation. Gabapentin was tested in

radioligand binding assays at concentrations up to 100 μM and did not exhibit affinity for a number of

other common receptor sites, including benzodiazepine, glutamate, N-methyl-D-aspartate (NMDA),

quisqualate, kainate, strychnine-insensitive or strychnine-sensitive glycine, alpha 1, alpha 2, or beta

adrenergic, adenosine A1 or A2, cholinergic muscarinic or nicotinic, dopamine D1 or D2, histamine

H1, serotonin S1 or S2, opiate mu, delta or kappa, cannabinoid 1, voltage-sensitive calcium channel sites

labeled with nitrendipine or diltiazem, or at voltage-sensitive sodium channel sites labeled with

batrachotoxinin A 20-alpha-benzoate. Furthermore, gabapentin did not alter the cellular uptake of

dopamine, noradrenaline, or serotonin.

In vitro studies with radiolabeled gabapentin have revealed a gabapentin binding site in areas of rat brain

including neocortex and hippocampus. A high-affinity binding protein in animal brain tissue has been

identified as an auxiliary subunit of voltage-activated calcium channels. However, functional correlates

of gabapentin binding, if any, remain to be elucidated.

Pharmacokinetics And Drug Metabolism

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

Dis tribution

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 (C

) 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 (see Special Populations: Adult Patients With Renal Insufficiency, below). In

elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced.

Gabapentin can be removed from plasma by hemodialysis.

Dosage adjustment in patients with compromised renal function or undergoing hemodialysis is

recommended (see DOSAGE AND ADMINISTRATION, Table 6).

Special Populations

Adult Patients With Renal Insufficiency: Subjects (N=60) with renal insufficiency (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.

Dosage adjustment in adult patients with compromised renal function is necessary (see DOSAGE AND

ADMINISTRATION). 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.

Dosage adjustment in patients undergoing hemodialysis is necessary (see DOSAGE AND

ADMINISTRATION).

Hepatic Disease:

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

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. Reduction of gabapentin dose may be required in

patients who have age related compromised renal function. (See PRECAUTIONS, Geriatric Use, and

DOSAGE AND ADMINISTRATION.)

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 TID. 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).

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.

Clinical Studies

Postherpetic Neuralgia:

Gabapentin was evaluated for the management of postherpetic neuralgia (PHN) in 2 randomized, double-

blind, placebo-controlled, multicenter studies; N=563 patients in the intent-to-treat (ITT) population

(Table 1). Patients were enrolled if they continued to have pain for more than 3 months after healing of

the herpes zoster skin rash.

TABLE 1. Controlled PHN Studies; Duration,

Dosages, and Number of Patients

Study Study

Duration

Gabapentin

(mg/day)

Target Dose

Patients

Receiving

Gabapentin

Patients

Receiving

Placebo

Given in 3 divided doses (TID)

8 weeks

3600

7 weeks 1800, 2400

Total

Each study included a 1-week baseline during which patients were screened for eligibility and a 7- or

8-week double-blind phase (3 or 4 weeks of titration and 4 weeks of fixed dose). Patients initiated

treatment with titration to a maximum of 900 mg/day gabapentin over 3 days. Dosages were then to be

titrated in 600 to 1200 mg/day increments at 3- to 7-day intervals to target dose over 3 to 4 weeks. In

Study 1, patients were continued on lower doses if not able to achieve the target dose. During baseline

and treatment, patients recorded their pain in a daily diary using an 11-point numeric pain rating scale

ranging from 0 (no pain) to 10 (worst possible pain). A mean pain score during baseline of at least 4 was

required for randomization (baseline mean pain score for Studies 1 and 2 combined was 6.4). Analyses

were conducted using the ITT population (all randomized patients who received at least one dose of

study medication).

Both studies showed significant differences from placebo at all doses tested.

A significant reduction in weekly mean pain scores was seen by Week 1 in both studies, and significant

differences were maintained to the end of treatment. Comparable treatment effects were observed in all

active treatment arms. Pharmacokinetic/pharmacodynamic modeling provided confirmatory evidence of

efficacy across all doses. Figures 1 and 2 show these changes for Studies 1 and 2.

The proportion of responders (those patients reporting at least 50% improvement in endpoint pain score

compared with baseline) was calculated for each study (Figure 3).

Epilepsy:

The effectiveness of gabapentin as adjunctive therapy (added to other antiepileptic drugs) was

established in multicenter placebo-controlled, double-blind, parallel-group clinical trials in adult and

pediatric patients (3 years and older) with refractory partial seizures.

Evidence of effectiveness was obtained in three trials conducted in 705 patients (age 12 years and

above) and one trial conducted in 247 pediatric patients (3 to 12 years of age). The patients enrolled had

a history of at least 4 partial seizures per month in spite of receiving one or more antiepileptic drugs at

therapeutic levels and were observed on their established antiepileptic drug regimen during a 12-week

baseline period (6 weeks in the study of pediatric patients). In patients continuing to have at least 2 (or 4

in some studies) seizures per month, gabapentin or placebo was then added on to the existing therapy

during a 12-week treatment period. Effectiveness was assessed primarily on the basis of the percent of

patients with a 50% or greater reduction in seizure frequency from baseline to treatment (the "responder

rate") and a derived measure called response ratio, a measure of change defined as (T - B)/(T + B),

where B is the patient’s baseline seizure frequency and T is the patient’s seizure frequency during

treatment. Response ratio is distributed within the range -1 to +1. A zero value indicates no change

while complete elimination of seizures would give a value of -1; increased seizure rates would give

positive values. A response ratio of -0.33 corresponds to a 50% reduction in seizure frequency. The

results given below are for all partial seizures in the intent-to-treat (all patients who received any doses

of treatment) population in each study, unless otherwise indicated.

One study compared gabapentin 1200 mg/day divided TID with placebo. Responder rate was 23%

(14/61) in the gabapentin group and 9% (6/66) in the placebo group; the difference between groups was

statistically significant. Response ratio was also better in the gabapentin group (-0.199) than in the

placebo group (-0.044), a difference that also achieved statistical significance.

A second study compared primarily 1200 mg/day divided TID gabapentin (N=101) with placebo

(N=98). Additional smaller gabapentin dosage groups (600 mg/day, N=53; 1800 mg/day, N=54) were

also studied for information regarding dose response. Responder rate was higher in the gabapentin

1200 mg/day group (16%) than in the placebo group (8%), but the difference was not statistically

significant. The responder rate at 600 mg (17%) was also not significantly higher than in the placebo,

but the responder rate in the 1800 mg group (26%) was statistically significantly superior to the

placebo rate. Response ratio was better in the gabapentin 1200 mg/day group (-0.103) than in the

placebo group (-0.022); but this difference was also not statistically significant (p = 0.224). A better

response was seen in the gabapentin 600 mg/day group (-0.105) and 1800 mg/day group (-0.222) than in

the 1200 mg/day group, with the 1800 mg/day group achieving statistical significance compared to the

placebo group.

A third study compared gabapentin 900 mg/day divided TID (N=111) and placebo (N=109). An

additional gabapentin 1200 mg/day dosage group (N=52) provided dose-response data. A statistically

significant difference in responder rate was seen in the gabapentin 900 mg/day group (22%) compared

to that in the placebo group (10%). Response ratio was also statistically significantly superior in the

gabapentin 900 mg/day group (-0.119) compared to that in the placebo group (-0.027), as was response

ratio in 1200 mg/day gabapentin (-0.184) compared to placebo.

Analyses were also performed in each study to examine the effect of gabapentin on preventing

secondarily generalized tonic-clonic seizures. Patients who experienced a secondarily generalized

tonic-clonic seizure in either the baseline or in the treatment period in all three placebo-controlled

studies were included in these analyses. There were several response ratio comparisons that showed a

statistically significant advantage for gabapentin compared to placebo and favorable trends for almost

all comparisons.

Analysis of responder rate using combined data from all three studies and all doses (N=162, gabapentin

; N=89, placebo) also showed a significant advantage for gabapentin over placebo in reducing the

frequency of secondarily generalized tonic-clonic seizures.

In two of the three controlled studies, more than one dose of gabapentin was used. Within each study the

results did not show a consistently increased response to dose. However, looking across studies, a

trend toward increasing efficacy with increasing dose is evident (see Figure 4).

In the figure, treatment effect magnitude, measured on the Y axis in terms of the difference in the

proportion of gabapentin and placebo assigned patients attaining a 50% or greater reduction in seizure

frequency from baseline, is plotted against the daily dose of gabapentin administered

(X axis).

Although no formal analysis by gender has been performed, estimates of response (Response Ratio)

derived from clinical trials (398 men, 307 women) indicate no important gender differences exist. There

was no consistent pattern indicating that age had any effect on the response to gabapentin. There were

insufficient numbers of patients of races other than Caucasian to permit a comparison of efficacy among

racial groups.

A fourth study in pediatric patients age 3 to 12 years compared 25-35 mg/kg/day gabapentin (N=118)

with placebo (N=127). For all partial seizures in the intent-to-treat population, the response ratio was

statistically significantly better for the gabapentin group (-0.146) than for the placebo group (-0.079).

For the same population, the responder rate for gabapentin (21%) was not significantly different from

placebo (18%).

A study in pediatric patients age 1 month to 3 years compared 40 mg/kg/day gabapentin (N=38) with

placebo (N=38) in patients who were receiving at least one marketed antiepileptic drug and had at least

one partial seizure during the screening period (within 2 weeks prior to baseline). Patients had up to 48

hours of baseline and up to 72 hours of double-blind video EEG monitoring to record and count the

occurrence of seizures. There were no statistically significant differences between treatments in either

the response ratio or responder rate.

INDICATIONS AND USAGE

Postherpetic Neuralgia

Gabapentin is indicated for the management of postherpetic neuralgia in adults.

Epileps y

Gabapentin is indicated as adjunctive therapy in the treatment of partial seizures with and without

secondary generalization in patients over 12 years of age with epilepsy.

Gabapentin is also indicated as adjunctive therapy in the treatment of partial seizures in pediatric patients

age 3-12 years.

CONTRAINDICATIONS

Gabapentin is contraindicated in patients who have demonstrated hypersensitivity to the drug or its

ingredients.

WARNINGS

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including gabapentin tablets, 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 (5-100 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

analys is

Indication

Placebo

Patients

with Events

Per 1000

Patients

Drug Patients

with Events

Per 1000

Patients

Relative Risk:

Incidence of

Events in Drug

Patients/Incidence

in Placebo

Patients

Risk

Difference:

Additional

Drug Patients

with Events

Per 1000

Patients

Epilepsy

Psychiatric

Other

Total

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 tablets 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.

Neuropsychiatric Adverse Events—Pediatric Patients 3-12 years of age: Gabapentin use in

pediatric patients with epilepsy 3-12 years of age is associated with the occurrence of central nervous

system related adverse events. 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 events were mild to moderate in intensity.

In controlled trials in pediatric patients 3-12 years of age, the incidence of these adverse events was:

emotional lability 6% (gabapentin-treated patients) vs 1.3% (placebo-treated patients); hostility 5.2% vs

1.3%; hyperkinesia 4.7% vs 2.9%; and thought disorder 1.7% vs 0%. One of these events, 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.

Withdrawal Precipitated Seizure, Status Epilepticus: Antiepileptic drugs should not be abruptly

discontinued because of the possibility of increasing seizure frequency.

In the placebo-controlled 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 2074 patients >12 years of age treated with gabapentin across all 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.

Tumorigenic Potential: In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly

high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. (See

PRECAUTIONS: Carcinogenesis,Mutagenesis, Impairment of Fertility.) 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 2085 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 pre-existing 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.

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 2203

patients treated (2103 patient-years of exposure).

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.

PRECAUTIONS

Information for Patients

Patients should be instructed to take gabapentin only as prescribed.

Patients, their caregivers, and families should be counseled that AEDs, including gabapentin, may

increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the

emergence or worsening of 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

Patients should be advised that gabapentin tablets may cause dizziness, somnolence and other symptoms

and signs of CNS depression. Accordingly, they should be advised neither to drive a car nor to operate

other complex machinery until they have gained sufficient experience on gabapentin to gauge whether

or not it affects their mental and/or motor performance adversely.

Patients who require concomitant treatment with morphine may experience increases in gabapentin

concentrations. Patients should be carefully observed for signs of CNS depression, such as

somnolence, and the dose of gabapentin or morphine should be reduced appropriately (see Drug

Interactions).

Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy

Registry if they become pregnant. This registry is collecting information about the safety of

antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334

(see PRECAUTIONS: Pregnancy section).

Laboratory Tests

Clinical trials data do not indicate that routine monitoring of clinical laboratory parameters is necessary

for the safe use of gabapentin. The value of monitoring gabapentin blood concentrations has not been

established. Gabapentin may be used in combination with other antiepileptic drugs without concern for

alteration of the blood concentrations of gabapentin or of other antiepileptic drugs.

Drug Interactions

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 μg/mL; 1 mM) was a slight degree of

inhibition (14%-30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested

was observed at gabapentin concentrations up to 171 μg/mL (approximately 15 times the C

at 3600

mg/day).

Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly

coadministered antiepileptic drugs.

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 TID) 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 TID; 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 TID; 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 TID; 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

and AUC values in a dose-dependent manner relative to administration of hydrocodone

alone; C

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 (see PRECAUTIONS). 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 QID (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 Contraceptives: 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 TID; N=13). The C

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 and Magnesium Hydroxide Suspension): Maalox® (Aluminum

Hydroxide and Magnesium Hydroxide Suspension) reduced the bioavailability of gabapentin (N=16) by

about 20%. This decrease in bioavailability was about 5% when gabapentin was administered 2 hours

after Maalox® (Aluminum Hydroxide and Magnesium Hydroxide Suspension). It is recommended that

gabapentin be taken at least 2 hours following Maalox® (Aluminum Hydroxide and Magnesium

Hydroxide Suspension) administration.

Effect Of 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.

Drug/Laboratory Tests 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250, 1000, and

2000 mg/kg/day for 2 years. A statistically significant increase in the incidence of pancreatic acinar cell

adenomas and carcinomas was found in male rats receiving the high dose; the no-effect dose for the

occurrence of carcinomas was 1000 mg/kg/day. Peak plasma concentrations of gabapentin in rats

receiving the high dose of 2000 mg/kg were 10 times higher than plasma concentrations in humans

receiving 3600 mg per day, and in rats receiving 1000 mg/kg/day peak plasma concentrations were 6.5

times higher than in humans receiving 3600 mg/day. The pancreatic acinar cell carcinomas did not affect

survival, did not metastasize and were not locally invasive. The relevance of this finding to

carcinogenic risk in humans is unclear.

Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis in rats

indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro and, thus, may be

acting as a tumor promoter by enhancing mitogenic activity. It is not known whether gabapentin has the

ability to increase cell proliferation in other cell types or in other species, including humans.

Gabapentin did not demonstrate mutagenic or genotoxic potential in three in vitro and four in vivo assays.

It was negative in the Ames test and the in vitro HGPRT forward mutation assay in Chinese hamster lung

cells; it did not produce significant increases in chromosomal aberrations in the in vitro Chinese hamster

lung cell assay; it was negative in the in vivo chromosomal aberration assay and in the in vivo

micronucleus test in Chinese hamster bone marrow; it was negative in the in vivo mouse micronucleus

assay; and it did not induce unscheduled DNA synthesis in hepatocytes from rats given gabapentin.

No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg

(approximately 5 times the maximum recommended human dose on a mg/m

basis).

Pregnancy

Pregnancy Category C: Gabapentin has been shown to be fetotoxic in rodents, causing delayed

ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. These effects occurred

when pregnant mice received oral doses of 1000 or 3000 mg/kg/day during the period of

organogenesis, or approximately 1 to 4 times the maximum dose of 3600 mg/day given to epileptic

patients on a mg/m

basis. The no-effect level was 500 mg/kg/day or approximately ½ of the human

dose on a mg/m

basis.

When rats were dosed prior to and during mating, and throughout gestation, pups from all dose groups

(500, 1000 and 2000 mg/kg/day) were affected. These doses are equivalent to less than approximately 1

to 5 times the maximum human dose on a mg/m

basis. There was an increased incidence of hydroureter

and/or hydronephrosis in rats in a study of fertility and general reproductive performance at 2000

mg/kg/day with no effect at 1000 mg/kg/day, in a teratology study at 1500 mg/kg/day with no effect at

300 mg/kg/day, and in a perinatal and postnatal study at all doses studied (500, 1000 and 2000

mg/kg/day). The doses at which the effects occurred are approximately 1 to 5 times the maximum human

dose of 3600 mg/day on a mg/m

basis; the no-effect doses were approximately 3 times (Fertility and

General Reproductive Performance study) and approximately equal to (Teratogenicity study) the

maximum human dose on a mg/m

basis. Other than hydroureter and hydronephrosis, the etiologies of

which are unclear, the incidence of malformations was not increased compared to controls in offspring

of mice, rats, or rabbits given doses up to 50 times (mice), 30 times (rats), and 25 times (rabbits) the

human daily dose on a mg/kg basis, or 4 times (mice), 5 times (rats), or 8 times (rabbits) the human daily

dose on a mg/m

basis.

In a teratology study in rabbits, an increased incidence of post implantation fetal loss occurred in dams

exposed to 60, 300 and 1500 mg/kg/day, or less than approximately ¼ to 8 times the maximum human

dose on a mg/m

basis. There are no adequate and well-controlled studies in pregnant women. This

drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

To provide information regarding the effects of in utero exposure to gabapentin, physicians are advised

to recommend that pregnant patients taking 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 website

http://www.aedpregnancyregistry.org/.

Use In 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.

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

PHARMACOLOGY, Clinical Studies).

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 events 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 CLINICAL PHARMACOLOGY, ADVERSE

REACTIONS, and DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS

Postherpetic Neuralgia

The most commonly observed adverse events associated with the use of gabapentin in adults, not seen at

an equivalent frequency among placebo-treated patients, were dizziness, somnolence, and peripheral

edema.

In the 2 controlled studies in postherpetic neuralgia, 16% of the 336 patients who received gabapentin

and 9% of the 227 patients who received placebo discontinued treatment because of an adverse event.

The adverse events that most frequently led to withdrawal in gabapentin-treated patients were dizziness,

somnolence, and nausea.

Incidence In Controlled Clinical Trials:

Table 3 lists treatment-emergent signs and symptoms that occurred in at least 1% of gabapentin treated

patients with postherpetic neuralgia participating in placebo-controlled trials and that were numerically

more frequent in the gabapentin group than in the placebo group. Adverse events were usually mild to

moderate in intensity.

TABLE 3. Treatment-Emergent Adverse Event

Incidence in Controlled Trials in Postherpetic

Neuralgia (Events in at least 1% of Gabapentin-

Treated Patients and Numerically More Frequent

Than in the Placebo Group)

Body System/

Preferred Term

Gabapentin

N=336

Placebo

N=227

Body as a Whole

Asthenia

Infection

Headache

Accidental injury

Abdominal pain

Digestive System

Diarrhea

Dry mouth

Reported as blurred vision

Constipation

Nausea

Vomiting

Flatulence

Metabolic and Nutritional Disorders

Peripheral edema

Weight gain

Hyperglycemia

Nervous System

Dizziness

28.0

Somnolence

21.4

Ataxia

Thinking abnormal

Abnormal gait

Incoordination

Amnesia

Hypesthesia

Respiratory System

Pharyngitis

Skin and Appendages

Rash

Special Senses

Amblyopia

Conjunctivitis

Diplopia

Otitis media

Other events in more than 1% of patients but equally or more frequent in the placebo group included

pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and flu syndrome.

There were no clinically important differences between men and women in the types and incidence of

adverse events. Because there were few patients whose race was reported as other than white, there are

insufficient data to support a statement regarding the distribution of adverse events by race.

Epilepsy:

The most commonly observed adverse events associated with the use of gabapentin in combination with

other antiepileptic drugs in patients >12 years of age, not seen at an equivalent frequency among

placebo-treated patients, were somnolence, dizziness, ataxia, fatigue, and nystagmus. The most

commonly observed adverse events reported with the use of gabapentin in combination with other

antiepileptic drugs in pediatric patients 3 to 12 years of age, not seen at an equal frequency among

placebo-treated patients, were viral infection, fever, nausea and/or vomiting, somnolence, and hostility

(see WARNINGS, Neurospychiatric Adverse Events).

Approximately 7% of the 2074 patients >12 years of age and approximately 7% of the 449 pediatric

patients 3 to 12 years of age who received gabapentin in premarketing clinical trials discontinued

treatment because of an adverse event. The adverse events most commonly associated with withdrawal

in patients >12 years of age were somnolence (1.2%), ataxia (0.8%), fatigue (0.6%), nausea and/or

vomiting (0.6%), and dizziness (0.6%). The adverse events most commonly associated with withdrawal

in pediatric patients were emotional lability (1.6%), hostility (1.3%), and hyperkinesia (1.1%).

Incidence In Controlled Clinical Trials: Table 4 lists treatment-emergent signs and symptoms that

occurred in at least 1% of gabapentin-treated patients >12 years of age with epilepsy participating in

placebo-controlled trials and were numerically more common in the gabapentin group. In these studies,

either gabapentin or placebo was added to the patient’s current antiepileptic drug therapy. Adverse

events were usually mild to moderate in intensity.

The prescriber should be aware that these figures, obtained when gabapentin was added to concurrent

antiepileptic drug therapy, cannot be used to predict the frequency of adverse events in the course of

usual medical practice where patient characteristics and other factors may differ from those prevailing

during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures

obtained from other clinical investigations involving different treatments, uses, or investigators. An

inspection of these frequencies, however, does provide the prescribing physician with one basis to

estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the

population studied.

Table 4. Treatment-Emergent Adverse Event Incidence

in Controlled Add-On Trials in Patients >12 Years of

Age (Events in at Least 1% of Gabapentin Patients and

Numerically More Frequent Than in the Placebo Group)

Body System/ Adverse Event

Gabapentin

N = 543

Placebo

N = 378

Body As A Whole

Fatigue

11.0

Weight Increase

Back Pain

Peripheral Edema

Cardiovascular

Vasodilatation

Digestive System

Dyspepsia

Mouth or Throat Dry

Constipation

Dental Abnormalities

Increased Appetite

Hematologic and Lymphatic Systems

Leukopenia

Musculoskeletal System

Myalgia

Fracture

Nervous System

Somnolence

19.3

Dizziness

17.1

Ataxia

12.5

Nystagmus

Tremor

Nervousness

Dysarthria

Amnesia

Plus background antiepileptic drug therapy

Amblyopia was often described as blurred vision.

Depression

Thinking Abnormal

Twitching

Coordination Abnormal

Respiratory System

Rhinitis

Pharyngitis

Coughing

Skin and Appendages

Abrasion

Pruritus

Urogenital System

Impotence

Special Senses

Diplopia

Amblyopia

Laboratory Deviations

WBC Decreased

Other events in more than 1% of patients >12 years of age but equally or more frequent in the placebo

group included: headache, viral infection, fever, nausea and/or vomiting, abdominal pain, diarrhea,

convulsions, confusion, insomnia, emotional lability, rash, acne.

Among the treatment-emergent adverse events occurring at an incidence of at least 10% of gabapentin

treated patients, somnolence and ataxia appeared to exhibit a positive dose-response relationship.

The overall incidence of adverse events and the types of adverse events seen were similar among men

and women treated with gabapentin. The incidence of adverse events increased slightly with increasing

age in patients treated with either gabapentin or placebo. Because only 3% of patients (28/921) in

placebo-controlled studies were identified as nonwhite (black or other), there are insufficient data to

support a statement regarding the distribution of adverse events by race.

Table 5 lists treatment-emergent signs and symptoms that occurred in at least 2% of gabapentin-treated

patients age 3 to 12 years of age with epilepsy participating in placebo-controlled trials and were

numerically more common in the gabapentin group. Adverse events were usually mild to moderate in

intensity.

Table 5. Treatment-Emergent Adverse Event

Incidence in Pediatric Patients Age 3 to 12 Years

in a Controlled Add-On Trial (Events in at Least

2% of Gabapentin Patients and Numerically

More Frequent Than in the Placebo Group)

Body System/Adverse EventGabapentin

N = 119

Placebo

N = 128

Body As A Whole

Viral Infection

10.9

Fever

10.1

Weight Increase

Plus background antiepileptic drug therapy

Fatigue

Digestive System

Nausea and/or Vomiting

Nervous System

Somnolence

Hostility

Emotional Lability

Dizziness

Hyperkinesia

Respiratory System

Bronchitis

Respiratory Infection

Other events in more than 2% of pediatric patients 3 to 12 years of age but equally or more frequent in

the placebo group included: pharyngitis, upper respiratory infection, headache, rhinitis, convulsions,

diarrhea, anorexia, coughing, and otitis media.

Other Adverse Events Observed During All Clinical Trials In Adults And Adolescents (Except Clinical

Trials In Neuropathic Pain):

Gabapentin has been administered to 4717 patients >12 years of age during all adjunctive therapy

clinical trials (except clinical trials in patients with neuropathic pain), only some of which were

placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators

using terminology of their own choosing. To provide a meaningful estimate of the proportion of

individuals having adverse events, similar types of events were grouped into a smaller number of

standardized categories using modified COSTART dictionary terminology. These categories are used

in the listing below. The frequencies presented represent the proportion of the 4717 patients >12 years

of age exposed to gabapentin who experienced an event of the type cited on at least one occasion while

receiving gabapentin. All reported events are included except those already listed in Table 4, those too

general to be informative, and those not reasonably associated with the use of the drug.

Events are further classified within body system categories and enumerated in order of decreasing

frequency using the following definitions: frequent adverse events are defined as those occurring in at

least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare

events are those occurring in fewer than 1/1000 patients.

Body as a whole: Frequent: asthenia, malaise, face edema; Infrequent: allergy, generalized edema, weight

decrease, chill; Rare: strange feelings, lassitude, alcohol intolerance, hangover effect.

Cardiovascular system: Frequent: hypertension; Infrequent: hypotension, angina pectoris, peripheral

vascular disorder, palpitation, tachycardia, migraine, murmur; Rare: atrial fibrillation, heart failure,

thrombophlebitis, deep thrombophlebitis, myocardial infarction, cerebrovascular accident, pulmonary

thrombosis, ventricular extrasystoles, bradycardia, premature atrial contraction, pericardial rub, heart

block, pulmonary embolus, hyperlipidemia, hypercholesterolemia, pericardial effusion, pericarditis.

Digestive system: Frequent: anorexia, flatulence, gingivitis; Infrequent: glossitis, gum hemorrhage, thirst,

stomatitis, increased salivation, gastroenteritis, hemorrhoids, bloody stools, fecal incontinence,

hepatomegaly; Rare: dysphagia, eructation, pancreatitis, peptic ulcer, colitis, blisters in mouth, tooth

discolor, perlèche, salivary gland enlarged, lip hemorrhage, esophagitis, hiatal hernia, hematemesis,

proctitis, irritable bowel syndrome, rectal hemorrhage, esophageal spasm.

Endocrine system: Rare: hyperthyroid, hypothyroid, goiter, hypoestrogen, ovarian failure, epididymitis,

swollen testicle, cushingoid appearance.

Hematologic and lymphatic system: Frequent: purpura most often described as bruises resulting from

physical trauma; Infrequent: anemia, thrombocytopenia, lymphadenopathy; Rare: WBC count increased,

lymphocytosis, non-Hodgkin’s lymphoma, bleeding time increased.

Musculoskeletal system: Frequent: arthralgia; Infrequent: tendinitis, arthritis, joint stiffness, joint swelling,

positive Romberg test; Rare: costochondritis, osteoporosis, bursitis, contracture.

Nervous system: Frequent: vertigo, hyperkinesia, paresthesia, decreased or absent reflexes, increased

reflexes, anxiety, hostility; Infrequent: CNS tumors, syncope, dreaming abnormal, aphasia, hypesthesia,

intracranial hemorrhage, hypotonia, dysesthesia, paresis, dystonia, hemiplegia, facial paralysis, stupor,

cerebellar dysfunction, positive Babinski sign, decreased position sense, subdural hematoma, apathy,

hallucination, decrease or loss of libido, agitation, paranoia, depersonalization, euphoria, feeling high,

doped-up sensation, suicidal, psychosis; Rare: choreoathetosis, orofacial dyskinesia, encephalopathy,

nerve palsy, personality disorder, increased libido, subdued temperament, apraxia, fine motor control

disorder, meningismus, local myoclonus, hyperesthesia, hypokinesia, mania, neurosis, hysteria,

antisocial reaction.

Respiratory system: Frequent: pneumonia; Infrequent: epistaxis, dyspnea, apnea; Rare: mucositis,

aspiration pneumonia, hyperventilation, hiccup, laryngitis, nasal obstruction, snoring, bronchospasm,

hypoventilation, lung edema.

Dermatological: Infrequent: alopecia, eczema, dry skin, increased sweating, urticaria, hirsutism,

seborrhea, cyst, herpes simplex; Rare: herpes zoster, skin discolor, skin papules, photosensitive

reaction, leg ulcer, scalp seborrhea, psoriasis, desquamation, maceration, skin nodules, subcutaneous

nodule, melanosis, skin necrosis, local swelling.

Urogenital system: Infrequent: hematuria, dysuria, urination frequency, cystitis, urinary retention, urinary

incontinence, vaginal hemorrhage, amenorrhea, dysmenorrhea, menorrhagia, breast cancer, unable to

climax, ejaculation abnormal; Rare: kidney pain, leukorrhea, pruritus genital, renal stone, acute renal

failure, anuria, glycosuria, nephrosis, nocturia, pyuria, urination urgency, vaginal pain, breast pain,

testicle pain.

Special senses: Frequent: abnormal vision; Infrequent: cataract, conjunctivitis, eyes dry, eye pain, visual

field defect, photophobia, bilateral or unilateral ptosis, eye hemorrhage, hordeolum, hearing loss,

earache, tinnitus, inner ear infection, otitis, taste loss, unusual taste, eye twitching, ear fullness; Rare:

eye itching, abnormal accommodation, perforated ear drum, sensitivity to noise, eye focusing problem,

watery eyes, retinopathy, glaucoma, iritis, corneal disorders, lacrimal dysfunction, degenerative eye

changes, blindness, retinal degeneration, miosis, chorioretinitis, strabismus, eustachian tube

dysfunction, labyrinthitis, otitis externa, odd smell.

Clinical Trials In Pediatric Patients With Epilepsy: Adverse events occurring during epilepsy clinical

trials in 449 pediatric patients 3 to 12 years of age treated with gabapentin that were not reported in

adjunctive trials in adults are:

Body as a whole: dehydration, infectious mononucleosis

Digestive system: hepatitis

Hemic and lymphatic system: coagulation defect

Nervous system: aura disappeared, occipital neuralgia

Psychobiologic function: sleepwalking

Respiratory system: pseudocroup, hoarseness

Clinical Trials In Adults With Neuropathic Pain Of Various Etiologies: Safety information was

obtained in 1173 patients during double-blind and open-label clinical trials including neuropathic pain

conditions for which efficacy has not been demonstrated. Adverse events reported by investigators

were grouped into standardized categories using modified COSTART IV terminology. Listed below

are all reported events except those already listed in Table 3 and those not reasonably associated with

the use of the drug.

Events are further classified within body system categories and enumerated in order of decreasing

frequency using the following definitions: frequent adverse events are defined as those occurring in at

least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients, rare

events are those occurring in fewer than 1/1000 patients.

Body as a whole: Infrequent: chest pain, cellulitis, malaise, neck pain, face edema, allergic reaction,

abscess, chills, chills and fever, mucous membrane disorder; Rare: body odor, cyst, fever, hernia,

abnormal BUN value, lump in neck, pelvic pain, sepsis, viral infection.

Cardiovascular system: Infrequent: hypertension, syncope, palpitation, migraine, hypotension, peripheral

vascular disorder, cardiovascular disorder, cerebrovascular accident, congestive heart failure,

myocardial infarction, vasodilatation; Rare: angina pectoris, heart failure increased capillary fragility,

phlebitis, thrombophlebitis, varicose vein.

Digestive system: Infrequent: gastroenteritis, increased appetite, gastrointestinal disorder, oral moniliasis,

gastritis, tongue disorder, thirst, tooth disorder, abnormal stools, anorexia, liver function tests abnormal,

periodontal abscess; Rare: cholecystitis, cholelithiasis, duodenal ulcer, fecal incontinence, gamma

glutamyl transpeptidase increased, gingivitis, intestinal obstruction, intestinal ulcer, melena, mouth

ulceration, rectal disorder, rectal hemorrhage, stomatitis.

Endocrine system: Infrequent: diabetes mellitus.

Hemic and lymphatic system: Infrequent: ecchymosis, anemia; Rare: lymphadenopathy, lymphoma-like

reaction, prothrombin decreased.

Metabolic and nutritional: Infrequent: edema, gout, hypoglycemia, weight loss; Rare: alkaline

phosphatase increased, diabetic ketoacidosis, lactic dehydrogenase increased.

Musculoskeletal:Infrequent: arthritis, arthralgia, myalgia, arthrosis, leg cramps, myasthenia; Rare: shin

bone pain, joint disorder, tendon disorder.

Nervous system: Frequent: confusion, depression; Infrequent: vertigo, nervousness, paresthesia,

insomnia, neuropathy, libido decreased, anxiety, depersonalization, reflexes decreased, speech

disorder, abnormal dreams, dysarthria, emotional lability, nystagmus, stupor, circumoral paresthesia,

euphoria, hyperesthesia, hypokinesia; Rare: agitation, hypertonia, libido increased, movement disorder,

myoclonus, vestibular disorder.

Respiratory system: Infrequent: cough increased, bronchitis, rhinitis, sinusitis, pneumonia, asthma, lung

disorder, epistaxis; Rare: hemoptysis, voice alteration.

Skin and appendages: Infrequent: pruritus, skin ulcer, dry skin, herpes zoster, skin disorder, fungal

dermatitis, furunculosis, herpes simplex, psoriasis, sweating, urticaria, vesiculobullous rash; Rare:

acne, hair disorder, maculopapular rash, nail disorder, skin carcinoma, skin discoloration, skin

hypertrophy.

Special senses:Infrequent: abnormal vision, ear pain, eye disorder, taste perversion, deafness; Rare:

conjunctival hyperemia, diabetic retinopathy, eye pain, fundi with microhemorrhage, retinal vein

thrombosis, taste loss.

Urogenital system:Infrequent: urinary tract infection, dysuria, impotence, urinary incontinence, vaginal

moniliasis, breast pain, menstrual disorder, polyuria, urinary retention: Rare: cystitis, ejaculation

abnormal, swollen penis, gynecomastia, nocturia, pyelonephritis, swollen scrotum, urinary frequency,

urinary urgency, urine abnormality.

Postmarketing And Other Experience:

In addition to the adverse experiences reported during clinical testing of gabapentin, the following

adverse experiences have been reported in patients receiving marketed gabapentin. These adverse

experiences have not been listed above and data are insufficient to support an estimate of their incidence

or to establish causation. The listing is alphabetized: angioedema, blood glucose fluctuation, breast

hypertrophy, erythema multiforme, elevated liver function tests, fever, hyponatremia, jaundice,

movement disorder, Stevens-Johnson syndrome. Adverse events following the abrupt discontinuation of

gabapentin have also been reported. The most frequently reported events were anxiety, insomnia,

nausea, pain and sweating.

DRUG ABUSE AND DEPENDENCE

The abuse and dependence potential of gabapentin has not been evaluated in human studies.

OVERDOSAGE

A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as high as

8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation,

hypoactivity, or excitation.

Acute oral overdoses of gabapentin up to 49 grams have been reported. In these cases, double vision,

slurred speech, drowsiness, lethargy and diarrhea were observed. All patients recovered with

supportive care.

Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few

overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant

renal impairment.

DOSAGE AND ADMINISTRATION

Gabapentin is given orally with or without food. Patients should be informed that, should they break the

scored 600 or 800 mg tablet in order to administer a half-tablet, they should take the unused half-tablet

as the next dose. Half-tablets not used within several days of breaking the scored tablet should be

discarded.

If gabapentin dose is reduced, discontinued or substituted 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).

Postherpetic Neuralgia

In adults with postherpetic neuralgia, gabapentin therapy may be initiated as a single 300-mg dose on

Day 1, 600 mg/day on Day 2 (divided BID), and 900 mg/day on Day 3 (divided TID). The dose can

subsequently be titrated up as needed for pain relief to a daily dose of 1800 mg (divided TID). In

clinical studies, efficacy was demonstrated over a range of doses from 1800 mg/day to 3600 mg/day

with comparable effects across the dose range. Additional benefit of using doses greater than 1800

mg/day was not demonstrated.

Epileps y

Gabapentin is recommended for add-on therapy in patients 3 years of age and older. Effectiveness in

pediatric patients below the age of 3 years has not been established.

Patients >12 Years Of Age

The effective dose of gabapentin is 900 to 1800 mg/day and given in divided doses (three times a day)

using 600 or 800 mg tablets. The starting dose is

300 mg three times a day. If necessary, the dose may be increased using 600 or 800 mg tablets three

times a day up to 1800 mg/day. Dosages up to 2400 mg/day have been well tolerated in long-term

clinical studies. Doses of 3600 mg/day have also been administered to a small number of patients for a

relatively short duration, and have been well tolerated. The maximum time between doses in the TID

schedule should not exceed 12 hours.

Pediatric Patients Age 3-12 Years

The starting dose should range from 10-15 mg/kg/day in 3 divided doses, and the effective dose

reached by upward titration over a period of approximately 3 days. The effective dose of gabapentin in

patients 5 years of age and older is 25-35 mg/kg/day and given in divided doses (three times a day). The

effective dose in pediatric patients ages 3 and 4 years is 40 mg/kg/day and given in divided doses (three

times a day). (See CLINICAL PHARMACOLOGY, Pediatrics.) Dosages up to 50 mg/kg/day have been

well tolerated in a long-term clinical study. The maximum time interval between doses should not

exceed 12 hours.

It is not necessary to monitor gabapentin plasma concentrations to optimize gabapentin therapy. Further,

because there are no significant pharmacokinetic interactions among gabapentin and other commonly

used antiepileptic drugs, the addition of gabapentin does not alter the plasma levels of these drugs

appreciably.

If gabapentin is discontinued and/or an alternate anticonvulsant medication is added to the therapy, this

should be done gradually over a minimum of 1 week.

Dosage In Renal Impairment

Creatinine clearance is difficult to measure in outpatients. In patients with stable renal function,

creatinine clearance (C

) can be reasonably well estimated using the equation of Cockcroft and Gault:

for females C

= (0.85) (140-age) (weight)/[(72)(S

for males C

= (140-age) (weight)/[(72)(S

where age is in years, weight is in kilograms and S

is serum creatinine in mg/dL.

Dosage adjustment in patients ≥ 12 years of age with compromised renal function or undergoing

hemodialysis is recommended as follows (see dosing recommendations above for effective doses in

each indication).

Table 6. Gabapentin Dosage Based on Renal Function

Renal/Function

Creatinine

Clearance

(mL/min)

Total

Daily

Dose

Range

(mg/day)

Dose Regimen

(mg)

For patients with creatinine clearance <15 mL/min, reduce daily dose in

proportion to creatinine clearance (e.g., patients with a creatinine clearance

of 7.5 mL/min should receive one-half the daily dose that patients with a

creatinine clearance of 15 mL/min receive).

Patients on hemodialysis should receive maintenance doses based on

>60

900-3600

600 TID

1200

>30-59

400-1400

400 BID

>15-29

200-700 200 QD 300 QD

400 QD

500 QD 700 QD

100-300 100 QD 125 QD

150 QD

200 QD 300 QD

Post-Hemodialysis Supplemental Dose

(mg)b

Hemodialysis

estimates of creatinine clearance as indicated in the upper portion of the table

and a supplemental post-hemodialysis dose administered after each 4 hours

of hemodialysis as indicated in the lower portion of the table.

The use of gabapentin in patients <12 years of age with compromised renal function has not been

studied.

Dosage In Elderly:

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.

HOW SUPPLIED

800 mg tablets:

White to off white, biconvex, oval shape, coated tablet scored on both sides and debossed with "204"

on one side, available in:

NDC: 60760-0038-60 BOTTLE OF 60

60760-0038-90 BOTTLE OF 90

60760-0038-30 BOTTLE OF 30

Storage

Store at 25 degrees C (77 degrees F); excursions permitted to 15 degrees to 30 degrees C (59 degrees

to 86 degrees F) See USP Controlled Room Temperature

The following are registered trademarks of their respective manufacturers: Maalox Alovartis

Consumer Health Canada Inc.; Ames N-Multistix SG Miles Laboratories, Inc.

Manufactured by:

Sun Pharmaceutical Industries Ltd.

Acme Plaza, Andheri-Kurla Road,

Andheri (East), Mumbai - 400 059, India.

Distributed by:

Caraco Pharmaceutical Laboratories, Ltd.

1150 Elijah McCoy Drive, Detroit MI 48202

MEDICATION GUIDE

GABAPENTIN - gabapentin capsule

GABAPENTIN - gabapentin tablet, film coated

Sun Pharmaceutical Industries Limited

----------

MEDICATION GUIDE

Gabapentin Capsules, USP

Gabapentin Tablets, USP

(GA ba PEN tin)

What is the most important information I should know about gabapentin?

Do not stop taking gabapentin without first talking to your healthcare provider.

Stopping gabapentin suddenly can cause serious problems.

Gabapentin can cause serious side effects including:

1. Suicidal Thoughts. Like other antiepileptic drugs, gabapentin may cause suicidal thoughts or actions

in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new,

worse, or worry you:

thoughts about suicide or dying

attempts to commit suicide

new or worse depression

new or worse anxiety

feeling agitated or restless

panic attacks

trouble sleeping (insomnia)

new or worse irritability

acting aggressive, being angry, or violent

acting on dangerous impulses

an extreme increase in activity and talking (mania)

other unusual changes in behavior or mood

How can I watch for early symptoms of suicidal thoughts and actions?

Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.

Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Do not stop taking gabapentin without first talking to a healthcare provider.

Stopping gabapentin suddenly can cause serious problems. Stopping a seizure medicine suddenly in a

patient who has epilepsy can cause seizures that will not stop (status epilepticus).

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts

or actions, your healthcare provider may check for other causes.

2. Changes in behavior and thinking - Using gabapentin in children 3 to 12 years of age can cause

emotional changes, aggressive behavior, problems with concentration, restlessness, changes in school

performance, and hyperactivity.

3. Gabapentin may cause serious or life-threatening allergic reactions that may affect your skin or other

parts of your body such as your liver or blood cells. This may cause you to be hospitalized or to stop

gabapentin. You may or may not have a rash with an allergic reaction caused by gabapentin. Call a

healthcare provider right away if you have any of the following symptoms:

skin rash

hives

difficulty breathing

fever

swollen glands that do not go away

swelling of your face, lips, throat, or tongue

yellowing of your skin or of the whites of the eyes

unusual bruising or bleeding

severe fatigue or weakness

unexpected muscle pain

frequent infections

These symptoms may be the first signs of a serious reaction. A healthcare provider should examine you

to decide if you should continue taking gabapentin.

What is gabapentin?

Gabapentin is a prescription medicine used to treat:

Pain from damaged nerves (postherpetic pain) that follows healing of shingles (a painful rash that comes

after a herpes zoster infection) in adults.

Partial seizures when taken together with other medicines in adults and children 3 years of age and older

with seizures.

Who should not take gabapentin?

Do not take gabapentin if you are allergic to gabapentin or any of the other ingredients in gabapentin.

See the end of this Medication Guide for a complete list of ingredients in gabapentin.

What should I tell my healthcare provider before taking gabapentin?

Before taking gabapentin, tell your healthcare provider if you:

have or have had kidney problems or are on hemodialysis

have or have had depression, mood problems, or suicidal thoughts or behavior

have diabetes

are pregnant or plan to become pregnant. It is not known if gabapentin can harm your unborn baby. Tell

your healthcare provider right away if you become pregnant while taking gabapentin. You and your

healthcare provider will decide if you should take gabapentin while you are pregnant.

Pregnancy Registry: If you become pregnant while taking gabapentin, talk to your healthcare provider

about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The

purpose of this registry is to collect information about the safety of antiepileptic drugs during

pregnancy. You can enroll in this registry by calling 1-888-233-2334.

are breast-feeding or plan to breast-feed. Gabapentin can pass into breast milk. You and your healthcare

provider should decide how you will feed your baby while you take gabapentin.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-

counter medicines, vitamins, and herbal supplements.

Taking gabapentin with certain other medicines can cause side effects or affect how well they work. Do

not start or stop other medicines without talking to your healthcare provider.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and

pharmacist when you get a new medicine.

How should I take gabapentin?

Take gabapentin exactly as prescribed. Your healthcare provider will tell you how much gabapentin to

take.

Do not change your dose of gabapentin without talking to your healthcare provider.

If you take gabapentin tablets and break a tablet in half, the unused half of the tablet should be taken at

your next scheduled dose. Half tablets not used within 28 days of breaking should be thrown away.

Take gabapentin capsules with water.

Gabapentin tablets can be taken with or without food. If you take an antacid containing aluminum and

magnesium, such as Maalox®*, Mylanta®*, Gelusil®*, Gaviscon®*, or Di-Gel®*, you should wait at

least 2 hours before taking your next dose of gabapentin.

If you take too much gabapentin, call your healthcare provider or your local Poison Control Center

right away at 1-800-222-1222.

What should I avoid while taking gabapentin?

Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking gabapentin

without first talking with your healthcare provider. Taking gabapentin with alcohol or drugs that cause

sleepiness or dizziness may make your sleepiness or dizziness worse.

Do not drive, operate heavy machinery, or do other dangerous activities until you know how gabapentin

affects you. Gabapentin can slow your thinking and motor skills.

What are the possible side effects of gabapentin?

Gabapentin may cause serious side effects including:

See “What is the most important information I should know about gabapentin?”

problems driving while using gabapentin. See “What I should avoid while taking Neurontin?”

sleepiness and dizziness, which could increase the occurrence of accidental injury, including falls

The most common side effects of gabapentin include:

lack of coordination

feeling tired

viral infection

fever

feeling drowsy

jerky movements

nausea and vomiting

difficulty with coordination

difficulty with speaking

double vision

tremor

unusual eye movement

swelling, usually of legs and feet

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of gabapentin. For more information, ask your healthcare

provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

How should I store gabapentin?

Store gabapentin capsules and tablets at 20° to 25°C (68 to 77°F)

Keep gabapentin and all medicines out of the reach of children.

General information about the safe and effective use of gabapentin

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use gabapentin for a condition for which it was not prescribed. Do not give gabapentin to other people,

even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about gabapentin. If you would like

more information, talk with your healthcare provider. You can ask your healthcare provider or

pharmacist for information about gabapentin that was written for healthcare professionals.

For more information, call 1-800-818-4555.

What are the ingredients in gabapentin?

Active ingredient: gabapentin

Inactive ingredients in the capsules: calcium carbonate, calcium sulfate dihydrate, glyceryl behenate,

and pregelatinized maize starch. The capsule shell contains gelatin, titanium dioxide, sodium lauryl

sulfate, yellow iron oxide (300 mg and 400 mg) and red iron oxide (400 mg). The imprinting ink

contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong

ammonia solution, black iron oxide, potassium hydroxide, and purified water.

Inactive ingredients in the tablets: glyceryl behenate, hydroxypropyl cellulose, low substituted

hydroxypropyl cellulose, magnesium stearate, mannitol, talc, pregelatinized maize starch and Opadry

YS-1-7003 (hypromellose, titanium dioxide, polyethylene glycol, and polysorbate 80).

This Medication Guide has been approved by the U.S. Food and Drug Administration.

* All trademark names are the property of their respective owners.

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

Manufactured by:

Sun Pharmaceutical Industries Ltd.

Halol-Baroda Highway,

Halol-389 350, Gujarat, India.

ISS. 11/2017

PJPI0121H

Revised: 11/2017

Document Id: 55e62f9c-ff35-494d-aa1b-ed759bc59512

34391-3

Set id: c9a05f0c-b5f0-422c-9d67-6d0efc921a74

Version: 14

Effective Time: 20171118

Sun Pharmaceutical Industries Limited

PACKAGE DISPLAY PANEL

GABAPENTIN

gabapentin tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 0 76 0 -0 38 (NDC:6 2756 -20 4)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

GABAPENTIN (UNII: 6 CW7F3G59 X) (GABAPENTIN - UNII:6 CW7F3G59 X)

GABAPENTIN

8 0 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CALCIUM STEARATE (UNII: 776 XM70 47L)

CRO SPO VIDO NE (UNII: 6 8 40 19 6 0 MK)

HYDRO XYPRO PYL CELLULO SE (UNII: RFW2ET6 71P)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

PO LYETHYLENE GLYCO L (UNII: 3WJQ0 SDW1A)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

Product Characteristics

Color

white (o ff white)

S core

2 pieces

S hap e

OVAL (20 4)

S iz e

20 mm

Flavor

Imprint Code

20 4

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 0 76 0 -0 38 -30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

12/0 3/20 10

2

NDC:6 0 76 0 -0 38 -6 0

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

12/0 3/20 10

3

NDC:6 0 76 0 -0 38 -9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

12/0 3/20 10

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 77525

12/0 3/20 10

Labeler -

St Marys Medical Park Pharmacy (063050751)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

St Marys Medical Park Pharmacy

0 6 30 50 751

repack(6 0 76 0 -0 38 ) , relabel(6 0 76 0 -0 38 )

St Marys Medical Park Pharmacy

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Sun Pharmaceutical Ind Ltd.

7259 59 238

ma nufa c ture (6 0 76 0 -0 38 )

Revised: 12/2017

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