Gabapentin Tablets USP are supplied as oval shaped, film-coated,
biconvex scored tablets containing 600 mg and 800mg of gabapentin.
The inactive ingredients for the tablets are Corn Starch, Copovidone,
Poloxamer 407, Magnesium Stearate, Polyethylene Glycol, Hypromellose, Titanium
Dioxide, Talc, Macrogol, Polysorbate 80 and purified water.
Gabapentin USP is described as 1-(aminomethyl)cyclohexaneacetic acid with a
molecular formula of C9 H17NO2 and a molecular weight of 171.24. The structural
formula of gabapentin is:
Gabapentin USP 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.
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 GABAA or GABAB 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 ÎĽM 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 Cmax). 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, steadystate
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
(see Special
Populations: 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
5). 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 greater than 60 mL/min) to 52 hours (creatinine
clearance less than 30 mL/min) and gabapentin renal clearance from about 90 mL/min
(greater than 60 mL/min group) to about 10 mL/ min (less than 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 less than 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 valueswere observed in children less than 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 less than 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.
This pharmacokinetic data indicates 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 StudiesPostherpetic Neuralgia Gabapentin tablets were 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
*Â Given in 3 divided doses (TID)
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.
Figure 1. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 1
Figure 2. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 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).
Figure 3. Proportion of Responders (patients with ≥50% reduction in pain score)
at Endpoint: Controlled PHN Studies
Epilepsy The effectiveness of gabapentin tablets 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 tablets 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 tablets 1200 mg/day divided TID with placebo.
Responder rate was 23% (14/61) in the gabapentin tablets group and 9% (6/66) in
the placebo group; the difference between groups was statistically significant.
Response ratio was also better in the gabapentin tablets 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 tablets
(N=101) with placebo (N=98). Additional smaller gabapentin tablets 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 tablets
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 tablets 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 tablets 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 tablets 900 mg/day divided TID (N=111) and
placebo (N=109). An additional gabapentin tablets 1200 mg/day dosage group
(N=52) provided dose-response data. A statistically significant difference in
responder rate was seen in the gabapentin tablets 900 mg/day group (22%)
compared to that in the placebo group (10%). Response ratio was also
statistically significantly superior in the gabapentin tablets 900 mg/day group
(-0.119) compared to that in the placebo group (-0.027), as was response ratio
in 1200 mg/day gabapentin tablets (-0.184) compared to placebo.
Analyses were also performed in each study to examine the effect of
gabapentin tablets 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
tablets 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 tablets; N=89, placebo) also showed a significant
advantage for gabapentin tablets 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
tablets 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).
Figure 4. Responder Rate in Patients Receiving gabapentin tablets Expressed as a
Difference fFigure 4. Responder Rate in Patients Receiving gabapentin tablets Expressed as a
Difference from Placebo by Dose and Study: Adjunctive Therapy Studies in
Patients ≥12 Years of Age with Partial Seizures
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 tablets. 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 tablets (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 tablets group (-0.146) than for the
placebo group (-0.079). For the same population, the responder rate for
gabapentin tablets (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 tablets (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 tablets are indicated for the management of
postherpetic neuralgia in adults. Epilepsy Gabapentin tablets are 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 tablets are also
indicated as adjunctive therapy in the treatment of partial seizures in
pediatric patients age 3 – 12 years.
Contraindications
Gabapentin tablets are 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
analysis
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
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical
trials for epilepsy than in clinical trials for psychiatric or other conditions,
but the absolute risk differences were similar for the epilepsy and psychiatric
indications.
Anyone considering prescribing gabapentin 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 tablets 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 tablets 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
tablets 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
tablets. 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
preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate)
during or up to 2 years following discontinuation of gabapentin tablets. Without
knowledge of the background incidence and recurrence in a similar population not
treated with gabapentin tablets, 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
tablets 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
tablets (ranging from 0.0005 for the general population of epileptics to 0.003
for a clinical trial population similar to that in the gabapentin tablets
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 tablets cohort and the
accuracy of the estimates provided.
Precautions
Information for patients Patients should be instructed to take gabapentin tablets only as
prescribed.
Patients, their caregivers, and families should be counseled that AEDs,
including gabapentin tablets, 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 tablets 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
tablets 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 1888-233-2334 (see PRECAUTIONS:
Pregnancy). Laboratory tests Clinical trials data do not indicate that routine monitoring of
clinical laboratory parameters is necessary for the safe use of gabapentin
tablets. The value of monitoring gabapentin blood concentrations has not been
established. Gabapentin tablets 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 mcg/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 mcg/mL (approximately 15 times the Cmax
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 tablets 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 tablets (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 tablets (125 to 500 mg;N=48)
decreases hydrocodone (10 mg; N=50) Cmax and AUC values in a dose-dependent
manner relative to administration of hydrocodone alone; Cmax and AUC values are
3% to 4% lower, respectively, after administration of 125 mg gabapentin tablets
and 21% to 22% lower, respectively, after administration of 500 mg gabapentin
tablets. 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 60mg 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 tablets 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 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
TID; N=13). The Cmax of norethindrone was 13% higher when
it was coadministered with gabapentin; this interaction is not expected to be of
clinical importance. Antacid (Maalox®): Maalox 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. It is recommended that gabapentin be taken at
least 2 hours following Maalox 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/m2 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/m2 basis. The
no-effect level was 500 mg/kg/day or approximately ½ of the human dose on a
mg/m2 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/m2 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/m2
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/m2 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/m2 basis.
In a teratology study in rabbits, an increased incidence of postimplantation
fetal loss occurred in dams exposed to 60, 300, and 1500 mg/kg/day, or less than
approximately ÂĽ to 8 times the maximum human dose on a mg/m2 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 tablets, physicians are advised to recommend that pregnant patients
taking gabapentin tablets 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/.
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 tablets should be used in women who are nursing
only if the benefits clearly outweigh the risks. Pediatric use Safety and effectiveness of gabapentin tablets 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 tablets 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 tablets 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 sections).
Adverse Reactions
Postherpetic Neuralgia The most commonly observed adverse events associated with the use
of gabapentin tablets 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 tablets 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 tablets-treated
patients were dizziness, somnolence, and nausea. Incidence in Controlled Clinical Trials TABLE 2
uls treatment-emergent signs and symptoms that occurred in at least 1% of
gabapentin tablets-treated patients with postherpetic neuralgia participating in
placebo-controlled trials and that were numerically more frequent in the
gabapentin tablets group than in the placebo group. Adverse events were usually
mild to moderate in intensity.
TABLE 2. Treatment-Emergent Adverse Event Incidence in Controlled Trials in Postherpetic Neuralgia (Events in at least 1% of gabapentin tablets treated Patients and Numerically More Frequent Than in the Placebo Group)
Body System/Preferred Term
Gabapentin tabletsN=336%
PlaceboN=227%
Body as a Whole
  Asthenia  Infection  Headache  Accidental injury  Abdominal pain
5.75.13.33.32.7
4.83.53.11.32.6
Digestive System
  Diarrhea  Dry mouth  Constipation  Nausea  Vomiting  Flatulence
5.74.83.93.93.32.1
3.11.31.83.11.81.8
Metabolic and Nutritional Disorders
  Peripheral edema  Weight gain  Hyperglycemia
8.31.81.2
2.20.00.4
Nervous System
  Dizziness  Somnolence  Ataxia  Thinking abnormal  Abnormal gait  Incoordination  Amnesia  Hyperthesia
28.021.43.32.71.51.51.21.2
7.55.30.00.00.00.00.90.9
Respiratory System
  Pharyngitis
1.2
0.4
Skin and Appendages
  Rash
1.2
0.9
Special Senses
  Amblyopiaa
  Conjunctivitis  Diplopia  Otitis media
2.71.21.21.2
0.90.00.00.0
a Reported as blurred vision
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 tablets 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 tablets 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,
Neuropsychiatric 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
tablets 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 3
uls treatment-emergent signs and symptoms that occurred in at least 1% of
gabapentin tablets-treated patients >12 years of age with epilepsy
participating in placebo-controlled trials and were numerically more common in
the gabapentin tablets group. In these studies, either gabapentin tablets 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
tablets 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 3. Treatment-Emergent Adverse Event Incidence in Controlled Add-On Trials In Patients >12 years of age (Events in at least 1% of gabapentin tablets patients and numerically more frequent than in the placebo group
Body System/Adverse Event
Gabapentin tabletsa
N=543%
Placeboa
N=378%
Body As A Whole
  Fatigue  Weight Increase  Back Pain  Peripheral Edema
11.02.91.81.7
5.01.60.50.5
Cardiovascular
  Vasodilatation
1.1
0.3
Digestive System
  Dyspepsia  Mouth or Throat Dry  Constipation  Dental Abnormalities  Increased Appetite
2.21.71.51.51.1
0.50.50.80.30.8
Hematologic and Lymphatic Systems
  Leukopenia
1.1
0.5
Musculoskeletal System
  Myalgia  Fracture
2.01.1
1.90.8
Nervous System
  Somnolence  Dizziness  Ataxia  Nystagmus  Tremor  Nervousness  Dysarthria  Amnesia  Depression  Thinking Abnormal  Twitching  Coordination Abnormal
19.317.112.58.36.82.42.42.21.81.71.31.1
8.76.95.64.03.21.90.50.01.11.30.50.3
Respiratory System
  Rhinitis  Pharyngitis  Coughing
4.12.81.8
3.71.61.3
Skin and Appendages
  Abrasion  Pruritus
1.31.3
0.00.5
Urogenital System
  Impotence
1.5
1.1
Special Senses
  Diplopia  Amblyopiab
5.94.2
1.91.1
Laboratory Deviations
  WBC Decreased
1.1
0.5
a  Plus background antiepileptic drug therapy
b  Amblyopia was often described as blurred vision
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 tablets-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 tablets. The incidence
of adverse events increased slightly with increasing age in patients treated
with either gabapentin tablets 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 4 uls
treatment-emergent signs and symptoms that occurred in at least 2% of gabapentin
tablets-treated patients age 3 to 12 years of age with epilepsy participating in
placebo-controlled trials and were numerically more common in the gabapentin
tablets group. Adverse events were usually mild to moderate in intensity.
TABLE 4. 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 tablets patients and numerically more frequent than in the placebo group)
Body System/Adverse Event
Gabapentin tabletsa
N=119%
Placeboa
N=128%
Body As A Whole
  Viral Infection  Fever  Weight Increase  Fatigue
10.910.13.43.4
3.13.10.81.6
Digestive System
  Nausea and/or Vomiting
8.4
7.0
Nervous System
  Somnolence  Hostility  Emotional Lability  Dizziness  Hyperkinesia
8.47.64.22.52.5
4.72.31.61.60.8
Respiratory System
  Bronchitis  Respiratory Infection
3.42.5
0.80.8
a  Plus background antiepileptic drug therapy
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
TrialsClinical Trials in Adults and Adolescents (Except
Clinical Trials in Neuropathic Pain) Gabapentin tablets have 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 uling below. The frequencies presented represent the proportion of
the 4717 patients >12 years of age exposed to gabapentin tablets who
experienced an event of the type cited on at least one occasion while receiving
gabapentin tablets. All reported events are included except those already uled
in Table 3, 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, bulers 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, suicide attempt,
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, suicide. 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 uled in Table 2 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; suicide
attempt; 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 tablets, the following adverse experiences have been
reported in patients receiving marketed gabapentin tablets. These adverse
experiences have not been uled above and data are insufficient to support an
estimate of their incidence or to establish causation. The uling is
alphabetized: angioedema, blood glucose fluctuation, 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 tablets 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 tablets 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 tablets USP are 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 tablets USP 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 tablets USP
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. Epilepsy Gabapentin tablets USP are 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 tablets USP 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 tablets USP 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 tablets USP therapy. Further, because there are no significant
pharmacokinetic interactions among gabapentin tablets USP and other commonly
used antiepileptic drugs, the addition of gabapentin tablets USP does not alter
the plasma levels of these drugs appreciably.
If gabapentin tablets USP 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 (CCr) can be
reasonably well estimated using the equation of Cockcroft and Gault:
for females CCr=(0.85)(140-age)(weight)/[(72)(SCr)]
for males CCr=(140-age)(weight)/[(72)(SCr)]
where age is in years, weight is in kilograms and SCr is serum creatinine in
mg/dL.
Dosage adjustment in patients greater than or equal to 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 5. Gabapentin tablets USP Dosage Based on Renal Function Renal Function Total Daily
Renal FunctionCreatinine Clearance(mL/min)
Total DailyDose Range(mg/day)
Dose Regimen(mg)
>60
900-3600
300 TID
400 TID
600 TID
800 TID
1200 TID
>30-59
400-1400
200 BID
300 BID
400 BID
500 BID
700 BID
>15-29
200-700
200 QD
300 QD
400 QD
500 QD
700 QD
15a
100-300
100 QD
125 QD
150 QD
200 QD
300 QD
Post-
Hemodialysis
Supplemental
Dose (mg)b
Hemodiaylsis
125b
150b
200b
250b
350b
a For patients with creatinine clearance less than 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 thedaily dose that patients with creatinine clearance of 15 mL/min receive).
b Patients on hemodialysis should receive maintenance doses based on estimates of creatinineclearance 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 tablets USP in patients less than 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
600 mg tablets;
White to off white film-coated, oval shaped, biconvex scored tablets debossed
with “G” and “31” on one side.
available in :
NDC 54868-5219-3
Bottles of 10
NDC 54868-5219-1
Bottles of 20
NDC 54868-5219-6
Bottles of 30
NDC 54868-5219-0
Bottles of 60
NDC 54868-5219-2
Bottles of 90
NDC 54868-5219-5
Bottles of 100
NDC 54868-5219-4
Bottles of 120
800 mg tablets;
White to off white film-coated, oval shaped, biconvex scored tablets debossed
with “G” and “13” on one side.
available in :
NDC 54868-5195-1
Bottles of 10
NDC 54868-5195-2
Bottles of 30
NDC 54868-5195-4
Bottles of 60
NDC 54868-5195-3
Bottles of 90
NDC 54868-5195-0
Bottles of 100
NDC 54868-5195-5
Bottles of 120
Store at 25°C (77°F); excursions permitted to
15° - 30°C (59° - 86°F) [see USP Controlled Room Temperature].
Manufactured by:
Glenmark Generics
Ltd.
Colvale-Bardez, Goa 403 513, India
Relabeling and Repackaging by:
Physicians Total Care, Inc.
Tulsa, Oklahoma    74146
Principal Display Panel
Gabapentin Tablets USP
600 mg
Gabapentin Tablets USP
800 mg
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