GABAPENTIN
DESCRIPTION:
Neurontin(R) (gabapentin capsules) is supplied as imprinted hard shell capsules
containing 300 mg, and 400 mg of gabapentin. The inactive ingredients
are lactose, corn starch, and talc.
Gabapentin is described as 1-(aminomethyl)cyclohexaneacetic acid with an
empirical formula of C9H17NO2 and a molecular weight of 171.24.
Gabapentin is a white to off-white crystalline solid. It is freely soluble in
water and both basic and acidic aqueous solutions.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION
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 interact with GABA receptors, 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 microM 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, voltage-sensitive calcium channel
sites labeled with nitrendipine or diltiazem, or at voltage-sensitive sodium
channel sites with batrachotoxinin A 20-alpha- benzoate.
Several test systems ordinarily used to assess activity at the NMDA receptor
have been examined. Results are contradictory. Accordingly, no general statement
about the effects, if any, of gabapentin at the NMDA receptor can be made.
In Vitro studies with radiolabeled gabapentin have revealed a gabapentin binding
site in areas of rat brain including neocortex and hippocampus. The identity and
function of this binding site 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. A 400-mg dose, for
example, is about 25% less bioavailable than a 100-mg dose. Over the recommended
dose range of 300 to 600 mg T.I.D., however, the differences in bioavailability
are not large, and bioavailability is about 60 percent. Food has no effect on
the rate and extent of absorption of gabapentin.
DISTRIBUTION: Gabapentin circulates largely unbound (<3%) to plasma protein.
The apparent volume of distribution of gabapentin after 150 mg intravenous
administration is 58 +/- 6 L (Mean +/- SD). In patients with epilepsy, steady-
state predose (Cmin) concentrations of gabapentin in cerebrospinal fluid were
approximately 20% of the corresponding plasma concentrations.
ELIMINATION: Gabapentin is eliminated from the systemic circulation by renal
excretion as unchanged drug. Gabapentin is not appreciably metabolized in
humans.
Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or
following multiple dosing. Gabapentin elimination rate constant, plasma
clearance, and renal clearance are directly proportional to creatinine clearance
(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 2).
SPECIAL POPULATIONS: 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 patients with compromised renal function is necessary (see
DOSAGE AND ADMINISTRATION).
Hemodialysis: In a study in anuric subjects (N=11), the apparent elimination
half-life of gabapentin on nondialysis days was about 132 hours; dialysis three
times a week (4 hours duration) lowered the apparent half-life of gabapentin by
about 60%, from 132 hours to 51 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: No pharmacokinetic data are available in pediatric patients below the
age of 18 years.
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:
The effectiveness of Neurontin(R) as adjunctive therapy (added to other
antiepileptic drugs) was established in three multicenter placebo- controlled,
double-blind, parallel-group clinical trials in 705 adults with refractory
partial seizures. 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. In patients continuing to have at
least 2 (or 4 in some studies) seizures per month, Neurontin(R) 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 Neurontin(R) 1200 mg/day T.I.D. with placebo. Responder rate
was 23% (14/61) in the Neurontin(R) group and 9% (6/66) in the placebo group;
the difference between groups was statistically significant. Response ratio was
also better in the Neurontin(R) 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 T.I.D. Neurontin(R) (N=101) with
placebo (N=98). Additional smaller Neurontin(R) 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 Neurontin(R) 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
Neurontin(R) 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 Neurontin(R) 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 Neurontin(R) 900 mg/day T.I.D. (N=111) and placebo (N =
109). An additional Neurontin(R) 1200 mg/day dosage group (N=52) provided dose-
response data. A statistically significant difference in responder rate was seen
in the Neurontin(R) 900 mg/day group (22%) compared to that in the placebo group
(10%). Response ratio was also statistically significantly superior in the
Neurontin(R) 900 mg/day group (-0.119) compared to that in the placebo group (-
0.027), as was response ratio in 1200 mg/day Neurontin(R) (-0.184) compared to
placebo.
Analyses were also performed in each study to examine the effect of Neurontin(R)
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 Neurontin(R) 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, Neurontin(R); N=89, placebo) also showed a significant advantage
for Neurontin(R) over placebo in reducing the frequency of secondarily
generalized tonic-clonic seizures.
In two of the three controlled studies, more than one dose of Neurontin(R) 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 1).
Click here for illustration(s).
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 Neurontin(R). There were insufficient
numbers of patients of races other than Caucasian to permit a comparison of
efficacy among racial groups.
INDICATIONS AND USAGE:
Neurontin(R) (gabapentin) is indicated as adjunctive therapy in the treatment of
partial seizures with and without secondary generalization in adults with
epilepsy.
CONTRAINDICATIONS:
Neurontin(R) is contraindicated in patients who have demonstrated
hypersensitivity to the drug or its ingredients.
WARNINGS:
WITHDRAWAL PRECIPITATED SEIZURE, STATUS EPILEPTICUS
In the placebo-controlled studies, the incidence of status epilepticus in
patients receiving Neurontin(R) was 0.6% (3 of 543) versus 0.5% in patients
receiving placebo (2 of 378). Among the 2074 patients treated with Neurontin(R)
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 Neurontin(R) is associated with a higher or lower rate of status
epilepticus than would be expected to occur in a similar population not treated
with Neurontin(R).
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 comprising 2085 patient-years of exposure, 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 Neurontin(R). Without knowledge of the background incidence
and recurrence in a similar population NOT treated with Neurontin(R), it is
impossible to know whether the incidence seen in this cohort is or is not
affected by treatment.
SUDDEN AND UNEXPLAINED DEATHS
During the course of premarketing development of Neurontin(R), 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
Neurontin(R) (ranging from 0.0005 for the general population of epileptics, to
0.003 for a clinical trial population similar to that in the Neurontin(R)
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 Neurontin(R) cohort and the accuracy of
the estimates provided.
PRECAUTIONS:
INFORMATION FOR PATIENTS
Patients should be instructed to take Neurontin(R) only as prescribed.
Patients should be advised that Neurontin(R) 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 Neurontin(R) to gauge whether or not it affects
their mental and/or motor performance adversely.
LABORATORY TESTS
Clinical trials data do not indicate that routine monitoring of clinical
laboratory parameters is necessary for the safe use of Neurontin(R). The value
of monitoring Neurontin(R) blood concentrations has not been established.
Neurontin(R) 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
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 patients with epilepsy.
PHENYTOIN: In a single and multiple dose study of Neurontin(R) (400 mg T.I.D.)
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
T.I.D.; 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 (400mg T.I.D.; N=17)
were not different and neither were gabapentin pharmacokinetics parameters
affected by valproic acid.
PHENOBARBITAL: Estimates of steady-state pharmacokinetic parameters for
phenobarbital or gabapentin (300 mg T.I.D.; N=12) are identical whether the
drugs are administered alone or together.
CIMETIDINE: In the presence of cimetidine at 300mg Q.I.D. (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 mcgm of ethinyl
estradiol were similar with and without coadministration of gabapentin (400 mg
T.I.D.; 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(R)): 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(R)
dipstick test for urinary protein when gabapentin was added to the 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. Studies to
attempt to define a mechanism by which this relatively rare tumor type is
occurring are in progress. The relevance of this finding to carcinogenic risk in
humans is unclear.
Gabapentin did not demonstrate mutagenic or genotoxic potential in three In
Vitro and two 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.
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(squared) 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(squared) basis. The no-effect level was 500 mg/kg/day or
approximately 1/2 of the human dose on a mg/M(squared) 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(squared) 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(squared) 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(squared) 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(squared) 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 1/4 to 8 times the maximum human dose on a mg/M(squared) basis.
There are no adequate and well-controlled studies in pregnant women. Because
animal reproduction studies are not always predictive of human response, this
drug should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
USE IN NURSING MOTHERS
It is not known if gabapentin is excreted in human milk and the effect on the
nursing infant is unknown. However, because many drugs are excreted in human
milk, Neurontin(R) should be used in women who are nursing only if the benefits
clearly outweigh the risks.
PEDIATRIC USE
Safety and effectiveness in pediatric patients below the age of 12 years have
not been established.
GERIATRIC USE
No systematic studies in geriatric patients have been conducted. Adverse
clinical events reported among 59 Neurontin(R) exposed patients over age 65 did
not differ in kind from those reported for younger individuals. The small number
of older individuals evaluated, however, limits the strength of any conclusions
reached about the influence, if any, of age on the kind and incidence of adverse
events or laboratory abnormality associated with the use of Neurontin(R).
Because Neurontin(R) is eliminated primarily by renal excretion, the dose of
Neurontin(R) should be adjusted as noted in DOSAGE AND ADMINISTRATION (Table 2)
for elderly patients with compromised renal function. Creatinine clearance is
difficult to measure in outpatients and serum creatinine may be reduced in the
elderly because of decreased muscle mass. Creatinine clearance (CCr) can be
reasonably well estimated using the equation of Cockcroft and Gault:
for females CCr = (0.85)(140-age)(wt)/((72)(SCr))
for males CCr = (140-age)(wt)/((72)(SCr))
where age is in years, wt is in kilograms and SCr is serum creatinine in mg/dL.
DRUG INTERACTIONS:
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 patients with epilepsy.
PHENYTOIN: In a single and multiple dose study of Neurontin(R) (400 mg T.I.D.)
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
T.I.D.; 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 (400mg T.I.D.; N=17)
were not different and neither were gabapentin pharmacokinetics parameters
affected by valproic acid.
PHENOBARBITAL: Estimates of steady-state pharmacokinetic parameters for
phenobarbital or gabapentin (300 mg T.I.D.; N=12) are identical whether the
drugs are administered alone or together.
CIMETIDINE: In the presence of cimetidine at 300mg Q.I.D. (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 mcgm of ethinyl
estradiol were similar with and without coadministration of gabapentin (400 mg
T.I.D.; 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(R)): 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.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The most commonly observed adverse events associated with the use of
Neurontin(R) in combination with other antiepileptic drugs, not seen at an
equivalent frequency among placebo- treated patients, were somnolence,
dizziness, ataxia, fatigue, and nystagmus.
Approximately 7% of the 2074 individuals who received Neurontin(R) in
premarketing clinical trials discontinued treatment because of an adverse event.
The adverse events most commonly associated with withdrawal were somnolence
(1.2%), ataxia (0.8%), fatigue (0.6%), nausea and/or vomiting (0.6%), and
dizziness (0.6%).
INCIDENCE IN CONTROLLED CLINICAL TRIALS
Table 1 lists treatment-emergent signs and symptoms that occurred in at least 1%
of Neurontin(R)-treated patients with epilepsy participating in placebo-
controlled trials and were numerically more common in the Neurontin(R) group. In
these studies, either Neurontin(R) 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 Neurontin(R)
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 1. Treatment-Emergent Adverse Event Incidence in Controlled Add-On Trials
(Events in at least 1% of Neurontin patients and numerically more frequent than
in the placebo group)
Neurontin(R)(a) Placebo(a)
Body System/ N=543 N=378
Adverse Event % %
--------------------------------------------------------------------------------------------------------------------------------
Body As A Whole
Fatigue 11.0 5.0
Weight Increase 2.9 1.6
Back Pain 1.8 0.5
Peripheral Edema 1.7 0.5
Cardiovascular
Vasodilatation 1.1 0.3
Digestive System
Dyspepsia 2.2 0.5
Mouth or Throat Dry 1.7 0.5
Constipation 1.5 0.8
Dental Abnormalities 1.5 0.3
Increased Appetite 1.1 0.8
Hematologic and Lymphatic Systems
Leukopenia 1.1 0.5
Musculoskeletal System
Myalgia 2.0 1.9
Fracture 1.1 0.8
Nervous System
Somnolence 19.3 8.7
Dizziness 17.1 6.9
Ataxia 12.5 5.6
Nystagmus 8.3 4.0
Tremor 6.8 3.2
Nervousness 2.4 1.9
Dysarthria 2.4 0.5
Amnesia 2.2 0.0
Depression 1.8 1.1
Thinking Abnormal 1.7 1.3
Twitching 1.3 0.5
Coordination Abnormal 1.1 0.3
Respiratory System
Rhinitis 4.1 3.7
Pharyngitis 2.8 1.6
Coughing 1.8 1.3
Skin and Appendages
Abrasion 1.3 0.0
Pruritus 1.3 0.5
Urogenital System
Impotence 1.5 1.1
Special Senses
Diplopia 5.9 1.9
Amblyopia(b) 4.2 1.1
Laboratory Deviations
WBC Decreased 1.1 0.5
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(a)Plus background antiepileptic drug therapy
(b)Amblyopia was often described as blurred vision.
Other events in more than 1% of patients 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 Neurontin-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 Neurontin(R). The incidence of
adverse events increased slightly with increasing age in patients treated with
either Neurontin(R) 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.
OTHER ADVERSE EVENTS OBSERVED DURING ALL CLINICAL TRIALS
Neurontin(R) has been administered to 2074 individuals during all clinical
trials, 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 2074 individuals exposed to
Neurontin(R) who experienced an event of the type cited on at least one occasion
while receiving Neurontin(R). All reported events are included except those
already listed in the previous table, 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, perleche, 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,
suicide gesture.
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.
POSTINTRODUCTION REPORTS
Adverse events associated with Neurontin that have been received since market
introduction, that are not listed above, and that may have no causal
relationship to drug, include the following: erythema multiforme, Stevens-
Johnson syndrome and elevated liver function tests.
DRUG ABUSE AND DEPENDENCE:
The abuse and dependence potential of Neurontin(R) 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 Neurontin(R) 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:
Neurontin(R) is recommended for add-on therapy in patients over 12 years of age.
Evidence bearing on its safety and effectiveness in pediatric patients below the
age of 12 is not available.
Neurontin(R) is given orally with or without food.
The effective dose of Neurontin(R) is 900 to 1800mg/day and given in divided
doses (three times a day) using 300- or 400-mg capsules. Titration to an
effective dose can take place rapidly, over a few days, giving 300 mg on Day 1,
300 mg twice a day on Day 2, and 300 mg three times a day on Day 3. To minimize
potential side effects, especially somnolence, dizziness, fatigue, and ataxia,
the first dose on Day 1 may be administered at bedtime. If necessary, the dose
may be increased using 300- or 400-mg capsules 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 T.I.D. schedule should not exceed 12 hours.
It is not necessary to monitor gabapentin plasma concentrations to optimize
Neurontin(R) therapy. Further, because there are no significant pharmacokinetic
interactions among Neurontin(R) and other commonly used antiepileptic drugs, the
addition of Neurontin(R) does not alter the plasma levels of these drugs
appreciably.
If Neurontin(R) is discontinued and/or alternate anticonvulsant medication is
added to the therapy, this should be done gradually over a minimum of 1 week.
Dosage adjustment in patients with compromised renal function or undergoing
hemodialysis is recommended as follows:
TABLE 2. Neurontin(R) Dosage Based on Renal Function
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Renal Function Total
Creatinine Clearance Daily Dose Dose Regimen
(mL/min) (mg/day) (mg)
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<60 1200 400 T.I.D.
30--60 600 300 B.I.D.
15--30 300 300 Q.D.
<15 150 300 Q.O.D.(a)
Hemodialysis -- 200-300(b)
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(a) Every other day
(b) Loading dose of 300 to 400 mg in patients who have never received
Neurontin(R), then 200 to 300 mg Neurontin(R) following each 4 hours of
hemodialysis
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