HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ----------------------------- ADVERSE REACTIONS -------------------------------------- GRALISE safely and effectively. See full prescribing information for
The most common adverse reaction (greater than or equal to 5% and twice
GRALISE. GRALISE® (gabapentin) tablets Initial U.S. Approval: 1993 To report SUSPECTED ADVERSE REACTIONS, contact Depomed, Inc. at 1-866-458-6389 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ------------------------- INDICATIONS AND USAGE ------------------------------ ------------------------------DRUG INTERACTIONS --------------------------------
GRALISE is indicated for the management of Postherpetic Neuralgia (PHN).
● An increase in gabapentin AUC values have been reported when administered
Important Limitation: GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that
● An increase in gabapentin AUC values have been reported when administered
affect the frequency of administration (See Warnings and Precautions) -------------------- DOSAGE AND ADMINISTRATION -------------------------- ● An antacid containing aluminum hydroxide and magnes iu
● GRALISE should be titrated to an 1800 mg dose taken orally, once-daily,
reduced the bioavailability of gabapentin immediate release by about
with the evening meal. GRALISE tablets should be swallowed whole.
approximately 20%, but by only 5% when gabapentin was taken 2 hours after
Do not crush, split, or chew the tablets. (2.1)
antacids. It is recommended that GRALISE be taken at least 2 hours following
● If GRALISE dose is reduced, discontinued, or substituted with an
alternative medication, this should be done gradually over a minimum of
---------------------- USE IN SPECIFIC POPULATIONS -------------------------------
1 week or longer (at the discretion of the prescriber). (2.1)
● Pregnancy: GRALISE should be used during pregnancy only if the potential
● Renal impairment: Dose should be adjusted in patients with reduced renal
benefit justifies the potential risk to the fetus. (8.1)
function. GRALISE should not be used in patients with CrCl less than
● Nursing Mothers: GRALISE should be used in women who are nursing only
30 or in patients on hemodialysis. (2.2)
if the benefits clearly outweigh the risks. (8.3)
-------------------DOSAGE FORMS AND STRENGTHS ------------------------ ● Elderly: Reductions in GRALISE dose should be made i n
related compromised renal function. (8.5)
--------------------------- CONTRAINDICATIONS --------------------------------- ● Renal impairment: Dosage adjustment is necessary for p
GRALISE is contraindicated in patients who have demonstrated
hypersensitivity to the drug or its ingredients. (4)
---------------------WARNINGS AND PRECAUTIONS -------------------------- See 17 for PATIENT COUNSELING INFORMATION a edication
● GRALISE is not interchangeable with other gabapentin products
● Antiepileptic drugs, including gabapentin, the active ingredient in
GRALISE, increase the risk of suicidal thoughts or behavior (5.1)
● Increased seizure frequency may occur in patients with seizure disorders
if GRALISE is rapidly discontinued. Withdraw GRALISE gradually over a minimum of 1 week. (5.2)
FULL PRESCRIBING INFORMATION: CONTENTS* USE IN SPECIFIC POPULATIONS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS DRUG ABUSE AND DEPENDENCE 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY
5.4 Drug Reaction with Eosinophilia and Systemic Symptoms
6 ADVERSE REACTIONS 13 NONCLINICAL TOXICOLOGY
6.2 Postmarketing and Other Experience with other Formulations of
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES 7 DRUG INTERACTIONS 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed
7.10 Antacid (containing aluminum hydroxide and magnesium
FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE
GRALISE is indicated for the management of postherpetic neuralgia.
GRALISE is not interchangeable with other gabapentin products because of differing
pharmacokinetic profiles that affect the frequency of administration.
DOSAGE AND ADMINISTRATION 2.1 Postherpetic Neuralgia
Do not use GRALISE interchangeably with other gabapentin products.
Titrate GRALISE to an 1800 mg dose taken orally once daily with the evening meal.
GRALISE tablets should be swallowed whole. Do not split, crush, or chew the tablets.
If GRALISE dose is reduced, discontinued, or substituted with an alternative medication,
this should be done gradually over a minimum of one week or longer (at the discretion of the
In adults with postherpetic neuralgia, GRALISE therapy should be initiated and titrated
Table 1: GRALISE Recommended Titration Schedule Days 3–6 Days 7–10 Days 11–14 2.2 Patients with Renal Impairment
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.
The dose of GRALISE should be adjusted in patients with reduced renal function,
according to Table 2. Patients with reduced renal function must initiate GRALISE at a daily dose
of 300 mg. GRALISE should be titrated following the schedule outlined in Table 1. Daily
dosing in patients with reduced renal function must be individualized based on tolerability and
Table 2: GRALISE Dosage Based on Renal Function Once-daily dosing
GRALISE Dose (once daily with evening meal)
DOSAGE FORMS AND STRENGTHS
Tablets: 300 mg and 600 mg [see Description (11) and How Supplied/Storage and CONTRAINDICATIONS
GRALISE is contraindicated in patients with demonstrated hypersensitivity to the drug or
WARNINGS AND PRECAUTIONS
GRALISE is not interchangeable with other gabapentin products because of differing
pharmacokinetic profiles that affect the frequency of administration.
The safety and effectiveness of GRALISE in patients with epilepsy has not been studied.
5.1 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including gabapentin, the active ingredient in GRALISE,
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
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 3 shows
absolute and relative risk by indication for all evaluated AEDs.
Table 3: Risk by Indication for Antiepileptic Drugs (including gabapentin, the active ingredient in GRALISE) in the Pooled Analysis Relative Risk: Risk Difference: Drug Patients Incidence of Events Additional Drug Patients with with Events Indication Patients with Events Per Patients/Incidence Events Per 1000 1000 Patients Patients in Placebo Patients Patients
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 GRALISE must balance the risk of suicidal thoughts or
behavior with the risk of untreated illness. Epilepsy and many other illnesses for which
products containing active components that are AEDs (such as gabapentin, the active
component in GRALISE) 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 GRALISE contains
gabapentin which is also used to treat epilepsy and 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.
5.2 Withdrawal of Gabapentin
Gabapentin should be withdrawn gradually. If GRALISE is discontinued, this should be
done gradually over a minimum of 1 week or longer (at the discretion of the prescriber).
5.3 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.
The clinical significance of this finding is unknown.
In clinical trials of gabapentin therapy in epilepsy comprising 2,085 patient-years of
exposure in patients over 12 years of age, new tumors were reported in 10 patients, and pre-
existing tumors worsened in 11 patients, during or within 2 years after discontinuing the drug.
However, no similar patient population untreated with gabapentin was available to provide
background tumor incidence and recurrence information for comparison. Therefore, the effect
of gabapentin therapy on the incidence of new tumors in humans or on the worsening or
recurrence of previously diagnosed tumors is unknown.
5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as
Multiorgan Hypersensitivity, has been reported in patients taking antiepileptic drugs, including
GRALISE. Some of these events have been fatal or life-threatening. DRESS typically, although
not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other
organ system involvement, such as hepatitis, nephritis, hematological abnormalities,
myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often
present. Because this disorder is variable in its expression, other organ systems not noted here
It is important to note that early manifestations of hypersensitivity, such as fever or
lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms
are present, the patient should be evaluated immediately. GRALISE should be discontinued if
an alternative etiology for the signs or symptoms cannot be established.
5.5 Laboratory Tests
Clinical trial data do not indicate that routine monitoring of clinical laboratory procedures
is necessary for the safe use of GRALISE. The value of monitoring gabapentin blood
concentrations has not been established.
ADVERSE REACTIONS 6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
trials of another drug and may not reflect the rates observed in practice.
A total of 359 patients with neuropathic pain associated with postherpetic neuralgia have
received GRALISE at doses up to 1800 mg daily during placebo-controlled clinical studies. In
clinical trials in patients with postherpetic neuralgia, 9.7% of the 359 patients treated with
GRALISE and 6.9% of 364 patients treated with placebo discontinued prematurely due to
adverse reactions. In the GRALISE treatment group, the most common reason for
discontinuation due to adverse reactions was dizziness. Of GRALISE-treated patients who
experienced adverse reactions in clinical studies, the majority of those adverse reactions were
either "mild" or "moderate”.
Table 4 lists all adverse reactions, regardless of causality, occurring in at least 1% of
patients with neuropathic pain associated with postherpetic neuralgia in the GRALISE group for
which the incidence was greater than in the placebo group.
Table 4: Treatment-Emergent Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Postherpetic Neuralgia (Events in at Least 1% of all GRALISE-Treated Patients and More Frequent Than in the Placebo Group) Body System – Preferred Term Ear and Labyrinth Disorders Gastrointestinal Disorders General Disorders Infections and Infestations Investigations Musculoskeletal and Connective Tissue Disorders Nervous System Disorders
In addition to the adverse reactions reported in Table 4 above, the following adverse
reactions with an uncertain relationship to GRALISE were reported during the clinical
development for the treatment of postherpetic neuralgia. Events in more than 1% of patients but
equally or more frequently in the GRALISE-treated patients than in the placebo group included
blood pressure increase, confusional state, gastroenteritis viral, herpes zoster, hypertension, joint
swelling, memory impairment, nausea, pneumonia, pyrexia, rash, seasonal allergy, and upper
6.2 Postmarketing and Other Experience with other Formulations of Gabapentin
In addition to the adverse experiences reported during clinical testing of gabapentin, the
following adverse experiences have been reported in patients receiving other formulations of
marketed gabapentin. These adverse experiences have not been listed above and data are
insufficient to support an estimate of their incidence or to establish causation. The listing is
alphabetized: angioedema, blood glucose fluctuation, breast enlargement, elevated creatine
kinase, elevated liver function tests, erythema multiforme, fever, hyponatremia, jaundice,
movement disorder, Stevens-Johnson syndrome.
Adverse events following the abrupt discontinuation of gabapentin immediate release have
also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain
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; 1mM) was a slight degree of inhibition (14% to 30%) of isoform CYP2A6
observed. No inhibition of any of the other isoforms tested was observed at gabapentin
concentrations up to 171 mcg/mL (approximately 15 times the 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.
In a single (400 mg) and multiple dose (400 mg three times daily) study of gabapentin
immediate release 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.
Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide
concentrations were not affected by concomitant gabapentin immediate release (400 mg three
times daily; N=12) administration. Likewise, gabapentin pharmacokinetics were unaltered by
7.3 Valproic Acid
The mean steady-state trough serum valproic acid concentrations prior to and during
concomitant gabapentin immediate release administration (400 mg three times daily; N=17)
were not different and neither were gabapentin pharmacokinetic parameters affected by
Estimates of steady-state pharmacokinetic parameters for phenobarbital or gabapentin
immediate release (300 mg three times daily; N=12) are identical whether the drugs are
Coadministration of single doses of naproxen (250 mg) and gabapentin immediate release
(125 mg) to 18 volunteers increased gabapentin absorption by 12% to 15%. Gabapentin
immediate release had no effect on naproxen pharmacokinetics. The doses are lower than the
therapeutic doses for both drugs. The effect of coadministration of these drugs at therapeutic
Coadministration of gabapentin immediate release (125 mg and 500 mg) and hydrocodone
(10 mg) reduced hydrocodone Cmax by 3% and 21%, respectively, and AUC by 4% and 22%,
respectively. The mechanism of this interaction is unknown. Gabapentin AUC values were
increased by 14%; the magnitude of the interaction at other doses is not known.
When a single dose (60 mg) of controlled-release morphine capsule was administered 2
hours prior to a single dose (600 mg) of gabapentin immediate release in 12 volunteers, mean
gabapentin AUC values increased by 44% compared to gabapentin immediate release
administered without morphine. The pharmacokinetics of morphine were not affected by
administration of gabapentin immediate release 2 hours after morphine. The magnitude of this
interaction at other doses is not known.
Cimetidine 300 mg decreased the apparent oral clearance of gabapentin by 14% and
creatinine clearance by 10%. The effect of gabapentin immediate release on cimetidine was not
evaluated. This decrease is not expected to be clinically significant.
7.9 Oral Contraceptives
Gabapentin immediate release (400 mg three times daily) had no effect on the
pharmacokinetics of norethindrone (2.5 mg) or ethinyl estradiol (50 mcg) administered as a
single tablet, except that the Cmax of norethindrone was increased by 13%. This interaction is
not considered to be clinically significant.
7.10 Antacid (containing aluminum hydroxide and magnesium hydroxide)
An antacid containing aluminum hydroxide and magnesium hydroxide reduced the
bioavailability of gabapentin immediate release by about approximately 20%, but by only 5%
when gabapentin immediate release was taken 2 hours after the antacid. It is recommended that
GRALISE be taken at least 2 hours following the antacid (containing aluminum hydroxide and
Gabapentin immediate release pharmacokinetic parameters were comparable with and
without probenecid, indicating that gabapentin does not undergo renal tubular secretion by the
7.12 Drug/Laboratory Test Interactions
False positive readings were reported with the Ames-N-Multistix SG® dipstick test for
urine protein when gabapentin was added to other antiepileptic drugs; therefore, the more
specific sulfosalicylic acid precipitation procedure is recommended to determine the presence
USE IN SPECIFIC POPULATIONS 8.1 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 3 to 8 times the maximum dose of 1800 mg/day given
to PHN patients on a mg/m2 basis. The no effect level was 500 mg/kg/day representing
approximately the maximum recommended human dose [MRHD] on a mg/m2 body surface area
(BSA) 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 approximately 3 to 11 times the MRHD on a mg/m2 BSA 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 3 to 11 times the maximum human dose of 1800 mg/day on a mg/m2 basis; the no-
effect doses were approximately 5 times (Fertility and General Reproductive Performance study)
and approximately equal to (Teratogenicity study) the maximum human dose on a mg/m2 BSA
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 100 times (mice), 60 times (rats), and 50 times (rabbits) the human
daily dose on a mg/kg basis, or 8 times (mice), 10 times (rats), or 16 times (rabbits) the human
daily dose on a mg/m2 BSA 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 0.6 to
16 times the maximum human dose on a mg/m2 BSA 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 GRALISE,
physicians are advised to recommend that pregnant patients taking GRALISE 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
8.3 Nursing Mothers
Gabapentin is secreted into human milk following oral administration. A nursed infant
could be exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the
effect on the nursing infant is unknown, GRALISE should be used in women who are nursing
only if the benefits clearly outweigh the risks.
8.4 Pediatric Use
The safety and effectiveness of GRALISE in the management of postherpetic neuralgia in
patients less than 18 years of age has not been studied.
8.5 Geriatric Use
The total number of patients treated with GRALISE in controlled clinical trials in patients
with postherpetic neuralgia was 359, of which 63% were 65 years of age or older. The types
and incidence of adverse events were similar across age groups except for peripheral edema,
which tended to increase in incidence with age.
GRALISE is known to be substantially excreted by the kidney. Reductions in GRALISE
dose should be made in patients with age-related compromised renal function. [see Dosage and 8.6 Hepatic Impairment
Because gabapentin is not metabolized, studies have not been conducted in patients with
GRALISE is known to be substantially excreted by the kidney. Dosage adjustment is
necessary in patients with impaired renal function. GRALISE should not be administered in
patients with CrCL between 15 and 30 or in patients undergoing hemodialysis.[see Dosage and DRUG ABUSE AND DEPENDENCE
The abuse and dependence potential of GRALISE has not been evaluated in human studies.
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 immediate release in humans 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.
Gabapentin is 1-(aminomethyl)cyclohexaneacetic acid; γ-amino-2-cyclohexyl-butyric acid
with a molecular formula of C9H17NO2 and a molecular weight of 171.24.
Gabapentin is a white to off-white crystalline solid with a pKa1 of 3.7 and a pKa2 of 10.7.
It is freely soluble in water and acidic and basic solutions. The log of the partition coefficient
(n-octanol/ 0.05M phosphate buffer) at pH 7.4 is -1.25.
GRALISE is supplied as tablets containing 300 mg or 600 mg of gabapentin. GRALISE
tablets swell in gastric fluid and gradually release gabapentin. Each 300 mg tablet contains the
inactive ingredients copovidone, hypromellose, magnesium stearate, microcrystalline cellulose,
polyethylene oxide, and Opadry® II white. Opadry® II white contains polyvinyl alcohol,
titanium dioxide, talc, polyethylene glycol 3350, and lecithin (soya). Each 600 mg tablet
contains the inactive ingredients copovidone, hypromellose, magnesium stearate, polyethylene
oxide, and Opadry® II beige. Opadry® II beige contains polyvinyl alcohol, titanium dioxide, talc,
polyethylene glycol 3350, iron oxide yellow, and iron oxide red.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action
The mechanism of action 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).
Gabapentin prevents pain-related responses in several models of neuropathic pain in rats and
mice (e.g., spinal nerve ligation models, spinal cord injury model, acute herpes zoster infection
model). Gabapentin also decreases pain-related responses after peripheral inflammation
(carrageenan footpad test, late phase of formulin test), but does not alter immediate pain-related
behaviors (rat tail flick test, formalin footpad acute phase). The relevance of these models to
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. In radioligand binding assays at concentrations up to 100 μM, gabapentin did not
exhibit affinity for a number of other 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 A20-
alpha-benzoate. Gabapentin did not alter the cellular uptake of dopamine, noradrenaline, or
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.
It is hypothesized that gabapentin antagonizes thrombospondin binding to α2δ-1 as a receptor
involved in excitatory synapse formation and suggested that gabapentin may function
therapeutically by blocking new synapse formation.
No pharmacodynamic studies have been conducted with GRALISE.
12.3 Pharmacokinetics Absorption and Bioavailability
Gabapentin is absorbed from the proximal small bowel by a saturable L-amino transport
system. Gabapentin bioavailability is not dose proportional; as the dose is increased,
When GRALISE (1800 mg once daily) and gabapentin immediate release (600 mg three
times a day) were administered with high fat meals (50% of calories from fat), GRALISE has a
higher Cmax and lower AUC at steady state compared to gabapentin immediate release (Table 5).
Time to reach maximum plasma concentration (Tmax) for GRALISE is 8 hours, which is about
4-6 hours longer compared to gabapentin immediate release.
Table 5: Mean (SD) Steady-State Pharmacokinetics for GRALISE and Gabapentin Immediate Release in Plasma of Healthy Subjects (Day 5, n = 21) Pharmacokinetic Gabapentin Parameters Immediate Release 1800 mg QD (Mean ± SD) 600 mg TID
(ng ● hr/mL) Cmax (ng/mL) Cmin (ng/mL) Tmax (hr) median (range) * = relative to most recent dose
Do not use GRALISE interchangeably with other gabapentin products because of differing
pharmacokinetic profiles that affect frequency of administration.
GRALISE should be taken with evening meals. If it is taken on an empty stomach, the
bioavailability will be substantially lower.
Administration of GRALISE with food increases the rate and extent of absorption of
gabapentin compared to the fasted state. Cmax of gabapentin increases 33-84% and AUC of
gabapentin increases 33-118% with food depending on the fat content of the meal. GRALISE
Gabapentin is less than 3% bound to plasma proteins. After 150 mg intravenous
administration, the mean ± SD volume of distribution is 58 ± 6 L. Metabolism and Excretion
Gabapentin is eliminated by renal excretion as unchanged drug. Gabapentin is not
appreciably metabolized in humans. In patients with normal renal function given gabapentin
immediate release 1200 to 3000 mg/day, the drug elimination half-life (t1/2) was 5 to 7 hours.
Elimination kinetics do not change with dose level or multiple doses.
Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly
proportional to creatinine clearance. In elderly patients and patients with impaired renal
function, plasma clearance is reduced. Gabapentin can be removed from plasma by
Dosage adjustment in patients with compromised renal function is necessary. In patients
undergoing hemodialysis, GRALISE should not be administered [see Dosage and 12.4 Special Populations Renal Insufficiency: As renal function decreases, renal and plasma clearances and the
apparent elimination rate constant decrease, while Cmax and t1/2 increase.
In patients (N=60) with creatinine clearance of at least 60, 30 to 59, or less than
30 mL/min, the median renal clearance rates for a 400 mg single dose of gabapentin immediate
release were 79, 36, and 11 mL/min, respectively, and the median t1/2 values were 9.2, 14, and
Dosage adjustment is necessary in patients with impaired renal function [see Dosage and 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. GRALISE should not be administered in patients
undergoing hemodialysis. Alternative formulations of gabapentin products should be
considered in patients undergoing hemodialysis.
Elderly: Apparent oral and renal clearances of gabapentin decrease with increasing age,
although this may be related to the decline in renal function with age. Reductions in gabapentin
dose should be made in patients with age-related compromised renal function [see Dosage and Hepatic Impairment: Because gabapentin is not metabolized, studies have not been
conducted in patients with hepatic impairment.
Pediatrics: The pharmacokinetics of GRALISE have not been studied in patients less than 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.
13 NONCLINICAL TOXICOLOGY 13.1 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 adenoma 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/day were more than
10 times higher than plasma concentrations in humans receiving 1800 mg per day and in rats
receiving 1000 mg/kg/day peak plasma concentrations were more than 6.5 times higher than in
humans receiving 1800 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
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
Gabapentin did not demonstrate mutagenic or genotoxic potential in 3 in vitro and 4 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 11 times the maximum recommended human dose on an mg/m2
14 CLINICAL STUDIES
The efficacy of GRALISE for the management of postherpetic neuralgia was established
in a double-blind, placebo-controlled, multicenter study. This study enrolled patients between
the age of 21 to 89 with postherpetic neuralgia persisting for at least 6 months following healing
of herpes zoster rash and a minimum baseline pain intensity score of at least 4 on an 11-point
numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain).
This 11-week study compared GRALISE 1800 mg once daily with placebo. A total of 221
and 231 patients were treated with GRALISE or placebo, respectively. The study treatment
including titration for all patients comprised a 10-week treatment period followed by 1-week of
dose tapering. Double-blind treatment began with titration starting at 300 mg/day and titrated
up to a total daily dose of 1800 mg over 2 weeks, followed by 8 weeks fixed dosing at 1800 mg
once daily, and then 1 week of dose tapering. During the 8-week stable dosing period, patients
took 3 active or placebo tablets each night with the evening meal. During baseline and
treatment, patients recorded their pain in a daily diary using an 11-point numeric pain rating
scale. The mean baseline pain score was 6.6 and 6.5 for GRALISE and placebo-treated patients,
Treatment with GRALISE statistically significantly improved the endpoint mean pain
score from baseline. For various degrees of improvement in pain from baseline to study
endpoint, Figure 1 shows the fraction of patients achieving that degree of improvement. The
figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also
included at every level of improvement below 50%. Patients who did not complete the study
Percent Improvement in Pain from Baseline Figure 1: Percent of Patients Achieving Various Levels of Pain Relief 16 HOW SUPPLIED/STORAGE AND HANDLING
GRALISE (gabapentin) Tablets are supplied as follows:
300 mg tablets:
GRALISE 300 mg tablets are white, oval shaped tablets debossed with “SLV” on one side
600 mg tablets:
GRALISE 600 mg tablets are beige, oval shaped tablets debossed with “SLV” on one side
30-Day Starter Pack:
NDC 13913-006-16 (Blister package containing 78 tablets: 9 x 300 mg tablets and 69 x
Store at 25ºC (77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) [see USP
17 PATIENT COUNSELING INFORMATION
• Advise patients that GRALISE is not interchangeable with other formulations of
• Advise patients to take GRALISE only as prescribed. GRALISE may cause dizziness,
somnolence, and other signs and symptoms of CNS depression.
• Advise patients not to drive or operate other complex machinery until they have gained
sufficient experience on GRALISE to gauge whether or not it adversely affects their
mental and/or motor performance. Advise patients who require concomitant treatment
with morphine to tell their prescriber if they develop signs of CNS depression such as
somnolence. If this occurs the dose of GRALISE or morphine should be reduced
• Advise patients that if they miss a dose of GRALISE to take it with food as soon as they
remember. If it is almost time for the next dose, just skip the missed dose and take the
next dose at the regular time. Do not take two doses at the same time.
• Advise patients that if they take too much GRALISE, to call their healthcare provider or
poison control center, or go to the nearest emergency room right away.
17.1 Medication Guide
Advise patients of the availability of a Medication Guide, and instruct them to read the
Medication Guide prior to taking GRALISE.
17.2 Suicidal Thoughts and Behavior
Advise patients, their caregivers, and families that AEDs, including gabapentin, the active
ingredient in GRALISE, 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 [see Warnings and Precautions (5.1)]. 17.3 Dosing and Administration
Advise patients that GRALISE should be taken orally once-daily with the evening meal.
GRALISE tablets should be swallowed whole. Do not split, crush, or chew the tablets [see Dosage and Administration (2.1)]. Marketed by:
Opadry® is a registered trademark of BPSI Holdings, LLC.
U.S. Patents: 7,438,927; 6,340,475; 6,488,962; 6,635,280; 6,723,340; 7,731,989; 8,192,756; 8,252,332
MEDICATION GUIDE GRALISE® (gra leez’) (gabapentin) Tablets
Read this Medication Guide before you start taking GRALISE and each time you get a refill.
There may be new information. This information does not take the place of talking to your
healthcare provider about your medical condition or treatment. If you have any questions about
GRALISE, ask your healthcare provider or pharmacist.
What is the most important information I should know about GRALISE? Do not stop taking GRALISE without first talking with your healthcare provider. Stopping
GRALISE suddenly can cause serious problems.
Like other antiepileptic drugs, gabapentin, the active ingredient in GRALISE, may cause suicidal
thoughts or actions in a very small number of people, about 1 in 500. However, it is not known
if GRALISE is safe and effective in people with seizure problems (epilepsy). Therefore,
GRALISE should not be used in place of other gabapentin products.
Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
● acting aggressive, being angry, or violent
● an extreme increase in activity and talking (mania)
● other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
● Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts,
● Keep all follow-up visits with your healthcare provider as scheduled.
● Call your healthcare provider between visits as needed, especially if you are worried
Do not stop taking GRALISE without first talking with your healthcare provider.
• Stopping GRALISE suddenly can cause serious problems.
What is GRALISE?
GRALISE is a prescription medicine used in adults, 18 years and older, to treat:
● pain from damaged nerves (neuropathic pain) that follows healing of shingles (a painful
rash that comes after a herpes zoster infection).
It is not known if GRALISE is safe and effective in people with seizure problems (epilepsy).
It is not known if GRALISE is safe and effective in children under 18 years of age with
GRALISE is not interchangeable with other gabapentin products.
Who should not take GRALISE?
Do not take GRALISE if you are allergic to gabapentin or any of the ingredients in GRALISE.
See the end of this Medication Guide for a complete list of ingredients in GRALISE.
What should I tell my healthcare provider before taking GRALISE?
Before taking GRALISE, tell your healthcare provider if you:
● have or have had depression, mood problems or suicidal thoughts or behavior
● have kidney problems or get kidney dialysis
● are pregnant or plan to become pregnant. It is not known if GRALISE can harm your
unborn baby. Tell your healthcare provider right away if you become pregnant while
taking GRALISE. You and your healthcare provider will decide if you should take
o If you become pregnant while taking GRALISE, talk to your healthcare provider
about registering with the North American Antiepileptic Drug (NAAED)
Pregnancy Registry. The purpose of this registry is to collect information about
the safety of antiepileptic drugs, including gabapentin, the active ingredient in
GRALISE, during pregnancy. You can enroll in this registry by calling 1-888-
● are breastfeeding or plan to breastfeed. GRALISE can pass into your breast milk. You
and your healthcare provider should decide how you will feed your baby while you take
Tell your healthcare provider about all the medicines you take including prescription and non-
prescription medicines, vitamins or herbal supplements.
Taking GRALISE with certain other medicines can cause side effects or affect how well they
work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
How should I take GRALISE?
● Take GRALISE exactly as prescribed. Your healthcare provider will tell you how much
GRALISE to take and when to take it. Take GRALISE at the same time each day.
• Do not change your dose or stop taking GRALISE without talking with your healthcare provider. If you stop taking GRALISE suddenly, you may experience side
effects. Talk with your healthcare provider about how to stop GRALISE slowly.
● Take GRALISE with food one time each day with your evening meal.
• Take GRALISE tablets whole. Do not split, crush, or chew GRALISE tablets before
● Your healthcare provider may change your dose of GRALISE. Do not change your dose
of GRALISE without talking to your healthcare provider.
● If you miss a dose, take it as soon as you remember with food. If it is almost time for
your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take two doses at the same time.
● If you take too much GRALISE, call your healthcare provider or poison control center,
or go to the nearest emergency room right away.
• If you are taking an antacid containing aluminum hydroxide and magnesium hydroxide,
it is recommended that GRALISE be taken at least 2 hours following administration of
What should I avoid while taking GRALISE?
• Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking
GRALISE without first talking to your healthcare provider. Taking GRALISE with
alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or
• Do not operate heavy machines or do other dangerous activities until you know how
GRALISE affects you. GRALISE can slow your thinking and motor skills.
What are the possible side effects of GRALISE?
The most common side effect of GRALISE is:
Tell your healthcare provider about any side effect that bothers you or that does not go away.
These are not all the possible side effects of GRALISE. For more information, ask your
Call your doctor for medical advice about side effects. You may report side effects to FDA at
How should I store GRALISE?
Store GRALISE at 59ºF to 86ºF (15ºC to 30ºC)
● Keep GRALISE and all medicines out of the reach of children. General information about the safe and effective use of GRALISE
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use GRALISE for a condition for which it was not prescribed. Do not give GRALISE to
other people, even if they have the same symptoms you have. It may harm them.
This Medication Guide summarizes the most important information about GRALISE. If you
would like more information, talk with your healthcare provider. You can ask your healthcare
provider or pharmacist for information about GRALISE that is written for health professionals.
For more information about GRALISE, call 1-866-458-6389.
What are the ingredients in GRALISE?
300 mg tablet: copovidone, hypromellose, magnesium stearate, microcrystalline cellulose,
polyethylene oxide, and Opadry® II white. Opadry® II white contains polyvinyl alcohol,
titanium dioxide, talc, polyethylene glycol 3350, and lecithin (soya).
600 mg tablet: copovidone, hypromellose, magnesium stearate, polyethylene oxide, and
Opadry® II beige. Opadry® II beige contains polyvinyl alcohol, titanium dioxide, talc,
polyethylene glycol 3350, iron oxide yellow, and iron oxide red.
Opadry® is a registered trademark of BPSI Holdings, LLC.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Correspondence Infant mortality (per thousand livebirths) group on HIV in women and children. Mortality among infected and uninfectedAfrica: a pooled analysis. Lancet 2004; 364: Abrams EJ, Wiener J, Carter R, et al. Maternalhealth factors and early pediatric antiretroviraltherapy inﬂuence the rate of perinatal HIV-Idisease progression in children. AIDS , 2003; Table: Infant m