GRALISE gabapentin tablet film coated

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

Buy It Now

Active ingredient:
GABAPENTIN (UNII: 6CW7F3G59X) (GABAPENTIN - UNII:6CW7F3G59X)
Available from:
Unit Dose Services
INN (International Name):
GABAPENTIN
Composition:
GABAPENTIN 600 mg
Prescription type:
PRESCRIPTION DRUG
Authorization status:
New Drug Application

GRALISE - gabapentin tablet, film coated

Unit Dose Services

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use GRALISE safely and effectively. See full

prescribing information for GRALISE.

GRALISE (gabapentin) tablets

Initial U.S. Approval: 1993

INDICATIONS AND USAGE

GRALISE is indicated for the management of Postherpetic Neuralgia (PHN).

Important Limitation: GRALISE is not interchangeable with other gabapentin products because of differing

pharmacokinetic profiles that affect the frequency of administration (See Warnings and Precautions)

DOSAGE AND ADMINISTRATION

GRALISE should be titrated to an 1800 mg dose taken orally, once-daily, with the evening meal. GRALISE tablets

should be swallowed whole. Do not crush, split, or chew the tablets. (2.1)

If GRALISE dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually

over a minimum of 1 week or longer (at the discretion of the prescriber). (2.1)

Renal impairment: Dose should be adjusted in patients with reduced renal function. GRALISE should not be used in

patients with CrCl less than 30 or in patients on hemodialysis. (2.2)

DOSAGE FORMS AND STRENGTHS

300 and 600 mg tablets (3)

CONTRAINDICATIONS

GRALISE is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. (4)

WARNINGS AND PRECAUTIONS

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)

ADVERSE REACTIONS

The most common adverse reaction (greater than or equal to 5% and twice placebo) is dizziness. (6.1)

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

DRUG INTERACTIONS

An increase in gabapentin AUC values have been reported when administered with hydrocodone. (7.6)

An increase in gabapentin AUC values have been reported when administered with morphine. (7.7)

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 was taken 2 hours after antacids. It is

recommended that GRALISE be taken at least 2 hours following antacid administration. (7.10)

USE IN SPECIFIC POPULATIONS

Pregnancy: GRALISE should be used during pregnancy only if the potential benefit justifies the potential risk to the

fetus. (8.1)

Nursing Mothers: GRALISE should be used in women who are nursing only if the benefits clearly outweigh the risks.

(8.3)

Elderly: Reductions in GRALISE dose should be made in patients with age-related compromised renal function. (8.5)

Renal impairment: Dosage adjustment is necessary for patients with impaired renal function. (8.7)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 11/2017

®

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Postherpetic Neuralgia

2.2 Patients with Renal Impairment

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Behavior and Ideation

5.2 Withdrawal of Gabapentin

5.3 Tumorigenic Potential

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity

5.5 Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing and Other Experience with other Formulations of Gabapentin

7 DRUG INTERACTIONS

7.1 Phenytoin

7.2 Carbamazepine

7.3 Valproic Acid

7.4 Phenobarbital

7.5 Naproxen

7.6 Hydrocodone

7.7 Morphine

7.8 Cimetidine

7.9 Oral Contraceptives

7.10 Antacid (containing aluminum hydroxide and magnesium hydroxide)

7.11 Probenecid

7.12 Drug/Laboratory Test Interactions

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

9 DRUG ABUSE AND DEPENDENCE

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Special Populations

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Medication Guide

17.2 Suicidal Thoughts and Behavior

17.3 Dosing and Administration

FULL PRESCRIBING INFORMATION

GRA-004-C.7 SEP 2015

GRALISE (gabapentin) Tablets Rx only

1 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.

2 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 prescriber).

In adults with postherpetic neuralgia, GRALISE therapy should be initiated and titrated as follows:

Table 1: GRALISE Recommended Titration Schedule

Day 1

Day 2

Days 3-6 Days 7-10

Days 11-

14

Day 15

Daily Dose

300 mg

600 mg

900 mg

1200 mg

1500 mg

1800 mg

2.2 Patients with Renal Impairment

In patients with stable renal function, creatinine clearance (C

) can be reasonably well estimated using

the equation of Cockcroft and Gault:

For females C

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

For males C

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

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

is serum creatinine in mg/dL.

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 desired clinical benefit.

Table 2: GRALISE Dosage Based on Renal Function

Once-daily dosing

Creatinine Clearance (mL/min)

GRALISE Dose (once daily with evening

Sections or subsections omitted from the full prescribing information are not listed.

Creatinine Clearance (mL/min)

meal)

≥ 60

1800 mg

30 - 60

600 mg to 1800 mg

< 30

GRALISE should not be administered

patients receiving hemodialysis

GRALISE should not be administered

3 DOSAGE FORMS AND STRENGTHS

Tablets: 300 mg and 600 mg [see Description (11) and How Supplied/Storage and Handling (16)]

4 CONTRAINDICATIONS

GRALISE is contraindicated in patients with demonstrated hypersensitivity to the drug or its ingredients.

5 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 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 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

Indication

Placebo Patients

with Events Per

Drug Patients

with Events Per

Relative Risk:

Incidence of

Events in Drug

Risk Difference:

Additional Drug

Patients with

Indication

with Events Per

1000 Patients

with Events Per

1000 Patients

Patients/Incidence

in Placebo

Patients

Patients with

Events Per

1000 Patients

Epilepsy

Psychiatric

Other

Total

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in

clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the

epilepsy and psychiatric indications.

Anyone considering prescribing 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

Hypers ens itivity

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 may be involved.

It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy,

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.

6 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

GRALISE

N = 359

%

Placebo

N = 364

%

Ear and Labyrinth Disorders

Vertigo

Gastrointestinal Disorders

Diarrhea

Dry mouth

Constipation

Dyspepsia

General Disorders

Peripheral edema

Pain

Infections and Infestations

Nasopharyngitis

Urinary tract infection

Inves tigations

Weight increased

Musculoskeletal and Connective

Tissue Disorders

Pain in extremity

Back pain

Nervous System Disorders

Dizziness

10.9

Somnolence

Headache

Lethargy

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 respiratory infection.

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 and sweating.

7 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 C

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.

7.1 Phenytoin

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.

7.2 Carbamazepine

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 carbamazepine administration.

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 valproic acid.

7.4 Phenobarbital

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 administered alone or together.

7.5 Naproxen

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 doses is not known.

7.6 Hydrocodone

Coadministration of gabapentin immediate release (125 mg and 500 mg) and hydrocodone (10 mg)

reduced hydrocodone C

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.

7.7 Morphine

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.

7.8 Cimetidine

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 C

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 magnesium hydroxide) administration.

7.11 Probenecid

Gabapentin immediate release pharmacokinetic parameters were comparable with and without

probenecid, indicating that gabapentin does not undergo renal tubular secretion by the pathway that is

blocked by probenecid.

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 of urine protein.

8 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/m basis. The no effect level was 500 mg/kg/day representing approximately the maximum

recommended human dose [MRHD] on a mg/m 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/m 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/m 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/m 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/m

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/m 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

http://www.aedpregnancyregistry.org/.

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 Administration (2.2)].

8.6 Hepatic Impairment

Because gabapentin is not metabolized, studies have not been conducted in patients with hepatic

impairment.

8.7 Renal Impairment

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 Administration (2.2)].

9 DRUG ABUSE AND DEPENDENCE

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

10 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 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.

11 DESCRIPTION

Gabapentin is 1-(aminomethyl)cyclohexaneacetic acid; γ-amino-2-cyclohexyl-butyric acid with a

molecular formula of C H NO and a molecular weight of 171.24.

The structural formula is:

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 human pain is not known.

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

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

GABA agonist, and it is not an inhibitor of GABA uptake or degradation. 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 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. 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.

12.2 Pharmacodynamics

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, bioavailability decreases.

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 C

lower AUC at steady state compared to gabapentin immediate release (Table 5). Time to reach maximum

plasma concentration (T

) 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

Parameters

(Mean ± SD)

GRALISE

1800 mg QD

Gabapentin Immediate

Releas e

600 mg TID

* = relative to most recent dose

AUC

(nghr/mL)

132,808 ± 34,701

141,301 ± 29,759

C

(ng/mL)

9,585 ± 2,326

8,536 ± 1,715

C

(ng/mL)

1,842 ± 654

2,588 ± 783

T

(hr) median (range)

8 (3-12)

2 (1-5)*

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. C

of gabapentin increases 33-84% and AUC of gabapentin increases

33-118% with food depending on the fat content of the meal. GRALISE should be taken with food.

Distribution

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 (t

) 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 hemodialysis.

Dosage adjustment in patients with compromised renal function is necessary. In patients undergoing

hemodialysis, GRALISE should not be administered [see Dosage and Administration (2.2)].

12.4 Special Populations

Renal Insufficiency: As renal function decreases, renal and plasma clearances and the apparent

elimination rate constant decrease, while C

and t

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 t

values were 9.2, 14, and 40 hours, respectively.

Dosage adjustment is necessary in patients with impaired renal function [see Dosage and Administration

(2.2)].

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

0 -24

max

min

max

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 Administration (2.2)].

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 18 years of

age.

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 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 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/m basis).

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, respectively.

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 were assigned 0% improvement.

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 50436-1262

NDC: 50436-1262-3 90 TABLET, FILM COATED in a BOTTLE

17 PATIENT COUNSELING INFORMATION

Advise patients that GRALISE is not interchangeable with other formulations of gabapentin.

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 accordingly.

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:

Depomed, Inc.

Newark, CA 94560

Opadry® is a registered trademark of BPSI Holdings, LLC.

© 2015 Depomed, Inc.

GRA-004-C.7 SEP 2015

Issued SEP 2015

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;

8,333,992

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:

thoughts about suicide or dying

attempts to commit suicide

new or worse depression

new or worse anxiety

feeling agitated or restless

panic attacks

trouble sleeping (insomnia)

new or worse irritability

acting aggressive, being angry, or violent

acting on dangerous impulses

an extreme increase in activity and talking (mania)

other unusual changes in behavior or mood

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

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

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

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

symptoms.

Do not stop taking 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 postherpetic

pain.

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 seizures

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 GRALISE while you are pregnant.

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 1-888-233-2334.

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 GRALISE.

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

pharmacist when you get a new medicine.

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 swallowing.

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 the antacid.

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 dizziness worse.

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:

dizziness

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 healthcare

provider or pharmacist.

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

1-800-FDA-1088.

How should I store GRALISE?

Store GRALISE at 59°F to 86°F (15°C to 30°C)

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?

Active ingredient: gabapentin

Inactive ingredients:

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

beige. Opadry

II beige contains polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol 3350,

iron oxide yellow, and iron oxide red.

Marketed by:

Depomed, Inc.

Newark, CA 94560

Opadry

is a registered trademark of BPSI Holdings, LLC.

© 2015 Depomed, Inc.

GRA-004-C.7 SEP 2015

Issued SEP 2015

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

GRALISE (GABAPENTIN) TABLET, FILM COATED GRALISE STARTER PACK

(GABAPENTIN) KIT

GRALISE

gabapentin tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:50 436 -126 2(NDC:139 13-0 0 5)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

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

GABAPENTIN

6 0 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CO PO VIDO NE K2 5-3 1 (UNII: D9 C330 MD8 B)

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO LYETHYLENE GLYCO L, UNSPECIFIED (UNII: 3WJQ0 SDW1A)

PO LYVINYL ALCO HO L, UNSPECIFIED (UNII: 532B59 J9 9 0 )

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TALC (UNII: 7SEV7J4R1U)

PO LYETHYLENE GLYCO L 3 3 50 (UNII: G2M7P15E5P)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

Product Characteristics

Color

bro wn

S core

no sco re

S hap e

OVAL

S iz e

19 mm

Flavor

Imprint Code

SLV;6 0 0

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:50 436 -126 2-3

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

0 1/28 /20 11

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 22544

0 1/28 /20 11

Labeler -

Unit Dose Services (831995316)

Establishment

Unit Dose Services

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Unit Do se Services

8 319 9 5316

REPACK(50 436 -126 2) , RELABEL(50 436 -126 2)

Revised: 11/2017

Similar products

Search alerts related to this product

Share this information