NDC 52427-815 Gralise

Gabapentin

NDC Product Code 52427-815

NDC CODE: 52427-815

Proprietary Name: Gralise What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Gabapentin What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Product Characteristics

Color(s):
WHITE (C48325)
BROWN (C48332 - BEIGE)
Shape: OVAL (C48345)
Size(s):
16 MM
19 MM
Imprint(s):
SLV;300
SLV;600
Score: 1

NDC Code Structure

  • 52427 - Almatica Pharma Llc

NDC 52427-815-99

Package Description: 1 KIT in 1 BLISTER PACK

NDC Product Information

Gralise with NDC 52427-815 is a a human prescription drug product labeled by Almatica Pharma Llc. The generic name of Gralise is gabapentin. The product's dosage form is kit and is administered via form.

Labeler Name: Almatica Pharma Llc

Dosage Form: Kit - A packaged collection of related material.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • COPOVIDONE K25-31 (UNII: D9C330MD8B)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)
  • POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • TALC (UNII: 7SEV7J4R1U)
  • POLYETHYLENE GLYCOL 3350 (UNII: G2M7P15E5P)
  • LECITHIN, SOYBEAN (UNII: 1DI56QDM62)
  • COPOVIDONE K25-31 (UNII: D9C330MD8B)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)
  • POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • TALC (UNII: 7SEV7J4R1U)
  • POLYETHYLENE GLYCOL 3350 (UNII: G2M7P15E5P)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • COPOVIDONE K25-31 (UNII: D9C330MD8B)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)
  • POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • TALC (UNII: 7SEV7J4R1U)
  • POLYETHYLENE GLYCOL 3350 (UNII: G2M7P15E5P)
  • LECITHIN, SOYBEAN (UNII: 1DI56QDM62)
  • COPOVIDONE K25-31 (UNII: D9C330MD8B)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)
  • POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • TALC (UNII: 7SEV7J4R1U)
  • POLYETHYLENE GLYCOL 3350 (UNII: G2M7P15E5P)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Almatica Pharma Llc
Labeler Code: 52427
FDA Application Number: NDA022544 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 10-01-2020 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Gralise Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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.

2.1 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
(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 desired clinical benefit. Table 2: GRALISE Dosage Based on Renal Function
Once-daily dosing Creatinine Clearance (mL/min) GRALISE Dose (once daily with
evening 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

300 mg: white, oval shaped tablets debossed with “SLV” on one side and “300” on the other side
600 mg: beige, oval shaped tablets debossed with “SLV” on one side and “600” on the other side

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 1000 Patients Drug Patients with Events Per
1000 Patients Relative Risk: Incidence of
Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional
Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in
clinical trials for epilepsy than in clinical trials for psychiatric or
other conditions, but the absolute risk differences were similar for the
epilepsy and psychiatric indications.Anyone considering prescribing 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 Respiratory Depression

There is evidence from case reports, human studies, and animal studies associating gabapentin with serious, life-threatening, or fatal respiratory depression when co-administrated with central nervous system (CNS) depressants, including opioids, or in the setting of underlying respiratory impairment. When the decision is made to co-prescribe GRALISE with another CNS depressant, particularly an opioid, or to prescribe GRALISE to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating GRALISE at a low dose. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including GRALISE).

5.3 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).

5.4 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.

5.5 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 may be involved.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.

5.6 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.

6.1 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 GRALISEN =
359% PlaceboN =
364% Ear and Labyrinth Disorders     Vertigo 1.4 0.5 Gastrointestinal Disorders     Diarrhea 3.3 2.7     Dry mouth 2.8 1.4     Constipation 1.4 0.3     Dyspepsia 1.4 0.8 General Disorders     Peripheral edema 3.9 0.3     Pain 1.1 0.5 Infections and Infestations     Nasopharyngitis 2.5 2.2     Urinary tract infection 1.7 0.5 Investigations     Weight increased 1.9 0.5 Musculoskeletal and Connective Tissue
Disorders     Pain in extremity 1.9 0.5     Back pain 1.7 1.1 Nervous System Disorders     Dizziness 10.9 2.2     Somnolence 4.5 2.7     Headache 4.2 4.1     Lethargy 1.1 0.3 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, bullous pemphigoid, 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.There are postmarketing reports of life-threatening or fatal respiratory depression in patients taking gabapentin with opioids or other central nervous system (CNS) depressants, or in the setting of underlying respiratory impairment.

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 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.

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 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.

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
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
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.

8.1 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 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

Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation.Acute oral overdoses of gabapentin have been reported. Symptoms include double-vision, tremor, slurred speech, drowsiness, altered mental status, dizziness, lethargy, and diarrhea. Fatal respiratory depression has been reported with gabapentin overdose, alone and in combination with other central nervous system (CNS) depressants.Gabapentin can be removed by hemodialysis. Hemodialysis has been performed in overdose cases reported, and 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
C9H17NO2 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.

12.1 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 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 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
BioavailabilityGabapentin 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 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)
PharmacokineticParameters(Mean ± SD)
GRALISE1800 mg QD Gabapentin
Immediate Release600 mg TID * = relative to most recent dose
AUC0-24 (ng•hr/mL) 132,808 ± 34,701 141,301 ± 29,759 Cmax (ng/mL) 9,585 ± 2,326 8,536 ± 1,715 Cmin (ng/mL) 1,842 ± 654 2,588 ± 783 Tmax (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. Cmax
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.DistributionGabapentin 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 ExcretionGabapentin 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 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 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 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 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.

13.1 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/m2 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

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 and "300" on the other side. NDC 52427-803-90 (Bottle of 90) 600 mg tablets:GRALISE 600 mg tablets are beige, oval shaped tablets debossed with "SLV" on one side and "600" on the other side.NDC 52427-806-90 (Bottle of 90)StorageStore at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].Keep out of reach of children.

17 Patient Counseling Information

  • Advise patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking GRALISE.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 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)].

17.2 Respiratory Depression

Inform patients about the risk of respiratory depression. Include information that the risk is greatest for those using concomitant central nervous system (CNS) depressants (such as opioid analgesics) or in those with underlying respiratory impairment. Teach patients how to recognize respiratory depression and advise them to seek medical attention immediately if it occurs [see Warnings and Precautions (5.2)].

17.3 Dosing And Administration

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.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)].

* Please review the disclaimer below.