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)
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
` ----------------------------- 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: 12/2012
`
`
`
`
`
` 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
`
`
`*Sections or subsections omitted from the full prescribing information are
`not listed
`
`
`
`
`
`
`Depomed Exhibit 2027, Page 1 of 24
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`

`
`FULL PRESCRIBING INFORMATION
` GRA-004-C.6 DEC 2012
`
`
`
`
`
`GRALISE® (gabapentin) Tablets
`
`INDICATIONS AND USAGE
`1
`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:
`
`
`Daily Dose
`
`Table 1: GRALISE Recommended Titration Schedule
`Day 1
`Day 2
`Days 3–6 Days 7–10 Days 11–14
`300 mg
`600 mg
`900 mg
`1200 mg
`1500 mg
`
`Day 15
`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.
`
`
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`

`
`Table 2: GRALISE Dosage Based on Renal Function
`Once-daily dosing
`GRALISE Dose (once daily with evening meal)
`1800 mg
`600 mg to 1800 mg
`GRALISE should not be administered
`GRALISE should not be administered
`
`Creatinine Clearance (mL/min)
`≥ 60
`30 - 60
`< 30
`patients receiving hemodialysis
`
` 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.
`
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`

`
`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
`
`Placebo
`Patients with
`Events Per
`1000 Patients
`
`Drug Patients
`with Events
`Per 1000
`Patients
`
`1.0
`5.7
`1.0
`2.4
`
`3.4
`8.5
`1.8
`4.3
`
`Relative Risk:
`Incidence of Events
`in Drug
`Patients/Incidence
`in Placebo Patients
`3.5
`1.5
`1.9
`1.8
`
`Risk Difference:
`Additional Drug
`Patients with
`Events Per 1000
`Patients
`2.4
`2.9
`0.9
`1.9
`
`Indication
`
`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).
`
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`
`5.3 Tumorigenic Potential
`In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high
`
`incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats.
`The clinical significance of this finding is unknown.
`
`In clinical trials of gabapentin therapy in epilepsy comprising 2,085 patient-years of
`exposure in patients over 12 years of age, new tumors were reported in 10 patients, and pre-
`existing tumors worsened in 11 patients, during or within 2 years after discontinuing the drug.
`However, no similar patient population untreated with gabapentin was available to provide
`background tumor incidence and recurrence information for comparison. Therefore, the effect
`of gabapentin therapy on the incidence of new tumors in humans or on the worsening or
`recurrence of previously diagnosed tumors is unknown.
`5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
`Hypersensitivity
`
`Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as
`Multiorgan Hypersensitivity, has been reported in patients taking antiepileptic drugs, including
`GRALISE. Some of these events have been fatal or life-threatening. DRESS typically, although
`not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other
`organ system involvement, such as hepatitis, nephritis, hematological abnormalities,
`myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often
`present. Because this disorder is variable in its expression, other organ systems not noted here
`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.
`5.5 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
`
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`

`
`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.
`
`Depomed Exhibit 2027, Page 6 of 24
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`

`
`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)
`
`
`Placebo
`N = 364
`%
`
`0.5
`
`2.7
`1.4
`0.3
`0.8
`
`0.3
`0.5
`
`2.2
`0.5
`
`0.5
`
`
`
`0.5
`1.1
`
`2.2
`2.7
`4.1
`0.3
`
`
`GRALISE
`N = 359
`%
`
`1.4
`
`3.3
`2.8
`1.4
`1.4
`
`3.9
`1.1
`
`2.5
`1.7
`
`1.9
`
`
`
`1.9
`1.7
`
`10.9
`4.5
`4.2
`1.1
`
`Body System – Preferred Term
`
`Ear and Labyrinth Disorders
`
`Vertigo
`Gastrointestinal Disorders
`
`Diarrhea
`
`Dry mouth
`
`Constipation
`
`Dyspepsia
`General Disorders
`
`Peripheral edema
`
`Pain
`Infections and Infestations
`
`Nasopharyngitis
`
`Urinary tract infection
`Investigations
`
`Weight increased
`Musculoskeletal and Connective
`Tissue Disorders
`
`Pain in extremity
`
`Back pain
`Nervous System Disorders
`
`Dizziness
`
`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
`
`Depomed Exhibit 2027, Page 7 of 24
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`

`
`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 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.
`
`Depomed Exhibit 2027, Page 8 of 24
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`

`
`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
`
`Depomed Exhibit 2027, Page 9 of 24
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`

`
`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/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.
`
`Depomed Exhibit 2027, Page 10 of 24
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`

`
`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.
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`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 C9H17NO2 and a molecular weight of 171.24.
`The structural formula is:
`
`CH2NH2
`
`CH2COOH
`
`
`
`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
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`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 Bioavailability
`Gabapentin is absorbed from the proximal small bowel by a saturable L-amino transport
`
`sys