Gralise

1 INDICATIONS AND USAGE GRALISE is indicated for the management of postherpetic neuralgia. GRALISE is not substitutable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration. GRALISE is indicated for the management of Postherpetic Neuralgia (PHN). Important Limitation: GRALISE is not substitutable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration (See Warnings and Precautions )

2 DOSAGE AND ADMINISTRATION GRALISE should be titrated to an 1,800 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 ) 2.1 Postherpetic Neuralgia Do not use GRALISE as a substitute for other gabapentin products. Titrate GRALISE to an 1,800 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 dosing 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 1,200 mg 1,500 mg 1,800 mg 2.2 Patients with Renal Impairment In patients with stable renal function, creatinine clearance (C Cr ) can be reasonably well estimated using the equation of Cockcroft and Gault: For females C Cr =(0.85)(140-age)(weight)/[(72)(S Cr )] For males C Cr =(140-age)(weight)/[(72)(S Cr )] where age is in years, weight is in kilograms and S Cr 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 1,800 mg 30 - 60 600 mg to 1,800 mg < 30 GRALISE should not be administered patients receiving hemodialysis GRALISE should not be administered

5 WARNINGS AND PRECAUTIONS GRALISE is not substitutable 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. GRALISE is not substitutable with other gabapentin products Antiepileptic drugs, including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior ( 5.1 ) Abrupt or rapid discontinuation may increase the risk for seizures. Withdrawal symptoms or suicidal behavior and ideation have been observed after discontinuation. Taper GRALISE gradually over a minimum of 1 week. ( 5.2 ) Respiratory depression may occur with GRALISE when used with concomitant CNS depressants or in the setting of underlying respiratory impairment. Monitor patients and adjust dosage as appropriate. ( 5.3 ) 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. Suicidal behavior and ideation have also been reported in patients after discontinuation of gabapentin [see Warnings and Precautions ( 5.3 )] . 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 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 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 p…

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

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 max at 3,600 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. 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 ) 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 max 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 n…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to gabapentin, including GRALISE, during pregnancy. Encourage women who are taking GRALISE during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll free number 1-888-233-2334 or visiting https://www.aedpregnancyregistry.org/. Risk Summary Available data from published prospective and retrospective cohort studies, and case reports over decades of use with gabapentin during pregnancy have not identified a drug-associated risk of major birth defects. The available data are insufficient to evaluate a drug-associated risk of miscarriage and other maternal or fetal outcomes. In nonclinical studies in mice, rats, and rabbits, gabapentin was developmentally toxic (increased fetal skeletal and visceral abnormalities, and increased embryofetal mortality) when administered to pregnant animals at doses similar to those used clinically (see Data) . Postmarketing data suggest that extended gabapentin use with opioids close to delivery mayincrease the risk of neonatal withdrawal versus opioids alone [see Clinical Considerations] . Although there is at least one report of neonatal withdrawal syndrome in an infant exposed togabapentin alone during pregnancy, there are no comparative epidemiologic studies evaluatingthis association. Therefore, it is not known whether exposure to gabapentin alone late inpregnancy may cause withdrawal signs and symptoms. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Neonatal withdrawal syndrome has been reported in newborns exposed to gabapentin in utero foran extended period of time when also exposed to opioids close to delivery. Neonatal withdrawal signs and symptoms reported have included tachypnea, vomiting, diarrhea, hypertonia, irritability, sneezing, poor feeding, hyperactivity, abnormal sleep pattern, and tremor. Reported signs and symptoms that may also be related to withdrawal include tongue thrusting, wandering eye movements while awake, back arching, and continuous extremity movements. Observe neonates exposed to GRALISE and opioids for signs and symptoms of neonatal withdrawal and manage accordingly. Data Animal Data When pregnant mice received oral doses of gabapentin (1,000 or 3,000 mg/kg/day, approximately 3 to 8 times the maximum recommended dose of 1,800 mg on a mg/m 2 basis) during the period of organogenesis, embryofetal toxicity (increased incidences of skeletal variations) was observed. The no effect level was 500 mg/kg/day, representing approximately the maximum recommended human dose [MRHD] on a mg/m 2 basis. When rats were dosed prior to and during mating, and throughout gestation, pups from all dose groups (500, 1,000 and 2,000 mg/kg/day) were affected. These doses are equivalent to approximately 3 to 11 times the MRHD on a mg/m 2 basis. There was an increased incidence of hydroureter and/or hydronephrosis in rats in a study of fertility and general reproductive performance at 2,000 mg/kg/day with no effect at 1,000 mg/kg/day, in a teratology study at 1,500 mg/kg/day with no effect at 300 mg/kg/day, and in a perinatal and postnatal study at all doses studied (500, 1,000 and 2,000 mg/kg/day). The doses at which the effects occurred are approximately 3 to 11 times the maximum recommended dose of 1,800 mg on a mg/m 2 basis; the no-effect doses were approximately 5 times (Fertility and General Reproductive Performance study) and approximately equal to (Teratogenicity study) the MRHD on a mg/m 2 basis. Other than hydrourete…

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.1 )] Increased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation [see Warnings and Precautions ( 5.2 )] Respiratory Depression [see Warnings and Precautions ( 5.3 )] Tumorigenic Potential [see Warnings and Precautions ( 5.4 )] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions ( 5.5 )] Laboratory Tests [see Warnings and Precautions ( 5.6 )] The most common adverse reaction (greater than or equal to 5% and twice placebo) is dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Almatica Pharma LLC at 1-877-447-7979 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 1,800 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 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…