HORIZANT

HORIZANT (gabapentin enacarbil) is a prodrug of gabapentin. Gabapentin enacarbil is described as (1-{[({(1 RS )-1-[(2-Methylpropanoyl)oxy]ethoxy}carbonyl)amino]methyl} cyclohexyl) acetic acid. It has a molecular formula of C 16 H 27 NO 6 and a molecular weight of 329.39. It is a racemate and has the following structural formula: Gabapentin enacarbil is a white to off-white crystalline solid with a melting onset of approximately 64°C and a solubility of 0.5 mg/mL in water and 10.2 mg/mL in phosphate buffer (pH 6.3). HORIZANT is administered orally. Each HORIZANT Extended-Release Tablet contains 300 mg or 600 mg of gabapentin enacarbil and the following inactive ingredients: colloidal silicon dioxide, dibasic calcium phosphate dihydrate, glyceryl behenate, magnesium stearate, sodium lauryl sulfate, and talc. Chemical Structure

HORIZANT is indicated for: treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) in adults. ( 1.1 ) management of postherpetic neuralgia (PHN) in adults. ( 1.2 ) 1.1 Treatment of Restless Legs Syndrome HORIZANT ® is indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) in adults. HORIZANT is not recommended for patients who are required to sleep during the daytime and remain awake at night. 1.2 Management of Postherpetic Neuralgia HORIZANT is indicated for the management of postherpetic neuralgia (PHN) in adults.

Instruct patients to swallow tablets whole and not to cut, crush, or chew tablets. Take with food. ( 2.1 ) RLS: 600 mg once daily taken at about 5 PM. ( 2.2 ) A dose of 1,200 mg once daily provided no additional benefit compared with the 600-mg dose, but caused an increase in adverse reactions. ( 2.2 ) If the dose is not taken at the recommended time, the next dose should be taken the following day as prescribed. ( 2.2 ) PHN: The starting dose is 600 mg in the morning for 3 days, then increase to 600 mg twice daily beginning on day 4. ( 2.3 ) A daily dose greater than 1,200 mg provided no additional benefit. ( 2.3 ) If the dose is not taken at the recommended time, skip this dose, and the next dose should be taken at the time of next scheduled dose. ( 2.3 ) Patients with renal impairment: Doses of HORIZANT must be adjusted in accordance with renal function. (2.4) 2.1 Dosage and Administration Overview Tablets should be swallowed whole and should not be cut, crushed, or chewed. Tablets should be taken with food. HORIZANT is not substitutable with other gabapentin products because of differing pharmacokinetic profiles [ see Warnings and Precautions (5.3) ]. 2.2 Recommended Dosage for Restless Legs Syndrome The recommended dosage for HORIZANT is 600 mg once daily at about 5 PM. A daily dose of 1,200 mg provided no additional benefit compared with the 600-mg dose, but caused an increase in adverse reactions [see Adverse Reactions (6.1) ] . If the dose is not taken at the recommended time, the next dose should be taken the following day as prescribed. 2.3 Recommended Dosage for Postherpetic Neuralgia The recommended dosage of HORIZANT is 600 mg twice daily. HORIZANT should be initiated at a dose of 600 mg in the morning for 3 days of therapy, then increased to 600 mg twice daily (1,200 mg/day) on day four. In the 12-week principal efficacy study, additional benefit of using doses greater than 1,200 mg a day was not demonstrated, and these higher doses resulted in an increase in adverse reactions [see Adverse Reactions (6.1) ] . If the dose is not taken at the recommended time, skip this dose, and the next dose should be taken at the time of the next scheduled dose. 2.4 Recommended Dosage for Renal Impairment Dosing of HORIZANT is adjusted in accordance with renal function, as represented by creatinine clearance [see Clinical Pharmacology (12.3) ] . Target dose regimens are listed in Table 1 and Table 2. Table 1. Dosage of HORIZANT for Patients With Restless Legs Syndrome in Accordance With Creatinine Clearance Creatinine Clearance (mL/min) Target Dose Regimen ≥60 600 mg per day 30 – 59 Start at 300 mg per day and increase to 600 mg as needed 15 – 29 300 mg per day <15 300 mg every other day <15 on hemodialysis Not recommended Table 2. Dosage of HORIZANT for Patients With Postherpetic Neuralgia in Accordance With Creatinine Clearance Creatinine Clearance (mL/min) Titration Maintenance Tapering ≥60 600 mg in AM for 3 days 600 mg twice daily 600 mg in AM for 1 week 30 – 59 300 mg in AM for 3 days 300 mg twice daily. Increase to 600 mg twice daily as needed Based on tolerability and efficacy Reduce current maintenance dose to once daily in AM for 1 week 15 – 29 300 mg in AM on Day 1 and Day 3 300 mg in AM. Increase to 300 mg twice daily if needed If taking 300 mg twice daily, reduce to 300 mg once daily in AM for 1 week. If taking 300 mg once daily, no taper needed. <15 None 300 mg every other day in AM. Increase to 300 mg once daily in AM if needed None <15 on hemodialysis None 300 mg following every dialysis. Increase to 600 mg following every dialysis if needed None In patients with stable renal function, CrCl can be estimated using the equation of Cockcroft and Gault: for males: CrCl = (140-age)(weight)/[(72)(SCr)] for females: CrCl = (0.85)(140-age)(weight)/[(72)(SCr)] where age is in years, weight is in kilograms, and SCr is serum creatinine in mg/dL.

None. None. ( 4 )

The following clinically significant adverse reactions are described in more detail in the Warnings and Precautions section of the labeling: Effects on Driving [see Warnings and Precautions (5.1) ] Somnolence/Sedation and Dizziness [see Warnings and Precautions (5.2) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.4) ] Increased Risk of Seizures and Other Adverse Reactions with Abrupt or Rapid Discontinuation [see Warnings and Precautions (5.5) ] Respiratory Depression [see Warnings and Precautions (5.6) ] Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.7) ] RLS: Most common adverse reactions (≥10% and at least 2 times the rate of placebo) were somnolence/sedation and dizziness. ( 6.1 ) PHN: Most common adverse reactions (≥10% and greater than placebo) were dizziness, somnolence, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. In all controlled and uncontrolled trials across various patient populations, more than 2,300 patients have received HORIZANT orally in daily doses ranging from 600 to 3,600 mg. Restless Legs Syndrome The exposure to HORIZANT in 1,201 patients with RLS included 613 exposed for at least 6 months and 371 exposed for at least 1 year. HORIZANT in the treatment of RLS was studied primarily in placebo-controlled trials (n = 642), and in long- term follow-up studies. The population with RLS ranged from 18 to 82 years of age, with 60% being female and 95% being Caucasian. The safety of HORIZANT in doses ranging from 600 to 2,400 mg has been evaluated in 515 patients with RLS in 3 double-blind, placebo-controlled, 12-week clinical trials. The 600-mg dose was studied in 2 of the 3 studies. Eleven out of 163 (7%) patients treated with 600 mg of HORIZANT discontinued treatment due to adverse reactions compared with 10 of the 245 (4%) patients who received placebo. The most commonly observed adverse reactions (≥5% and at least 2 times the rate of placebo) in these trials for the 600-mg dose of HORIZANT were somnolence/sedation and dizziness (see Table 4 ). Table 4 lists treatment-emergent adverse reactions that occurred in ≥2% of patients with RLS treated with HORIZANT and numerically greater than placebo. Table 4. Incidence of Adverse Reactions in 12-Week RLS Studies Reported in ≥2% of Patients Treated With 600 or 1,200 mg of HORIZANT and Numerically Greater Than Placebo Body System/Adverse Reaction Placebo a (N = 245) % HORIZANT 600 mg/day b (N = 163) % HORIZANT 1,200 mg/day c (N = 269) % Nervous system disorders Somnolence/sedation 6 20 27 Dizziness 4 13 22 Headache 11 12 15 Gastrointestinal disorders Nausea 5 6 7 Dry mouth 2 3 4 Flatulence <1 3 2 General disorders and administration site conditions Fatigue 4 6 7 Irritability 1 4 4 Feeling drunk 0 1 3 Feeling abnormal <1 <1 3 Peripheral edema 1 <1 3 Metabolism and nutritional disorders Weight increased 2 2 3 Increased appetite <1 2 2 Ear and labyrinth disorders Vertigo 0 1 3 Psychiatric disorders Depression <1 <1 3 Libido decreased <1 <1 2 a Placebo was a treatment arm in each of the 3 double-blind, placebo-controlled, 12-week clinical trials. b The 600-mg dose of HORIZANT was a treatment arm in 2 of the 3 double-blind, placebo- controlled, 12-week clinical trials. c The 1,200-mg dose of HORIZANT was a treatment arm in each of the 3 double-blind, placebo-controlled, 12-week clinical trials. Adverse reactions reported in these three 12-week studies in <2% of patients treated with 600 mg of HORIZANT and numerically greater than placebo were balance disorder, blurred vision, disorientation, feeling drunk, lethargy, and vertigo. The following adverse reactions were dose-related: somnolence/sedation, dizziness, feeling drunk, libido decreased, depression, headache, peripheral edema, and vertigo. Postherpetic Neuralgia The exposure to HORIZANT in 417 patients with PHN included 207 patients exposed for at least 3 months. Overall, the mean age of patients in the PHN studies ranged from 61 to 64 years of age across dose groups; the majority of patients were male (45% to 61%) and Caucasian (80% to 98%). The safety of HORIZANT in doses ranging from 1,200 to 3,600 mg has been evaluated in 417 patients with PHN in 3 clinical studies. The principal efficacy study evaluating the efficacy and safety of HORIZANT in the management of PHN was a 12-week, double-blind, multicenter study comparing 1,200 mg/day, 2,400 mg/day and 3,600 mg/day to placebo. Six out of 107 (6%) patients treated with 1,200 mg of HORIZANT discontinued treatment due to adverse events compared with 12 of the 95 (13%) patients who received placebo. The most commonly observed adverse reactions (≥10% and greater than placebo) in this trial for the 1,200 mg dose of HORIZANT were dizziness, somnolence, and headache (see Table 5). Table 5 lists treatment-emergent adverse reactions that occurred in ≥2% of patients with PHN treated with HORIZANT 1,200 mg/day and numerically greater than placebo. Table 5. Incidence of Adverse Reactions (in At Least 2% of Patients Treated With 1,200 mg/day of HORIZANT and Numerically Greater Than the Placebo Rate) Reported in All Patients in the 12-Week PHN Study Body System/Adverse Reaction Placebo (N = 95) % HORIZANT 1,200 mg/day (N = 107) % HORIZANT 2,400 mg/day (N = 82) % HORIZANT 3,600 mg/day (N = 87) % Nervous System Dizziness 15 17 26 30 Somnolence 8 10 11 14 Headache 9 10 10 7 Gastrointestinal disorders Nausea 5 8 4 9 General disorders and administration site conditions Fatigue/Asthenia 1 6 4 10 Peripheral edema 0 6 7 6 Psychiatric disorders Insomnia 2 3 5 7 Metabolism and nutritional disorders Weight increased 1 3 5 5 Eye disorders Blurred vision 0 2 5 2 The following adverse reactions were also reported as ≥2% at 2,400 mg/day and/or 3,600 mg/day and appeared to be dose-related but were <2% at 1,200 mg/day: balance disorder, confusional state, depression, dry mouth, flatulence, increased appetite, irritability, and vertigo. Dizziness, somnolence, fatigue, and insomnia appeared to show a dose relationship. 6.2 Postmarketing Experience The following adverse reactions have been reported in patients receiving gabapentin and have been identified during postapproval use of HORIZANT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: breast enlargement, gynecomastia, elevated creatine kinase, bullous pemphigoid. There are postmarketing reports of life-threatening or fatal respiratory depression in patients taking gabapentin with opioids or other CNS depressants, or in the setting of underlying respiratory impairment [see Warnings and Precautions ( 5.6 )]. There are postmarketing reports of withdrawal symptoms after discontinuation of gabapentin. Reported adverse reactions include, but are not limited to, seizures, depression, suicidal ideation and behavior, agitation, confusion, disorientation, psychotic symptoms, anxiety, insomnia, nausea, pain, sweating, tremor, headache, dizziness, and malaise [see Warnings and Precautions ( 5.5 )].

Gabapentin enacarbil is released faster from HORIZANT Extended-Release tablets in the presence of alcohol. Consumption of alcohol is not recommended when taking HORIZANT [see Clinical Pharmacology (12.3) ] . Morphine: HORIZANT taken in conjunction with morphine causes increased somnolence/sedation, dizziness, and nausea when compared with either drug alone [see Clinical Pharmacology (12.3) ].

Store at 25°C (77°F); excursions permitted 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] . Protect from moisture. Do not remove desiccants.