Horizant

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION 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.

5 WARNINGS AND PRECAUTIONS Driving impairment: Warn patients not to drive until they have gained sufficient experience with HORIZANT to assess whether it will impair their ability to drive. ( 5.1 ) Somnolence/sedation and dizziness: May impair the patient's ability to operate complex machinery. ( 5.2 ) HORIZANT is not substitutable with other gabapentin products. ( 5.3 ) Suicidal thoughts or behaviors: HORIZANT is a prodrug of gabapentin, an antiepileptic drug (AED). AEDs increase the risk of suicidal thoughts or behaviors. Monitor for suicidal thoughts or behaviors. ( 5.4 ) Abrupt or rapid discontinuation may increase the risk for seizures. Withdrawal symptoms, or suicidal behavior and ideation have been observed after discontinuation. ( 5.5 ) Respiratory depression: May occur with HORIZANT when used with concomitant central nervous system (CNS) depressants or in the setting of concurrent respiratory impairment. Monitor patients and adjust dosage as appropriate ( 5.6 ). 5.1 Effects on Driving HORIZANT may cause significant driving impairment [see Clinical Studies (14.3) ] . The duration of driving impairment after starting therapy with HORIZANT is unknown. Patients taking HORIZANT should not drive until they have gained sufficient experience to assess whether HORIZANT impairs their ability to drive. However, prescribers and patients should be aware that patients' ability to assess their own driving competence, as well as their ability to assess the degree of somnolence caused by HORIZANT, can be imperfect. Whether the impairment is related to somnolence [see Warnings and Precautions (5.2) ] or other effects of HORIZANT is unknown. 5.2 Somnolence/Sedation and Dizziness HORIZANT causes somnolence/sedation and dizziness (see Tables 4 and 5 ). Patients should be advised not to drive a car or operate other complex machinery until they have gained sufficient experience on HORIZANT to assess whether HORIZANT impairs their ability to perform these tasks. During the controlled trials in patients with RLS, somnolence/sedation was reported in 20% of patients treated with 600 mg of HORIZANT per day compared with 6% of patients receiving placebo. In those patients treated with HORIZANT who reported somnolence, the somnolence persisted during treatment in about 30%. In the remaining patients, symptoms resolved within 3 to 4 weeks. Dizziness was reported in 13% of patients receiving 600 mg of HORIZANT per day compared with 4% of patients receiving placebo. In those patients treated with HORIZANT who reported dizziness, symptoms persisted during treatment in about 20%. Somnolence/sedation led to withdrawal in 2% of patients receiving 600 mg of HORIZANT per day. Dizziness led to withdrawal in 1% of patients receiving 600 mg of HORIZANT per day. The incidence of these adverse reactions was greater in the patients receiving 1,200 mg per day. During the 12-week, controlled study in patients with PHN, somnolence was reported in 10% of patients treated with 1,200 mg of HORIZANT per day compared with 8% of patients receiving placebo. Fatigue/asthenia was reported in 6% of patients treated with 1,200 mg of HORIZANT per day compared with 1% of patients receiving placebo. In those patients treated with 1,200 mg of HORIZANT per day who reported somnolence (10%), the somnolence persisted during treatment in about 27%. In the remaining patients, symptoms resolved within 4 to 5 weeks. Dizziness was reported in 17% of patients receiving 1,200 mg of HORIZANT per day compared with 15% of patients receiving placebo. In those patients treated with 1,200 mg of HORIZANT per day who reported dizziness, symptoms persisted during treatment in about 6%. Somnolence led to withdrawal in <1% of patients receiving 1,200 mg of HORIZANT per day compared with 2% of patients receiving placebo. Dizziness led to withdrawal in 2% of patients receiving 1,200 mg of HORIZANT per day compared with 3% of patients receiving placebo. 5.3 Lack of Substitutability With Gabapentin HORIZ…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS 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) ].

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of HORIZANT in pregnant women. In nonclinical studies in rats and rabbits, administration of gabapentin enacarbil was developmentally toxic when administered to pregnant animals at doses and gabapentin exposures greater than those used clinically [see Data ] . Postmarketing data suggest that extended gabapentin use with opioids close to delivery may increase the risk of neonatal withdrawal versus opioids alone. Although there is at least one report of neonatal withdrawal syndrome in an infant exposed to gabapentin alone during pregnancy, there are no comparative epidemiologic studies evaluating this association. Therefore, whether exposure to gabapentin alone late in pregnancy may cause withdrawal signs and symptoms is not known [see Clinical Considerations ]. In the US 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. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Fetal/Neonatal Adverse Reactions Neonatal withdrawal syndrome has been reported in newborns exposed to gabapentin in utero for an 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 HORIZANT and opioids for signs and symptoms of neonatal withdrawal and manage accordingly. Data Animal data When pregnant rats were administered gabapentin enacarbil (oral doses of 200, 1,000, or 5,000 mg/kg/day) throughout the period of organogenesis, embryofetal mortality was increased at the 2 highest doses and fetal body weights were decreased at the high dose. The no-effect dose for embryofetal developmental toxicity in rats (200 mg/kg/day) represents approximately 2 times the gabapentin exposure associated with the maximum recommended human dose (MRHD) of 1,200 mg/day gabapentin enacarbil on an area under the curve (AUC) basis. When pregnant rabbits were administered gabapentin enacarbil (oral doses of 200, 500, or 2,500 mg/kg/day) throughout the period of organogenesis, embryofetal mortality was increased and fetal body weights were decreased at the high dose. The no-effect dose for embryofetal developmental toxicity in rabbits (500 mg/kg/day) represents approximately 9 times the gabapentin exposure associated with the MRHD of 1,200 mg/day gabapentin enacarbil on an AUC basis. When female rats were administered gabapentin enacarbil (oral doses of 200, 1,000, or 5,000 mg/kg/day) throughout the pregnancy and lactation periods, offspring growth and survival were decreased at the two highest doses. The no-effect dose for pre- and post-natal developmental toxicity in rats is approximately 2 times the MRHD on an AUC basis. In reproductive and developmental studies of gabapentin, developmental toxicity was observed at all doses tested. Increased incidences of hydroureter and/or hydronephrosis were observed in rat offspring following treatment of pregnant animals in studies of fertility and general reproductive performance, embryofetal development, and peri- and post-natal development. Overall, a no-effect dose was not established. In mice, treatment of pregnant animals with gabapentin during the period of organogenesis resulted in delayed fetal skeletal ossification at all but the lowest dose tested. When pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryofetal mortality was observed at all doses of gabapentin tested. In a publishe…

6 ADVERSE REACTIONS 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 balanc…