Gabapentin Enacarbil

FDA Drug Information • Also known as: Horizant

Brand Names: Horizant
Dosage Form: POWDER
Product Type: BULK INGREDIENT

Description

11 DESCRIPTION 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

What Is Gabapentin Enacarbil Used For?

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.

Dosage and Administration

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...

Side Effects (Adverse Reactions)

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...

Drug Interactions

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) ].

Contraindications

4 CONTRAINDICATIONS None. None. ( 4 )

Pregnancy and Breastfeeding

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)...

Overdosage

10 OVERDOSAGE 10.1 Human Overdose Experience The incidence of central nervous system adverse reactions, particularly dizziness and somnolence/sedation, is increased with HORIZANT doses greater than 600 mg daily. Acute oral overdoses of gabapentin have been reported. Symptoms have included 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 CNS depressants. 10.2 Overdosage Management In the event of an overdose, the patient should be treated supportively with appropriate monitoring as necessary. Gabapentin derived from gabapentin enacarbil can be removed from plasma by hemodialysis. The mean percentage of gabapentin recovered following hemodialysis in patients with end-stage renal disease was 29% (expressed as a proportion of the gabapentin released from HORIZANT). Further management should be as clinically indicated or as recommended by a poison control center.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING HORIZANT Extended-Release Tablets containing 300 mg of gabapentin enacarbil are white to off-white, with occasional black/grey spots, oval-shaped tablets debossed with "GS TF7". HORIZANT Extended-Release Tablets containing 600 mg of gabapentin enacarbil are white to off-white, with occasional black/grey spots, oval-shaped tablets debossed with "GS LFG". They are supplied as follows: 300 mg: NDC 53451-0103-1: Bottles of 30 600 mg: NDC 53451-0101-1: Bottles of 30 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.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.