HORIZANT

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. The 300 mg tablets also contain red ferric oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Gabapentin enacarbil is a prodrug of gabapentin and, accordingly, its therapeutic effects in RLS and PHN are attributable to gabapentin.

The precise mechanism by which gabapentin is efficacious in RLS and PHN is unknown.

The mechanism of action by which gabapentin is efficacious in PHN 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 formalin test), but does not alter immediate pain-related 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 gamma-aminobutyric acid (GABA) but has no effect on GABA binding, uptake, or degradation. Gabapentin enacarbil and gabapentin have been tested in radioligand binding assays, and neither exhibited affinity for a number of other common receptor, ion channel, or transporter proteins.

In vitro studies have shown that gabapentin binds with high affinity to the α2δ subunit of voltage-activated calcium channels; however, the relationship of this binding to the therapeutic effects of gabapentin enacarbil in RLS and PHN is unknown.

12.3 Pharmacokinetics

HORIZANT is an extended-release formulation of gabapentin enacarbil, a prodrug of gabapentin. HORIZANT provides approximately dose-proportional and extended exposure to gabapentin over the range 300 to 6,000 mg. HORIZANT and gabapentin are not interchangeable because the same daily dose of each results in different plasma concentrations of gabapentin.

For subjects with PHN taking HORIZANT 600 mg twice daily, the estimated steady state mean C_max was 5.35 μg/mL, mean AUC₂₄ was approximately 109 μg*hr/mL, mean C_min was 3.63 μg/mL, and mean peak trough ratio was 1.5.

Absorption: The pathway for absorption of gabapentin enacarbil is believed to include active transport via a proton-linked monocarboxylate transporter, MCT-1. This transporter is expressed at high levels in the intestinal tract and is not saturated by administration of high doses of HORIZANT. Mean bioavailability of gabapentin (based on urinary recovery of gabapentin) for HORIZANT in the fed state is about 75%. Bioavailability under fasting conditions has been estimated by gabapentin urinary recovery to be 42% to 65%. In a food effect study, the exposure of gabapentin increased by 24%, 34%, and 44% with low, moderate, and high fat meals, respectively. The T_max of gabapentin after administration of 600 mg of HORIZANT was 5.0 hours in fasted subjects and 7.3 hours in fed subjects. Steady state is reached in 2 days with daily administration.

Distribution: Plasma protein binding of gabapentin has been reported to be <3%. The apparent volume of distribution of gabapentin in subjects receiving HORIZANT is 76 L.

Metabolism: After oral administration, gabapentin enacarbil undergoes extensive first-pass hydrolysis by non-specific carboxylesterases primarily in enterocytes and to a lesser extent in the liver, to form gabapentin, carbon dioxide, acetaldehyde, and isobutyric acid. Levels of gabapentin enacarbil in blood are low and transient (≤2% of corresponding gabapentin plasma levels). Released gabapentin is not appreciably metabolized in humans. Neither gabapentin enacarbil nor gabapentin are substrates, inhibitors, or inducers of the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). Gabapentin enacarbil is neither a substrate nor an inhibitor of P-glycoprotein in vitro.

Elimination: Following hydrolysis of gabapentin enacarbil, the released gabapentin is excreted unchanged by the kidney. Gabapentin renal excretion is believed to involve a component of active secretion via an organic cation transporter (OCT2) present in the kidney. In a human pharmacokinetic study with immediate release ¹⁴C gabapentin enacarbil, mean recovery of total radioactivity in urine was 94%, with 5% of the radioactive dose recovered in feces.

Apparent oral clearance (CL/F) of gabapentin from plasma after dosing of HORIZANT with food ranged from 6.0 to 9.3 L/hr. Following oral dosing of HORIZANT, plasma clearance of gabapentin is approximately proportional to creatinine clearance. Renal clearance (CLr) of gabapentin ranged from 5 to 7 L/hr, regardless of food intake or food type. The elimination half-life (t_½) of gabapentin ranges from 5.1 to 6.0 hours and is unaltered by dose or following multiple doses of HORIZANT.

Special Populations: Race: In the population pharmacokinetic study, the majority (94%) of subjects in the clinical studies was Caucasian, and no single other race was greater than 4%; therefore, the effect of race could not be studied.

Gender: There are no clinically meaningful differences in pharmacokinetics of HORIZANT between male and female patients.

Geriatric Patients: There are no clinically significant differences in pharmacokinetics of HORIZANT between geriatric patients (≥65 years of age) and younger patients (18 to <65 years of age). However, the pharmacokinetics in geriatric patients may be affected by an age-related decline in renal function [see Use in Specific Populations (8.5)].

Renal Impairment: Gabapentin clearance after dosing with HORIZANT is approximately proportional to CrCl. Apparent oral clearance (CL/F) decreased in moderate (4.2 L/hr) and severe renal impairment patients (1.7 L/hr) compared with 6.0 to 9.3 L/hr in patients without renal impairment. Similarly, CLr was decreased to 3 and 1 L/hr in moderate and severe renal impairment patients, respectively, compared with 5 to 7 L/hr in non-renal impairment patients. Dosage reduction in patients with renal dysfunction not on dialysis is necessary.

Gabapentin is effectively 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). For patients with PHN on hemodialysis, dosage reduction is required [see Dosage and Administration (2.3)]. For patients with RLS on hemodialysis, treatment with HORIZANT is not recommended [see Dosage and Administration (2.3)].

Drug Interactions: Neither gabapentin enacarbil nor gabapentin are substrates, inhibitors, or inducers of the major cytochrome P450 enzymes. Gabapentin enacarbil is neither a substrate or an inhibitor of P-glycoprotein in vitro.

Pharmacokinetic drug-drug interaction studies were conducted to examine the potential for an interaction of gabapentin enacarbil with cimetidine and naproxen. No significant pharmacokinetic interactions were observed. No clinically relevant pharmacokinetic interactions are expected between HORIZANT and other substrates of organic cation transporter type 2 (OCT2) and monocarboxylate transporter type 1 (MCT-1).

Ethanol: An in vitro dissolution study was conducted to evaluate the impact of ethanol (5, 10, 20, and 40%), on the extended‑release characteristics of HORIZANT. The in vitro study showed that about 63% of the total gabapentin enacarbil dose was released at 1 hour at the highest alcohol level (40%), and about 43% of total drug was released at 1 hour with 5% alcohol. Ethanol causes a more rapid release of gabapentin enacarbil from the extended‑release tablets that may increase the risk for adverse events associated with HORIZANT. Consumption of alcohol is not recommended when taking HORIZANT.

Cimetidine: Gabapentin released from HORIZANT is eliminated by renal clearance via OCT2. Cimetidine is a known substrate for this same elimination pathway. Coadministration of 1,200 mg of HORIZANT once daily with cimetidine 400 mg 4 times daily showed no effect on cimetidine exposure. There was an increase in AUC of gabapentin (24%) and a decrease in renal clearance of gabapentin (20%); these effects are not expected to be clinically relevant. No clinically relevant pharmacokinetic interactions are expected between HORIZANT and other substrates of OCT2.

Naproxen: The pathway for absorption of gabapentin enacarbil includes active transport via a proton-linked MCT-1. Coadministration of 1,200 mg of HORIZANT once daily with naproxen 500 mg twice daily, a known substrate of MCT-1, showed no effect on naproxen exposure or steady-state gabapentin C_max and AUC. No clinically relevant pharmacokinetic interactions are expected between HORIZANT and other substrates of MCT-1.

Morphine:Administration of a single 600-mg dose of HORIZANT 2 hours after a single 60-mg dose of extended-release morphine sulfate in 18 subjects was associated with increased somnolence/sedation, dizziness, and nausea for the combination compared to HORIZANT or morphine alone as measured by the visual analog scale. No changes in C_max and AUC of gabapentin, morphine or its active metabolite morphine-6-glucuronide were observed.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Oral (gavage) carcinogenicity studies were conducted in mice and rats. In mice, gabapentin enacarbil was tested at doses of 500, 2,000, or 5,000 mg/kg/day for up to 104 weeks. There was no evidence of drug-related carcinogenicity. The highest dose tested is 16 times the MRHD of 1,200 mg/day, on a plasma AUC basis.

In rats, gabapentin enacarbil was tested at doses of 500, 2,000, or 5,000 mg/kg/day for up to 97 weeks in mid-dose males, 90 weeks in high-dose males, and 104 weeks in females. The plasma exposures (AUC) for gabapentin at these doses are approximately 4, 17, and 37 times, respectively, that in humans at the MRHD. Increases in the incidence of pancreatic acinar adenoma and carcinoma were found in mid-dose males and high-dose males and females.

In 2-year dietary carcinogenicity studies of gabapentin, no evidence of drug-related carcinogenicity was observed in mice treated at doses up to 2,000 mg/kg/day. In rats, increases in the incidence of pancreatic acinar cell adenoma and carcinoma were found in male rats receiving the highest dose (2,000 mg/kg), but not at doses of 250 or 1,000 mg/kg/day. At 1,000 mg/kg/day, the plasma AUC for gabapentin is estimated to be approximately 13 times that in humans at the MRHD.

Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro and thus may be acting as a tumor promoter by enhancing mitogenic activity. It is not known whether gabapentin has the ability to increase cell proliferation in other cell types or in other species, including human.

Mutagenesis: Gabapentin enacarbil was negative in in vitro bacterial reverse mutation (Ames) and in vivo rat micronucleus assays. In an in vitro human lymphocyte assay, there was an increase in the number of chromosomal aberrations with gabapentin enacarbil. This in vitro response was attributed to acetaldehyde released by hydrolysis of gabapentin enacarbil during the incubation period. Acetaldehyde is known to cause chromosome aberrations in vitro, but is readily metabolized in vivo. The small quantity of acetaldehyde formed from gabapentin enacarbil in vivo is rapidly cleared by normal metabolic activity.

Impairment of Fertility: Oral administration of gabapentin enacarbil (doses of 0, 200, 1,000, or 5,000 mg/kg/day) to male and female rats prior to and throughout mating and continuing in females up to day 7 of gestation resulted in no adverse effects on fertility. The highest dose tested is approximately 39 times the MRHD on an AUC basis.

14 CLINICAL STUDIES

14.1 Restless Legs Syndrome (RLS) 12-Week Pivotal Studies

The effectiveness of HORIZANT in the treatment of moderate-to-severe primary RLS was demonstrated in two 12-week clinical studies in adults diagnosed with RLS using the International Restless Legs Syndrome Study Group diagnostic criteria. Key diagnostic criteria for RLS are: an urge to move the legs usually accompanied or caused by uncomfortable and unpleasant leg sensations, symptoms begin or worsen during periods of rest or inactivity such as lying or sitting, symptoms are partially or totally relieved by movement such as walking or stretching at least as long as the activity continues, and symptoms are worse or occur only in the evening or night. Patients were required to have a total score of ≥15 on the International Restless Legs Syndrome (IRLS) Rating Scale at baseline. Patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, iron deficiency anemia) were excluded. In study 1, patients were randomized to receive 1,200 mg of HORIZANT (N = 112) or placebo (N = 108) taken once daily at about 5 PM with food. In study 2, patients were randomized to receive 600 mg of HORIZANT (N = 114), 1,200 mg of HORIZANT (N = 111), or placebo (N = 96) taken once daily at about 5 PM with food.

Efficacy was evaluated using the IRLS Rating Scale and Clinical Global Impression of Improvement (CGI-I) scores. The IRLS Rating Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence/sedation, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. The CGI-I Scale allows the investigator to rate the patient’s overall change in RLS symptoms since baseline, whether or not in the opinion of the investigator the change is related to study drug treatment. The change from baseline in the IRLS Rating Scale at Week 12 and the proportion of responders on the CGI-I Scale defined as a rating of “much improved” or “very much improved” at Week 12 were co-primary outcomes in these studies.

In these 2 studies, the mean age of patients studied was 50 years (range: 18 to 81 years); 59% of the patients were female. The racial distribution for these studies was as follows: Caucasian, 95%; black, 2%; and other, 3%.

Statistically significant differences (P<0.05) between the treatment groups receiving 600 and 1,200 mg of HORIZANT and the group receiving placebo were observed at Week 12 for both the mean change from baseline in the IRLS Scale total score and the proportion of responders (“much improved” or “very much improved”) on the CGI-I Scale as described in Table 6.

^aCGI-I Responders = “much improved” and “very much improved.”

Figure 1 presents the improvement in mean IRLS Rating Scale total score in patients treated with placebo or 600 or 1,200 mg of HORIZANT over the 12 weeks of treatment in study 2.

14.2 Postherpetic Neuralgia (PHN) 12‑Week Study

The efficacy of HORIZANT for the management of postherpetic neuralgia was established in a multicenter, randomized, double-blind, parallel-group, placebo-controlled, 12-week study evaluating the efficacy, safety, and dose response of 3 maintenance doses of HORIZANT (1,200, 2,400, and 3,600 mg/day, with 107, 82, and 87 patients in each dosing group, respectively). Patients greater than 18 years of age with a documented medical diagnosis of PHN of at least three months duration were enrolled. To ensure that patients had significant pain, randomized patients were required to have a minimum baseline 24-hour average Pain Intensity Numerical Rating Scale (PI-NRS) intensity score of at least 4.0 on the 11-point numerical PI-NRS, ranging from 0 (“no pain”) to 10 (“pain as bad as you can imagine”).

In this study, a total of 276 patients received HORIZANT while 95 patients received placebo. Following a 1-week baseline period during which patients were screened for eligibility, patients began a 1-week up-titration period followed by a 12-week maintenance treatment period, and then a 1-week down-titration period.

Treatment with HORIZANT statistically significantly improved the mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline at all doses tested. A benefit over placebo was observed for all 3 doses of HORIZANT as early as Week 1 and maintained to the end of treatment. Additional benefit of using doses of greater than 1,200 mg a day was not demonstrated.

For various degrees of improvement in pain from baseline to end of maintenance treatment, Figure 2 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement.

14.3 Effects on Driving

Driving performance was assessed in a three way crossover study in healthy volunteers (mean age 36 years). Subjects were dosed at approximately 5 pm with HORIZANT 600 mg (for five days), diphenhydramine 50 mg (1 dose), and placebo (for five days). After the last dose, driving was evaluated on a computer-based simulation for 1 hour in the evening approximately 2 to 4 hours after dosing (7 to 9 pm), in the morning after dosing (7 to 9 am), and at midday the day after dosing (11 am to 1 pm). The primary endpoint of the study was lane position variability. There was no difference in change from baseline in lane position variability for HORIZANT compared to placebo at any of the simulated driving timepoints. Secondary measures included speed variability and the occurrence of simulated crashes. Subjects in this study experienced simulated crashes as described in Table 7. At the times that simulated crashes occurred, there was an increase in average speed variability in the HORIZANT and diphenhydramine treated groups that was most notable in patients who experienced simulated crashes, but no increases in lane position variability. Later time points post-dosing or the effects of driving after more than five days of dosing with HORIZANT were not evaluated.

The results of a separate 2-week driving simulation study in patients (mean age 47 years) with moderate-to-severe primary RLS showed that once daily doses of 1,200 mg and 1,800 mg of HORIZANT significantly impaired simulated driving performance based on lane position variability. An increased number of simulated crashes were reported in patients tested near T_max after receiving 1,200 mg or 1,800 mg of HORIZANT compared to patients treated with diphenhydramine 50 mg. In addition, patients receiving 1,200 mg of HORIZANT experienced an increased number of simulated crashes at 14 to 16 hours after dosing compared with placebo, diphenhydramine, and 1,800 mg of HORIZANT.

The design limitations of these two studies do not permit inference regarding dose response relationship or the duration of the effect HORIZANT has on driving in patients with RLS.

The results of a separate driving simulation study comparing untreated RLS patients and healthy subjects showed no difference in lane position variability but an increase in speed variability associated with a greater number of simulated crashes in RLS patients relative to healthy subjects, which may indicate impaired driving in RLS patients in the absence of medication.

16 HOW SUPPLIED/STORAGE AND HANDLING

HORIZANT Extended-Release Tablets containing 300 mg of gabapentin enacarbil are red, 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 0173-0832-13: Bottles of 30

600 mg: NDC 0173-0806-01: Bottles of 30

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

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

Physicians should instruct their patients to read the Medication Guide before starting therapy with HORIZANT and to reread it upon prescription renewal for new information regarding the use of HORIZANT.

17.1 Effects on Driving

Patients should be told that HORIZANT may cause a significant driving impairment. Accordingly, they should be advised not to drive a car until they have gained sufficient experience on HORIZANT to assess whether HORIZANT impairs their ability to drive, although patients’ ability to determine their level of impairment can be unreliable. Patients should be told that it is not known how long this effect lasts.

17.2 Somnolence/Sedation and Dizziness

Patients should be told that HORIZANT can cause significant somnolence and dizziness. This typically resolves within several weeks of initiating treatment. Accordingly, they should be told not to operate dangerous machinery until they have gained sufficient experience on HORIZANT to assess whether HORIZANT impairs their ability to operate dangerous machinery safely.

17.3 Suicidal Behavior and Ideation

Patients, their caregivers, and families should be counseled that HORIZANT may increase the risk of suicidal thoughts and behavior, and should be advised of the need to be alert for the emergence or worsening of 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.

17.4 Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity

Patients should be instructed that multiorgan hypersensitivity reactions may occur with HORIZANT. Patients should contact their physician immediately if they experience any signs or symptoms of these conditions [see Warnings and Precautions (5.5)].

17.5 Lack of Interchangeability With Gabapentin

Patients should be advised that doses of HORIZANT and other gabapentin products are not interchangeable.

17.6 Dosing Instructions

• •Instruct patients to take HORIZANT only as prescribed.
• •Instruct patients to swallow tablets whole and do not cut, crush, or chew tablets.
• •Instruct patients to take HORIZANT with food.
• •For Restless Legs Syndrome, 600 mg HORIZANT should be taken once daily at about 5 PM. If the dose is not taken at the recommended time, the patient should take the next dose at about 5 PM the following day.
• •For Postherpetic Neuralgia, the starting dose is 600 mg HORIZANT in the morning for 3 days. Starting on day 4, 600 mg HORIZANT should be taken twice daily. If the dose is not taken at the recommended time, the next dose should be taken at the time of next scheduled dose.
• •Instruct patients about how to discontinue HORIZANT.

17.7 Alcohol

• •Advise patients to avoid alcohol when taking HORIZANT [see Drug Interactions (7); Clinical Pharmacology (12.3)].

HORIZANT is a registered trademark of GlaxoSmithKline.

Manufactured by:

Patheon Inc.

Research Triangle Park, NC 27709

©2013, GlaxoSmithKline. All rights reserved.

HZT:8PI

PHARMACIST—DETACH HERE AND GIVE TO PATIENT

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

MEDICATION GUIDE

HORIZANT^® (ho-ri' zant)

(gabapentin enacarbil)

Extended-Release Tablets

Read this Medication Guide before you start taking HORIZANT and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about HORIZANT?

HORIZANT can cause serious side effects:

1. Do not drive after taking your dose of HORIZANT until you know how HORIZANT affects you, including the morning after you take your dose.
Do not operate heavy machinery or do other dangerous activities until you know how HORIZANT affects you. HORIZANT can cause sleepiness, dizziness, slow thinking, and can affect your coordination. Ask your healthcare provider when it would be okay to do these activities.

2. HORIZANT may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• •thoughts about suicide or dying
• •attempt to commit suicide
• •new or worse depression
• •new or worse anxiety
• •feeling agitated
• •new or worse restlessness
• •panic attacks
• •new or worse trouble sleeping (insomnia)
• •new or worse irritability
• •acting aggressive, being angry, or violent
• •acting on dangerous impulses
• •an extreme increase in activity and talking (mania)
• •other unusual changes in behavior or mood

How can I watch for early symptoms of suicidal thoughts and actions?

• •Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
• •Keep all follow-up visits with your healthcare provider as scheduled.
• •Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Do not stop HORIZANT without first talking to a healthcare provider.

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

3. HORIZANT may cause a serious or life-threatening allergic reaction that may affect your skin or other parts of your body such as your liver or blood cells. You may or may not have rash with these types of reactions. Call a healthcare provider right away if you have any of the following symptoms:

• •skin rash
• •hives
• •fever
• •swollen glands that do not go away
• •swelling of your lips or tongue
• •yellowing of your skin or eyes
• •unusual bruising or bleeding
• •severe fatigue or weakness
• •unexpected, severe muscle pain
• •frequent infections

These symptoms may be the first signs of a serious reaction. A healthcare provider should examine you to decide if you should continue taking HORIZANT.

What is HORIZANT?

HORIZANT is a prescription medicine used to treat adults with:

• •moderate-to-severe primary Restless Legs Syndrome (RLS).
• •pain from damaged nerves (postherpetic pain) that follows healing of shingles (a painful rash that comes after a herpes zoster infection).

HORIZANT is not for people with RLS who need to sleep during the daytime and need to stay awake at night.

HORIZANT is not the same medicine as gabapentin (for example, NEURONTIN^® or GRALISE^®) and should not be used in its place.

It is not known if HORIZANT is safe and effective in children.

What should I tell my healthcare provider before taking HORIZANT?

Before taking HORIZANT, tell your healthcare provider if you:

• •have or have had kidney problems or are on hemodialysis.
• •have or have had depression, mood problems, or suicidal thoughts or behavior.
• •have or have had seizures.
• •have a history of drug abuse.
• •have any other medical conditions.
• •are pregnant or plan to become pregnant.
• •It is not known if HORIZANT will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant while taking HORIZANT. You and your healthcare provider will decide if you should take HORIZANT while you are pregnant.
• •are breastfeeding or plan to breastfeed. Your body turns HORIZANT into another drug (gabapentin) that passes into your milk. It is not known if this can harm your baby. You and your healthcare provider should decide if you will take HORIZANT or breastfeed.
• •drink alcohol.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take HORIZANT?

• •Take HORIZANT exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much HORIZANT to take and when to take it.
• •Take HORIZANT tablets whole. Do not cut, crush, or chew your tablet.
• •Take HORIZANT tablets with food.
• •Do not stop taking HORIZANT without talking to your healthcare provider first. If you stop taking HORIZANT suddenly, you may develop side effects.
• •If you forget to take your medicine at the time recommended by your healthcare provider, just skip the missed dose. Take the next dose at your regular time. Do not take 2 doses at one time.
• •If you take too much HORIZANT, call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid while taking HORIZANT?

• •Do not take other medicines that make you sleepy or dizzy while taking HORIZANT without first talking with your healthcare provider. Taking HORIZANT with medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
• •Do not take other gabapentin drugs (for example, NEURONTIN or GRALISE) while you take HORIZANT.
• •Do not consume alcohol when taking HORIZANT.

What are the possible side effects of HORIZANT?

• •See “What is the most important information I should know about HORIZANT?”

The most common side effects of HORIZANT include:

• •sleepiness
• •dizziness
• •headache

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of HORIZANT. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store HORIZANT?

• •Store HORIZANT between 59° and 86°F (15° and 30°C).
• •Keep HORIZANT dry and away from moisture.
• •Keep HORIZANT tightly closed in the bottle provided to you. Do not remove any moisture control packs that may come in the bottle.

Keep HORIZANT and all medicines out of the reach of children.

General Information about the safe and effective use of HORIZANT

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use HORIZANT for a condition for which it was not prescribed. Do not give HORIZANT to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about HORIZANT. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about HORIZANT that was written for healthcare professionals.

For more information about HORIZANT, go to www.gsk.com or call 1-888-825-5249.

What are the ingredients in HORIZANT?

Active ingredients: gabapentin enacarbil

Inactive ingredients: Both the 300 mg and 600 mg tablets contain colloidal silicon dioxide, dibasic calcium phosphate dihydrate, glyceryl behenate, magnesium stearate, sodium lauryl sulfate, and talc. The 300 mg tablets also contain red ferric oxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Patheon Inc.

Research Triangle Park, NC 27709

Revised: March 2013

HORIZANT is a registered trademark of GlaxoSmithKline. The other brands listed are trademarks of their respective owners and are not trademarks of GlaxoSmithKline. The makers of these brands are not affiliated with and do not endorse GlaxoSmithKline or its products.

©2013, GlaxoSmithKline. All rights reserved.

HZT:6MG

PRINCIPAL DISPLAY PANEL

NDC 0173-0832-13

Horizant^®

(gabapentinenacarbil)

Extended-Release Tablets

300 mg

Dispense the accompanying Medication Guide to each patient.

30 Tablets

Rx only

Tablets should be swallowed whole.

Do not cut, crush or chew tablets.

Each tablet contains 300 mg of gabapentin enacarbil.

See prescribing information for dosage information.

Store at 25°C (77°F); excursion permitted 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Protect from moisture.

Do not use if printed safety seal under cap is broken or missing.

Do not remove desiccants.

Manufactured by: Patheon Inc.

Research Triangle Park, NC 27709 for:

GlaxoSmithKline, RTP, NC 27709

Made in Switzerland

Licensed from:

XenoPort, Inc.

Santa Clara, CA 95051

HORIZANT is a registered trademark of GlaxoSmithKline.

10000000108616 Rev. 7/12