Dosage Form: tablet, extended release
FULL PRESCRIBING INFORMATION
Indications and Usage for Horizant
Horizant™ (gabapentin enacarbil) Extended-Release Tablets are 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.
Horizant Dosage and Administration
Restless Legs Syndrome
The recommended dosage for Horizant is 600 mg once daily taken with food 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.
Tablets should be swallowed whole and should not be cut, crushed, or chewed.
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.
| 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 |
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.
Dosage Forms and Strengths
Horizant Extended-Release Tablets, 300 mg, are red, oval-shaped tablets debossed with “GS TF7” and 600 mg, are white to off-white, oval-shaped tablets debossed with “GS LFG”. Both the 300 mg and 600 mg tablets may contain occasional black/grey spots.
Contraindications
None.
Warnings and Precautions
Effects on Driving
Horizant causes significant driving impairment. Patients being treated with 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.
In a 2-week simulated driving study in patients with RLS, a daily 1,200-mg dose of Horizant caused significant impairment within 2 hours and for up to 14 hours after dosing. The impairment was similar to that caused by the active control, a single oral dose of diphenhydramine 50 mg. The effect on driving at times other than 2 weeks is unknown. Whether the impairment is related to somnolence [see Warnings and Precautions (5.2)] or other effects of Horizant is unknown. The 600-mg dose was not studied. Because a 600-mg/day dose of Horizant can cause significant somnolence, similar to that of the 1,200-mg/day dose [see Warnings and Precautions (5.2)], the 600- and 1,200-mg/day doses may have similar effects on driving behavior.
Somnolence/Sedation and Dizziness
Horizant causes somnolence/sedation and dizziness (see Table 3). 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.
Lack of Interchangeability With Gabapentin
Horizant is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles. The same dose of Horizant results in different plasma concentrations of gabapentin relative to other gabapentin products. [See Clinical Pharmacology (12.3).]
The safety and effectiveness of Horizant in patients with epilepsy have not been studied.
Suicidal Behavior and Ideation
Horizant (gabapentin enacarbil) is a prodrug of gabapentin, an antiepileptic drug (AED). AEDs increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Because Horizant is a prodrug of gabapentin, Horizant also increases this risk. 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 (monotherapy and adjunctive therapy) of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately twice the risk [adjusted relative risk 1.8, 95% confidence interval (CI): 1.2, 2.7] of suicidal thinking or behavior compared with 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 with 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 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 1 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 to 100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
| 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 Horizant must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that Horizant increases the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and 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.
5.5 Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including gabapentin. Horizant is a prodrug of gabapentin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved.
It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Horizant should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Discontinuation of Horizant
When discontinuing Horizant, patients receiving the recommended dose of 600 mg daily can discontinue the drug without tapering. If the recommended dose is exceeded, the dose should be reduced to 600 mg daily for 1 week prior to discontinuation to minimize the potential of withdrawal seizure.
Tumorigenic Potential
In an oral carcinogenicity study, gabapentin enacarbil increased the incidence of pancreatic acinar cell adenoma and carcinoma in male and female rats [see Nonclinical Toxicology (13.1)]. The clinical significance of this finding is unknown.
In clinical studies of gabapentin as adjunctive therapy in epilepsy comprising 2,085 patient-years of exposure in patients >12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of gabapentin. Without knowledge of the background incidence and recurrence in a similar population not treated with gabapentin, it is impossible to know whether the incidence reported in this cohort is or is not affected by treatment.
Adverse Reactions
The following adverse reactions are described in more detail in the Warnings and Precautions section of the label:
- Somnolence/sedation and dizziness [see Warnings and Precautions (5.2)]
Clinical Trials Experience
In all controlled and uncontrolled trials across various patient populations prior to approval of Horizant, more than 2,300 patients have received Horizant orally in daily doses ranging from 600 to 3,600 mg.
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.
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.
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 3). Table 3 lists treatment-emergent adverse reactions that occurred in ≥2% of patients with RLS treated with Horizant and numerically greater than placebo.
| Body System/Adverse Reaction | Placeboa (N = 245) % | Horizant 600 mg/dayb (N = 163) % | Horizant 1,200 mg/dayc (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.
Adverse Events Associated With Gabapentin
The following adverse events have been reported in patients receiving gabapentin, either in clinical trials or postmarketing: breast enlargement and gynecomastia.
Drug Interactions
Neither gabapentin enacarbil nor gabapentin are substrates, inhibitors, or inducers of the major cytochrome P450 enzymes. Gabapentin enacarbil is neither a substrate nor 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) [see Clinical Pharmacology (12.3)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C. There are no adequate and well-controlled studies with Horizant in pregnant women. In nonclinical studies in rat and rabbits, administration of gabapentin enacarbil was developmentally toxic when administered to pregnant animals at doses and gabapentin exposures greater than those used clinically. Horizant should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
When pregnant rats were administered gabapentin enacarbil (oral doses of 200, 1,000, or 5,000 mg/kg/day) throughout the period of organogenesis, embryo-fetal mortality was increased at the 2 highest doses and fetal body weights were decreased at the high dose. The no-effect dose for embryo-fetal developmental toxicity in rats is approximately 3 times the recommended human dose (RHD) of 600 mg/day on a body surface area (mg/m2) basis.
When pregnant rabbits were administered gabapentin enacarbil (oral doses of 200, 500, or 2,500 mg/kg/day) throughout the period of organogenesis, embryo-fetal mortality was increased and fetal body weights were decreased at the high dose. The no-effect dose for embryo-fetal developmental toxicity in rabbits (500 mg/kg/day) is approximately 16 times the RHD on a mg/m2 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 3 times the RHD on a mg/m2 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, embryo-fetal 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 embryo-fetal mortality was observed at all doses of gabapentin tested.
In a published study, gabapentin (400 mg/kg/day) was administered by intraperitoneal injection to neonatal mice during the first postnatal week, a period of synaptogenesis in rodents (corresponding to the last trimester of pregnancy in humans). Gabapentin caused a marked decrease in neuronal synapse formation in brains of intact mice and abnormal neuronal synapse formation in a mouse model of synaptic repair. Gabapentin has been shown in vitro to interfere with activity of the α2δ subunit of voltage-activated calcium channels, a receptor involved in neuronal synaptogenesis. The clinical significance of these findings is unknown.
Labor and Delivery
The effect of Horizant on labor and delivery is unknown.
Nursing Mothers
It is not known whether gabapentin derived from Horizant is secreted in human milk; however, gabapentin is secreted into human milk following oral administration of gabapentin products. Because of the potential for adverse reactions in nursing infants from Horizant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness of Horizant in pediatric patients have not been studied.
Geriatric Use
Of the 515 patients treated with Horizant in the 3 double-blind, placebo-controlled, 12-week clinical trials for RLS, 11% were 65 to 74 years of age and 1% were 75 years of age and older. Clinical trials of Horizant did not include a sufficient number of patients 65 years and older to determine whether they respond differently from younger individuals.
Gabapentin is known to be almost exclusively excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, the frequency of dosing may need to be adjusted based on calculated creatinine clearance in these patients [see Dosage and Administration (2.2)].
Renal Impairment
The dose of Horizant should be adjusted in patients with renal impairment [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].
Overdosage
Human Overdose Experience
There have been no reports describing individuals who have taken an overdose of Horizant. The highest single dose of gabapentin enacarbil administered to date is 6,000 mg in healthy subjects. At this supratherapeutic dose there were no serious adverse events. The incidence of central nervous system adverse reactions, particularly dizziness and somnolence/sedation, is increased with doses greater than 600 mg daily.
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.
Horizant Description
Horizant (gabapentin enacarbil) is a prodrug of gabapentin. Gabapentin enacarbil is described as (1-{[({(1RS)-1-[(2-Methylpropanoyl)oxy]ethoxy}carbonyl)amino]methyl} cyclohexyl) acetic acid. It has a molecular formula of C16H27NO6 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. The 300 mg tablets also contain red ferric oxide.
Horizant - Clinical Pharmacology
Mechanism of Action
Gabapentin enacarbil is a prodrug of gabapentin and, accordingly, its therapeutic effects in RLS are attributable to gabapentin.
The precise mechanism by which gabapentin is efficacious in RLS is unknown. 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 is unknown.
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.
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 Tmax 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, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). It is not known if gabapentin enacarbil is an inhibitor of CYP2B6 and CYP2C8. 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 (t½) of gabapentin ranges from 5.1 to 6.0 hours and is unaltered by dose or following multiple doses of Horizant.
Special Populations:Race: The majority (94%) of subjects in the clinical studies were 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. For patients on hemodialysis, treatment with Horizant is not recommended [see Dosage and Administration (2.2)].
Drug Interactions: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 Cmax and AUC. No clinically relevant pharmacokinetic interactions are expected between Horizant and other substrates of MCT-1.
Nonclinical Toxicology
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 40 times the RHD of 600 mg/day, on a body surface area (mg/m2) 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 10, 38, and 75 times, respectively, that in humans at the RHD. 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 25 times that in humans at the RHD.
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 80 times the RHD on a mg/m2 basis.
Clinical Studies
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 4.
| Week 12 | Study 1 | Study 2 | |||
Horizant 1,200 mg (N = 112) | Placebo (N = 108) | Horizant 600 mg (N = 114) | Horizant 1,200 mg (N = 111) | Placebo (N = 96) | |
| Mean Change in IRLS Score | -13.2 | -8.8 | -13.8 | -13.0 | -9.8 |
| Proportion of Respondersa on CGI-I | 76% | 39% | 73% | 77% | 45% |
a CGI-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.
Figure 1. Study 2, Mean (±SD) IRLS Rating Scale Total Score Over 12 Weeks (Observed Case Data, Modified Intent-To-Treat Population)
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
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