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Gabapentin Enacarbil Extended-Release Tablets

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

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 is a racemate and has the following structural formula:

Molecular formula: C16H27NO6- Molecular weight: 329.39

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).

Gabapentin enacarbil is administered orally. Each gabapentin enacarbil extended-release (ER) tablet contains 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.

2. INDICATIONS AND USAGE

2.1 Treatment of Restless Legs Syndrome

Gabapentin enacarbil extended-release (ER) tablets are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) in adults.

Gabapentin enacarbil ER is not recommended for patients who are required to sleep during the daytime and remain awake at night.

2.2 Management of Postherpetic Neuralgia

Gabapentin enacarbil ER tablets are indicated for the management of postherpetic neuralgia (PHN) in adults.

3. DOSAGE AND ADMINISTRATION

Tablets should be swallowed whole and should not be cut, crushed, or chewed.

Tablets should be taken with food.

Gabapentin enacarbil ER is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles [see Warnings and Precautions].

3.1 Restless Legs Syndrome

The recommended dosage for gabapentin enacarbil ER 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].

If the dose is not taken at the recommended time, the next dose should be taken the following day as prescribed.

3.2 Postherpetic Neuralgia

The recommended dosage of gabapentin enacarbil ER is 600 mg twice daily. Gabapentin enacarbil ER 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].

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.

3.3 Renal Impairment

Dosing of gabapentin enacarbil ER is adjusted in accordance with renal function, as represented by creatinine clearance. Target dose regimens are listed in Table 1 and Table 2.

Table 1. Dosage of Gabapentin Enacarbil ER for Patients With Restless Legs Syndrome in Accordance With Creatinine Clearance

Table 2. Dosage of Gabapentin Enacarbil ER for Patients With Postherpetic Neuralgia in Accordance With Creatinine Clearance

a Based on tolerability and efficacy

_________________________________________________________________

In patients with stable renal function, CrCl can be estimated using the equation of Cockcroft and Gault:

where age is in years, weight is in kilograms, and serum creatinie is in mg/dL.

4. CONTRAINDICATIONS

None.

5. 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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies with gabapentin enacarbil ER 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. Gabapentin enacarbil ER 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 (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, 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) 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, 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.

6.2 Labor and Delivery

The effect of gabapentin enacarbil on labor and delivery is unknown.

6.3 Nursing Mothers

It is not known whether gabapentin derived from gabapentin enacarbil 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 gabapentin enacarbil, 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.

6.4 Pediatric Use

Safety and effectiveness of gabapentin enacarbil in pediatric patients have not been studied.

6.5 Geriatric Use

Of the 515 patients treated with gabapentin enacarbil 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 gabapentin enacarbil did not include a sufficient number of patients 65 years and older to determine whether they respond differently from younger individuals.

In the 12-week, double-blind, placebo-controlled study of gabapentin enacarbil ER for the management of PHN (n=276 patients treated with gabapentin enacarbil ER), 37% were 65 to 74 years of age and 13% were 75 years of age and older. The overall incidence of adverse events was comparable between the patients aged ≥18 to < 65 years and ≥65 to < 74 years. No overall differences in the safety and effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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].

6.6 Renal Impairment

The dose of gabapentin enacarbil should be adjusted in patients with renal impairment [see Dosage and Administration].

7. WARNINGS AND PRECAUTIONS

7.1 Effects on Driving

Gabapentin enacarbil causes significant driving impairment. Patients being treated with gabapentin enacarbil should not drive until they have gained sufficient experience to assess whether gabapentin enacarbil 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 gabapentin enacarbil, can be imperfect.

In a 2-week simulated driving study in patients with RLS, a daily 1,200-mg dose of gabapentin enacarbil 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] or other effects of gabapentin enacarbil is unknown. The 600-mg dose was not studied. Because a 600-mg/day dose of gabapentin enacarbil can cause significant somnolence, similar to that of the 1,200-mg/day dose [see Warnings and Precautions], the 600- and 1,200-mg/day doses may have similar effects on driving behavior.

7.2 Somnolence/Sedation and Dizziness

Gabapentin enacarbil causes somnolence/sedation and dizziness (see Table 2). Patients should be advised not to drive a car or operate other complex machinery until they have gained sufficient experience on gabapentin enacarbil to assess whether gabapentin enacarbil 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 gabapentin enacarbil per day compared with 6% of patients receiving placebo. In those patients treated with gabapentin enacarbil 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 gabapentin enacarbil per day compared with 4% of patients receiving placebo. In those patients treated with gabapentin enacarbil who reported dizziness, symptoms persisted during treatment in about 20%. Somnolence/sedation led to withdrawal in 2% of patients receiving 600 mg of gabapentin enacarbil per day. Dizziness led to withdrawal in 1% of patients receiving 600 mg of gabapentin enacarbil 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 gabapentin enacarbil ER per day compared with 8% of patients receiving placebo. Fatigue/asthenia was reported in 6% of patients treated with 1,200 mg of gabapentin enacarbil ER per day compared with 1% of patients receiving placebo. In those patients treated with 1,200 mg of gabapentin enacarbil ER 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 gabapentin enacarbil ER per day compared with 15% of patients receiving placebo. In those patients treated with 1,200 mg of gabapentin enacarbil ER 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 gabapentin enacarbil ER per day compared with 2% of patients receiving placebo. Dizziness led to withdrawal in 2% of patients receiving 1,200 mg of gabapentin enacarbil ER per day compared with 3% of patients receiving placebo.

7.3 Lack of Interchangeability With Gabapentin

Gabapentin enacarbil is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles. The same dose of gabapentin enacarbil results in different plasma concentrations of gabapentin relative to other gabapentin products.

The safety and effectiveness of gabapentin enacarbil in patients with epilepsy have not been studied.

7.4 Suicidal Behavior and Ideation

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 gabapentin enacarbil is a prodrug of gabapentin, gabapentin enacarbil 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 3 shows absolute and relative risk by indication for all evaluated AEDs.

Table 3. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

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 gabapentin enacarbil 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 gabapentin enacarbil 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.

7.5 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. Gabapentin enacarbil ER 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. Gabapentin enacarbil ER should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

7.6 Discontinuation of Gabapentin Enacarbil ER

When discontinuing gabapentin enacarbil, 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.

In patients with PHN receiving gabapentin enacarbil ER twice daily, the dose should be reduced to once daily for 1 week prior to discontinuation to minimize the potential of withdrawal seizure, see Table 2 [see Dosage and Administration].

7.7 Tumorigenic Potential

In an oral carcinogenicity study, gabapentin enacarbil increased the incidence of pancreatic acinar cell adenoma and carcinoma in male and female rats. 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.

8. 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]

8.1 Clinical Trials Experience

In all controlled and uncontrolled trials across various patient populations prior to approval of gabapentin enacarbil, more than 2,300 patients have received gabapentin enacarbil orally in daily doses ranging from 600 to 3,600 mg.

The exposure to gabapentin enacarbil in 1,201 patients with RLS included 613 exposed for at least 6 months and 371 exposed for at least 1 year. Gabapentin enacarbil 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 gabapentin enacarbil 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 gabapentin enacarbil 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 gabapentin enacarbil 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 gabapentin enacarbil 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 Gabapentin Enacarbil and Numerically Greater Than Placebo

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 gabapentin enacarbil was a treatment arm in 2 of the 3 double-blind, placebo- controlled, 12-week clinical trials.

c The 1,200-mg dose of gabapentin enacarbil was a treatment arm in each of the 3 double-blind, placebo-controlled, 12-week clinical trials.

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Adverse reactions reported in these three 12-week studies in < 2% of patients treated with 600 mg of gabapentin enacarbil and numerically greater than placebo were balance disorder, blurred vision, disorientation, feeling drunk, lethargy, and vertigo.

The following adverse reactions were dose-related: somnolence/sedation, dizziness, feeling drunk, libido decreased, depression, headache, peripheral edema, and vertigo.

Postherpetic Neuralgia: The exposure to gabapentin enacarbil ER in 417 patients with PHN included 207 patients exposed for at least 3 months. Overall, the mean age of patients in the PHN studies ranged from 61 to 64 years of age across dose groups; the majority of patients were male (45% to 61%) and Caucasian (80% to 98%).

The safety of gabapentin enacarbil ER in doses ranging from 1,200 to 3,600 mg has been evaluated in 417 patients with PHN in 3 clinical studies. The principal efficacy study evaluating the efficacy and safety of gabapentin enacarbil ER in the management of PHN was a 12-week, double-blind, multicenter study comparing 1,200 mg/day, 2,400 mg/day and 3,600 mg/day to placebo. Six out of 107 (6%) patients treated with 1,200 mg of gabapentin enacarbil ER discontinued treatment due to adverse events compared with 12 of the 95 (13%) patients who received placebo.

The most commonly observed adverse reactions (≥10% and greater than placebo) in this trial for the 1,200 mg dose of gabapentin enacarbil ER were dizziness, somnolence and headache (see Table 5). Table 5 lists treatment-emergent adverse reactions that occurred in ≥2% of patients with PHN treated with gabapentin enacarbil ER 1,200 mg/day and numerically greater than placebo.

Table 5. Incidence of Adverse Reactions (in At Least 2% of Patients Treated With 1,200 mg/day of Gabapentin Enacarbil ER and Numerically Greater Than the Placebo Rate) Reported in All Patients in the 12-Week PHN Study

The following adverse reactions were also reported as ≥2% at 2,400 mg/day and/or 3,600 mg/day and appeared to be dose-related but were < 2% at 1,200 mg/day: balance disorder, confusional state, depression, dry mouth, flatulence, increased appetite, irritability, and vertigo. Dizziness, somnolence, fatigue, and insomnia appeared to show a dose relationship.

8.2 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.

9. OVERDOSAGE

9.1 Human Overdose Experience

There have been no reports describing individuals who have taken an overdose of gabapentin enacarbil. 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.

9.2 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 by hemodialysis. Standard hemodialysis procedures result in significant clearance of gabapentin.

Further management should be as clinically indicated or as recommended by a poison control center.

10. 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 gabapentin enacarbil and other substrates of organic cation transporter type 2 (OCT2) and monocarboxylate transporter type 1 (MCT-1).

11. PHARMACOKINETICS

Gabapentin enacarbil is an extended-release formulation of gabapentin enacarbil, a prodrug of gabapentin. Gabapentin enacarbil provides approximately dose-proportional and extended exposure to gabapentin over the range 300 to 6,000 mg. Gabapentin enacarbil 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 gabapentin enacarbil. Mean bioavailability of gabapentin (based on urinary recovery of gabapentin) for gabapentin enacarbil 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 gabapentin enacarbil 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 gabapentin enacarbil 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 gabapentin enacarbil with food ranged from 6.0 to 9.3 L/hr. Following oral dosing of gabapentin enacarbil, 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 gabapentin enacarbil.

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 gabapentin enacarbil between male and female patients.

Geriatric Patients: There are no clinically significant differences in pharmacokinetics of gabapentin enacarbil 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].

Renal Impairment and Hemodialysis: Gabapentin clearance after dosing with gabapentin enacarbil 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 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 gabapentin enacarbil). For patients on hemodialysis, treatment with gabapentin enacarbil is not recommended [see Dosage and Administration].

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: HORIZANT, by GLAXOSMITHKLINE.

b) Generic drugs: None.

2) How Supplied:

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

3) Storage:

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. Dispense in original bottle.

Rx only

Rev 12/12