own. patients taking horizant should not drive until they have gained sufficient experience to assess whether horizant impairs their ability to drive. however, prescribers and patients should be aware that patients' ability to assess their own driving competence, as well as their ability to assess the degree of somnolence caused by horizant, can be imperfect. whether the impairment is related to somnolence [see warnings and precautions (5.2) ] or other effects of horizant is unknown. 5.2 somnolence/sedation and dizziness horizant causes somnolence/sedation and dizziness (see tables 4 and 5 ). patients should be advised not to drive a car or operate other complex machinery until they have gained sufficient experience on horizant to assess whether horizant impairs their ability to perform these tasks. during the controlled trials in patients with rls, somnolence/sedation was reported in 20% of patients treated with 600 mg of horizant per day compared with 6% of patients receiving placebo. in those patients treated with horizant who reported somnolence, the somnolence persisted during treatment in about 30%. in the remaining patients, symptoms resolved within 3 to 4 weeks. dizziness was reported in 13% of patients receiving 600 mg of horizant per day compared with 4% of patients receiving placebo. in those patients treated with horizant who reported dizziness, symptoms persisted during treatment in about 20%. somnolence/sedation led to withdrawal in 2% of patients receiving 600 mg of horizant per day. dizziness led to withdrawal in 1% of patients receiving 600 mg of horizant per day. the incidence of these adverse reactions was greater in the patients receiving 1,200 mg per day. during the 12-week, controlled study in patients with phn, somnolence was reported in 10% of patients treated with 1,200 mg of horizant per day compared with 8% of patients receiving placebo. fatigue/asthenia was reported in 6% of patients treated with 1,200 mg of horizant per day compared with 1% of patients receiving placebo. in those patients treated with 1,200 mg of horizant per day who reported somnolence (10%), the somnolence persisted during treatment in about 27%. in the remaining patients, symptoms resolved within 4 to 5 weeks. dizziness was reported in 17% of patients receiving 1,200 mg of horizant per day compared with 15% of patients receiving placebo. in those patients treated with 1,200 mg of horizant per day who reported dizziness, symptoms persisted during treatment in about 6%. somnolence led to withdrawal in <1% of patients receiving 1,200 mg of horizant per day compared with 2% of patients receiving placebo. dizziness led to withdrawal in 2% of patients receiving 1,200 mg of horizant per day compared with 3% of patients receiving placebo. 5.3 lack of 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. 5.4 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 3 shows absolute and relative risk by indication for all evaluated aeds. table 3. risk by indication for antiepileptic drugs in the pooled analysis 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 respiratory depression there is evidence from case reports, human studies, and animal studies associating gabapentin with serious, life-threatening, or fatal respiratory depression when co-administered with central nervous system (cns) depressants, including opioids, or in the setting of underlying respiratory impairment. when the decision is made to co-prescribe horizant with another cns depressant, particularly an opioid, or to prescribe horizant to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating horizant at a low dose. the management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of cns depressants (including horizant). 5.6 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, lymphadenopathy, and/or facial swelling, 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. 5.7 discontinuation of horizant when discontinuing horizant, patients with rls receiving 600 mg or less once 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 horizant 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 (2.3) ] . 5.8 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.

d be taken at the time of next scheduled dose. ( 2.2 ) patients with renal impairment: doses of horizant must be adjusted in accordance with renal function. ( 2.3 ) 2.1 restless legs syndrome the recommended dosage for horizant is 600 mg once daily at about 5 pm. a daily dose of 1,200 mg provided no additional benefit compared with the 600-mg dose, but caused an increase in adverse reactions [see adverse reactions (6.1) ] . if the dose is not taken at the recommended time, the next dose should be taken the following day as prescribed. 2.2 postherpetic neuralgia the recommended dosage of horizant is 600 mg twice daily. horizant should be initiated at a dose of 600 mg in the morning for 3 days of therapy, then increased to 600 mg twice daily (1,200 mg/day) on day four. in the 12-week principal efficacy study, additional benefit of using doses greater than 1,200 mg a day was not demonstrated, and these higher doses resulted in an increase in adverse reactions [see adverse reactions (6.1) ] . if the dose is not taken at the recommended time, skip this dose, and the next dose should be taken at the time of the next scheduled dose. 2.3 renal impairment dosing of horizant is adjusted in accordance with renal function, as represented by creatinine clearance [see clinical pharmacology (12.3) ] . target dose regimens are listed in table 1 and table 2. table 1. dosage of horizant for patients with restless legs syndrome in accordance with creatinine clearance creatinine clearance (ml/min) target dose regimen ≥60 600 mg per day 30 – 59 start at 300 mg per day and increase to 600 mg as needed 15 – 29 300 mg per day <15 300 mg every other day <15 on hemodialysis not recommended table 2. dosage of horizant for patients with postherpetic neuralgia in accordance with creatinine clearance creatinine clearance (ml/min) titration maintenance tapering ≥60 600 mg in am for 3 days 600 mg twice daily 600 mg in am for 1 week 30 – 59 300 mg in am for 3 days 300 mg twice daily. increase to 600 mg twice daily as needed based on tolerability and efficacy reduce current maintenance dose to once daily in am for 1 week 15 – 29 300 mg in am on day 1 and day 3 300 mg in am. increase to 300 mg twice daily if needed if taking 300 mg twice daily, reduce to 300 mg once daily in am for 1 week. if taking 300 mg once daily, no taper needed. <15 none 300 mg every other day in am. increase to 300 mg once daily in am if needed none <15 on hemodialysis none 300 mg following every dialysis. increase to 600 mg following every dialysis if needed none in patients with stable renal function, crcl can be estimated using the equation of cockcroft and gault: for males: crcl = (140-age)(weight)/[(72)(scr)] for females: crcl = (0.85)(140-age)(weight)/[(72)(scr)] where age is in years, weight is in kilograms, and scr is serum creatinine in mg/dl.

are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. in all controlled and uncontrolled trials across various patient populations, more than 2,300 patients have received horizant orally in daily doses ranging from 600 to 3,600 mg. restless legs syndrome the exposure to horizant in 1,201 patients with rls included 613 exposed for at least 6 months and 371 exposed for at least 1 year. horizant in the treatment of rls was studied primarily in placebo-controlled trials (n = 642), and in long- term follow-up studies. the population with rls ranged from 18 to 82 years of age, with 60% being female and 95% being caucasian. the safety of horizant in doses ranging from 600 to 2,400 mg has been evaluated in 515 patients with rls in 3 double-blind, placebo-controlled, 12-week clinical trials. the 600-mg dose was studied in 2 of the 3 studies. eleven out of 163 (7%) patients treated with 600 mg of horizant discontinued treatment due to adverse reactions compared with 10 of the 245 (4%) patients who received placebo. the most commonly observed adverse reactions (≥5% and at least 2 times the rate of placebo) in these trials for the 600-mg dose of horizant were somnolence/sedation and dizziness (see table 4 ). table 4 lists treatment-emergent adverse reactions that occurred in ≥2% of patients with rls treated with horizant and numerically greater than placebo. table 4. incidence of adverse reactions in 12-week rls studies reported in ≥2% of patients treated with 600 or 1,200 mg of horizant and numerically greater than placebo body system/adverse reaction placebo placebo was a treatment arm in each of the 3 double-blind, placebo-controlled, 12-week clinical trials. (n = 245) % horizant 600 mg/day the 600-mg dose of horizant was a treatment arm in 2 of the 3 double-blind, placebo- controlled, 12-week clinical trials. (n = 163) % horizant 1,200 mg/day the 1,200-mg dose of horizant was a treatment arm in each of the 3 double-blind, placebo-controlled, 12-week clinical trials. (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 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. postherpetic neuralgia the exposure to horizant 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 horizant 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 horizant 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 horizant 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 horizant 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 horizant 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 horizant and numerically greater than the placebo rate) reported in all patients in the 12-week phn study body system/adverse reaction placebo (n = 95) % horizant 1,200 mg/day (n = 107) % horizant 2,400 mg/day (n = 82) % horizant 3,600 mg/day (n = 87) % nervous system dizziness 15 17 26 30 somnolence 8 10 11 14 headache 9 10 10 7 gastrointestinal disorders nausea 5 8 4 9 general disorders and administration site conditions fatigue/asthenia 1 6 4 10 peripheral edema 0 6 7 6 psychiatric disorders insomnia 2 3 5 7 metabolism and nutritional disorders weight increased 1 3 5 5 eye disorders blurred vision 0 2 5 2 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. 6.2 postmarketing experience the following adverse reactions have been reported in patients receiving gabapentin and have been identified during postapproval use of horizant. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: breast enlargement, gynecomastia, elevated creatine kinase, bullous pemphigoid. there are postmarketing reports of life-threatening or fatal respiratory depression in patients taking gabapentin with opioids or other cns depressants, or in the setting of underlying respiratory impairment [see warnings and precautions (5.5) ].

high dose. the no-effect dose for embryofetal developmental toxicity in rats (200 mg/kg/day) represents approximately 2 times the gabapentin exposure associated with the maximum recommended human dose (mrhd) of 1,200 mg/day gabapentin enacarbil on an area under the curve (auc) basis. when pregnant rabbits were administered gabapentin enacarbil (oral doses of 200, 500, or 2,500 mg/kg/day) throughout the period of organogenesis, embryofetal mortality was increased and fetal body weights were decreased at the high dose. the no-effect dose for embryofetal developmental toxicity in rabbits (500 mg/kg/day) represents approximately 9 times the gabapentin exposure associated with the mrhd of 1,200 mg/day gabapentin enacarbil on an auc basis. when female rats were administered gabapentin enacarbil (oral doses of 200, 1,000, or 5,000 mg/kg/day) throughout the pregnancy and lactation periods, offspring growth and survival were decreased at the two highest doses. the no-effect dose for pre- and post-natal developmental toxicity in rats is approximately 2 times the mrhd on an auc basis. in reproductive and developmental studies of gabapentin, developmental toxicity was observed at all doses tested. increased incidences of hydroureter and/or hydronephrosis were observed in rat offspring following treatment of pregnant animals in studies of fertility and general reproductive performance, embryofetal development, and peri- and post-natal development. overall, a no-effect dose was not established. in mice, treatment of pregnant animals with gabapentin during the period of organogenesis resulted in delayed fetal skeletal ossification at all but the lowest dose tested. when pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryofetal mortality was observed at all doses of gabapentin tested. in a 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. 8.2 lactation risk summary 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 other gabapentin products. there are no data on the effects of gabapentin on the breastfed infant or the effects on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for horizant and any potential adverse effects on the breastfed infant from horizant or from the underlying maternal condition. 8.4 pediatric use safety and effectiveness in pediatric patients have not been studied. 8.5 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 for the treatment of rls 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 horizant for the management of phn (n = 276 patients treated with horizant), 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 (2.3) ] . 8.6 renal impairment the dose of horizant should be adjusted in patients with renal impairment [see dosage and administration (2.3) , clinical pharmacology (12.3) ] .

represents approximately 2 times the gabapentin exposure associated with the maximum recommended human dose (mrhd) of 1,200 mg/day gabapentin enacarbil on an area under the curve (auc) basis. when pregnant rabbits were administered gabapentin enacarbil (oral doses of 200, 500, or 2,500 mg/kg/day) throughout the period of organogenesis, embryofetal mortality was increased and fetal body weights were decreased at the high dose. the no-effect dose for embryofetal developmental toxicity in rabbits (500 mg/kg/day) represents approximately 9 times the gabapentin exposure associated with the mrhd of 1,200 mg/day gabapentin enacarbil on an auc basis. when female rats were administered gabapentin enacarbil (oral doses of 200, 1,000, or 5,000 mg/kg/day) throughout the pregnancy and lactation periods, offspring growth and survival were decreased at the two highest doses. the no-effect dose for pre- and post-natal developmental toxicity in rats is approximately 2 times the mrhd on an auc basis. in reproductive and developmental studies of gabapentin, developmental toxicity was observed at all doses tested. increased incidences of hydroureter and/or hydronephrosis were observed in rat offspring following treatment of pregnant animals in studies of fertility and general reproductive performance, embryofetal development, and peri- and post-natal development. overall, a no-effect dose was not established. in mice, treatment of pregnant animals with gabapentin during the period of organogenesis resulted in delayed fetal skeletal ossification at all but the lowest dose tested. when pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryofetal mortality was observed at all doses of gabapentin tested. in a 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.

hese 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. 12.2 pharmacodynamics cardiac electrophysiology at a dose of 6,000 mg, gabapentin enacarbil does not prolong qtc to a clinically relevant extent. 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 auc 24 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 14 c 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. specific 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 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). 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.

ate 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 14 c 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. specific 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 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). 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.

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.

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.

, 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. table 6. mean change in irls scale total score and proportion of responders on cgi-i scale at week 12 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 responders cgi-i responders = "much improved" and "very much improved." on cgi-i 76% 39% 73% 77% 45% 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) figure 1 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. figure 2. percent of patients achieving various levels of improvement in pain intensity figure 2 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. table 7. simulated crashes at evaluated timepoints (secondary measure) simulated driving timepoint and hours post dose baseline n = 36 n (%) placebo n = 36 n (%) horizant 600 mg n = 35 n (%) diphenhydramine 50 mg n = 36 n (%) day 5 evening (7 to 9 pm) 2 to 4 hours post dose 0 (0) 0 (0) 0 (0) 3 (9) day 6 morning (7 to 9 am) 14 to 16 hours post dose 2 (6) 1 (3) 1 (3) 0 (0) day 6 midday (11 am to 1 pm) 18 to 20 hours post dose 1 (3) 0 (0) 3 (9) 3 (8) 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.

nd precautions (5.2) ]. 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 [see warnings and precautions (5.4) ]. behaviors of concern should be reported immediately to healthcare providers. respiratory depression inform patients about the risk of respiratory depression. include information that the risk is greatest for those using concomitant cns depressants (such as opioid analgesics), or those with concurrent respiratory impairment. teach patients how to recognize respiratory depression and advise them to seek medical attention immediately if it occurs [see warnings and precautions (5.5) ] . 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) ] . lack of interchangeability with gabapentin patients should be advised that doses of horizant and other gabapentin products are not interchangeable [see warnings and precautions (5.3) ]. dosing instructions [see dosage and administration (2) ] 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. alcohol advise patients to avoid alcohol when taking horizant [see drug interactions (7) , clinical pharmacology (12.3) ] .