gabapentin 400 MG Oral Tablet

INDICATIONS AND USAGE Gabapentin tablets (Once-Daily) are indicated for the management of postherpetic neuralgia. Gabapentin tablets (Once-Daily) are not substitutable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration. Gabapentin tablets are indicated for the management of Postherpetic Neuralgia (PHN). Important Limitation: Gabapentin tablets (Once-Daily) is not substitutable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration ( See Warnings and Precautions )

DOSAGE AND ADMlNlSTRATION Postherpetic Neuralgia (2.1) Dose can be titrated up as needed to a dose of 1800 mg/day Day 1: Single 300 mg dose Day 2: 600 mg/day (i.e., 300 mg two times a day) Day 3: 900 mg/day (i.e., 300 mg three times a day) Epilepsy with Partial Onset Seizures (2.2) Patients 12 years of age and older: starting dose is 300 mg three times daily; may be titrated up to 600 mg three times daily Patients 3 to 11 years of age: starting dose range is 10 to 15 mg/kg/day, given in three divided doses; recommended dose in patients 3 to 4 years of age is 40 mg/kg/day, given in three divided doses; the recommended dose in patients 5 to 11 years of age is 25 to 35 mg/kg/day, given in three divided doses. The recommended dose is reached by upward titration over a period of approximately 3 days Dose should be adjusted in patients with reduced renal function ( 2.3 , 2.4 ) 2.1 Dosage for Postherpetic Neuralgia In adults with postherpetic neuralgia, Gabapentin may be initiated on Day 1 as a single 300 mg dose, on Day 2 as 600 mg/day (300 mg two times a day), and on Day 3 as 900 mg/day (300 mg three times a day). The dose can subsequently be titrated up as needed for pain relief to a dose of 1800 mg/day (600 mg three times a day). In clinical studies, efficacy was demonstrated over a range of doses from 1800 mg/day to 3600 mg/day with comparable effects across the dose range; however, in these clinical studies, the additional benefit of using doses greater than 1800 mg/day was not demonstrated 2.2 Dosage for Epilepsy with Partial Onset Seizures Patients 12 years of age and above The starting dose is 300 mg three times a day. The recommended maintenance dose of Gabapentin is 300 mg to 600 mg three times a day. Dosages up to 2400 mg/day have been well tolerated in long-term clinical studies. Doses of 3600 mg/day have also been administered to a small number of patients for a relatively short duration, and have been well tolerated. Administer Gabapentin three times a day using 300 mg or 400 mg capsules. The maximum time between doses should not exceed 12 hours. Pediatric Patients Age 3 to 11 years The starting dose range is 10 mg/kg/day to 15 mg/kg/day, given in three divided doses, and the recommended maintenance dose reached by upward titration over a period of approximately 3 days. The recommended maintenance dose of Gabapentin in patients 3 to 4 years of age is 40 mg/kg/day, given in three divided doses. The recommended maintenance dose of Gabapentin in patients 5 to 11 years of age is 25 mg/kg/day to 35 mg/kg/day, given in three divided doses. Gabapentin may be administered as the capsule formulations. Dosages up to 50 mg/kg/day have been well tolerated in a long-term clinical study. The maximum time interval between doses should not exceed 12 hours. 2.3 Dosage Adjustment in Patients with Renal Impairment Dosage adjustment in patients 12 years of age and older with renal impairment or undergoing hemodialysis is recommended, as follows (see dosing recommendations above for effective doses in each indication): TABLE 1. Gabapentin Dosage Based on Renal Function TID = Three times a day; BID = Two times a day; QD = Single daily dose Renal Function Creatinine Clearance (mL/min) Total Daily Dose Range (mg/day) Dose Regimen (mg) ≥60 900 to 3600 300 TID 400 TID 600 TID 800 TID 1200 TID >30 to 59 400 to 1400 200 BID 300 BID 400 BID 500 BID 700 BID >15 to 29 200 to 700 200 QD 300 QD 400 QD 500 QD 700 QD 15 For patients with creatinine clearance <15 mL/min, reduce daily dose in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients with a creatinine clearance of 15 mL/min receive) 100 to 300 100 QD 125 QD 150 QD 200 QD 300 QD Post-Hemodialysis Supplemental Dose (mg) Patients on hemodialysis should receive maintenance doses based on estimates of creatinine clearance as indicated in the upper portion of the table and a supplemental post-hemodialysis dose administered after each 4 hours of hemodialysis as indicated in the lower portion of the table. Hemodialysis 125 150 200 250 350 Creatinine clearance (CLCr) is diffcult to measure in outpatients. In patients with stable renal function, creatinine clearance can be reasonably well estimated using the equation of Cockcroft and Gault: The use of Gabapentin in patients less than 12 years of age with compromised renal function has not been studied. 2.4 Dosage in Elderly Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and dose should be adjusted based on creatinine clearance values in these patients. 2.5 Administration Information Administer Gabapentin orally with or without food. Gabapentin capsules should be swallowed whole with water. If the Gabapentin dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of 1 week (a longer period may be needed at the discretion of the prescriber). 2.1 Dosage for Postherpetic Neuralgia In adults with postherpetic neuralgia, Gabapentin may be initiated on Day 1 as a single 300 mg dose, on Day 2 as 600 mg/day (300 mg two times a day), and on Day 3 as 900 mg/day (300 mg three times a day). The dose can subsequently be titrated up as needed for pain relief to a dose of 1800 mg/day (600 mg three times a day). In clinical studies, efficacy was demonstrated over a range of doses from 1800 mg/day to 3600 mg/day with comparable effects across the dose range; however, in these clinical studies, the additional benefit of using doses greater than 1800 mg/day was not demonstrated 2.2 Dosage for Epilepsy with Partial Onset Seizures Patients 12 years of age and above The starting dose is 300 mg three times a day. The recommended maintenance dose of Gabapentin is 300 mg to 600 mg three times a day. Dosages up to 2400 mg/day have been well tolerated in long-term clinical studies. Doses of 3600 mg/day have also been administered to a small number of patients for a relatively short duration, and have been well tolerated. Administer Gabapentin three times a day using 300 mg or 400 mg capsules. The maximum time between doses should not exceed 12 hours. Pediatric Patients Age 3 to 11 years The starting dose range is 10 mg/kg/day to 15 mg/kg/day, given in three divided doses, and the recommended maintenance dose reached by upward titration over a period of approximately 3 days. The recommended maintenance dose of Gabapentin in patients 3 to 4 years of age is 40 mg/kg/day, given in three divided doses. The recommended maintenance dose of Gabapentin in patients 5 to 11 years of age is 25 mg/kg/day to 35 mg/kg/day, given in three divided doses. Gabapentin may be administered as the capsule formulations. Dosages up to 50 mg/kg/day have been well tolerated in a long-term clinical study. The maximum time interval between doses should not exceed 12 hours. 2.3 Dosage Adjustment in Patients with Renal Impairment Dosage adjustment in patients 12 years of age and older with renal impairment or undergoing hemodialysis is recommended, as follows (see dosing recommendations above for effective doses in each indication): TABLE 1. Gabapentin Dosage Based on Renal Function TID = Three times a day; BID = Two times a day; QD = Single daily dose Renal Function Creatinine Clearance (mL/min) Total Daily Dose Range (mg/day) Dose Regimen (mg) ≥60 900 to 3600 300 TID 400 TID 600 TID 800 TID 1200 TID >30 to 59 400 to 1400 200 BID 300 BID 400 BID 500 BID 700 BID >15 to 29 200 to 700 200 QD 300 QD 400 QD 500 QD 700 QD 15 For patients with creatinine clearance <15 mL/min, reduce daily dose in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients with a creatinine clearance of 15 mL/min receive) 100 to 300 100 QD 125 QD 150 QD 200 QD 300 QD Post-Hemodialysis Supplemental Dose (mg) Patients on hemodialysis should receive ma

WARNINGS AND PRECAUTIONS Drug Reaction with Eosinophilia and Systemic Symptoms (Multiorgan hypersensitivity): Discontinue if alternative etiology is not be established (5.1) Anaphylaxis and Angioedema: Discontinue and evaluate patient immediately (5.2) Driving impairment; Somnolence/Sedation and Dizziness: Warn patients not to drive until they have gained sufficient experience to assess whether their ability to drive or operate heavy machinery will be impaired (5.3, 5.4) Increased seizure frequency may occur in patients with seizure disorders if Gabapentin is abruptly discontinued (5.5) Suicidal Behavior and Ideation: Monitor for suicidal thoughts / behavior (5.6) Respiratory depression: May occur with gabapentin when used with concomitant central nervous system (CNS) depressants, including opioids, or in the setting of underlying respiratory impairment. Monitor patients and adjust dosage as appropriate ( 5.7 ) Neuropsychiatric Adverse Reactions in Children 3 to 12 Years of Age: Monitor for such events ( 5.8 ) 5.1 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with Gabapentin. Some of these reactions 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. This disorder is variable in its expression, and 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 should be discontinued if an alternative etiology for the signs or symptoms cannot be established. 5.2 Anaphylaxis and Angioedema Gabapentin can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms in reported cases have included difficulty breathing, swelling of the lips, throat, and tongue, and hypotension requiring emergency treatment. Patients should be instructed to discontinue Gabapentin and seek immediate medical care should they experience signs or symptoms of anaphylaxis or angioedema. 5.3 Effects on Driving and Operating Heavy Machinery Patients taking Gabapentin should not drive until they have gained sufficient experience to assess whether Gabapentin impairs their ability to drive. Driving performance studies conducted with a prodrug of gabapentin (gabapentin enacarbil tablet, extended-release) indicate that gabapentin may cause significant driving impairment. 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, can be imperfect. The duration of driving impairment after starting therapy with Gabapentin is unknown. Whether the impairment is related to somnolence [see Warnings and Precautions (5.4) ] or other effects of Gabapentin is unknown. Moreover, because Gabapentin causes somnolence and dizziness [see Warnings and Precautions (5.4) ], patients should be advised not to operate complex machinery until they have gained sufficient experience on Gabapentin to assess whether Gabapentin impairs their ability to perform such tasks. 5.4 Somnolence/Sedation and Dizziness During the controlled epilepsy trials in patients older than 12 years of age receiving doses of Gabapentin up to 1800 mg daily, somnolence, dizziness, and ataxia were reported at a greater rate in patients receiving Gabapentin compared to placebo: i.e., 19% in drug versus 9% in placebo for somnolence, 17% in drug versus 7% in placebo for dizziness, and 13% in drug versus 6% in placebo for ataxia. In these trials somnolence, ataxia and fatigue were common adverse reactions leading to discontinuation of Gabapentin in patients older than 12 years of age, with 1.2%, 0.8% and 0.6% discontinuing for these events, respectively. During the controlled trials in patients with post-herpetic neuralgia, somnolence, and dizziness were reported at a greater rate compared to placebo in patients receiving Gabapentin, in dosages up to 3600 mg per day: i.e., 21% in Gabapentin-treated patients versus 5% in placebo-treated patients for somnolence and 28% in Gabapentin-treated patients versus 8% in placebo-treated patients for dizziness. Dizziness and somnolence were among the most common adverse reactions leading to discontinuation of Gabapentin. Patients should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence and sedation, when Gabapentin is used with other drugs with sedative properties because of potential synergy. In addition, patients who require concomitant treatment with morphine may experience increases in gabapentin concentrations and may require dose adjustment [ see Drug Interactions (7.1) ]. 5.5 Withdrawal Precipitated Seizure, Status Epilepticus Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency. In the placebo-controlled epilepsy studies in patients >12 years of age, the incidence of status epilepticus in patients receiving Gabapentin was 0.6% (3 of 543) vs. 0.5% in patients receiving placebo (2 of 378). Among the 2074 patients >12 years of age treated with Gabapentin across all epilepsy studies (controlled and uncontrolled), 31 (1.5%) had status epilepticus. Of these, 14 patients had no prior history of status epilepticus either before treatment or while on other medications. Because adequate historical data are not available, it is impossible to say whether or not treatment with Gabapentin is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with Gabapentin. 5.6 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Gabapentin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. 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 (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to 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 to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four 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 one 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. Th

CONTRAINDICATIONS Gabapentin tablets (Once-Daily) are contraindicated in patients with demonstrated hypersensitivity to the drug or its ingredients. Gabapentin tablets (Once-Daily) are contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. ( 4 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanisms by which gabapentin produces its analgesic and antiepileptic actions are unknown. Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but has no effect on GABA binding, uptake, or degradation. 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 is unknown. 12.3 Pharmacokinetics All pharmacological actions following gabapentin administration are due to the activity of the parent compound; gabapentin is not appreciably metabolized in humans. Oral Bioavailability Gabapentin bioavailability is not dose proportional; i.e., as dose is increased, bioavailability decreases. Bioavailability of gabapentin is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided doses, respectively. Food has only a slight effect on the rate and extent of absorption of gabapentin (14% increase in AUC and C max ). Distribution Less than 3% of gabapentin circulates bound to plasma protein. The apparent volume of distribution of gabapentin after 150 mg intravenous administration is 58±6 L (mean ±SD). In patients with epilepsy, steady-state predose (C min ) concentrations of gabapentin in cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations. Elimination Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug. Gabapentin is not appreciably metabolized in humans. Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance. In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin can be removed from plasma by hemodialysis. Specific Populations Age The effect of age was studied in subjects 20-80 years of age. Apparent oral clearance (CL/F) of gabapentin decreased as age increased, from about 225 mL/min in those under 30 years of age to about 125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr adjusted for body surface area also declined with age; however, the decline in the renal clearance of gabapentin with age can largely be explained by the decline in renal function. [see Dosage and Administration (2.4) and Use in Specific Populations (8.5)] . Gender Although no formal study has been conducted to compare the pharmacokinetics of gabapentin in men and women, it appears that the pharmacokinetic parameters for males and females are similar and there are no significant gender differences. Race Pharmacokinetic differences due to race have not been studied. Because gabapentin is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected. Pediatric Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the ages of 1 month and 12 years following a dose of approximately 10 mg/kg. Peak plasma concentrations were similar across the entire age group and occurred 2 to 3 hours postdose. In general, pediatric subjects between 1 month and <5 years of age achieved approximately 30% lower exposure (AUC) than that observed in those 5 years of age and older. Accordingly, oral clearance normalized per body weight was higher in the younger children. Apparent oral clearance of gabapentin was directly proportional to creatinine clearance. Gabapentin elimination half-life averaged 4.7 hours and was similar across the age groups studied. A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month and 13 years of age. Patients received 10 to 65 mg/kg/day given three times a day. Apparent oral clearance (CL/F) was directly proportional to creatinine clearance and this relationship was similar following a single dose and at steady-state. Higher oral clearance values were observed in children <5 years of age compared to those observed in children 5 years of age and older, when normalized per body weight. The clearance was highly variable in infants <1 year of age. The normalized CL/F values observed in pediatric patients 5 years of age and older were consistent with values observed in adults after a single dose. The oral volume of distribution normalized per body weight was constant across the age range. These pharmacokinetic data indicate that the effective daily dose in pediatric patients with epilepsy ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations similar to those achieved in patients 5 years of age and older receiving gabapentin at 30 mg/kg/day [see Dosage and Administration (2.2)] . Adult Patients with Renal Impairment Subjects (N=60) with renal impairment (mean creatinine clearance ranging from 13-114 mL/min) were administered single 400 mg oral doses of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours (patients with creatinine clearance >60 mL/min) to 52 hours (creatinine clearance <30 mL/min) and gabapentin renal clearance from about 90 mL/min (>60 mL/min group) to about 10 mL/min (<30 mL/min). Mean plasma clearance (CL/F) decreased from approximately 190 mL/min to 20 mL/min [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)] . Pediatric patients with renal insufficiency have not been studied. Hemodialysis In a study in anuric adult subjects (N=11), the apparent elimination half-life of gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin elimination in anuric subjects [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)] . Hepatic Disease Because gabapentin is not metabolized, no study was performed in patients with hepatic impairment. Drug Interactions In Vitro Studies In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations. Only at the highest concentration tested (171 mcg/mL; 1 mM) was a slight degree of inhibition (14% to 30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 mcg/mL (approximately 15 times the C max at 3600 mg/day). In Vivo Studies The drug interaction data described in this section were obtained from studies involving healthy adults and adult patients with epilepsy. Phenytoin In a single (400 mg) and multiple dose (400 mg three times a day) study of gabapentin in epileptic patients (N=8) maintained on phenytoin monotherapy for at least 2 months, gabapentin had no effect on the steady-state trough plasma concentrations of phenytoin and phenytoin had no effect on gabapentin pharmacokinetics. Carbamazepine Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide concentrations were not affected by concomitant gabapentin (400 mg three times a day; N=12) administration. Likewise, gabapentin pharmacokinetics were unaltered by carbamazepine administration. Valproic Acid The mean steady-state trough serum valproic acid concentrations prior to and during concomitant gabapentin administration (400 mg three times a day; N=17) were not different and neither were gabapentin pharmacokinetic parameters affected by valproic acid. Phenobarbital Estimates of steady-state pharmacokinetic parameters for phenobarbital or gabapentin (300 mg three times a day; N=12) are identical whether the drugs are administered alone or together. Naproxen Coadmini