GABAPENTIN

Gabapentin tablets (Once-Daily) contain gabapentin, a gamma-aminobutyric acid (GABA) analogue, as the active pharmaceutical ingredient. Gabapentin’s chemical name is 1-(aminomethyl) cyclohexaneacetic acid; with a molecular formula of C 9 H 17 NO 2 and a molecular weight of 171.24 g/mol. Gabapentin chemical structural formula is: Gabapentin is a white to off-white crystalline solid with a pKa1 of 3.7 and a pKa2 of 10.7. It is freely soluble in water and acidic and basic solutions. The log of the partition coefficient (n-octanol/ 0.05M phosphate buffer) at pH 7.4 is -1.25. Gabapentin tablets (Once-Daily) are intended for oral administration and is supplied as tablets containing 300 mg, 600 mg of gabapentin USP. Each 300 mg tablet contains the inactive ingredients Copovidone NF, Hypromellose USP, Magnesium Stearate NF, Microcrystalline Cellulose NF, Polyethylene Oxide NF, and White film coating (Polyethylene Glycol, Polyvinyl Alcohol, Talc, and Titanium Oxide). Each 600 mg tablet contains the inactive ingredients Copovidone NF, Hypromellose USP, Magnesium Stearate NF, Polyethylene Oxide NF, and Beige film coating (Polyethylene Glycol, Polyvinyl Alcohol, Talc, Titanium Oxide, Iron Oxide Yellow, and Iron Oxide Red). Image

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 )

Gabapentin tablets (Once-Daily) should be titrated to an 1,800 mg dose taken orally, once-daily, with the evening meal. Gabapentin (Once-Daily) tablets should be swallowed whole. Do not crush, split, or chew the tablets. ( 2.1 ) If gabapentin tablets (Once-Daily) dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber). ( 2.1 ) Renal impairment: Dose should be adjusted in patients with reduced renal function. Gabapentin tablets (Once-Daily) should not be used in patients with CrCl less than 30 or in patients on hemodialysis. ( 2.2 ) 2.1 Postherpetic Neuralgia Do not use gabapentin tablets (Once-Daily) as a substitute for other gabapentin products. Titrate gabapentin tablets (Once-Daily) to an 1,800 mg dose taken orally once daily with the evening meal. Gabapentin tablets (Once-Daily) should be swallowed whole. Do not split, crush, or chew the tablets. If gabapentin tablets (Once-Daily) dosing is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of one week or longer (at the discretion of the prescriber). In adults with postherpetic neuralgia, gabapentin tablets (Once-Daily) therapy should be initiated and titrated as follows: Table 1: Gabapentin tablets (Once-Daily) Recommended Titration Schedule Day-1 Day-2 Days-3-6 Day-7-10 Day-11-14 Day-15 Daily Dose 300 mg 600 mg 900 mg 1,200 mg 1,500 mg 1,800 mg 2.2 Patients with Renal Impairment In patients with stable renal function, creatinine clearance (C Cr ) can be reasonably well estimated using the equation of Cockcroft and Gault: For females C Cr =(0.85)(140-age)(weight)/[(72)(S Cr )] For males C Cr =(140-age)(weight)/[(72)(S Cr )] where age is in years, weight is in kilograms and S Cr is serum creatinine in mg/dL. The dose of gabapentin tablets (Once-Daily) should be adjusted in patients with reduced renal function, according to Table 2. Patients with reduced renal function must initiate gabapentin tablets (Once-Daily) at a daily dose of 300 mg. Gabapentin tablets (Once-Daily) should be titrated following the schedule outlined in Table 1. Daily dosing in patients with reduced renal function must be individualized based on tolerability and desired clinical benefit. Table 2: Gabapentin tablets (Once-Daily) Dosage Based on Renal Function Once-daily dosing Creatinine Clearance (mL/min) Gabapentin tablets Dose (once daily with evening meal) ≥ 60 1,800 mg 30 - 60 600 mg to 1,800 mg < 30 Gabapentin tablets (Once-Daily) should not be administered patients receiving hemodialysis Gabapentin tablets (Once-Daily) should not be administered

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 )

The following adverse reactions are described elsewhere in the labeling: Suicidal Behavior and Ideation [see Warnings and Precautions (5.1) ] Increased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation [see Warnings and Precautions (5.2) ] Respiratory Depression [see Warnings and Precautions (5.3) ] Tumorigenic Potential [see Warnings and Precautions (5.4) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.5) ] Laboratory Tests [see Warnings and Precautions (5.6) ] The most common adverse reaction (greater than or equal to 5% and twice placebo) is dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ScieGen Pharmaceuticals, Inc. at 1-855-724-3436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 359 patients with neuropathic pain associated with postherpetic neuralgia have received gabapentin tablets (Once-Daily) at doses up to 1,800 mg daily during placebo-controlled clinical studies. In clinical trials in patients with postherpetic neuralgia, 9.7% of the 359 patients treated with gabapentin tablets (Once-Daily) and 6.9% of 364 patients treated with placebo discontinued prematurely due to adverse reactions. In the gabapentin tablets (Once-Daily) treatment group, the most common reason for discontinuation due to adverse reactions was dizziness. Of gabapentin tablets (Once-Daily)-treated patients who experienced adverse reactions in clinical studies, the majority of those adverse reactions were either "mild" or "moderate”. Table 4 lists all adverse reactions, regardless of causality, occurring in at least 1% of patients with neuropathic pain associated with postherpetic neuralgia in the gabapentin tablets (Once-Daily) group for which the incidence was greater than in the placebo group. Table 4: Treatment-Emergent Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Postherpetic Neuralgia (Events in at Least 1% of all GABAPENTIN TABLETS (ONCE-DAILY)-Treated Patients and More Frequent Than in the Placebo Group) Body System – Preferred Term GABAPENTIN TABLETS (ONCE-DAILY) N = 359 % Placebo N = 364 % Ear and Labyrinth Disorders Vertigo 1.4 0.5 Gastrointestinal Disorders Diarrhea Dry mouth Constipation Dyspepsia 3.3 2.8 1.4 1.4 2.7 1.4 0.3 0.8 General Disorders Peripheral edema Pain 3.9 1.1 0.3 0.5 Infections and Infestations Nasopharyngitis Urinary tract infection 2.5 1.7 2.2 0.5 Investigations Weight increased 1.9 0.5 Musculoskeletal and Connective Tissue Disorders Pain in extremity Back pain 1.9 1.7 0.5 1.1 Nervous System Disorders Dizziness Somnolence Headache Lethargy 10.9 4.5 4.2 1.1 2.2 2.7 4.1 0.3 In addition to the adverse reactions reported in Table 4 above, the following adverse reactions with an uncertain relationship to gabapentin tablets (Once-Daily) were reported during the clinical development for the treatment of postherpetic neuralgia. Events in more than 1% of patients but equally or more frequently in the gabapentin tablets (Once-Daily)-treated patients than in the placebo group included blood pressure increase, confusional state, gastroenteritis viral, herpes zoster, hypertension, joint swelling, memory impairment, nausea, pneumonia, pyrexia, rash, seasonal allergy, and upper respiratory infection. 6.2 Postmarketing and Other Experience with other Formulations of Gabapentin In addition to the adverse experiences reported during clinical testing of gabapentin, the following adverse experiences have been reported in patients receiving other formulations of marketed gabapentin. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose fluctuation, breast enlargement, bullous pemphigoid, elevated creatine kinase, elevated liver function tests, erythema multiforme, fever, hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome. There are postmarketing reports of withdrawal symptoms after discontinuation of gabapentin. Reported adverse reactions include, but are not limited to, seizures, depression, suicidal ideation and behavior, agitation, confusion, disorientation, psychotic symptoms, anxiety, insomnia, nausea, pain, sweating, tremor, headache, dizziness, and malaise [see Warnings and Precautions (5.2) ] . There are postmarketing reports of life-threatening or fatal respiratory depression in patients taking gabapentin with opioids or other central nervous system (CNS) depressants, or in the setting of underlying respiratory impairment.

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; 1mM) 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 3,600 mg/day). Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs. The drug interaction data described in this section were obtained from studies involving healthy adults and adult patients with epilepsy. An increase in gabapentin AUC values have been reported when administered with hydrocodone. ( 7.6 ) An increase in gabapentin AUC values have been reported when administered with morphine. ( 7.7 ) An antacid containing aluminum hydroxide and magnesium hydroxide reduced the bioavailability of gabapentin immediate release by about approximately 20%, but by only 5% when gabapentin was taken 2 hours after antacids. It is recommended that gabapentin tablets (Once-Daily) be taken at least 2 hours following antacid administration. ( 7.10 ) 7.1 Phenytoin In a single (400 mg) and multiple dose (400 mg three times daily) study of gabapentin immediate release 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. 7.2 Carbamazepine Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide concentrations were not affected by concomitant gabapentin immediate release (400 mg three times daily; N=12) administration. Likewise, gabapentin pharmacokinetics were unaltered by carbamazepine administration. 7.3 Valproic Acid The mean steady-state trough serum valproic acid concentrations prior to and during concomitant gabapentin immediate release administration (400 mg three times daily; N=17) were not different and neither were gabapentin pharmacokinetic parameters affected by valproic acid. 7.4 Phenobarbital Estimates of steady-state pharmacokinetic parameters for phenobarbital or gabapentin immediate release (300 mg three times daily; N=12) are identical whether the drugs are administered alone or together. 7.5 Naproxen Coadministration of single doses of naproxen (250 mg) and gabapentin immediate release (125 mg) to 18 volunteers increased gabapentin absorption by 12% to 15%. Gabapentin immediate release had no effect on naproxen pharmacokinetics. The doses are lower than the therapeutic doses for both drugs. The effect of coadministration of these drugs at therapeutic doses is not known. 7.6 Hydrocodone Coadministration of gabapentin immediate release (125 mg and 500 mg) and hydrocodone (10 mg) reduced hydrocodone C max by 3% and 21%, respectively, and AUC by 4% and 22%, respectively. The mechanism of this interaction is unknown. Gabapentin AUC values were increased by 14%; the magnitude of the interaction at other doses is not known. 7.7 Morphine When a single dose (60 mg) of controlled-release morphine capsule was administered 2 hours prior to a single dose (600 mg) of gabapentin immediate release in 12 volunteers, mean gabapentin AUC values increased by 44% compared to gabapentin immediate release administered without morphine. The pharmacokinetics of morphine were not affected by administration of gabapentin immediate release 2 hours after morphine. The magnitude of this interaction at other doses is not known. 7.8 Cimetidine Cimetidine 300 mg decreased the apparent oral clearance of gabapentin by 14% and creatinine clearance by 10%. The effect of gabapentin immediate release on cimetidine was not evaluated. This decrease is not expected to be clinically significant. 7.9 Oral Contraceptives Gabapentin immediate release (400 mg three times daily) had no effect on the pharmacokinetics of norethindrone (2.5 mg) or ethinyl estradiol (50 mcg) administered as a single tablet, except that the C max of norethindrone was increased by 13%. This interaction is not considered to be clinically significant. 7.10 Antacid (containing aluminum hydroxide and magnesium hydroxide) An antacid containing aluminum hydroxide and magnesium hydroxide reduced the bioavailability of gabapentin immediate release by about approximately 20%, but by only 5% when gabapentin immediate release was taken 2 hours after the antacid. It is recommended that gabapentin tablets (Once-Daily) be taken at least 2 hours following the antacid (containing aluminum hydroxide and magnesium hydroxide) administration. 7.11 Probenecid Gabapentin immediate release pharmacokinetic parameters were comparable with and without probenecid, indicating that gabapentin does not undergo renal tubular secretion by the pathway that is blocked by probenecid. 7.12 Drug/Laboratory Test Interactions False positive readings were reported with the Ames-N-Multistix SG ® dipstick test for urine protein when gabapentin was added to other antiepileptic drugs; therefore, the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein.