PREGABALIN- pregabalin_tablet, extended release

Pregabalin binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of pregabalin has not been fully elucidated, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha2-delta subunit may be involved in pregabalin's anti-nociceptive and antiseizure effects in animals. In animal models of nerve damage, pregabalin has been shown to reduce calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord, possibly by disrupting alpha2-delta containing-calcium channel trafficking and/or reducing calcium currents. Evidence from other animal models of nerve damage and persistent pain suggest the anti-nociceptive activities of pregabalin may also be mediated through interactions with descending noradrenergic and serotonergic pathways originating from the brainstem that modulate pain transmission in the spinal cord. While pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABAA, GABAB, or benzodiazepine receptors, does not augment GABAA responses in cultured neurons, does not alter rat brain GABA concentration or have acute effects on GABA uptake or degradation. However, in cultured neurons prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport. Pregabalin does not block sodium channels, is not active at opiate receptors, and does not alter cyclooxygenase enzyme activity. It is inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake. Pregabalin extended-release tablets have linear pharmacokinetics with dose-proportional increases in maximum plasma concentration (C max Pregabalin extended-release tablets administered once daily following an evening meal has equivalent AUC and lower C max max Table 5. Steady-State Pharmacokinetics for Pregabalin Extended-Release Tablets 165 mg Once Daily and Pregabalin Capsules or Oral Solution 75 mg Twice Daily Pregabalin extended-release tablets Once Daily Pregabalin Capsules or Oral Solution BID N 24 24 C max 2. 2 (21) T max 8. 5) AUC 24 29. 5 (18) C min 0. 59 (25) Note: Geometric mean (% CV) for AUC 24 max min max Abbreviations: AUC 24 max min max Absorption Pregabalin is absorbed from the small intestine and proximal colon. Pregabalin extended-release tablets absorption is linear and dose proportional. The bioavailability of pregabalin extended-release tablets are reduced if taken on an empty stomach. The AUC is approximately 30% lower when pregabalin extended-release tablets are administered fasted relative to following an evening meal. When pregabalin extended-release tablets are administered following a 600 to 750 calorie (50% carbohydrates, 20% protein, 30% fat) evening meal, peak plasma concentrations occur within approximately 8 to 10 hours and AUC is approximately 93% to 97% relative to a comparative dose of pregabalin Capsules or Oral Solution. The rate and extent of pregabalin extended-release tablets absorption is similar when administered following a 400 to 500 calorie, 30% fat or an 800 to 1000 calorie, 15%, 30%, or 50% fat evening meal. When pregabalin extended-release tablets are administered following an 800 to 1000 calorie (50% carbohydrates, 20% protein, 30% fat) morning meal, peak plasma concentrations occur within approximately 12 hours and AUC is 99% relative to a comparative dose of pregabalin Capsules or Oral Solution. AUC decreases approximately 13% to 25% when pregabalin extended-release tablets are administered following a 400 to 500 calorie or 600 to 750 calorie (50% carbohydrates, 20% protein, 30% fat) morning meal relative to the 800 to 1000 calorie meal, while C max Distribution Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0. Pregabalin is a substrate for system L transporter which is responsible for the transport of large amino acids across the blood brain barrier. Although there are no data in humans, pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys. In addition, pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats. Elimination Metabolism Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabeled pregabalin, approximately 90% of the administered dose was recovered in the urine as unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0. 9% of the dose. In preclinical studies, pregabalin (S-enantiomer) did not undergo racemization to the R-enantiomer in mice, rats, rabbits, or monkeys. Excretion Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with a mean elimination half-life of 6. 3 hours in subjects with normal renal function. Mean renal clearance was estimated to be 67. 9 mL/min in young healthy subjects. Because pregabalin is not bound to plasma proteins this clearance rate indicates that renal tubular reabsorption is involved. Pregabalin elimination is nearly proportional to CLcr [see Dosage and Administration (2. 5)] Specific Populations Age: Geriatric Patients Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in CLcr. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function [see Dosage and Administration (2. 5)] Sex Population pharmacokinetic analyses of the clinical studies showed that the relationship between daily dose and pregabalin drug exposure is similar between genders. Race/Ethnicity In population pharmacokinetic analyses of the clinical studies of pregabalin, the pharmacokinetics of pregabalin were not significantly affected by race (Caucasians, Blacks, and Hispanics). Renal Impairment Pregabalin clearance is nearly proportional to CLcr. Dosage reduction in patients with reduced renal function is necessary. Pregabalin is effectively removed from plasma by hemodialysis. Following a 4 hour hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%. For patients on hemodialysis, treatment with pregabalin extended-release tablets are not recommended [see Dosage and Administration (2. 5)] Drug Interaction Studies In Vitro Studies In vitro In vitro In Vivo Studies With the exception of erythromycin, the interactions of pregabalin extended-release tablets with co-administration of other drugs have not been systematically evaluated. Additional studies have been performed with pregabalin Capsules or Oral Solution [see Drug Interactions (7)] The drug interaction studies described in this section were conducted in healthy adults, and across various patient populations. Erythromycin Multiple-dose administration of erythromycin (500 mg every 6 hours for 18 hours) in healthy subjects resulted in a 17% decrease in AUC of pregabalin extended-release tablets (330 mg single dose). Ethanol Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of ethanol single-dose pharmacokinetics and single-dose administration of ethanol (0. 7 g/kg) had no effect on the steady-state pharmacokinetics of pregabalin. Additive effects on cognitive and gross motor functioning were seen when pregabalin Capsules or Oral Solution was co-administered with ethanol. No clinically important effects on respiration were seen [see Drug Interactions (7)] Gabapentin The pharmacokinetic interactions of pregabalin and gabapentin were investigated in 12 healthy subjects following concomitant single-dose administration of 100 mg pregabalin and 300 mg gabapentin and in 18 healthy subjects following concomitant multiple-dose administration of 200 mg pregabalin every 8 hours and 400 mg gabapentin every 8 hours. Gabapentin pharmacokinetics following single- and multiple-dose administration were unaltered by pregabalin co-administration. The extent of pregabalin absorption was unaffected by gabapentin co-administration, although there was a small reduction in rate of absorption. Lorazepam Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of lorazepam single-dose pharmacokinetics and single-dose administration of lorazepam (1 mg) had no effect on the steady-state pharmacokinetics of pregabalin. Additive effects on cognitive and gross motor functioning were seen when pregabalin Capsules or Oral Solution was co-administered with lorazepam. No clinically important effects on respiration were seen [see Drug Interactions (7)] Oral Contraceptive Pregabalin co-administration (200 mg 3 times a day) had no effect on the steady-state pharmacokinetics of norethindrone and ethinyl estradiol (1 mg/35 mcg, respectively) in healthy subjects. Oxycodone Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of oxycodone single-dose pharmacokinetics. Single-dose administration of oxycodone (10 mg) had no effect on the steady-state pharmacokinetics of pregabalin. Additive effects on cognitive and gross motor functioning were seen when pregabalin Capsules or Oral Solution was co-administered with oxycodone. No clinically important effects on respiration were seen [see Drug Interactions (7)] Carbamazepine, Lamotrigine, Phenobarbital, Phenytoin, Topiramate and Valproic Acid Steady-state trough plasma concentrations of phenytoin, carbamazepine, and carbamazepine 10,11 epoxide, valproic acid, and lamotrigine were not affected by concomitant pregabalin (200 mg 3 times a day) administration. Population pharmacokinetic analyses in patients treated with pregabalin and various concomitant medications suggest the following: Therapeutic class Specific concomitant drug studied Concomitant drug has no effect on the pharmacokinetics of pregabalin Hypoglycemics Diuretics Antiepileptic Drugs Glyburide, insulin, metformin Furosemide Tiagabine Concomitant drug has no effect on the pharmacokinetics of pregabalin and pregabalin has no effect on the pharmacokinetics of concomitant drug Antiepileptic Drugs Carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproic acid.

Pregabalin extended-release tablets are indicated for the management of: Neuropathic pain associated with diabetic peripheral neuropathy Postherpetic neuralgia Efficacy of pregabalin extended-release tablets have not been established for the management of fibromyalgia or as adjunctive therapy for adult patients with partial onset seizures. Pregabalin extended-release tablets are indicated for the management of: Neuropathic pain associated with diabetic peripheral neuropathy (DPN) (1) Postherpetic neuralgia (PHN) (1) Efficacy of pregabalin extended-release tablets have not been established for the management of fibromyalgia or as adjunctive therapy for adult patients with partial onset seizures.

Pregabalin extended-release tablets should be administered once daily after an evening meal. It should be swallowed whole and should not be split, crushed, or chewed. 1) Dosing recommendations for Pregabalin extended-release tablets: Indication Dosing Regimen Initial Dose Maximum Dose DPN Pain (2. 2) Single dose per day 165 mg/day 330 mg/day within 1 week. 3) Single dose per day 165 mg/day 330 mg/day within 1 week. Maximum dose of 660 mg/day. Conversion from Pregabalin Capsules or Oral Solution to Pregabalin Extended-Release Tablets: See full prescribing information. 4) Dose modification recommended in patients with renal impairment. 5) Pregabalin extended-release tablets should be administered once daily after an evening meal. Pregabalin extended-release tablets should be swallowed whole and should not be split, crushed, or chewed. When discontinuing pregabalin extended-release tablets, taper gradually over a minimum of 1 week. Instruct patients that if they miss taking their dose of pregabalin extended-release tablets after an evening meal, then they should take their usual dose of pregabalin extended-release tablets prior to bedtime following a snack. If they miss taking the dose of pregabalin extended-release tablets prior to bedtime, then they should take their usual dose of pregabalin extended-release tablets following a morning meal. If they miss taking the dose of pregabalin extended-release tablets following the morning meal, then they should take their usual dose of pregabalin extended-release tablets at the usual time that evening following an evening meal [see Patient Counseling Information (17)] Begin dosing at 165 mg once daily and increase to 330 mg once daily within 1 week based on individual patient response and tolerability. The maximum recommended dose of pregabalin extended-release tablets are 330 mg once daily. Although pregabalin was studied at 600 mg/day, there was no evidence that this dose conferred additional significant benefit and this dose was less well tolerated. In view of the dose-dependent adverse reactions with pregabalin, treatment with doses above 330 mg/day is not recommended for pregabalin extended-release tablets. Begin dosing at 165 mg once daily and increase to 330 mg once daily within 1 week based on individual patient response and tolerability. Patients who do not experience sufficient pain relief following 2 to 4 weeks of treatment with 330 mg once daily and who are able to tolerate pregabalin extended-release tablets, may be treated with up to 660 mg once daily. In view of the dose-dependent adverse reactions and the higher rate of treatment discontinuation due to adverse reactions, dosing above 330 mg/day should be reserved only for those patients who have on-going pain and are tolerating 330 mg daily. The maximum recommended dose of pregabalin extended-release tablets are 660 mg once daily. When switching from Pregabalin Capsules or Oral Solution to Pregabalin Extended-Release Tablets Table 1. Conversion from Pregabalin Capsules or Oral Solution to Pregabalin Extended-Release Tablets Pregabalin Capsules or Oral Solution Total Daily Dose (dosed 2 or 3 times daily) Pregabalin extended-release tablets Dose (dosed once a day) 75 mg/daily 82. 5 mg/day 150 mg/daily 165 mg/day 225 mg/daily 247. 5 mg/day a 300 mg/daily 330 mg/day 450 mg/daily 495 mg/day b 600 mg/daily 660 mg/day c 247. 5 mg = 3 times 82. 5 mg tablets taken once a day. 495 mg = 3 times 165 mg tablets taken once a day. 660 mg = 2 times 330 mg tablets taken once a day. Use of pregabalin extended-release tablets are not recommended for patients with creatinine clearance (CL cr In view of dose-dependent adverse reactions and because pregabalin is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on CL cr cr in mL/min is needed. CL cr Cockcroft and Gault equation: CL Cr [140-age (years)] x weight (kg) (x 0. 85 for female patients) 72 x serum creatinine (mg/dL) Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CL cr (For example: A patient initiating pregabalin extended-release tablets therapy for postherpetic neuralgia with normal renal function [CL cr cr Table 2. Pregabalin extended-release tablets Dosage Adjustment Based on Renal Function Creatinine Clearance (CL cr (mL/min) Total pregabalin extended-release tablets Daily Dose (mg/day) Dose Regimen greater than or equal to 60 165 330 495 a 660 b Once a day 30 to 60 82. 5 c 330 Once a day less than 30/hemodialysis Dose with pregabalin Capsules or Oral Solution 495 mg = 3 times 165 mg tablets taken once a day.

The following adverse reactions are described elsewhere in the labeling: Angioedema [see Warnings and Precautions (5. 1)] Hypersensitivity Reactions [see Warnings and Precautions (5. 2)] Suicidal Behavior and Ideation [see Warnings and Precautions (5. 3)] Respiratory Depression [see Warnings and Precautions (5. 4)] Dizziness and Somnolence [see Warnings and Precautions (5. 5)] Risks Associated with Abrupt or Rapid Discontinuation [see Warnings and Precautions (5. 6)] Peripheral Edema [see Warnings and Precautions (5. 7)] Weight Gain [see Warnings and Precautions (5. 8)] Ophthalmological Effects [see Warnings and Precautions (5. 10)] Creatine Kinase Elevations [see Warnings and Precautions (5. 11)] Decreased Platelet Count [see Warnings and Precautions (5. 12)] Most common adverse reactions reported in greater than or equal to 4% of patients treated with pregabalin extended-release tablets are dizziness, somnolence, headache, fatigue, peripheral edema, nausea, blurred vision, dry mouth, and weight gain. 1) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-5555 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. Two randomized placebo-controlled clinical trials were conducted in patients with postherpetic neuralgia and fibromyalgia in which a total of 1242 patients received pregabalin extended-release tablets. Both studies were randomized withdrawal design where a 6-week single-blind, dose optimization phase was followed by a 13-week double-blind phase. The most common adverse events leading to discontinuation from the single-blind phase of the study occurring in greater than or equal to 0. 3% of patients were dizziness, somnolence, peripheral edema, fatigue, blurred vision, and increased weight. Sixty four percent of patients experienced adverse events during the single-blind phase, with the most common adverse events occurring in greater than or equal to 4% of patients being dizziness, somnolence, headache, fatigue, peripheral edema, nausea, blurred vision, dry mouth, and weight gain. Controlled Study in Postherpetic Neuralgia Adverse Reactions Leading to Discontinuation In a clinical trial in patients with postherpetic neuralgia, 8. 9% of patients treated with pregabalin extended-release tablets discontinued prematurely during the single-blind phase due to adverse reactions. The most common reasons for discontinuation due to adverse reactions were dizziness (2. 1%), somnolence (0. 87%), and peripheral edema (0. Most Common Adverse Reactions Table 4 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of patients with postherpetic neuralgia who received pregabalin extended-release tablets, regardless of the phase of the study. Incidence of Adverse Reactions Reported in Greater Than or Equal to 1% of Subjects in Any Phase of the pregabalin extended-release tablets Study in Patients With Postherpetic Neuralgia * System Organ Class Preferred Term Single-Blind Phase Double-Blind Phase Pregabalin extended-release tablets [N = 801] n (%) Pregabalin extended-release tablets [N = 208] n (%) Placebo [N = 205] n (%) Ear and labyrinth disorders Vertigo 31 (3. 5) Eye disorders Vision blurred 30 (3. 5) 0 Diplopia 8 (1. 5) 0 Gastrointestinal disorders Dry mouth 30 (3. 5) 0 Nausea 24 (3. 4) 0 Constipation 22 (2. 7) 0 0 Diarrhea 11 (1. 5) Vomiting 9 (1. 5) General disorders and administration site conditions Edema peripheral 39 (4. 5) Fatigue 31 (3. 0) Edema 3 (0. 4) 0 Infections and infestations Nasopharyngitis 12 (1. 4) 0 Urinary tract infection 11 (1. 5) Bronchitis 4 (0. 0) Respiratory tract infection viral 3 (0. 5) Sinusitis 3 (0. 0) 0 Gastroenteritis viral 2 (0. 0) 0 Investigations Weight increased 20 (2. 0) Alanine aminotransferase increased 2 (0. 4) 0 Aspartate aminotransferase increased 2 (0. 0) 0 Musculoskeletal and connective tissue disorders Arthralgia 6 (0. 5) Joint swelling 0 4 (1. 9) 0 Nervous system disorders Dizziness 137 (17. 5) Somnolence 91 (11. 5) 0 Headache 31 (3. 5) Balance disorder 21 (2. 5) 0 Reproductive system and breast disorders Erectile dysfunction 2 (0. 4) 0 Respiratory, thoracic, and mediastinal disorders Cough 2 (0. 5) Skin and subcutaneous tissue disorders Dermatitis contact 0 2 (1. 0) 0 * Table is limited to adverse reactions that occurred with higher incidence in pregabalin extended-release tablets -treated patients than in placebo-treated patients for the DB Phase of the study. Other Adverse Reactions Observed During Clinical Studies with Pregabalin Capsules or Oral Solution and Pregabalin Extended-Release Tablets In addition to the adverse reactions reported during the controlled studies with pregabalin extended-release tablets in postherpetic neuralgia, the following adverse reactions have been reported in patients treated with pregabalin Capsules or Oral Solution and pregabalin extended-release tablets during all clinical studies. This listing does not include those adverse reactions already listed above. The adverse reactions are categorized by system organ class and listed in order of decreasing frequency according to the following definitions: frequent infrequent rare Warnings and Precautions Cardiac Disorders en dash Infrequent: Rare: Eye Disorders en dash Infrequent: Gastrointestinal Disorders en dash Frequent: Infrequent: General Disorders en dash Frequent: Infrequent: Rare: Hemic and Lymphatic System Disorders en dash Frequent: Infrequent: Rare: Infections and Infestations en dash Infrequent: Investigations en dash Rare: Rare: Musculoskeletal and Connective Tissue Disorders en dash Frequent: Infrequent: Joint stiffness; Rare: Nervous System Disorders en dash Frequent: Infrequent: Rare: Psychiatric Disorders en dash Infrequent: Respiratory System Disorders en dash Rare: Skin Disorders en dash Frequent: Rare: Special Senses en dash Frequent: Urogenital System Disorders en dash Frequent: Infrequent: The following adverse reactions have been identified during post-approval use of pregabalin Capsules or Oral Solution. These adverse reactions have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: breast enlargement, bullous pemphigoid, gynecomastia. There are postmarketing reports of life-threatening or fatal respiratory depression in patients taking pregabalin with opioids or other CNS depressants, or in the setting of underlying respiratory impairment. In addition, there are postmarketing reports of events related to reduced lower gastrointestinal tract function (e. , intestinal obstruction, paralytic ileus, constipation) when pregabalin Capsules or Oral Solution was co-administered with medications that have the potential to produce constipation, such as opioid analgesics.

Pregabalin extended-release tablets are contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy [see Warnings and Precautions (5. 2), Adverse Reactions (6)] Known hypersensitivity to pregabalin or any of its components.

Pregnancy: May cause fetal harm. Advise of potential risk to the fetus. 1) Lactation: Breastfeeding is not recommended. 2) Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to pregabalin during pregnancy. To provide information regarding the effects of in utero Risk Summary There are no adequate and well-controlled studies with pregabalin in pregnant women. However, in animal reproduction studies, increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including skeletal malformations, retarded ossification, and decreased fetal body weight were observed in the offspring of rats and rabbits given pregabalin orally during organogenesis, at doses that produced plasma pregabalin exposures (AUC) greater than or equal to 18 times human exposure at the maximum recommended dose (MRD) of 660 mg/day [see Data] Data Animal Data When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at greater than or equal to 1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 18 times human exposure at the MRD of 660 mg/day. A no-effect dose for rat embryo-fetal developmental toxicity was not established. When pregnant rabbits were given pregabalin (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 17 times human exposure at the MRD. In a study in which female rats were dosed with pregabalin (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at greater than or equal to 100 mg/kg and offspring survival was decreased at greater than or equal to 250 mg/kg. The effect on offspring survival was pronounced at doses greater than or equal to 1250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at greater than or equal to 250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures greater than or equal to 50 times the mean human exposure (AUC (0 to 24) of 123 mcg∙hr/mL) at the MRD. Risk Summary Small amounts of pregabalin have been detected in the milk of lactating women. A pharmacokinetic study in lactating women detected pregabalin in breast milk at average steady state concentrations approximately 76% of those in maternal plasma. The estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 0. 31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal dose [see Data] Based on animal studies, there is a potential risk of tumorigenicity with pregabalin exposure via breast milk to the breastfed infant [see Nonclinical Toxicology (13. 1)] [see Warnings and Precautions (5. 9)] Data A pharmacokinetic study in ten lactating women, who were at least 12 weeks postpartum, evaluated the concentrations of pregabalin in plasma and breast milk. Pregabalin 150 mg oral capsule was given every 12 hours (300 mg daily dose) for a total of 4 doses. Pregabalin was detected in breast milk at average steady-state concentrations approximately 76% of those in maternal plasma. 31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal dose. The study did not evaluate the effects of pregabalin on milk production. Infants did not receive breast milk obtained during the dosing period, therefore, the effects of pregabalin on the breastfed infant were not evaluated. Infertility Males Effects on Spermatogenesis In a randomized, double-blind, placebo-controlled non-inferiority study to assess the effect of pregabalin on sperm characteristics, healthy male subjects received pregabalin at a daily dose up to 600 mg (n=111) or placebo (n = 109) for 13 weeks (1 complete sperm cycle) followed by a 13 week washout period (off-drug). A total of 65 subjects in the pregabalin group (59%) and 62 subjects in the placebo group (57%) were included in the per protocol (PP) population. These subjects took study drug for at least 8 weeks, had appropriate timing of semen collections and did not have any significant protocol violations. Among these subjects, approximately 9% of the pregabalin group (6/65) vs. 3% in the placebo group (2/62) had greater than or equal to 50% reduction in mean sperm concentrations from baseline at Week 26 (the primary endpoint). The difference between pregabalin and placebo was within the pre-specified non-inferiority margin of 20%. There were no adverse effects of pregabalin on sperm morphology, sperm motility, serum FSH or serum testosterone levels as compared to placebo. In subjects in the PP population with greater than or equal to 50% reduction in sperm concentration from baseline, sperm concentrations were no longer reduced by greater than or equal to 50% in any affected subject after an additional 3 months off-drug. In 1 subject, however, subsequent semen analyses demonstrated reductions from baseline of greater than or equal to 50% at 9 and 12 months off-drug. The clinical relevance of these data is unknown. In the animal fertility study with pregabalin in male rats, adverse reproductive and developmental effects were observed [see Nonclinical Toxicology (13. The safety and effectiveness of pregabalin in pediatric patients have not been established. Juvenile Animal Toxicity Data In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses greater than or equal to 50 mg/kg. The neurobehavioral changes of acoustic startle persisted at greater than or equal to 250 mg/kg and locomotor activity and water maze performance at greater than or equal to 500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 660 mg/day. A no-effect dose was not established. In controlled clinical studies of pregabalin Capsules or Oral Solution in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older. In controlled clinical studies of pregabalin Capsules or Oral Solution in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older. In the pregabalin extended-release tablets neuropathic pain associated with postherpetic neuralgia study, 422 patients 65 years of age and older received pregabalin. No overall differences in safety and effectiveness were observed between these patients and younger patients, 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. Pregabalin is known to be substantially 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, care should be taken in dose selection, and it may be useful to monitor renal function. See Dosage and Administration (2.

Since pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (less than 2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro [see Clinical Pharmacology (12)] The interactions of pregabalin extended-release tablets with co-administration of other drugs have not been systematically evaluated. Co-administration of the prokinetic drug erythromycin with pregabalin extended-release tablets did not result in any clinically important changes in the pharmacokinetics of pregabalin extended-release tablets [see Clinical Pharmacology (12)] Additional studies have been performed with pregabalin Capsules or Oral Solution. No pharmacokinetic interactions were observed between pregabalin Capsules or Oral Solution and carbamazepine, gabapentin, lamotrigine, oral contraceptive, phenobarbital, phenytoin, topiramate, and valproic acid. A similar lack of pharmacokinetic interactions would be expected to occur with pregabalin extended-release tablets. Pharmacodynamics Although no pharmacokinetic interactions were seen, with pregabalin Capsules or Oral Solution and ethanol, lorazepam, or oxycodone, additive effects on cognitive and gross motor functioning were seen when pregabalin Capsules or Oral Solution was co-administered with these drugs. No clinically important effects on respiration were seen in studies of pregabalin Capsules or Oral Solution.

OVERDOSAGE
Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans In the postmarketing experience, the most commonly reported adverse events observed with pregabalin when taken in overdose include reduced consciousness, depression/anxiety, confusional state, agitation, and restlessness. Seizures and heart block have also been reported. Deaths have been reported in the setting of lone pregabalin overdose and in combination with other CNS depressants. Treatment or Management of Overdose There is no specific antidote for overdose with pregabalin. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up-to-date information on the management of overdose with pregabalin. Pregabalin can be removed by hemodialysis. Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours).
NONCLINICAL TOXICOLOGY
Carcinogenesis A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in 2 strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for 2 years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was approximately equal to the human exposure at the maximum recommended human dose (MRD) of 660 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established. No evidence of carcinogenicity was seen in 2 studies in Wistar rats following dietary administration of pregabalin for 2 years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 15 and 26 times, respectively, human exposure at the MRD. Mutagenesis Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro in vitro in vivo Impairment of Fertility In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse reproductive and developmental effects were observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities. Effects on sperm and fertility parameters were reversible in studies of this duration (3 to 4 months). The no-effect dose for male reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 4 times human exposure at the MRD of 660 mg/day. In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of 4 weeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma exposure approximately 10 times human exposure at the MRD. In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 10 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established. Dermatopathy Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the MRD of 660 mg/day, there is a 2 fold safety margin for the dermatological lesions. The more severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in clinical studies. Ocular Lesions Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor cells] and/or corneal inflammation/mineralization) were observed in 2 lifetime carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin exposures (AUC) greater than or equal to 2 times those achieved in humans given the maximum recommended dose of 660 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in 2 strains of mice or in monkeys treated for 1 year.
CLINICAL STUDIES
Support for efficacy of pregabalin extended-release tablets for the management of PHN and diabetic peripheral neuropathy (DPN) was based on the efficacy of pregabalin Capsules or Oral Solution for these indications along with an adequate and well-controlled study in adults with PHN. This 19 week randomized withdrawal study compared daily doses of pregabalin extended-release tablets 82. 5 mg, 165 mg, 247. 5 mg, 330 mg, 495 mg, or 660 mg with placebo. Those enrolled were required to have pain present for more than 3 months after healing of the herpes zoster skin rash and a baseline pain score of greater than or equal to 4 on the numeric rating scale (NRS)-Pain (assessed over a 1 week recall period). The baseline mean pain scores were 6. 83 for pregabalin extended-release tablets-treated patients vs. 85 for placebo-treated patients. A total of 82. 4% of patients completed the single-blind phase of the study. Patients were considered responders if they had at least a 50% reduction in pain in the single-blind phase. Those who responded to treatment were then randomized in the double-blind phase to treatment with either the pregabalin extended-release tablets dose achieved in the single-blind phase or placebo. Patients were treated for up to 3 months following randomization. A total of 87. 5% of pregabalin extended-release tablets-treated patients and 78% of placebo-treated patients completed the double-blind phase of the study. Pregabalin extended-release tablets treatment demonstrated statistically significant improvement in the endpoint change in mean pain score from baseline compared to placebo. For a range of levels of improvement in pain intensity from baseline to study endpoint, Figure 1 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. In the pregabalin extended-release tablets group, 79. 8% of subjects achieved at least a 30% improvement and 73. 6% at least 50% improvement in pain intensity. In the placebo group, 64. 9% of subjects achieved at least a 30% improvement and 54. 6% at least a 50% improvement in pain intensity. Percent of Patients Achieving Various Levels of Improvement in Pain Intensity (N = 413) figure 1 A double-blind, placebo-controlled, randomized withdrawal trial of pregabalin extended-release tablets in adults with fibromyalgia failed to demonstrate efficacy. A double-blind, placebo-controlled, randomized trial of pregabalin extended-release tablets as adjunctive therapy in adults with partial onset seizures failed to demonstrate efficacy.
Medication Guide
MEDICATION GUIDE PREGABALIN [pree gabʹ a lin] EXTENDED-RELEASE TABLETS, CV Rx Only Read this Medication Guide before you start taking pregabalin extended-release tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about pregabalin extended-release tablets, ask your healthcare provider or pharmacist. What is the most important information I should know about pregabalin extended-release tablets? Pregabalin extended-release tablets may cause serious side effects including: Serious, even life-threatening, allergic reactions Swelling of your hands, legs and feet Suicidal thoughts or actions Dizziness and sleepiness Serious breathing problems These serious side effects are described below: Serious, even life-threatening, allergic reactions. Stop taking pregabalin extended-release tablets and call your healthcare provider right away if you have any of these signs of a serious allergic reaction: swelling of your face, mouth, lips, gums, tongue, throat, or neck trouble breathing rash, hives (raised bumps), or blisters skin redness Pregabalin extended-release tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. thoughts about suicide or dying attempts to commit suicide new or worse depression new or worse anxiety feeling agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood Stopping pregabalin extended-release tablets suddenly can cause serious problems. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. How can I watch for early symptoms of suicidal thoughts and actions? Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Serious breathing problems Swelling of your hands, legs and feet Dizziness and sleepines What are pregabalin extended-release tablets? Pregabalin extended-release tablets are prescription medicine used to treat: pain from damaged nerves (neuropathic pain) that happens with diabetes pain from damaged nerves (neuropathic pain) that follows healing of shingles It is not known if pregabalin extended-release tablets are safe and effective in children. It is not known if pregabalin extended-release tablets are effective when used for the treatment of fibromyalgia, or when taken with other seizure medicines for adults with partial onset seizures. Who Should Not Take pregabalin extended-release tablets? Do not take pregabalin extended-release tablets if you are allergic to pregabalin or any of the ingredients in pregabalin extended-release tablets. See “What is the most important information I should know about pregabalin extended-release tablets?” for the signs of an allergic reaction. See the end of this leaflet for a complete list of ingredients in pregabalin extended-release tablets. What should I tell my healthcare provider before taking pregabalin extended-release tablets? Before taking pregabalin extended-release tablets, tell your healthcare provider about all your medical conditions, including if you: have or have had depression, mood problems or suicidal thoughts or behavior have breathing problems have kidney problems or get kidney dialysis have heart problems including heart failure have a bleeding problem or a low blood platelet count have abused prescription medicines, street drugs, or alcohol in the past have ever had swelling of your face, mouth, tongue, lips, gums, neck, or throat (angioedema) plan to father a child. Animal studies have shown that pregabalin, the active ingredient in pregabalin extended-release tablets, made male animals less fertile and caused sperm to change. Also, in animal studies, birth defects were seen in the offspring (babies) of male animals treated with pregabalin. It is not known if these problems can happen in people who take pregabalin extended-release tablets. are pregnant or plan to become pregnant. It is not known if pregabalin extended-release tablets will harm your unborn baby. If you become pregnant while taking pregabalin extended-release tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs, including pregabalin, the active ingredient in pregabalin extended-release tablets. Information about the registry can be found at the website, http://www.aedpregnancyregistry.org/. are breastfeeding or plan to breastfeed. Pregabalin passes into your breast milk. It is not known if pregabalin extended-release tablets can harm your baby. Tell your healthcare provider about all the medicines you take, angiotensin converting enzyme (ACE) inhibitors, which are used to treat many conditions, including high blood pressure. You may have a higher chance for swelling and hives if these medicines are taken with pregabalin extended-release tablets. See "What is the most important information I should know about pregabalin extended-release tablets?" Avandia (rosiglitazone), Avandamet (contains rosiglitazone and metformin), or Actos (pioglitazone) for diabetes. You may have a higher chance of weight gain or swelling of your hands or feet if these medicines are taken with pregabalin extended-release tablets. See "What are the possible side effects of pregabalin extended-release tablets." any opioid pain medicine (such as oxycodone), or medicines for anxiety (such as lorazepam) or insomnia (such as zolpidem). You may have a higher chance for dizziness, sleepiness or serious breathing problems if these medicines are taken with pregabalin extended-release tablets. any medicines that make you sleepy Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider. How should I take pregabalin extended-release tablets? Take pregabalin extended-release tablets exactly as prescribed. Your healthcare provider will tell you how much pregabalin extended-release tablets to take and when to take it. Take pregabalin extended-release tablets at the same time each day. Pregabalin extended-release tablets must be taken after Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider. Do not stop taking pregabalin extended-release tablets without talking to your healthcare provider. If you stop taking pregabalin extended-release tablets suddenly you may have headaches, nausea, diarrhea, trouble sleeping, or you may feel anxious. If you have epilepsy, are taking pregabalin extended-release tablets for pain, and stop taking pregabalin extended-release tablets suddenly, you may have seizures more often. Talk with your healthcare provider about how to stop pregabalin extended-release tablets slowly. If you miss a dose after your evening meal, take it prior to bedtime following a snack. If you miss the dose prior to bedtime, then take it following your morning meal. If you do not take the dose the following morning, then take the next dose at your regular time after your evening meal. Do not take 2 doses at the same time. If you take too much pregabalin extended-release tablets, call your healthcare provider or poison control center, or go to the nearest emergency room right away. What should I avoid while taking pregabalin extended-release tablets? Do not drive a car, work with machines, or do other dangerous activities until you know how pregabalin extended-release tablets affect you. Do not drink alcohol while taking pregabalin extended-release tablets. What are the possible side effects of pregabalin extended-release tablets? Pregabalin extended-release tablets may cause serious side effects, including: muscle problems, muscle pain, soreness, or weakness problems with your eyesight, including blurry vision. weight gain. Feeling “high” The most common side effects of pregabalin extended-release tablets are: dizziness blurry vision weight gain sleepiness fatigue (tiredness) swelling of hands and feet dry mouth nausea Pregabalin extended-release tablets caused skin sores in animal studies. Skin sores did not happen in studies in people. If you have diabetes, you should pay attention to your skin while taking pregabalin extended-release tablets and tell your healthcare provider about any sores or skin problems. Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of pregabalin extended-release tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store pregabalin extended-release tablets? Store pregabalin extended-release tablets at room temperature between 68° F to 77° F (20° C to 25° C) in its original package. Safely throw away any pregabalin extended-release tablets that is out of date or no longer needed. Keep pregabalin extended-release tablets and all medicines out of the reach of children. General information about the safe and effective use of pregabalin extended-release tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use pregabalin extended-release tablets for a condition for which it was not prescribed. Do not give pregabalin extended-release tablets to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacists or healthcare provider for information about pregabalin extended-release tablets that is written for health professionals. For more information, call 1-800-406-7984 What are the ingredients in pregabalin extended-release tablets? Active ingredient: Inactive ingredients: All trademarks are property of their respective owners. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: Sun Pharmaceutical Industries Limited, MOHALI, INDIA Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 July 2020 FDA-03

Sun Pharmaceutical Industries, Inc.

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