Pregabalin Extended Release

RECENT MAJOR CHANGES SECTION Warnings and Precautions, Respiratory Depression ( 5.4 ) 4/2020

1 INDICATIONS AND USAGE 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 has 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 has not been established for the management of fibromyalgia or as adjunctive therapy for adult patients with partial onset seizures.

2 DOSAGE AND ADMINISTRATION 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. ( 2.1 ) 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. PHN ( 2.3 ) Single dose per day 165 mg/day 330 mg/day within 1 week. Maximum dose of 660 mg/day. Conversion from LYRICA Capsules or Oral Solution to pregabalin extended-release tablets: See full prescribing information. ( 2.4 ) Dose modification recommended in patients with renal impairment. ( 2.5 ) 2.1 Important Dosage and Administration Instructions 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 )] . 2.2 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy 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 is 330 mg once daily. Although LYRICA 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 LYRICA, treatment with doses above 330 mg/day is not recommended for pregabalin extended-release tablets. 2.3 Postherpetic Neuralgia 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 is 660 mg once daily. 2.4 Conversion from LYRICA Capsules or Oral Solution to Pregabalin Extended-Release Tablets When switching from LYRICA to pregabalin extended-release tablets on the day of the switch, instruct patients to take their morning dose of LYRICA as prescribed and initiate pregabalin extended-release tablets therapy after an evening meal. Table 1. Conversion from LYRICA Capsules or Oral Solution to Pregabalin Extended-Release Tablets LYRICA 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 247.5 mg = 3 × 82.5 mg tablets taken once a day. 300 mg/daily 330 mg/day 450 mg/daily 495 mg/day 495 mg = 3 × 165 mg tablets taken once a day. 600 mg/daily 660 mg/day 660 mg = 2 × 330 mg tablets taken once a day. 2.5 Patients with Renal Impairment Use of pregabalin extended-release tablets is not recommen …

3 DOSAGE FORMS AND STRENGTHS Extended-release tablets: 82.5 mg, 165 mg, and 330 mg [see Description (11) and How Supplied/Storage and Handling (16) ] . Pregabalin Extended-Release Tablets Tablet Strength (mg) Tablet Description 82.5 mg White to off white, almond-shaped, film-coated tablets debossed with “SG” on one side and “462” on the other side 165 mg Beige, almond-shaped, film-coated tablets debossed with “SG” on one side and “463” on the other side 330 mg Peach, almond-shaped, film-coated tablets debossed with “SG” on one side and “464” on the other side Extended-release tablets: 82.5 mg, 165 mg, and 330 mg. ( 3 )

4 CONTRAINDICATIONS 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 (5.1 , 5.2) , Adverse Reactions (6) ] . Known hypersensitivity to pregabalin or any of its components. ( 4 )

6 ADVERSE REACTIONS 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. ( 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. 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 (0.50%). 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. Table 4. 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 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. 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 (3.9) 2 (1.0) 1 (0.5) Eye disorders Vision blurred 30 (3.7) 1 (0.5) 0 Diplopia 8 (1.0) 1 (0.5) 0 Gastrointestinal disorders Dry mouth 30 (3.7) 1 (0.5) 0 Nausea 24 (3.0) 7 (3.4) 0 Constipation 22 (2.7) 0 0 Diarrhea 11 (1.4) 2 (1.0) 1 (0.5) Vomiting 9 (1.1) 3 (1.4) 1 (0.5) General disorders and administr …

7 DRUG INTERACTIONS 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 studies showed that pregabalin is unlikely to be involved in significant pharmacokinetic drug interactions [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 LYRICA. No pharmacokinetic interactions were observed between LYRICA 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 LYRICA and ethanol, lorazepam, or oxycodone, additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with these drugs. No clinically important effects on respiration were seen in studies of LYRICA.

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. Advise of potential risk to the fetus. ( 8.1 ) Lactation: Breastfeeding is not recommended. ( 8.2 ) 8.1 Pregnancy 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 exposure to pregabalin extended-release tablets, physicians are advised to recommend that pregnant patients taking pregabalin extended-release tablets enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ . Risk Summary There are no adequate and well-controlled studies with pregabalin extended-release tablets 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 ] . In an animal development study, lethality, growth retardation, and nervous and reproductive system functional impairment were observed in the offspring of rats given pregabalin during gestation and lactation. The no-effect dose for developmental toxicity was approximately twice the human exposure at MRD. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Advise pregnant women of the potential risk to a fetus. Data Animal Data When pregnant rats were given pregabalin (500 mg/kg, 1250 mg/kg, 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 mg/kg, 500 mg/kg, 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 mg/kg, 100 mg/kg, 250 mg/kg, 1250 mg/kg, 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 …

12.1 Mechanism of Action Pregabalin binds with high affinity to the alpha 2 -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 alpha 2 -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 alpha 2 -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 GABA A , GABA B , or benzodiazepine receptors, does not augment GABA A 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.

11 DESCRIPTION Pregabalin extended-release tablets are for oral use and contain pregabalin. Pregabalin is described chemically as (S) -3-(aminomethyl)-5-methylhexanoic acid. The molecular formula is C 8 H 17 NO 2 and the molecular weight is 159.23. The chemical structure of pregabalin is: Pregabalin is a white to off-white, crystalline solid with a pK a1 of 4.2 and a pK a2 of 10.6. It is freely soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is – 1.35. Pregabalin extended-release tablets are administered orally and contain 82.5 mg, 165 mg, or 330 mg of pregabalin, USP, along with carbomer, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, red iron oxide, yellow iron oxide, and black iron oxide. Formula

10 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 LYRICA 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).

16 HOW SUPPLIED/STORAGE AND HANDLING Pregabalin extended-release tablets are supplied in the following strengths and package configurations: Pregabalin Extended-Release Tablets, 82.5 mg are white to off white, almond shaped, film-coated tablets debossed with “SG” on one side and “462” on the other side. Bottle of 30 NDC 50228-462-30 Bottle of 500 NDC 50228-462-05 Pregabalin Extended-Release Tablets, 165 mg are beige, almond shaped, film-coated tablets debossed with “SG” on one side and “463” on the other side. Bottle of 30 NDC 50228-463-30 Bottle of 500 NDC 50228-463-05 Pregabalin Extended-Release Tablets, 330 mg are peach, almond shaped, film-coated tablets debossed with “SG” on one side and “464” on the other side. Bottle of 30 NDC 50228-464-30 Bottle of 500 NDC 50228-464-05 Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (between 59°F and 86°F) in the original package. (See USP Controlled Room Temperature)