Pregabalin Extended Release

Pregabalin · Tablet, Film Coated, Extended Release · Oral

Prescription (Rx)

Uses

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.

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 recommended for patients with creatinine clearance (CLcr) less than 30 mL/min or who are undergoing hemodialysis. Those patients should receive LYRICA. 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 CLcr, as indicated in Table 2. To use the dosing tables, an estimate of the patient's CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation: 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 (CLcr greater than or equal to 60 mL/min). Then refer to Table 2 to determine the corresponding renal adjusted dose. (For example: A patient initiating pregabalin extended-release tablets therapy for postherpetic neuralgia with normal renal function [CLcr greater than or equal to 60 mL/min], receives a single daily dose of 165 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a single daily dose of 82.5 mg.) Table 2: Pregabalin Extended-Release Tablets Dosage Adjustment Based on Renal Function Creatinine Clearance (CLcr) (mL/min) Total Pregabalin Extended-Release Tablets Daily Dose (mg/day) Dose Regimen greater than or equal to 60 165 330 495 495 mg = 3 × 165 mg tablets taken once a day. 660 660 mg = 2 × 330 mg tablets taken once a day. Once a day 30–60 82.5 165 247.5 247.5 mg = 3 × 82.5 mg tablets taken once a day 330 Once a day less than 30/hemodialysis Dose with LYRICA PRINCIPAL DISPLAY PANEL - 50 mg/500 mg Tablet Bottle Label

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 )

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 )

Warnings and precautions

Angioedema: Angioedema [e.g., swelling of the face, mouth (tongue, lips, and gums) and neck (throat and larynx)] can occur and may be associated with life-threatening respiratory compromise requiring emergency treatment. Discontinue pregabalin extended-release tablets immediately in patients with these symptoms. ( 5.1 ) Hypersensitivity reactions: Hypersensitivity reactions (e.g., hives, dyspnea, and wheezing) can occur. Discontinue pregabalin extended-release tablets immediately in these patients. ( 5.2 ) Suicidal Behavior and Ideation: Antiepileptic drugs, including pregabalin, the active ingredient in pregabalin extended-release tablets, increase the risk of suicidal thoughts or behavior. ( 5.3 ) Respiratory Depression: May occur with LYRICA when used with concomitant CNS depressants or in the setting of underlying respiratory impairment. Monitor patients and adjust dosage as appropriate. ( 5.4 ) Dizziness and Somnolence: May cause dizziness and somnolence and impair patients ability to drive or operate machinery. ( 5.5 ) Increased seizure frequency may occur in patients with seizure disorders if pregabalin extended-release tablets is rapidly discontinued. Withdraw pregabalin extended-release tablets gradually over a minimum of 1 week. ( 5.6 ) Peripheral Edema : May cause peripheral edema. Monitor patients for the development of edema when co-administering pregabalin extended-release tablets and thiazolidinedione antidiabetic agents. ( 5.7 ) 5.1 Angioedema There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue pregabalin extended-release tablets immediately in patients with these symptoms. Exercise caution when prescribing pregabalin extended-release tablets to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing angioedema. 5.2 Hypersensitivity Reactions There have been postmarketing reports of hypersensitivity reactions in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue pregabalin extended-release tablets immediately in patients with these symptoms. 5.3 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including pregabalin, the active ingredient in pregabalin extended-release tablets, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication 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. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients With Events per 1000 Patients Drug Patients With Events per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients With Events per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing pregabalin extended-release tablets must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Side effects

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 administration site conditions Edema peripheral 39 (4.9) 8 (3.8) 1 (0.5) Fatigue 31 (3.9) 3 (1.4) 2 (1.0) Edema 3 (0.4) 3 (1.4) 0 Infections and infestations Nasopharyngitis 12 (1.5) 3 (1.4) 0 Urinary tract infection 11 (1.4) 3 (1.4) 1 (0.5) Bronchitis 4 (0.5) 3 (1.4) 2 (1.0) Respiratory tract infection viral 3 (0.4) 3 (1.4) 1 (0.5) Sinusitis 3 (0.4) 2 (1.0) 0 Gastroenteritis viral 2 (0.2) 2 (1.0) 0 Investigations Weight increased 20 (2.5) 8 (3.8) 2 (1.0) Alanine aminotransferase increased 2 (0.2) 3 (1.4) 0 Aspartate aminotransferase increased 2 (0.2) 2 (1.0) 0 Musculoskeletal and connective tissue disorders Arthralgia 6 (0.7) 2 (1.0) 1 (0.5) Joint swelling 0 4 (1.9) 0 Nervous system disorders Dizziness 137 (17.1) 7 (3.4) 1 (0.5) Somnolence 91 (11.4) 1 (0.5) 0 Headache 31 (3.9) 4 (1.9) 1 (0.5) Balance disorder 21 (2.6) 1 (0.5) 0 Reproductive system and breast disorders Erectile dysfunction 2 (0.6) 1 (1.4) 0 Respiratory, thoracic, and mediastinal disorders Cough 2 (0.2) 2 (1.0) 1 (0.5) Skin and subcutaneous tissue disorders Dermatitis contact 0 2 (1.0) 0 Other Adverse Reactions Observed During Clinical Studies with LYRICA 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 LYRICA 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 adverse reactions are those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

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.

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 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 (0–24) of 123 mcg∙hr/mL) at the MRD. 8.2 Lactation 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 ] . The study did not evaluate the effects of pregabalin on milk production or the effects of pregabalin on the breastfed infant. 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) ] . Available clinical study data in patients greater than 12 years of age do not provide a clear conclusion about the potential risk of tumorigenicity with pregabalin [see Warnings and Precautions (5.9) ] . Because of the potential risk of tumorigenicity, breastfeeding is not recommended during treatment with pregabalin extended-release tablets. 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. LYRICA 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. 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.

Pregnancy

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 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 (0–24) of 123 mcg∙hr/mL) at the MRD.

Pediatric use

8.4 Pediatric Use The safety and effectiveness of pregabalin extended-release tablets in pediatric patients have not been established. Juvenile Animal Toxicity Data In studies in which pregabalin (50 mg/kg 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.

Geriatric use

8.5 Geriatric Use In controlled clinical studies of LYRICA 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 LYRICA 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 (2.5) for recommendations for dosing in patients with renal impairment .

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).

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

Mechanism of action

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.

How supplied

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)

Patient information

Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Angioedema Advise patients that pregabalin extended-release tablets may cause angioedema, with swelling of the face, mouth (lip, gum, tongue) and neck (larynx and pharynx) that can lead to life-threatening respiratory compromise. Instruct patients to discontinue pregabalin extended-release tablets and immediately seek medical care if they experience these symptoms [see Warnings and Precautions (5.1) ] . Hypersensitivity Advise patients that pregabalin extended-release tablets has been associated with hypersensitivity reactions such as skin redness, blisters, hives, rash, dyspnea, and wheezing. Instruct patients to discontinue pregabalin extended-release tablets and immediately seek medical care if they experience these symptoms [see Warnings and Precautions (5.2) ] . Suicidal Thinking and Behavior Counsel patients, their caregivers, and families that AEDs, including pregabalin, the active ingredient in pregabalin extended-release tablets, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to a healthcare provider [see Warnings and Precautions (5.3) ] . Respiratory Depression Inform patients about the risk of respiratory depression. Include information that the risk is greatest for those using concomitant central nervous system (CNS) depressants (such as opioid analgesics) or in those with underlying respiratory impairment. Teach patients how to recognize respiratory depression and advise them to seek medical attention immediately if it occurs [see Warnings and Precautions (5.4) ] . Dizziness and Somnolence Inform patients that pregabalin extended-release tablets may cause dizziness, somnolence, blurred vision, and other CNS signs and symptoms. Accordingly, advise patients not to drive, operate complex machinery, or engage in other hazardous activities until they have gained sufficient experience on pregabalin extended-release tablets to gauge whether or not it affects their mental, visual, and/or motor performance adversely [see Warnings and Precautions (5.5) ] . CNS Depressants Inform patients who require concomitant treatment with central nervous system depressants such as opiates or benzodiazepines that they may experience additive CNS side effects, such as respiratory depression, somnolence, and dizziness [see Warnings and Precautions (5.4 , 5.5) and Drug Interactions (7) ] . Advise patients to avoid consuming alcohol while taking pregabalin extended-release tablets, as pregabalin extended-release tablets may potentiate the impairment of motor skills and sedating effects of alcohol [see Drug Interactions (7) ] . Abrupt or Rapid Discontinuation Advise patients to take pregabalin extended-release tablets as prescribed. Abrupt or rapid discontinuation may result in insomnia, nausea, headache, anxiety, or diarrhea. Advise patients with seizure disorders that abrupt or rapid discontinuation may increase seizure frequency [see Warnings and Precautions (5.6) ] . Missed Dose 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. Weight Gain and Edema Inform patients that pregabalin extended-release tablets may cause edema and weight gain. Advise patients that concomitant treatment with pregabalin extended-release tablets and a thiazolidinedione antidiabetic agent may lead to an additive effect on edema and weight gain. Advise patients with preexisting cardiac conditions that this may increase the risk of heart failure [see Warnings and Precautions (5.7 , 5.8) ] . Ophthalmological Effects Counsel patients that pregabalin extended-release tablets may cause visual disturbances. Inform patients that if changes in vision occur, they should notify their physician [see Warnings and Precautions (5.10) ] . Creatine Kinase Elevations Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever [see Warnings and Precautions (5.11) ] . Use in Pregnancy Advise pregnant patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry [see Use in Specific Populations (8.1) ] . Lactation Advise nursing mothers that breastfeeding is not recommended during treatment with pregabalin extended-release tablets [ see Use in Specific Populations (8.2) ] . Male Fertility Inform men being treated with pregabalin extended-release tablets who plan to father a child of the potential risk of male-mediated teratogenicity [see Nonclinical Toxicology (13.1) and Use in Specific Populations (8.3) ] . Dermatopathy Instruct diabetic patients to pay particular attention to skin integrity while being treated with pregabalin extended-release tablets [see Nonclinical Toxicology (13.2) ] .

Label text from the FDA structured product label by ScieGen Pharmaceuticals, INC. (revised Sep 19, 2022). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Pregabalin in 3 products

Pregabalin Extended Release NDC products (3)

NDC	Strength & form	Labeler	Type
50228-462	Pregabalin 82.5 mg/1 Tablet, Film Coated, Extended Release	ScieGen Pharmaceuticals, INC.	ANDA · DEA CV
50228-463	Pregabalin 165 mg/1 Tablet, Film Coated, Extended Release	ScieGen Pharmaceuticals, INC.	ANDA · DEA CV
50228-464	Pregabalin 330 mg/1 Tablet, Film Coated, Extended Release	ScieGen Pharmaceuticals, INC.	ANDA · DEA CV

Frequently asked questions

What is Pregabalin Extended Release used for?

What are the side effects of Pregabalin Extended Release?

Who makes Pregabalin Extended Release?

Pregabalin Extended Release is listed by 1 labeler in the FDA NDC directory, including ScieGen Pharmaceuticals, INC..