LYRICA CR- pregabalin_tablet, film coated, extended release

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 (0-24)
CLINICAL PHARMACOLOGY
Pregabalin binds with high affinity to the alpha 2 2 2 While pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABA A B A LYRICA CR has linear pharmacokinetics with dose‑proportional increases in maximum plasma concentration (C max LYRICA CR administered once daily following an evening meal has equivalent AUC and lower C max max Table 5. Steady-State Pharmacokinetics for LYRICA CR 165 mg Once Daily and LYRICA 75 mg Twice Daily Note: Geometric mean (%CV) for AUC 24 max min max Abbreviations: AUC 24 max min max LYRICA CR LYRICA N 24 24 C max 2. 2 (21) T max 8. 5) AUC 24 29. 5 (18) C min 0. 59 (25) Pregabalin is absorbed from the small intestine and proximal colon. LYRICA CR absorption is linear and dose proportional. The bioavailability of LYRICA CR is reduced if taken on an empty stomach. The AUC is approximately 30% lower when LYRICA CR is administered fasted relative to following an evening meal. When LYRICA CR is 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 LYRICA. The rate and extent of LYRICA CR 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 LYRICA CR is 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 LYRICA. AUC decreases approximately 13% to 25% when LYRICA CR is 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 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. 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. 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) 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) Population pharmacokinetic analyses of the clinical studies showed that the relationship between daily dose and LYRICA CR drug exposure is similar between genders. In population pharmacokinetic analyses of the clinical studies of LYRICA and LYRICA CR, the pharmacokinetics of pregabalin were not significantly affected by race (Caucasians, Blacks, and Hispanics). 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 LYRICA CR is not recommended [see Dosage and Administration (2. 5) In vitro In vitro With the exception of erythromycin, the interactions of LYRICA CR with co-administration of other drugs have not been systematically evaluated. Additional studies have been performed with LYRICA [see Drug Interactions (7) The drug interaction studies described in this section were conducted in healthy adults, and across various patient populations. Multiple-dose administration of erythromycin (500 mg every 6 hours for 18 hours) in healthy subjects resulted in a 17% decrease in AUC of LYRICA CR (330 mg single dose). 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 LYRICA was co-administered with ethanol. No clinically important effects on respiration were seen [see Drug Interactions (7) 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. 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 LYRICA was co‑administered with lorazepam. No clinically important effects on respiration were seen [see Drug Interactions (7) 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 mug, respectively) in healthy subjects. 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 LYRICA was co‑administered with oxycodone. No clinically important effects on respiration were seen [see Drug Interactions (7) 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 Glyburide, insulin, metformin Diuretics Furosemide Antiepileptic Drugs 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.
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 67.0 to 80.9 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)
In Vitro Studies
In vitro In vitro

LYRICA CR is indicated for the management of: Efficacy of LYRICA CR has not been established for the management of fibromyalgia or as adjunctive therapy for adult patients with partial onset seizures. LYRICA CR is indicated for the management of: 1 1 Efficacy of LYRICA CR has not been established for the management of fibromyalgia or as adjunctive therapy for adult patients with partial onset seizures.

1 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. 5 LYRICA CR should be administered once daily after an evening meal. LYRICA CR should be swallowed whole and should not be split, crushed, or chewed. When discontinuing LYRICA CR, taper gradually over a minimum of 1 week. Instruct patients that if they miss taking their dose of LYRICA CR after an evening meal, then they should take their usual dose of LYRICA CR prior to bedtime following a snack. If they miss taking the dose of LYRICA CR prior to bedtime, then they should take their usual dose of LYRICA CR following a morning meal. If they miss taking the dose of LYRICA CR following the morning meal, then they should take their usual dose of LYRICA CR 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 LYRICA CR 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 LYRICA CR. 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 LYRICA CR, 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 LYRICA CR is 660 mg once daily. When switching from LYRICA to LYRICA CR on the day of the switch, instruct patients to take their morning dose of LYRICA as prescribed and initiate LYRICA CR therapy after an evening meal. Conversion from LYRICA Capsules or Oral Solution to LYRICA CR LYRICA LYRICA CR 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. Use of LYRICA CR 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 LYRICA CR 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. LYRICA CR Dosage Adjustment Based on Renal Function Creatinine Clearance (CLcr) Total LYRICA CR Daily Dose 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. 330 Once a day less than 30/hemodialysis Dose with LYRICA Cockcroft and Gault equation.

ADVERSE REACTIONS
The following adverse reactions are described elsewhere in the labeling: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 5) ] [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 7) [see Warnings and Precautions (5. 8) [see Warnings and Precautions (5. 10) [see Warnings and Precautions (5. 11) [see Warnings and Precautions (5. 12) Most common adverse reactions reported in greater than or equal to 4% of patients treated with LYRICA CR are dizziness, somnolence, headache, fatigue, peripheral edema, nausea, blurred vision, dry mouth, and weight gain. 1 To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1-877-446-3679 (1-877-4-INFO-RX) 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 LYRICA CR. 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. In a clinical trial in patients with postherpetic neuralgia, 8. 9% of patients treated with LYRICA CR 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. Table 4 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of patients with postherpetic neuralgia who received LYRICA CR, 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 LYRICA CR Study in Patients with Postherpetic Neuralgia* * Table is limited to adverse reactions that occurred with higher incidence in LYRICA CR-treated patients than in placebo-treated patients for the DB Phase of the study. System Organ Class Single-Blind Phase Double-Blind Phase LYRICA CR LYRICA CR Placebo 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 In addition to the adverse reactions reported during the controlled studies with LYRICA CR in postherpetic neuralgia, the following adverse reactions have been reported in patients treated with LYRICA and LYRICA CR 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 5 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 Metabolic and Nutritional Disorders en dash Rare Musculoskeletal and Connective Tissue Disorders en dash Frequent Infrequent 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 LYRICA. 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 LYRICA was co-administered with medications that have the potential to produce constipation, such as opioid analgesics. There are postmarketing reports of withdrawal symptoms after discontinuation of pregabalin. Reported adverse reactions include, but are not limited to, seizures, depression, suicidal ideation and behavior, agitation, confusion, disorientation, psychotic symptoms, anxiety, insomnia, nausea, pain, sweating, tremor, headache, dizziness, malaise, and diarrhea.
Adverse Reactions Leading to Discontinuation
In a clinical trial in patients with postherpetic neuralgia, 8.9% of patients treated with LYRICA CR 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 LYRICA CR, 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 LYRICA CR Study in Patients with Postherpetic Neuralgia* * Table is limited to adverse reactions that occurred with higher incidence in LYRICA CR-treated patients than in placebo-treated patients for the DB Phase of the study. System Organ Class Single-Blind Phase Double-Blind Phase LYRICA CR LYRICA CR Placebo 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
Fetal/Neonatal Adverse Reactions
Neonatal withdrawal syndrome has been reported in newborns exposed to gabapentinoids in utero for an extended period of time when also exposed to opioids close to delivery. Neonatal withdrawal signs and symptoms reported have included tachypnea, vomiting, diarrhea, hypertonia, irritability, sneezing, poor feeding, hyperactivity, abnormal sleep pattern, and tremor. Reported signs and symptoms that may also be related to withdrawal include tongue thrusting, wandering eye movements while awake, back arching, and continuous extremity movements. Observe neonates exposed to LYRICA CR and opioids for signs and symptoms of neonatal withdrawal and manage accordingly.

LYRICA CR is 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.

USE IN SPECIFIC POPULATIONS
2 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 Observational studies on the use of Lyrica CR during pregnancy suggest a possible small increase in the rate of overall major birth defects, but there was no consistent or specific pattern of major birth defects identified (see Data Postmarketing data suggest that extended gabapentinoid use with opioids close to delivery may increase the risk of neonatal withdrawal versus opioids alone (see Clinical Considerations 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 The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Neonatal withdrawal syndrome has been reported in newborns exposed to gabapentinoids in utero for an extended period of time when also exposed to opioids close to delivery. Neonatal withdrawal signs and symptoms reported have included tachypnea, vomiting, diarrhea, hypertonia, irritability, sneezing, poor feeding, hyperactivity, abnormal sleep pattern, and tremor. Reported signs and symptoms that may also be related to withdrawal include tongue thrusting, wandering eye movements while awake, back arching, and continuous extremity movements. Observe neonates exposed to LYRICA CR and opioids for signs and symptoms of neonatal withdrawal and manage accordingly. One database study, which included over 2,700 pregnancies exposed to pregabalin (monotherapy) during the first trimester compared to 3,063,251 pregnancies unexposed to antiepileptics demonstrated prevalence ratios for major malformations overall of 1. 14 (CI 95% 0. 35) for pregabalin, 1. 29 (CI 95% 1. 65) for lamotrigine, 1. 39 (CI 95% 1. 82) for duloxetine, and 1. 24 (CI 95% 1. 54) for exposure to either lamotrigine or duloxetine. Important study limitations include uncertainty of whether women who filled a prescription took the medication and inability to adequately control for the underlying disease and other potential confounders. A published study included results from two separate databases. One database, which included 353 pregnancies exposed to pregabalin (monotherapy) during the first trimester compared to 368,489 pregnancies unexposed to antiepileptics, showed no increase in risk of major birth defects; adjusted relative risk 0. 87 (CI 95% 0. The second database, which included 118 pregnancies exposed to pregabalin (monotherapy) during the first trimester compared to 380,347 pregnancies unexposed to antiepileptics, suggested a small increase in risk of major birth defects; adjusted relative risk 1. 26 (CI 95% 0. The risk estimates crossed the null, and the study had limitations similar to the prior study. Other published epidemiologic studies reported inconsistent findings. No specific pattern of birth defects was identified across studies. All of the studies had limitations due to their retrospective design. 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 (0-24) 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) 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. 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. 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. 1) The safety and effectiveness of LYRICA CR in pediatric patients have not been established. 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 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 LYRICA CR 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.
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 (13.1)
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 LYRICA CR drug exposure is similar between genders.
Race/Ethnicity
In population pharmacokinetic analyses of the clinical studies of LYRICA and LYRICA CR, the pharmacokinetics of pregabalin were not significantly affected by race (Caucasians, Blacks, and Hispanics).

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 [see Clinical Pharmacology (12) The interactions of LYRICA CR with co-administration of other drugs have not been systematically evaluated. Co-administration of the prokinetic drug erythromycin with LYRICA CR did not result in any clinically important changes in the pharmacokinetics of LYRICA CR [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 LYRICA CR. 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.
In Vivo Studies
With the exception of erythromycin, the interactions of LYRICA CR with co-administration of other drugs have not been systematically evaluated. Additional studies have been performed with LYRICA [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 LYRICA CR (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 LYRICA was co-administered with ethanol. No clinically important effects on respiration were seen [see Drug Interactions (7)
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 LYRICA 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 mug, 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 LYRICA 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 Glyburide, insulin, metformin Diuretics Furosemide Antiepileptic Drugs 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

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.

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LYRICA CR- pregabalin_tablet, film coated, extended release Product manual source documgent