LYRICA- pregabalin_capsule

LYRICA (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 Pregabalin is well absorbed after oral administration, is eliminated largely by renal excretion, and has an elimination half-life of about 6 hours. Absorption and Distribution Following oral administration of LYRICA capsules under fasting conditions, peak plasma concentrations occur within 1. Pregabalin oral bioavailability is greater than or equal to 90% and is independent of dose. Following single- (25 to 300 mg) and multiple- dose (75 to 900 mg/day) administration, maximum plasma concentrations (C max The rate of pregabalin absorption is decreased when given with food, resulting in a decrease in C max 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. Metabolism and Elimination 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 creatinine clearance (CLcr) [see Dosage and Administration (2. 6) Pharmacokinetics in Special Populations Race In population pharmacokinetic analyses of the clinical studies in various populations, the pharmacokinetics of LYRICA were not significantly affected by race (Caucasians, Blacks, and Hispanics). Gender Population pharmacokinetic analyses of the clinical studies showed that the relationship between daily dose and LYRICA drug exposure is similar between genders. Renal Impairment and Hemodialysis Pregabalin clearance is nearly proportional to creatinine clearance (CLcr). Dosage reduction in patients with renal dysfunction 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, dosing must be modified [ see Dosage and Administration (2. 6) Elderly 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. 6) Pediatric Pharmacokinetics Pharmacokinetics of pregabalin have not been adequately studied in pediatric patients. Drug Interactions In Vitro Studies Pregabalin, at concentrations that were, in general, 10-times those attained in clinical trials, does not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 enzyme systems. In vitro drug interaction studies demonstrate that pregabalin does not induce CYP1A2 or CYP3A4 activity. Therefore, an increase in the metabolism of coadministered CYP1A2 substrates (e. theophylline, caffeine) or CYP 3A4 substrates (e. , midazolam, testosterone) is not anticipated. In Vivo Studies The drug interaction studies described in this section were conducted in healthy adults, and across various patient populations. Gabapentin The pharmacokinetic interactions of pregabalin and gabapentin were investigated in 12 healthy subjects following concomitant single-dose administration of 100-mg pregabalin and 300-mg gabapentin and in 18 healthy subjects following concomitant multiple-dose administration of 200-mg pregabalin every 8 hours and 400-mg gabapentin every 8 hours. Gabapentin pharmacokinetics following single- and multiple-dose administration were unaltered by pregabalin coadministration. The extent of pregabalin absorption was unaffected by gabapentin coadministration, although there was a small reduction in rate of absorption. Oral Contraceptive Pregabalin coadministration (200 mg three times a day) had no effect on the steady-state pharmacokinetics of norethindrone and ethinyl estradiol (1 mg/35 µg, respectively) in healthy subjects. 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. 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. 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. Phenytoin, carbamazepine, valproic acid, and lamotrigine 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 three 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.

LYRICA is indicated for: Management of neuropathic pain associated with diabetic peripheral neuropathy Management of postherpetic neuralgia Adjunctive therapy for adult patients with partial onset seizures Management of fibromyalgia Management of neuropathic pain associated with spinal cord injury LYRICA is indicated for: Neuropathic pain associated with diabetic peripheral neuropathy (DPN) ( 1 Postherpetic neuralgia (PHN) ( 1 Adjunctive therapy for adult patients with partial onset seizures ( 1 Fibromyalgia ( 1 Neuropathic pain associated with spinal cord injury ( 1.

LYRICA is given orally with or without food. When discontinuing LYRICA, taper gradually over a minimum of 1 week. For all indications, begin dosing at 150 mg/day. 5 Dosing recommendations: INDICATION Dosing Regimen Maximum Dose DPN Pain ( 2. 1 3 divided doses per day 300 mg/day within 1 week PHN ( 2. 2 2 or 3 divided doses per day 300 mg/day within 1 week. Maximum dose of 600 mg/day. Adjunctive Therapy for Adult Patients with Partial Onset Seizures ( 2. 3 2 or 3 divided doses per day Maximum dose of 600 mg/day. Fibromyalgia ( 2. 4 2 divided doses per day 300 mg/day within 1 week. Neuropathic Pain Associated with Spinal Cord Injury ( 2. 5 2 divided doses per day 300 mg/day within 1 week. Dose should be adjusted in patients with reduced renal function. 6 Oral Solution Concentration and Dispensing ( 2. 7 The maximum recommended dose of LYRICA is 100 mg three times a day (300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Begin dosing at 50 mg three times a day (150 mg/day). The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function [see Dosage and Administration (2. 6) Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers additional significant benefit and this dose was less well tolerated. In view of the dose-dependent adverse reactions, treatment with doses above 300 mg/day is not recommended [see Adverse Reactions (6. 1) The recommended dose of LYRICA is 75 to 150 mg two times a day, or 50 to 100 mg three times a day (150 to 300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Begin dosing at 75 mg two times a day, or 50 mg three times a day (150 mg/day). 6) Patients who do not experience sufficient pain relief following 2 to 4 weeks of treatment with 300 mg/day, and who are able to tolerate LYRICA, may be treated with up to 300 mg two times a day, or 200 mg three times a day (600 mg/day). In view of the dose-dependent adverse reactions and the higher rate of treatment discontinuation due to adverse reactions, reserve dosing above 300 mg/day for those patients who have on-going pain and are tolerating 300 mg daily [see Adverse Reactions (6. 1) LYRICA at doses of 150 to 600 mg/day has been shown to be effective as adjunctive therapy in the treatment of partial onset seizures in adults. Both the efficacy and adverse event profiles of LYRICA have been shown to be dose-related. Administer the total daily dose in two or three divided doses. In general, it is recommended that patients be started on a total daily dose no greater than 150 mg/day (75 mg two times a day, or 50 mg three times a day). Based on individual patient response and tolerability, the dose may be increased to a maximum dose of 600 mg/day. 6) The effect of dose escalation rate on the tolerability of LYRICA has not been formally studied. The efficacy of add-on LYRICA in patients taking gabapentin has not been evaluated in controlled trials. Consequently, dosing recommendations for the use of LYRICA with gabapentin cannot be offered. The recommended dose of LYRICA for fibromyalgia is 300 to 450 mg/day. Begin dosing at 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient benefit with 300 mg/day may be further increased to 225 mg two times a day (450 mg/day). Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers additional benefit and this dose was less well tolerated. In view of the dose-dependent adverse reactions, treatment with doses above 450 mg/day is not recommended [see Adverse Reactions (6. 1) [see Dosage and Administration (2. 6) The recommended dose range of LYRICA for the treatment of neuropathic pain associated with spinal cord injury is 150 to 600 mg/day. The recommended starting dose is 75 mg two times a day (150 mg/day). Patients who do not experience sufficient pain relief after 2 to 3 weeks of treatment with 150 mg two times a day and who tolerate LYRICA may be treated with up to 300 mg two times a day [see Clinical Studies (14. 5) [see Dosage and Administration (2. 6) In view of dose-dependent adverse reactions and since LYRICA 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 creatinine clearance (CLcr), as indicated in Table 1. To use this dosing table, 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 1 to determine the corresponding renal adjusted dose. (For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr greater than or equal to 60 mL/min), receives a total daily dose of 150 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses. ) For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1 Table 1. Pregabalin Dosage Adjustment Based on Renal Function Creatinine Clearance (CLcr) Total Pregabalin Daily Dose Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. Dose Regimen TID= Three divided doses; BID = Two divided doses; QD = Single daily dose. >=60 150 300 450 600 BID or TID 30en dash60 75 150 225 300 BID or TID 15en dash30 25en dash50 75 100en dash150 150 QD or BID <15 25 25en dash50 50en dash75 75 QD Supplementary dosage following hemodialysis (mg) Supplementary dose is a single additional dose. Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg Patients on the 25en dash50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg Patients on the 50en dash75 mg QD regimen: take one supplemental dose of 75 mg or 100 mg Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg Cockcroft and Gault equation The oral solution is 20 mg pregabalin per milliliter (mL) and prescriptions should be written in milligrams (mg). The pharmacist will calculate the applicable dose in mL for dispensing (e. , 150 mg equals 7. 5 mL oral solution).

Most common adverse reactions (greater than or equal to 5% and twice placebo) are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain and thinking abnormal (primarily difficulty with concentration/attention). 1 To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at (800) 438-1985 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. In all controlled and uncontrolled trials across various patient populations during the premarketing development of LYRICA, more than 10,000 patients have received LYRICA. Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients were treated for at least 2 years. Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all populations combined, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (4%). In the placebo group, 1% of patients withdrew due to dizziness and less than 1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the LYRICA group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each). Most Common Adverse Reactions in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all patient populations combined, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and "thinking abnormal" (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with LYRICA than by subjects treated with placebo (greater than or equal to 5% and twice the rate of that seen in placebo). Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy Adverse Reactions Leading to Discontinuation In clinical trials in patients with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with LYRICA and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, less than 1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the LYRICA group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of patients. Most Common Adverse Reactions Table 3 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of patients with neuropathic pain associated with diabetic neuropathy in the combined LYRICA group for which the incidence was greater in this combined LYRICA group than in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of "mild" or "moderate". Treatment-emergent adverse reaction incidence in controlled trials in neuropathic pain associated with diabetic peripheral neuropathy (events in at least 1% of all LYRICA-treated patients and at least numerically more in all LYRICA than in the placebo group) Body system 75 mg/day 150 mg/day 300 mg/day 600 mg/day All PGB PGB: pregabalin Placebo [N=979] [N=459] Body as a whole Asthenia 4 2 4 7 5 2 Accidental injury 5 2 2 6 4 3 Back pain 0 2 1 2 2 0 Chest pain 4 1 1 2 2 1 Face edema 0 1 1 2 1 0 Digestive system Dry mouth 3 2 5 7 5 1 Constipation 0 2 4 6 4 2 Flatulence 3 0 2 3 2 1 Metabolic and nutritional disorders Peripheral edema 4 6 9 12 9 2 Weight gain 0 4 4 6 4 0 Edema 0 2 4 2 2 0 Hypoglycemia 1 3 2 1 2 1 Nervous system Dizziness 8 9 23 29 21 5 Somnolence 4 6 13 16 12 3 Neuropathy 9 2 2 5 4 3 Ataxia 6 1 2 4 3 1 Vertigo 1 2 2 4 3 1 Confusion 0 1 2 3 2 1 Euphoria 0 0 3 2 2 0 Incoordination 1 0 2 2 2 0 Thinking abnormal Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. 1 0 1 3 2 0 Tremor 1 1 1 2 1 0 Abnormal gait 1 0 1 3 1 0 Amnesia 3 1 0 2 1 0 Nervousness 0 1 1 1 1 0 Respiratory system Dyspnea 3 0 2 2 2 1 Special senses Blurry vision Investigator term; summary level term is amblyopia 3 1 3 6 4 2 Abnormal vision 1 0 1 1 1 0 Controlled Studies in Postherpetic Neuralgia Adverse Reactions Leading to Discontinuation In clinical trials in patients with postherpetic neuralgia, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (4%) and somnolence (3%). Other reasons for discontinuation from the trials, occurring in greater frequency in the LYRICA group than in the placebo group, were confusion (2%), as well as peripheral edema, asthenia, ataxia, and abnormal gait (1% each). Most Common Adverse Reactions Table 4 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of patients with neuropathic pain associated with postherpetic neuralgia in the combined LYRICA group for which the incidence was greater in this combined LYRICA group than in the placebo group. In addition, an event is included, even if the incidence in the all LYRICA group is not greater than in the placebo group, if the incidence of the event in the 600 mg/day group is more than twice that in the placebo group. Overall, 12. 4% of all pregabalin-treated patients and 9. 0% of all placebo-treated patients had at least one severe event while 8% of pregabalin-treated patients and 4. 3% of placebo-treated patients had at least one severe treatment-related adverse event. Treatment-emergent adverse reaction incidence in controlled trials in neuropathic pain associated with postherpetic neuralgia (events in at least 1% of all LYRICA-treated patients and at least numerically more in all LYRICA than in the placebo group) Body system 75 mg/d 150 mg/d 300 mg/d 600 mg/d All PGB PGB: pregabalin Placebo Body as a whole Infection 14 8 6 3 7 4 Headache 5 9 5 8 7 5 Pain 5 4 5 5 5 4 Accidental injury 4 3 3 5 3 2 Flu syndrome 1 2 2 1 2 1 Face edema 0 2 1 3 2 1 Digestive system Dry mouth 7 7 6 15 8 3 Constipation 4 5 5 5 5 2 Flatulence 2 1 2 3 2 1 Vomiting 1 1 3 3 2 1 Metabolic and nutritional disorders Peripheral edema 0 8 16 16 12 4 Weight gain 1 2 5 7 4 0 Edema 0 1 2 6 2 1 Musculoskeletal system Myasthenia 1 1 1 1 1 0 Nervous system Dizziness 11 18 31 37 26 9 Somnolence 8 12 18 25 16 5 Ataxia 1 2 5 9 5 1 Abnormal gait 0 2 4 8 4 1 Confusion 1 2 3 7 3 0 Thinking abnormal Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. 0 2 1 6 2 2 Incoordination 2 2 1 3 2 0 Amnesia 0 1 1 4 2 0 Speech disorder 0 0 1 3 1 0 Respiratory system Bronchitis 0 1 1 3 1 1 Special senses Blurry vision Investigator term; summary level term is amblyopia 1 5 5 9 5 3 Diplopia 0 2 2 4 2 0 Abnormal vision 0 1 2 5 2 0 Eye Disorder 0 1 1 2 1 0 Urogenital System Urinary Incontinence 0 1 1 2 1 0 Controlled Add-On Studies in Adjunctive Therapy for Adult Patients with Partial Onset Seizures Adverse Reactions Leading to Discontinuation Approximately 15% of patients receiving LYRICA and 6% of patients receiving placebo in add-on epilepsy trials discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (6%), ataxia (4%), and somnolence (3%). In comparison, less than 1% of patients in the placebo group withdrew due to each of these events. Other adverse reactions that led to discontinuation of at least 1% of patients in the LYRICA group and at least twice as frequently compared to the placebo group were asthenia, diplopia, blurred vision, thinking abnormal, nausea, tremor, vertigo, headache, and confusion (which each led to withdrawal in 2% or less of patients). Most Common Adverse Reactions Table 5 lists all dose-related adverse reactions occurring in at least 2% of all LYRICA-treated patients. Dose-relatedness was defined as the incidence of the adverse event in the 600 mg/day group was at least 2% greater than the rate in both the placebo and 150 mg/day groups. In these studies, 758 patients received LYRICA and 294 patients received placebo for up to 12 weeks. Because patients were also treated with 1 to 3 other AEDs, it is not possible to determine whether the following adverse reactions can be ascribed to LYRICA alone, or the combination of LYRICA and other AEDs. Dose-related treatment-emergent adverse reaction incidence in controlled trials in adjunctive therapy for adult patients with partial onset seizures (events in at least 2% of all LYRICA-treated patients and the adverse reaction in the 600 mg/day group was greater than or equal to 2% the rate in both the placebo and 150 mg/day groups) 150 mg/d 300 mg/d 600 mg/d All PGB PGB: pregabalin Placebo Body System [N = 185] [N = 90] [N = 395] [N = 670] Excludes patients who received the 50 mg dose in Study E1. [N = 294] % % % % % Body as a Whole Accidental Injury 7 11 10 9 5 Pain 3 2 5 4 3 Digestive System Increased Appetite 2 3 6 5 1 Dry Mouth 1 2 6 4 1 Constipation 1 1 7 4 2 Metabolic and Nutritional Disorders Weight Gain 5 7 16 12 1 Peripheral Edema 3 3 6 5 2 Nervous System Dizziness 18 31 38 32 11 Somnolence 11 18 28 22 11 Ataxia 6 10 20 15 4 Tremor 3 7 11 8 4 Thinking Abnormal Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. 4 8 9 8 2 Amnesia 3 2 6 5 2 Speech Disorder 1 2 7 5 1 Incoordination 1 3 6 4 1 Abnormal Gait 1 3 5 4 0 Twitching 0 4 5 4 1 Confusion 1 2 5 4 2 Myoclonus 1 0 4 2 0 Special Senses Blurred Vision Investigator term; summary level term is amblyopia. 5 8 12 10 4 Diplopia 5 7 12 9 4 Abnormal Vision 3 1 5 4 1 Controlled Studies with Fibromyalgia Adverse Reactions Leading to Discontinuation In clinical trials of patients with fibromyalgia, 19% of patients treated with pregabalin (150en dash600 mg/day) and 10% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (6%) and somnolence (3%). In comparison, less than 1% of placebo-treated patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group, were fatigue, headache, balance disorder, and weight increased. Each of these adverse reactions led to withdrawal in approximately 1% of patients. Most Common Adverse Reactions Table 6 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 2% of patients with fibromyalgia in the 'all pregabalin' treatment group for which the incidence was greater than in the placebo treatment group. A majority of pregabalin-treated patients in clinical studies experienced adverse reactions with a maximum intensity of "mild" or "moderate". Treatment-emergent adverse reaction incidence in controlled trials in fibromyalgia (events) in at least 2% of all LYRICA-treated patients and occurring more frequently in the all pregabalin-group than in the placebo treatment group) System Organ Class 150 mg/d 300 mg/d 450 mg/d 600 mg/d All PGB PGB: pregabalin Placebo [N=132] [N=502] [N=505] [N=378] [N=1517] [N=505] Ear and Labyrinth Disorders Vertigo 2 2 2 1 2 0 Eye Disorders Vision blurred 8 7 7 12 8 1 Gastrointestinal Disorders Dry mouth 7 6 9 9 8 2 Constipation 4 4 7 10 7 2 Vomiting 2 3 3 2 3 2 Flatulence 1 1 2 2 2 1 Abdominal distension 2 2 2 2 2 1 General Disorders and Administrative Site Conditions Fatigue 5 7 6 8 7 4 Edema peripheral 5 5 6 9 6 2 Chest pain 2 1 1 2 2 1 Feeling abnormal 1 3 2 2 2 0 Edema 1 2 1 2 2 1 Feeling drunk 1 2 1 2 2 0 Infections and Infestations Sinusitis 4 5 7 5 5 4 Investigations Weight increased 8 10 10 14 11 2 Metabolism and Nutrition Disorders Increased appetite 4 3 5 7 5 1 Fluid retention 2 3 3 2 2 1 Musculoskeletal and Connective Tissue Disorders Arthralgia 4 3 3 6 4 2 Muscle spasms 2 4 4 4 4 2 Back pain 2 3 4 3 3 3 Nervous System Disorders Dizziness 23 31 43 45 38 9 Somnolence 13 18 22 22 20 4 Headache 11 12 14 10 12 12 Disturbance in attention 4 4 6 6 5 1 Balance disorder 2 3 6 9 5 0 Memory impairment 1 3 4 4 3 0 Coordination abnormal 2 1 2 2 2 1 Hypoesthesia 2 2 3 2 2 1 Lethargy 2 2 1 2 2 0 Tremor 0 1 3 2 2 0 Psychiatric Disorders Euphoric Mood 2 5 6 7 6 1 Confusional state 0 2 3 4 3 0 Anxiety 2 2 2 2 2 1 Disorientation 1 0 2 1 2 0 Depression 2 2 2 2 2 2 Respiratory, Thoracic and Mediastinal Disorders Pharyngolaryngeal pain 2 1 3 3 2 2 Controlled Studies in Neuropathic Pain Associated with Spinal Cord Injury Adverse Reactions Leading to Discontinuation In clinical trials of patients with neuropathic pain associated with spinal cord injury, 13% of patients treated with pregabalin and 10% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were somnolence (3%) and edema (2%). In comparison, none of the placebo-treated patients withdrew due to somnolence and edema. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group, were fatigue and balance disorder. Each of these adverse reactions led to withdrawal in less than 2% of patients. Most Common Adverse Reactions Table 7 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 2% of patients with neuropathic pain associated with spinal cord injury in the controlled trials. Treatment-emergent adverse reaction incidence in controlled trials in neuropathic pain associated with spinal cord injury (events in at least 2% of all LYRICA-treated patients and occurring more frequently in the all pregabalin-group than in the placebo treatment group) System Organ Class PGB PGB: Pregabalin Placebo (N=174) % % Ear and labryrinth disorders Vertigo 2. 1 Eye disorders Vision blurred 6. 1 Gastrointestinal disorders Dry mouth 11. 9 Constipation 8. 0 Vomiting 2. 1 General disorders and administration site conditions Fatigue 11. 0 Edema peripheral 10. 1 Infections and infestations Nasopharyngitis 8. 6 Investigations Weight increased 3. 1 Blood creatine phosphokinase increased 2. 7 0 Musculoskeletal and connective tissue disorders Muscular weakness 4. 7 Pain in extremity 3. 3 Neck pain 2. 1 Back pain 2. 7 Joint swelling 2. 2 0 Nervous system disorders Somnolence 35. 5 Dizziness 20. 9 Disturbance in attention 3. 8 0 Memory impairment 3. 1 Paresthesia 2. 6 Psychiatric disorders Insomnia 3. 9 Euphoric mood 2. 6 Renal and urinary disorders Urinary incontinence 2. 1 Skin and subcutaneous tissue disorders Decubitus ulcer 2. 1 Vascular disorders Hypertension 2. 1 Hypotension 2. 2 0 Other Adverse Reactions Observed During the Clinical Studies of LYRICA Following is a list of treatment-emergent adverse reactions reported by patients treated with LYRICA during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent infrequent rare Warnings and Precautions Body as a Whole en dash Frequent: Infrequent: Rare: Cardiovascular System en dash Infrequent: Rare: Digestive System en dash Frequent: Infrequent: Rare: Hemic and Lymphatic System en dash Frequent: Infrequent: Rare: Metabolic and Nutritional Disorders en dash Rare: Musculoskeletal System en dash Frequent: Infrequent: Rare: Nervous System en dash Frequent: Infrequent: Rare: Respiratory System en dash Rare: Skin and Appendages en dash Frequent: Infrequent: Rare: Special senses en dash Frequent: Infrequent: Rare: Urogenital System en dash Frequent: Infrequent: Rare: Comparison of Gender and Race The overall adverse event profile of pregabalin was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse experience reports by race. The following adverse reactions have been identified during postapproval use of LYRICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System Disorders en dash Headache Gastrointestinal Disorders en dash Nausea, Diarrhea Reproductive System and Breast Disorders en dash Gynecomastia, Breast Enlargement In addition, there are post-marketing 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 also post-marketing reports of respiratory failure and coma in patients taking pregabalin and other CNS depressant medications.

LYRICA 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. Known hypersensitivity to pregabalin or any of its components.

Pregnancy: May cause fetal harm. Advise of potential risk to the fetus. 1 Lactation: Breastfeeding is not recommended. 2 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LYRICA during pregnancy. To provide information regarding the effects of in utero http://www. aedpregnancyregistry. Risk Summary There are no adequate and well-controlled studies with LYRICA 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 16 times human exposure at the maximum recommended dose (MRD) of 600 mg/day [see Data Data Animal Data When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at greater than or equal to 1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose for rat embryo-fetal developmental toxicity was not established. When pregnant rabbits were given LYRICA (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 16 times human exposure at the MRD. In a study in which female rats were dosed with LYRICA (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 (0en dash24) Risk Summary Small amounts of pregabalin have been detected in the milk of lactating women. A pharmacokinetic study in lactating women detected pregabalin in breast milk at average steady state concentrations approximately 76% of those in maternal plasma. The estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 0. 31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal dose [see Data Based on animal studies, there is a potential risk of tumorigenicity with pregabalin exposure via breast milk to the breastfed infant [see Nonclinical Toxicology (13. 1) [see Warnings and Precautions (5. 9) Data A pharmacokinetic study in ten lactating women, who were at least 12 weeks postpartum, evaluated the concentrations of pregabalin in plasma and breast milk. LYRICA 150 mg oral capsule was given every 12 hours (300 mg daily dose) for a total of four 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 LYRICA on milk production. Infants did not receive breast milk obtained during the dosing period, therefore, the effects of Lyrica on the breast fed infant were not evaluated. Infertility Male 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 (one 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 one 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 efficacy of pregabalin 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 600 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 controlled clinical studies of LYRICA in epilepsy, there were only 10 patients 65 to 74 years of age, and 2 patients who were 75 years of age or older. No overall differences in safety and efficacy were observed between these patients and younger patients. In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were 65 years of age or older. Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy. LYRICA is known to be substantially excreted by the kidney, and the risk of toxic reactions to LYRICA may be greater in patients with impaired renal function. Because LYRICA is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment [see Dosage and Administration (2.

Since LYRICA 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 in vivo [see Clinical Pharmacology (12) Pharmacodynamics Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, 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.

MEDICATION GUIDE
LYRICA (LEER-i-kah) LYRICA (LEER-i-kah) Read this Medication Guide before you start taking LYRICA and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about LYRICA, ask your healthcare provider or pharmacist. What is the most important information I should know about LYRICA? LYRICA may cause serious side effects including: Serious, even life-threatening, allergic reactions Suicidal thoughts or actions Swelling of your hands, legs and feet Dizziness and sleepiness These serious side effects are described below: 1. Serious, even life-threatening, allergic reactions. Stop taking LYRICA and call your healthcare provider right away if you have any of these signs of a serious allergic reaction: swelling of your face, mouth, lips, gums, tongue, throat or neck trouble breathing rash, hives (raised bumps) or blisters 2. Like other antiepileptic drugs, LYRICA may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying attempts to commit suicide new or worse depression new or worse anxiety feeling agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood If you have suicidal thoughts or actions, do not stop LYRICA without first talking to a healthcare provider. Stopping LYRICA suddenly can cause serious problems. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. How can I watch for early symptoms of suicidal thoughts and actions? Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. 3. Swelling of your hands, legs and feet 4. Dizziness and sleepiness. Do not drive a car, work with machines, or do other dangerous activities until you know how LYRICA affects you. Ask your healthcare provider about when it will be okay to do these activities. What is LYRICA? LYRICA is a prescription medicine used in adults, 18 years and older, to treat: pain from damaged nerves (neuropathic pain) that happens with diabetes pain from damaged nerves (neuropathic pain) that follows healing of shingles partial seizures when taken together with other seizure medicines fibromyalgia (pain all over your body) pain from damaged nerves (neuropathic pain) that follows spinal cord injury LYRICA has not been studied in children under 18 years of age. Who should not take LYRICA? Do not take LYRICA if you are allergic to pregabalin or any of the ingredients in LYRICA. See " What is the most important information I should know about LYRICA See the end of this leaflet for a complete list of ingredients in LYRICA. What should I tell my healthcare provider before taking LYRICA? Before taking LYRICA, tell your healthcare provider about all your medical conditions, including if you: have or have had depression, mood problems or suicidal thoughts or behavior have kidney problems or get kidney dialysis have heart problems including heart failure have a bleeding problem or a low blood platelet count have abused prescription medicines, street drugs, or alcohol in the past have ever had swelling of your face, mouth, tongue, lips, gums, neck, or throat (angioedema) plan to father a child. Animal studies have shown that pregabalin, the active ingredient in LYRICA, made male animals less fertile and caused sperm to change. Also, in animal studies, birth defects were seen in the offspring (babies) of male animals treated with pregabalin. It is not known if these problems can happen in people who take LYRICA. are pregnant or plan to become pregnant. It is not known if LYRICA will harm your unborn baby. If you become pregnant while taking LYRICA, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. Information about the registry can also be found at the website, http://www.aedpregnancyregistry.org/. are breastfeeding or plan to breastfeed. LYRICA passes into your breast milk. It is not known if Lyrica can harm your baby. Tell your healthcare provider about all the medicines you take, angiotensin converting enzyme (ACE) inhibitors, which are used to treat many conditions, including high blood pressure. You may have a higher chance for swelling and hives if these medicines are taken with LYRICA. See " What is the most important information I should know about LYRICA? Avandia (rosiglitazone), Avandamet (contains rosiglitazone and metformin), or Actos (pioglitazone) for diabetes. You may have a higher chance of weight gain or swelling of your hands or feet if these medicines are taken with LYRICA. See " What are the possible side effects of LYRICA? any narcotic pain medicine (such as oxycodone), tranquilizers or medicines for anxiety (such as lorazepam). You may have a higher chance for dizziness and sleepiness if these medicines are taken with LYRICA. any medicines that make you sleepy Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider. How should I take LYRICA? Take LYRICA exactly as prescribed. Your healthcare provider will tell you how much LYRICA to take and when to take it. Take LYRICA at the same times each day. LYRICA may be taken with or without food. Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider. Do not stop taking LYRICA without talking to your healthcare provider. If you stop taking LYRICA suddenly you may have headaches, nausea, diarrhea, trouble sleeping, increased sweating, or you may feel anxious. If you have epilepsy and you stop taking LYRICA suddenly, you may have seizures more often. Talk with your healthcare provider about how to stop LYRICA slowly. If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take two doses at the same time. If you take too much LYRICA, call your healthcare provider or poison control center, or go to the nearest emergency room right away. What should I avoid while taking LYRICA? Do not drive a car, work with machines, or do other dangerous activities until you know how LYRICA affects you. Do not drink alcohol while taking LYRICA. What are the possible side effects of LYRICA? LYRICA may cause serious side effects, including: See " What is the most important information I should know about LYRICA muscle problems, muscle pain, soreness, or weakness problems with your eyesight, including blurry vision. weight gain. feeling "high" The most common side effects of LYRICA are: dizziness blurry vision weight gain sleepiness trouble concentrating swelling of hands and feet dry mouth LYRICA caused skin sores in animal studies. Skin sores did not happen in studies in people. If you have diabetes, you should pay attention to your skin while taking LYRICA and tell your healthcare provider about any sores or skin problems. Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of LYRICA. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store LYRICA? Store LYRICA capsules and oral solution at room temperature, 68°F to 77°F (20°C to 25°C) in its original package. Safely throw away any LYRICA that is out of date or no longer needed. Keep LYRICA and all medicines out of the reach of children. General information about LYRICA Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use LYRICA for a condition for which it was not prescribed. Do not give LYRICA to other people, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes the most important information about LYRICA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about LYRICA that is written for health professionals. You can also visit the LYRICA website at www.LYRICA.com or call 1-866-459-7422 (1-866-4LYRICA). What are the ingredients in LYRICA? Active ingredient: pregabalin Inactive ingredients: LYRICA capsules: Capsule shell: gelatin and titanium dioxide; Orange capsule shell: red iron oxide; White capsule shell: sodium lauryl sulfate, colloidal silicon dioxide. Colloidal silicon dioxide is a manufacturing aid that may or may not be present in the capsule shells. Imprinting ink: shellac, black iron oxide, propylene glycol, potassium hydroxide. LYRICA oral solution: This Medication Guide has been approved by the U.S. Food and Drug Administration. LAB-0299-13.0 March 2016">OVERDOSAGE
Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans There is limited experience with overdose of LYRICA. The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, and there were no notable clinical consequences. Treatment or Management of Overdose There is no specific antidote for overdose with LYRICA. 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 LYRICA. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient''s clinical state or in patients with significant renal impairment. Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours).
NONCLINICAL TOXICOLOGY
Carcinogenesis A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was approximately equal to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established. No evidence of carcinogenicity was seen in two studies in Wistar rats following dietary administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 14 and 24 times, respectively, human exposure at the MRD. Mutagenesis Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro in vitro in vivo Impairment of Fertility In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse reproductive and developmental effects were observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities. Effects on sperm and fertility parameters were reversible in studies of this duration (3en dash4 months). The no-effect dose for male reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four weeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD. In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established. Dermatopathy Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The more severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in clinical studies. Ocular Lesions Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor cells] and/or corneal inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin exposures (AUC) greater than or equal to 2 times those achieved in humans given the maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year.
CLINICAL STUDIES
The efficacy of the maximum recommended dose of LYRICA for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in three double-blind, placebo-controlled, multicenter studies with three times a day dosing, two of which studied the maximum recommended dose. Patients were enrolled with either Type 1 or Type 2 diabetes mellitus and a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for 1 to 5 years. A total of 89% of patients completed Studies DPN 1 and DPN 2. The patients had a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). The baseline mean pain scores across the two studies ranged from 6. Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin. Patients recorded their pain daily in a diary. Study DPN 1: [see Adverse Reactions (6. 1) Figure 1: Figure 1 Study DPN 2: Figure 2: Figure 2 The efficacy of LYRICA for the management of postherpetic neuralgia was established in three double-blind, placebo-controlled, multicenter studies. These studies enrolled patients with neuralgia persisting for at least 3 months following healing of herpes zoster rash and a minimum baseline score of greater than or equal to 4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). Seventy-three percent of patients completed the studies. The baseline mean pain scores across the 3 studies ranged from 6 to 7. Study PHN 1: Figure 3: Figure 3 Study PHN 2: Figure 4: Figure 4 Study PHN 3: Figure 5: Figure 5 The efficacy of LYRICA as adjunctive therapy in partial onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter studies in adult patients. Patients were enrolled who had partial onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant antiepileptic drugs (AEDs). Patients taking gabapentin were required to discontinue gabapentin treatment 1 week prior to entering baseline. During an 8-week baseline period, patients had to experience at least 6 partial onset seizures with no seizure-free period exceeding 4 weeks. The mean duration of epilepsy was 25 years in these 3 studies and the mean and median baseline seizure frequencies were 22. 5 and 10 seizures per month, respectively. Approximately half of the patients were taking 2 concurrent AEDs at baseline. Among the LYRICA-treated patients, 80% completed the double-blind phase of the studies. Table 8 shows median baseline seizure rates and median percent reduction in seizure frequency by dose. Seizure Response in Controlled, Add-On Epilepsy Studies Daily Dose of Pregabalin Dosing Regimen N Baseline Seizure Frequency/mo Median % Change from Baseline p-value, vs. placebo Study E1 Placebo BID 100 9. 5 0 50 mg/day BID 88 10. 4230 150 mg/day BID 86 8. 0001 300 mg/day BID 90 9. 0001 600 mg/day BID 89 9. 0001 Study E2 Placebo TID 96 9. 3 1 150 mg/day TID 99 11. 0007 600 mg/day TID 92 12. 0001 Study E3 Placebo BID/TID 98 11 -1 600 mg/day BID 103 9. 0001 600 mg/day TID 111 10 -48 0. 0001 In the first study (E1), there was evidence of a dose-response relationship for total daily doses of Lyrica between 150 and 600 mg/day; a dose of 50 mg/day was not effective. In the first study (E1), each daily dose was divided into two equal doses (twice a day dosing). In the second study (E2), each daily dose was divided into three equal doses (three times a day dosing). In the third study (E3), the same total daily dose was divided into two equal doses for one group (twice a day dosing) and three equal doses for another group (three times a day dosing). While the three times a day dosing group in Study E3 performed numerically better than the twice a day dosing group, this difference was small and not statistically significant. A secondary outcome measure included the responder rate (proportion of patients with greater than or equal to 50% reduction from baseline in partial seizure frequency). The following figure displays responder rate by dose for two of the studies. Figure 6: Figure 7: Subset evaluations of the antiseizure efficacy of LYRICA showed no clinically important differences as a function of age, gender, or race. Figure 6 Figure 7 The efficacy of LYRICA for management of fibromyalgia was established in one 14-week, double-blind, placebo-controlled, multicenter study (F1) and one six-month, randomized withdrawal study (F2). Studies F1 and F2 enrolled patients with a diagnosis of fibromyalgia using the American College of Rheumatology (ACR) criteria (history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites). The studies showed a reduction in pain by visual analog scale. In addition, improvement was demonstrated based on a patient global assessment (PGIC), and on the Fibromyalgia Impact Questionnaire (FIQ). Study F1 see Adverse Reactions (6. 1) For various levels of improvement in pain intensity from baseline to study endpoint, Figure 8 shows the fraction of patients achieving that level of improvement. The figure is cumulative. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study. Figure 8: Table 9. Patient Global Response in Fibromyalgia Study F1 Patient Global Impression of Change Treatment Group % Any Improvement 95% CI PGB = Pregabalin Placebo 47. 2) PGB 300 68. 3) PGB 450 77. 0) PGB 600 66. 1) Figure 8 Study F2 When considering return of pain or withdrawal due to adverse events as loss of response (LTR), treatment with LYRICA resulted in a longer time to loss of therapeutic response than treatment with placebo. Fifty-three percent of the pregabalin-treated subjects compared to 33% of placebo patients remained on study drug and maintained a therapeutic response to Week 26 of the study. Treatment with LYRICA also resulted in a longer time to loss of response based on the FIQ Time to worsening of the FIQ was defined as the time to a 1-point increase from double-blind baseline in each of the subscales, and a 5-point increase from double-blind baseline evaluation for the FIQ total score. Time to PGIC lack of improvement was defined as time to PGIC assessments indicating less improvement than "much improvement. " Figure 9: Figure 9 The efficacy of LYRICA for the management of neuropathic pain associated with spinal cord injury was established in two double-blind, placebo-controlled, multicenter studies. Patients were enrolled with neuropathic pain associated with spinal cord injury that persisted continuously for at least three months or with relapses and remissions for at least six months. A total of 63% of patients completed study 1 and 84% completed study 2. Patients were allowed to take opioids, non-opioid analgesics, antiepileptic drugs, muscle relaxants, and antidepressant drugs if the dose was stable for 30 days prior to screening. Patients were allowed to take acetaminophen and nonsteroidal anti-inflammatory drugs during the studies. Study SCI 1 Figure 10 Figure 10 Study SCI 2 Figure 11 Figure 11.
MEDICATION GUIDE
LYRICA (LEER-i-kah) LYRICA (LEER-i-kah) Read this Medication Guide before you start taking LYRICA and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about LYRICA, ask your healthcare provider or pharmacist. What is the most important information I should know about LYRICA? LYRICA may cause serious side effects including: Serious, even life-threatening, allergic reactions Suicidal thoughts or actions Swelling of your hands, legs and feet Dizziness and sleepiness These serious side effects are described below: 1. Serious, even life-threatening, allergic reactions. Stop taking LYRICA and call your healthcare provider right away if you have any of these signs of a serious allergic reaction: swelling of your face, mouth, lips, gums, tongue, throat or neck trouble breathing rash, hives (raised bumps) or blisters 2. Like other antiepileptic drugs, LYRICA may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying attempts to commit suicide new or worse depression new or worse anxiety feeling agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood If you have suicidal thoughts or actions, do not stop LYRICA without first talking to a healthcare provider. Stopping LYRICA suddenly can cause serious problems. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. How can I watch for early symptoms of suicidal thoughts and actions? Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. 3. Swelling of your hands, legs and feet 4. Dizziness and sleepiness. Do not drive a car, work with machines, or do other dangerous activities until you know how LYRICA affects you. Ask your healthcare provider about when it will be okay to do these activities. What is LYRICA? LYRICA is a prescription medicine used in adults, 18 years and older, to treat: pain from damaged nerves (neuropathic pain) that happens with diabetes pain from damaged nerves (neuropathic pain) that follows healing of shingles partial seizures when taken together with other seizure medicines fibromyalgia (pain all over your body) pain from damaged nerves (neuropathic pain) that follows spinal cord injury LYRICA has not been studied in children under 18 years of age. Who should not take LYRICA? Do not take LYRICA if you are allergic to pregabalin or any of the ingredients in LYRICA. See " What is the most important information I should know about LYRICA See the end of this leaflet for a complete list of ingredients in LYRICA. What should I tell my healthcare provider before taking LYRICA? Before taking LYRICA, tell your healthcare provider about all your medical conditions, including if you: have or have had depression, mood problems or suicidal thoughts or behavior have kidney problems or get kidney dialysis have heart problems including heart failure have a bleeding problem or a low blood platelet count have abused prescription medicines, street drugs, or alcohol in the past have ever had swelling of your face, mouth, tongue, lips, gums, neck, or throat (angioedema) plan to father a child. Animal studies have shown that pregabalin, the active ingredient in LYRICA, made male animals less fertile and caused sperm to change. Also, in animal studies, birth defects were seen in the offspring (babies) of male animals treated with pregabalin. It is not known if these problems can happen in people who take LYRICA. are pregnant or plan to become pregnant. It is not known if LYRICA will harm your unborn baby. If you become pregnant while taking LYRICA, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. Information about the registry can also be found at the website, http://www.aedpregnancyregistry.org/. are breastfeeding or plan to breastfeed. LYRICA passes into your breast milk. It is not known if Lyrica can harm your baby. Tell your healthcare provider about all the medicines you take, angiotensin converting enzyme (ACE) inhibitors, which are used to treat many conditions, including high blood pressure. You may have a higher chance for swelling and hives if these medicines are taken with LYRICA. See " What is the most important information I should know about LYRICA? Avandia (rosiglitazone), Avandamet (contains rosiglitazone and metformin), or Actos (pioglitazone) for diabetes. You may have a higher chance of weight gain or swelling of your hands or feet if these medicines are taken with LYRICA. See " What are the possible side effects of LYRICA? any narcotic pain medicine (such as oxycodone), tranquilizers or medicines for anxiety (such as lorazepam). You may have a higher chance for dizziness and sleepiness if these medicines are taken with LYRICA. any medicines that make you sleepy Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider. How should I take LYRICA? Take LYRICA exactly as prescribed. Your healthcare provider will tell you how much LYRICA to take and when to take it. Take LYRICA at the same times each day. LYRICA may be taken with or without food. Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider. Do not stop taking LYRICA without talking to your healthcare provider. If you stop taking LYRICA suddenly you may have headaches, nausea, diarrhea, trouble sleeping, increased sweating, or you may feel anxious. If you have epilepsy and you stop taking LYRICA suddenly, you may have seizures more often. Talk with your healthcare provider about how to stop LYRICA slowly. If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take two doses at the same time. If you take too much LYRICA, call your healthcare provider or poison control center, or go to the nearest emergency room right away. What should I avoid while taking LYRICA? Do not drive a car, work with machines, or do other dangerous activities until you know how LYRICA affects you. Do not drink alcohol while taking LYRICA. What are the possible side effects of LYRICA? LYRICA may cause serious side effects, including: See " What is the most important information I should know about LYRICA muscle problems, muscle pain, soreness, or weakness problems with your eyesight, including blurry vision. weight gain. feeling "high" The most common side effects of LYRICA are: dizziness blurry vision weight gain sleepiness trouble concentrating swelling of hands and feet dry mouth LYRICA caused skin sores in animal studies. Skin sores did not happen in studies in people. If you have diabetes, you should pay attention to your skin while taking LYRICA and tell your healthcare provider about any sores or skin problems. Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of LYRICA. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store LYRICA? Store LYRICA capsules and oral solution at room temperature, 68°F to 77°F (20°C to 25°C) in its original package. Safely throw away any LYRICA that is out of date or no longer needed. Keep LYRICA and all medicines out of the reach of children. General information about LYRICA Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use LYRICA for a condition for which it was not prescribed. Do not give LYRICA to other people, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes the most important information about LYRICA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about LYRICA that is written for health professionals. You can also visit the LYRICA website at www.LYRICA.com or call 1-866-459-7422 (1-866-4LYRICA). What are the ingredients in LYRICA? Active ingredient: pregabalin Inactive ingredients: LYRICA capsules: Capsule shell: gelatin and titanium dioxide; Orange capsule shell: red iron oxide; White capsule shell: sodium lauryl sulfate, colloidal silicon dioxide. Colloidal silicon dioxide is a manufacturing aid that may or may not be present in the capsule shells. Imprinting ink: shellac, black iron oxide, propylene glycol, potassium hydroxide. LYRICA oral solution: This Medication Guide has been approved by the U.S. Food and Drug Administration. LAB-0299-13.0 March 2016

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