Pregabalin

Indications and Usage ( 1 ) 5/2019 Dosage and Administration, Adjunctive Therapy for Partial-Onset Seizures in Patients 17 years of Age and Older ( 2.4 ) 5/2019 Warnings and Precautions, Respiratory Depression ( 5.4 ) 4/2020 Warnings and Precautions, Dizziness and Somnolence ( 5.5 ) 5/2019

1 INDICATIONS AND USAGE Pregabalin capsules are indicated for:Pregabalin capsules are indicated for: • Management of neuropathic pain associated with diabetic peripheral neuropathy • Management of postherpetic neuralgia • Adjunctive therapy for the treatment of partial-onset seizures in patients 17 years of age and older • Management of fibromyalgia • Management of neuropathic pain associated with spinal cord injury Pediatric use information is approved for Pfizer’s LYRICA (pregabalin) Capsules and Oral Solution products. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Pregabalin capsules are indicated for: Neuropathic pain associated with diabetic peripheral neuropathy (DPN) ( 1 ) Postherpetic neuralgia (PHN) ( 1 ) Adjunctive therapy for the treatment of partial onset seizures in patients 17 years of age and older ( 1 ) Fibromyalgia ( 1 ) Neuropathic pain associated with spinal cord injury ( 1 )

2 DOSAGE AND ADMINISTRATION For adult indications, begin dosing at 150 mg/day. For partial-onset seizure dosing in pediatric patients 1 month of age and older, refer to section 2.4. ( 2.2 , 2.3 , 2.4 , 2.5 , 2.6 ) Dosing recommendations: INDICATION Dosing Regimen Maximum Dose DPN Pain ( 2.2 ) 3 divided doses per day 300 mg/day within 1 week PHN ( 2.3 ) 2 or 3 divided doses per day 300 mg/day within 1 week. Maximum dose of 600 mg/day. Adjunctive Therapy for Partial-Onset Seizures in Pediatric and Adult Patients Weighing 30 kg or More ( 2.4 ) 2 or 3 divided doses per day Maximum dose of 600 mg/day. Adjunctive Therapy for Partial-Onset Seizures in Pediatric Patients Weighing Less than 30 kg ( 2.4 ) 1 month to less than 4 years : 3 divided doses per day 4 years and older : 2 or 3 divided doses per day 14 mg/kg/day. Fibromyalgia ( 2.5 ) 2 divided doses per day 300 mg/day within 1 week. Maximum dose of 450 mg/day. Neuropathic Pain Associated with Spinal Cord Injury ( 2.6 ) 2 divided doses per day 300 mg/day within 1 week. Maximum dose of 600 mg/day. Dose should be adjusted in adult patients with reduced renal function. ( 2.7 ) 2.1 Important Administration Instructions Pregabalin capsules are given orally with or without food. When discontinuing pregabalin, taper gradually over a minimum of 1 week. [see Warnings and Precautions (5.6) ]. Because pregabalin is eliminated primarily by renal excretion, adjust the dose in adult patients with reduced renal function [see Dosage and Administration (2.7) ]. 2.2 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy in Adults The maximum recommended dose of pregabalin capsule 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. Although pregabalin 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) ] . 2.3 Postherpetic Neuralgia in Adults The recommended dose of pregabalin capsule 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). The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability. 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 pregabalin, 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) ] . 2.3 Postherpetic Neuralgia in Adults The recommended dose of pregabalin capsule 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). The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability. 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 pregabalin, 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) ] . 2.4 …

3 DOSAGE FORMS AND STRENGTHS Pregabalin Capsules are available in 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg strengths [see Description (11 ) and How Supplied/Storage and Handling (16) ]. Pregabalin capsules, 25 mg are supplied as white, hard gelatin capsule printed with black ink “AN” on cap & “1310” on body. Pregabalin capsules, 50 mg are supplied as white, hard gelatin capsule printed with black ink “AN” on cap & “1311” on body. Pregabalin capsules, 75 mg are supplied as white/orange, hard gelatin capsule printed with black ink “AN” on cap & “1312” on body. Pregabalin capsules, 100 mg are supplied as orange, hard gelatin capsule printed with black ink “AN” on cap & “1313” on body. Pregabalin capsules, 150 mg are supplied as white, hard gelatin capsule printed with black ink “AN” on cap & “1314” on body. Pregabalin capsules, 200 mg are supplied as light orange, hard gelatin capsule printed with black ink “AN” on cap & “1315” on body. Pregabalin capsules, 225 mg are supplied as white/light orange, hard gelatin capsule printed with black ink “AN” on cap & “1316” on body. Pregabalin capsules, 300 mg are supplied as white/orange, hard gelatin capsule printed with black ink “AN” on cap & “1317” on body. Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg. ( 3 )

4 CONTRAINDICATIONS Pregabalin capsules are contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy [see Warnings and Precautions ( Error! Hyperlink reference not valid. )] . • Known hypersensitivity to pregabalin or any of its components. ( Error! Hyperlink reference not valid. )

The following serious adverse reactions are described elsewhere in the labeling: Angioedema [see WARNINGS AND PRECAUTIONS (5.1)] Hypersensitivity [see WARNINGS AND PRECAUTIONS (5.2)] Suicidal Behavior and Ideation [see WARNINGS AND PRECAUTIONS (5.3)] Respiratory Depression [see WARNINGS AND PRECAUTIONS (5.4)] Dizziness and Somnolence [see WARNINGS AND PRECAUTIONS (5.5)] Increased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation [see WARNINGS AND PRECAUTIONS (5.6)] Peripheral Edema [see WARNINGS AND PRECAUTIONS (5.7)] Weight Gain [see WARNINGS AND PRECAUTIONS (5.8)] Tumorigenic Potential [see WARNINGS AND PRECAUTIONS (5.9)] Ophthalmological Effects [see WARNINGS AND PRECAUTIONS (5.10)] Creatine Kinase Elevations [see WARNINGS AND PRECAUTIONS (5.11)] Decreased Platelet Count [see WARNINGS AND PRECAUTIONS (5.12)] PR Interval Prolongation [see WARNINGS AND PRECAUTIONS (5.13)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In all controlled and uncontrolled trials across various patient populations during the premarketing development of pregabalin, more than 10,000 patients have received pregabalin. 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 pregabalin and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin 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 pregabalin 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 Controlled Clinical Studies in Adults In premarketing controlled trials of all adult patient populations combined (including DPN, PHN, and adult patients with partial-onset seizures), 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 pregabalin 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 adults with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with pregabalin and 4% 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 (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 pregabalin 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 4 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 pregabalin group for whic …

7 DRUG INTERACTIONS Since pregabalin capsules are 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 and in vivo studies showed that pregabalin capsules are unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between pregabalin capsules and commonly used antiepileptic drugs [see Clinical Pharmacology ( 12 )] . Pharmacodynamics Multiple oral doses of pregabalin capsules 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 pregabalin capsules were co-administered with these drugs. No clinically important effects on respiration were seen.

8 USE IN SPECIFIC POPULATIONS • Lactation: Breastfeeding is not recommended. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to pregabalin during pregnancy. To provide information regarding the effects of in utero exposure to pregabalin, physicians are advised to recommend that pregnant patients taking pregabalin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ . Risk Summary Observational studies on the use of pregabalin 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 ). Available postmarketing data on miscarriage and other maternal, fetal, and long term developmental adverse effects were insufficient to identify risk associated with pregabalin. 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 ). In an animal development study, lethality, growth retardation, and nervous and reproductive system functional impairment were observed in the offspring of rats given pregabalin during gestation and lactation. The no-effect dose for developmental toxicity was approximately twice the human exposure at MRD. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Data Human Data 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% 0.96-1.35) for pregabalin, 1.29 (CI 95% 1.01-1.65) for lamotrigine, 1.39 (CI 95% 1.07-1.82) for duloxetine, and 1.24 (CI 95% 1.00-1.54) 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% 0.53-1.42). 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% 0.64-2.49). 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. Animal Data When pregnant rats were given pregabalin (500 mg/kg, 1,250 mg/kg, or 2,500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (pre …

12.1 Mechanism of Action Pregabalin Capsules (pregabalin) binds with high affinity to the alpha 2 -delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of pregabalin has not been fully elucidated, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha 2 -delta subunit may be involved in pregabalin's anti-nociceptive and antiseizure effects in animals. In animal models of nerve damage, pregabalin has been shown to reduce calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord, possibly by disrupting alpha 2 -delta containing-calcium channel trafficking and/or reducing calcium currents. Evidence from other animal models of nerve damage and persistent pain suggest the anti-nociceptive activities of pregabalin may also be mediated through interactions with descending noradrenergic and serotonergic pathways originating from the brainstem that modulate pain transmission in the spinal cord. While pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABA A , GABA B , or benzodiazepine receptors, does not augment GABA A responses in cultured neurons, does not alter rat brain GABA concentration or have acute effects on GABA uptake or degradation. However, in cultured neurons prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport. Pregabalin does not block sodium channels, is not active at opiate receptors, and does not alter cyclooxygenase enzyme activity. It is inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake.

11 DESCRIPTION Pregabalin is described chemically as ( S )-3-(aminomethyl)-5-methylhexanoic acid. The molecular formula is C 8 H 17 NO 2 and the molecular weight is 159.23. The chemical structure of pregabalin is: Pregabalin is a white to off-white, crystalline solid with a pKa 1 of 4.2 and a pKa 2 of 10.6. It is freely soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is - 1.35. Pregabalin capsules are administered orally and are supplied as imprinted hard-shell capsules containing 25, 50, 75, 100, 150, 200, 225, and 300 mg of pregabalin, along with lactose monohydrate, cornstarch, and talc as inactive ingredients. The capsule shells contain gelatin and titanium dioxide. In addition, the orange capsule shells contain red iron oxide, sodium lauryl sulfate and colloidal silicon dioxide, water and the white capsule shells contain sodium lauryl sulfate and colloidal silicon dioxide, water. Colloidal silicon dioxide is a manufacturing aid that may or may not be present in the capsule shells. The imprinting ink contains shellac, black iron oxide, propylene glycol, and potassium hydroxide, dehydrated alcohol, isopropyl alcohol, butyl alcohol, strong ammonia solution and purified water. str

10 OVERDOSAGE Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans In the postmarketing experience, the most commonly reported adverse events observed with pregabalin when taken in overdose include reduced consciousness, depression/anxiety, confusional state, agitation, and restlessness. Seizures and heart block have also been reported. Deaths have been reported in the setting of lone pregabalin capsules overdose and in combination with other CNS depressants. Treatment or Management of Overdose There is no specific antidote for overdose with pregabalin capsules. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up-to-date information on the management of overdose with pregabalin capsules. Pregabalin capsules can be removed by hemodialysis. Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50 % in 4 hours).

16 HOW SUPPLIED/STORAGE AND HANDLING 25 mg capsules: White to off white powder filled in size "4" hard gelatin capsules with white opaque colored cap and white opaque colored body imprinted "SG" on cap and "350" on body with black ink; available in Bottles of 30: NDC 71205-869-30 Bottles of 60: NDC 71205-869-60 Bottles of 90: NDC 71205-869-90 Bottles of 100: NDC 71205-869-00 Bottles of 120: NDC 71205-869-72 Bottles of 180: NDC 71205-869-78 Bottles of 270: NDC 71205-869-67 Bottles of 500: NDC 71205-869-55 Bottles of 1000: NDC 71205-869-11 50 mg capsules: White to off white powder filled in size "3" hard gelatin capsules with white opaque colored cap and white opaque colored body imprinted "SG" on cap and "351" on body with black ink; available in Bottles of 30: NDC 71205-870-30 Bottles of 60: NDC 71205-870-60 Bottles of 90: NDC 71205-870-90 Bottles of 100: NDC 71205-870-00 Bottles of 120: NDC 71205-870-72 Bottles of 180: NDC 71205-870-78 Bottles of 270: NDC 71205-870-67 Bottles of 500: NDC 71205-870-55 Bottles of 1000: NDC 71205-870-11 75 mg capsules: White to off white powder filled in size "4" hard gelatin capsules with orange opaque colored cap and white opaque colored body imprinted "SG" on cap and "352" on body with black ink; available in Bottles of 30: NDC 71205-871-30 Bottles of 60: NDC 71205-871-60 Bottles of 90: NDC 71205-871-90 Bottles of 100: NDC 71205-871-00 Bottles of 120: NDC 71205-871-72 Bottles of 180: NDC 71205-871-78 Bottles of 270: NDC 71205-871-67 Bottles of 500: NDC 71205-871-55 Bottles of 1000: NDC 71205-871-11 100 mg capsules: White to off white powder filled in size "3" hard gelatin capsules with orange opaque colored cap and orange opaque colored body imprinted "SG" on cap and "353" on body with black ink; available in Bottles of 30: NDC 71205-872-30 Bottles of 60: NDC 71205-872-60 Bottles of 90: NDC 71205-872-90 Bottles of 100: NDC 71205-872-00 Bottles of 120: NDC 71205-872-72 Bottles of 180: NDC 71205-872-78 Bottles of 270: NDC 71205-872-67 Bottles of 500: NDC 71205-872-55 Bottles of 1000: NDC 71205-872-11 150 mg capsules: White to off white powder filled in size "2" hard gelatin capsules with white opaque colored cap and white opaque colored body imprinted "SG" on cap and "354" on body with black ink; available in Bottles of 30: NDC 71205-873-30 Bottles of 60: NDC 71205-873-60 Bottles of 90: NDC 71205-873-90 Bottles of 100: NDC 71205-873-00 Bottles of 120: NDC 71205-873-72 Bottles of 180: NDC 71205-873-78 Bottles of 270: NDC 71205-873-67 Bottles of 500: NDC 71205-873-55 Bottles of 1000: NDC 71205-873-11 200 mg capsules: White to off white powder filled in size "1" hard gelatin capsules with light orange colored cap and light orange colored body imprinted "SG" on cap and "355" on body with black ink; available in Bottles of 30: NDC 71205-874-30 Bottles of 60: NDC 71205-874-60 Bottles of 90: NDC 71205-874-90 Bottles of 100: NDC 71205-874-00 Bottles of 120: NDC 71205-874-72 Bottles of 180: NDC 71205-874-78 Bottles of 270: NDC 71205-874-67 Bottles of 500: NDC 71205-874-55 Bottles of 1000: NDC 71205-874-11 225 mg capsules: White to off white powder filled in size "1" hard gelatin capsules with light orange colored cap and white opaque colored body imprinted "SG" on cap and "356" on body with black ink; available in Bottles of 30: NDC 71205-875-30 Bottles of 60: NDC 71205-875-60 Bottles of 90: NDC 71205-875-90 Bottles of 100: NDC 71205-875-00 Bottles of 120: NDC 71205-875-72 Bottles of 180: NDC 71205-875-78 Bottles of 270: NDC 71205-875-67 Bottles of 500: NDC 71205-875-55 Bottles of 1000: NDC 71205-875-11 300 mg capsules: White to off white powder filled in size "0" hard gelatin capsules with orange opaque colored cap and white opaque colored body imprinted "SG" on cap and "357" on body with black ink; available in Bottles of 30: NDC 71205-876-30 Bottles of 60: NDC 71205-876-60 Bottles of 90: NDC 71205-876-90 Bottles of 100: NDC 71205-876-00 Bottles of 120: NDC 71205-876-72 Bottles of 180: NDC 71205-876-7 …