Pregablin

Warnings and Precautions ( 5.3 , 5.4 ) 04/2025

1 INDICATIONS AND USAGE 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 1 month of age and older Management of fibromyalgia Management of neuropathic pain associated with spinal cord injury 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 1 month 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 is given orally with or without food. When discontinuing pregabalin capsules, taper gradually over a minimum of 1 week [see Warnings and Precautions ( 5.4 )]. Because pregabalin capsules 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 capsules are 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 capsules were 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 capsules are 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 capsules, 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 Adjunctive Therapy for Partial-Onset Seizures in Patients 1 Month of Age and Older The recommended dosages for adults and pediatric patients 1 month of age and older are included in Table 1. Administer the total daily dosage orally in two or three divided doses as indicated in Table 1. In pediatric patients, the recommended dosing regimen is dependent upon body weight. Based on clinical response and tolerability, dosage may be increased, approximately weekly. Table 1. Recommended Dosage for Adults and Pediatric Patients 1 Month and Older Age and Body Weight Recommended Initial Dosage Recommended Maximum Dosage Frequency of Administration Adults (17 years and older) 150 mg/day 600 mg/day 2 or 3 divided doses Pediatric patients weighing 30 kg or more 2.5 mg/kg/day 10 mg/kg/day (not to exceed 600 mg/day) 2 or 3 divided doses Pediatric patients weighing …

3 DOSAGE FORMS AND STRENGTHS Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg [see Description ( 11 ) and How Supplied/Storage and Handling ( 16 )] . Capsules: 25mg, 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 ( 5.2 )]. Known hypersensitivity to pregabalin or any of its components. ( 4 )

6 ADVERSE REACTIONS 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 )] Increased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation [see Warnings and Precautions ( 5.4 )] Respiratory Depression [see Warnings and Precautions ( 5.5 )] Dizziness and Somnolence [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 )] Most common adverse reactions (greater than or equal to 5% and twice placebo) in adults are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and thinking abnormal (primarily difficulty with concentration/attention). ( 6.1 ) Most common adverse reactions (greater than or equal to 5% and twice placebo) in pediatric patients for the treatment of partial-onset seizures are increased weight and increased appetite. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384. or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In all controlled and uncontrolled trials across various patient populations during the premarketing development of pregabalin capsules, more than 10,000 patients have received pregabalin capsules. 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 adult populations combined, 14% of patients treated with pregabalin capsules and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin capsules 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 capsules 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 capsules 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 capsules and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin …

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 was 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 capsules during pregnancy. To provide information regarding the effects of in utero exposure to pregabalin capsules, physicians are advised to recommend that pregnant patients taking pregabalin capsules 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. Postmarketing data suggest that extended gabapentinoid use with opioids close to delivery may increase the risk of neonatal withdrawal versus opioids alone (see Clinical Considerations). There are no comparative epidemiologic studies evaluating this association. Therefore, it is not known whether exposure to pregabalin alone late in pregnancy may cause withdrawal signs and symptoms. 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 estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Neonatal withdrawal syndrome has been reported in newborns exposed to gabapentinoids in utero for an extended period of time when also exposed to opioids close to delivery. Neonatal withdrawal signs and symptoms reported have included tachypnea, vomiting, diarrhea, hypertonia, irritability, sneezing, poor feeding, hyperactivity, abnormal sleep pattern, and tremor. Reported signs and symptoms that may also be related to withdrawal include tongue thrusting, wandering eye movements while awake, back arching, and continuous extremity movements. Observe neonates exposed to pregabalin capsules and opioids for signs and symptoms of neonatal withdrawal and manage accordingly. 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 …

12.1 Mechanism of Action Pregabalin binds with high affinity to the alpha2-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 alpha2-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 alpha2-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 GABAA 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, USP is described chemically as ( S )-3-(aminomethyl)-5-methylhexanoic acid. The molecular formula is C 8 H 17 NO 2 and the molecular weight is 159.23. The chemical structure of pregabalin is: Pregabalin is a white to off-white, crystalline solid with a pK a1 of 4.2 and a pK a2 of 10.6. It is freely soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is - 1.35. Pregabalin 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, pregelatinized starch, talc as inactive ingredients. The capsule shells contain gelatin, sodium lauryl sulfate and titanium dioxide. In addition, the orange capsule shells contain red iron oxide and the imprinting ink contains shellac, black iron oxide, propylene glycol, and potassium hydroxide. pregabalin-struct.jpg

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 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/white, size '4' hard gelatin capsules imprinted with 'M1'on cap and '25mg' on body containing white colored powder. Bottles of 90: NDC 33342-165-10 50 mg capsules: White/white, size '3' hard gelatin capsules imprinted with 'M2' on cap and '50mg' on body containing white colored powder. Bottles of 90: NDC 33342-166-10 75 mg capsules: Orange/white, size '4' hard gelatin capsules imprinted with 'M3' on cap and '75mg' on body containing white colored powder. Bottles of 90: NDC 33342-167-10 100 mg capsules: Orange/orange, size '3' hard gelatin capsules imprinted with 'M4' on cap and '100mg' on body containing white colored powder. Bottles of 90: NDC 33342-168-10 150 mg capsules: White/white, size '2' hard gelatin capsules imprinted with 'M5' on cap and '150mg' on body containing white colored powder. Bottles of 90: NDC 33342-169-10 200 mg capsules: Light orange/Light orange, size '1' hard gelatin capsules imprinted with 'M6' on cap and '200mg' on body containing white colored powder. Bottles of 90: NDC 33342-170-10 225 mg capsules: Light orange/white, size '1' hard gelatin capsules imprinted with 'M7' on cap and '225mg' on body containing white colored powder. Bottles of 90: NDC 33342-171-10 300 mg capsules: Orange/white, size '0' hard gelatin capsules imprinted with 'M8' on cap and '300mg' on body containing white colored powder. Bottles of 90: NDC 33342-172-10 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature].