PRAVASTATIN SODIUM

5 WARNINGS AND PRECAUTIONS Myopathy and Rhabdomyolysis : Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher pravastatin sodium tablets dosage. Discontinue pravastatin sodium tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue pravastatin sodium tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing pravastatin sodium tablets dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. ( 5.1 , 7.1 , 8.5 , 8.6 ) Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported. Discontinue pravastatin sodium tablets if IMNM is suspected ( 5.2 ). Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue ( 5.3 ). 5.1 Myopathy and Rhabdomyolysis Pravastatin sodium tablets may cause myopathy and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including pravastatin sodium tablets. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CK) to greater than 10 times the upper limit of normal (ULN), occurred <0.1% in pravastatin sodium tablets-treated patients in clinical trials. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher pravastatin sodium tablets dosage [see Drug Interactions ( 7.1 )] . Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Pravastatin sodium tablets are not recommended in patients taking gemfibrozil [see Drug Interactions ( 7 )]. There are pravastatin sodium tablets dosage restrictions for patients taking cyclosporin and select macrolide antibiotics [see Dosage and Administration ( 2.5 )] . The following drugs when used concomitantly with pravastatin sodium tablets may also increase the risk of myopathy and rhabdomyolysis: niacin, fibrates, and colchicine [see Drug Interactions ( 7 )]. Discontinue pravastatin sodium tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases may resolve if pravastatin sodium tablets is discontinued. Temporarily discontinue pravastatin sodium tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the pravastatin sodium tablets dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. 5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue pravastatin sodium tablets if IMNM is suspected. 5.3 Hepatic Dysfunction Increases in serum transaminases have been reported with use of pravastatin sodium tablets [see Adverse Reactions ( 6.1 ) ] . In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 1% of patients receiving either pravastatin sodium tablets or placebo in clinical studies. Marked persistent increases of hepatic transaminases have also occurred with pravastatin sodium tablets. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pravastatin sodium tablets. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Consider liver enzyme testing before pravastatin sodium tablets initiation and when clinically indicated thereafter. Pravastatin sodium tablets are contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications ( 4 )] . If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue pravastatin sodium tablets. 5.4 Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including pravastatin sodium tablets. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.1 )] Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions ( 5.2 )] Hepatic Dysfunction [see Warnings and Precautions ( 5.3 )] Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.4)] In short-term clinical trials, the most commonly reported adverse reactions (≥2% and greater than placebo) were: musculoskeletal pain, nausea/vomiting, upper respiratory infection, diarrhea, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In pravastatin sodium tablets placebo-controlled clinical trials, 1313 patients (age range 20 to 76 years, 32% women, 93.5% White, 5% Black, 0.9% Hispanic, 0.4% Asian, 0.2% Other) with a median treatment duration of 14 weeks, 3.3% of patients on pravastatin sodium tablets and 1.2% patients on placebo discontinued due to adverse reactions (regardless of causality). The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: hepatic transaminase elevations, nausea, anxiety/depression, and dizziness. Adverse reactions (regardless of causality) reported in ≥2% of pravastatin sodium tablets-treated patients in placebo-controlled trials of up to 8 months duration are identified in Table 1: Table 1: Adverse Reactions in ≥ 2% of Patients Treated with Pravastatin (Any Dose) and at an Incidence Greater Than Placebo in Short-Term Placebo-Controlled Trials % Placebo N=411 % Any Dose N=902 Nausea/Vomiting 7.1 7.4 Diarrhea 5.6 6.7 Headache 4.6 6.3 Upper Respiratory Infection 5.8 5.9 Angina Pectoris 3.4 4.5 Rash 1.4 4.5 CPK Increased 3.6 4.1 Dizziness 3.4 3.5 ALT Increased 1.2 2.9 Chest Pain 1.9 2.7 Cough 1.7 2.5 Myalgia 1.2 2.3 Influenza 0.7 2.0 g-GT Increased 1.2 2.0 Adverse Reactions (regardless of causality) The safety and tolerability of pravastatin sodium tablets at a dose of 80 mg in 2 controlled trials with a mean exposure of 8.6 months was similar to that of pravastatin sodium tablets at lower doses except that 4 out of 464 patients taking 80 mg of pravastatin had a single elevation of CK >10 times ULN compared to 0 out of 115 patients taking 40 mg of pravastatin. In pravastatin sodium tablets placebo-controlled clinical trials, 21,483 patients (age range 24 to 75 years, 10.3% women, 52.3% White, 0.8% Black, 0.5% Hispanic, 0.1% Asian, 0.1% Other, 46.1% not recorded) had a median treatment duration of 261 weeks. Adverse reactions (regardless of causality) were pooled from 7 double-blind, placebo-controlled trials (West of Scotland Coronary Prevention Study [WOS]; Cholesterol and Recurrent Events study [CARE]; Long-term Intervention with Pravastatin in Ischemic Disease study [LIPID] ; Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids and Atherosclerosis in the Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated with pravastatin 40 mg and 10,719 patients treated with placebo. Patients were exposed to pravastatin for a mean of 4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9 years in PLAC I, PLAC II, KAPS, and REGRESS. Adverse reactions (regardless of causality) occurring in ≥5% of patients treated with pravastatin sodium tablets in these studies are identified in Table 2: Table 2: Adverse Events in ≥ 5% of Patients Treated with Pravastatin 40 mg and at an Incidence Greater Than Placebo in Long-Term Placebo-Controlled Trials Placebo (N=10,719) % of patients Pravastatin Sodium Tablets (N=10,764) % of patients Musculoskeletal Pain 24.4 24.9 Upper Respiratory Tract Infection 20.2 21.2 Musculoskeletal Traumatism 9.6 10.2 Chest Pain 9.8 10.0 Influenza 9.0 9.2 Fatigue 7.8 8.4 Cough 7.4 8.2 Dizziness 6.6 7.3 Rash (including dermatitis) 7.1 7.2 Sinus Abnormality 6.7 7.0 Muscle Cramp 4.6 5.1 Adverse Reactions (regardless of causality) No new adverse reactions were identified in a study of pediatric patients with HeFH. Laboratory Abnormalities Increases in ALT, AST values and CK have been observed. Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been reported with statins. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of pravastatin sodium tablets. 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. Musculoskeletal: myopathy, rhabdomyolysis, tendon disorder, polymyositis, immune-mediated necrotizing myopathy associated with statin use. Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), peripheral nerve palsy. Rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal necrolysis, erythema multiforme (including Stevens-Johnson syndrome). Gastrointestinal: abdominal pain, constipation, pancreatitis, hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, fatal and non-fatal hepatic failure. Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails), lichen planus. Renal: urinary abnormality (including dysuria, frequency, nocturia). Respiratory: dyspnea, interstitial lung disease. Psychiatric: nightmare. Reproductive: gynecomastia. Laboratory Abnormalities: liver function test abnormalities, thyroid function abnormalities.

<table frame="box" rules="all"><tbody><tr><td> </td><td><content styleCode="bold">% Placebo </content><content styleCode="bold">N=411</content><content styleCode="bold"/></td><td><content styleCode="bold">% Any Dose</content><content styleCode="bold">N=902</content><content styleCode="bold"/></td></tr><tr><td> Nausea/Vomiting </td><td> 7.1 </td><td> 7.4 </td></tr><tr><td> Diarrhea </td><td> 5.6 </td><td> 6.7 </td></tr><tr><td> Headache </td><td> 4.6 </td><td> 6.3 </td></tr><tr><td> Upper Respiratory Infection </td><td> 5.8 </td><td> 5.9 </td></tr><tr><td> Angina Pectoris </td><td> 3.4 </td><td> 4.5 </td></tr><tr><td> Rash </td><td> 1.4 </td><td> 4.5 </td></tr><tr><td> CPK Increased </td><td> 3.6 </td><td> 4.1 </td></tr><tr><td> Dizziness </td><td> 3.4 </td><td> 3.5 </td></tr><tr><td> ALT Increased </td><td> 1.2 </td><td> 2.9 </td></tr><tr><td> Chest Pain </td><td> 1.9 </td><td> 2.7 </td></tr><tr><td> Cough </td><td> 1.7 </td><td> 2.5 </td></tr><tr><td> Myalgia </td><td> 1.2 </td><td> 2.3 </td></tr><tr><td> Influenza </td><td> 0.7 </td><td> 2.0 </td></tr><tr><td> g-GT Increased </td><td> 1.2 </td><td> 2.0 </td></tr></tbody></table>

<table frame="box" rules="all"><tbody><tr><td><content styleCode="bold"> </content></td><td><content styleCode="bold">Placebo </content><content styleCode="bold">(N=10,719)</content><content styleCode="bold">% of patients</content></td><td><content styleCode="bold">Pravastatin Sodium Tablets </content><content styleCode="bold">(N=10,764)</content><content styleCode="bold">% of patients</content></td></tr><tr><td> Musculoskeletal Pain </td><td> 24.4 </td><td> 24.9 </td></tr><tr><td> Upper Respiratory Tract Infection </td><td> 20.2 </td><td> 21.2 </td></tr><tr><td> Musculoskeletal Traumatism </td><td> 9.6 </td><td> 10.2 </td></tr><tr><td> Chest Pain </td><td> 9.8 </td><td> 10.0 </td></tr><tr><td> Influenza </td><td> 9.0 </td><td> 9.2 </td></tr><tr><td> Fatigue </td><td> 7.8 </td><td> 8.4 </td></tr><tr><td> Cough </td><td> 7.4 </td><td> 8.2 </td></tr><tr><td> Dizziness </td><td> 6.6 </td><td> 7.3 </td></tr><tr><td> Rash (including dermatitis) </td><td> 7.1 </td><td> 7.2 </td></tr><tr><td> Sinus Abnormality </td><td> 6.7 </td><td> 7.0 </td></tr><tr><td> Muscle Cramp </td><td> 4.6 </td><td> 5.1 </td></tr></tbody></table>