pravastatin

Pravastatin sodium tablets are indicated: To reduce the risk of myocardial infarction, myocardial revascularization procedures, and cardiovascular mortality in adults with elevated low-density lipoprotein cholesterol (LDL-C) without clinically evident coronary heart disease (CHD). To reduce the risk of coronary death, myocardial infarction, myocardial revascularization procedures, stroke or transient ischemic attack, and slow the progression of coronary atherosclerosis in adults with clinically evident CHD. As an adjunct to diet to reduce LDL-C in adults with primary hyperlipidemia. As an adjunct to diet to reduce LDL-C in pediatric patients ages 8 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia. Pravastatin sodium tablets are an HMG-CoA reductase inhibitor (statin) indicated : To reduce the risk of myocardial infarction, myocardial revascularization procedures, and cardiovascular mortality in adults with elevated low-density lipoprotein cholesterol (LDL-C) without clinically evident coronary heart disease (CHD). To reduce the risk of coronary death, myocardial infarction, myocardial revascularization procedures, stroke or transient ischemic attack, and slow the progression of coronary atherosclerosis in adults with clinically evident CHD. As an adjunct to diet to reduce LDL-C in adults with primary hyperlipidemia. As an adjunct to diet to reduce LDL-C in pediatric patients ages 8 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia.

Take orally once daily at any time of the day, with or without food . For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving pravastatin sodium tablets 80 mg daily, prescribe alternative LDL-C-lowering treatment . Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating pravastatin sodium tablets, and adjust the dosage if necessary . Adults: recommended starting dosage is pravastatin sodium tablets 40 mg to 80 mg once daily. Pediatric Patients : aged 8 to 13 years, the recommended dosage is 20 mg once daily. aged 14 to 18 years, the recommended starting dosage is 40 mg once daily. Severe renal impairment: recommended starting dosage is pravastatin sodium 10 mg once daily. Use another pravastatin sodium product to initiate dosing. Recommended maximum pravastatin sodium tablets dosage is 40 mg once daily. See full prescribing information for dosage modifications due to drug interactions . 2.1 Important Dosage and Administration Information Take pravastatin sodium tablets orally once daily as a single dose at any time of the day, with or without food. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving pravastatin sodium tablets 80 mg daily, prescribe alternative LDL-C-lowering treatment. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating pravastatin sodium tablets, and adjust the dosage if necessary. 2.2 Recommended Dosage in Adult Patients The recommended starting dosage is pravastatin sodium tablets 40 mg to 80 mg once daily. 2.3 Recommended Dosage in Pediatric Patients 8 Years of Age and Older with HeFH In pediatric patients aged 8 to 13 years, the recommended dosage is pravastatin sodium tablets 20 mg once daily. In pediatric patients aged 14 to 18 years, the recommended starting dosage is pravastatin sodium tablets 40 mg once daily. 2.4 Recommended Dosage in Patients with Renal Impairment In patients with severe renal impairment, the recommended starting dosage is pravastatin sodium 10 mg once daily. The maximum recommended dosage of pravastatin sodium tablets in patients with severe renal impairment is 40 mg once daily [see Clinical Pharmacology ]. The recommended dosage of pravastatin sodium tablets for patients with mild or moderate renal impairment is the same as patients with normal renal function. 2.5 Dosage and Administration Modifications Due to Drug Interactions In patients taking a bile acid sequestrant, administer pravastatin sodium tablets at least 1 hour before or 4 hours after the bile acid sequestrant [see Drug Interactions ]. Concomitant use of pravastatin sodium tablets with the following drugs requires dosage modifications of pravastatin sodium tablet s [see Warnings and Precautions and Drug Interactions ]: Cyclosporine In patients taking cyclosporine, the recommended starting dosage is pravastatin sodium 10 mg once daily. The maximum recommended dosage of pravastatin sodium tablets in patients taking cyclosporine is 20 mg once daily. Clarithromycin and Erythromycin The maximum recommended dosage is pravastatin sodium tablets 40 mg once daily .

12.1 Mechanism of Action Pravastatin is a reversible inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol.

The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis [see Warnings and Precautions ] Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions ] Hepatic Dysfunction [see Warnings and Precautions ] Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions ] 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. 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 placebo-controlled clinical trials, 1,313 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 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-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

Diarrhea 5.6

Headache 4.6

Upper Respiratory Infection 5.8

Angina Pectoris 3.4

Rash 1.4

CPK Increased 3.6

Dizziness 3.4

ALT Increased 1.2

Chest Pain 1.9

Cough 1.7

Myalgia 1.2

Influenza 0.7 2.0 g-GT Increased 1.2

2.0 Adverse Reactions (regardless of causality) The safety and tolerability of pravastatin at a dose of 80 mg in 2 controlled trials with a mean exposure of 8.6 months was similar to that of pravastatin 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 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 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 in these studies are identified in Table 2: Table 2: Adverse Reaction s 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 (N=10,764) % of patients Musculoskeletal Pain 24.4

Upper Respiratory Tract Infection 20.2

Musculoskeletal Traumatism 9.6

Chest Pain 9.8

Influenza 9.0

Fatigue 7.8

Cough 7.4

Dizziness 6.6

Rash (including dermatitis) 7.1

Sinus Abnormality 6.7

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. 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). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. 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.

See full prescribing information for details regarding concomitant use of pravastatin sodium tablets with other drugs that increase the risk of myopathy and rhabdomyolysis. Bile Acid Sequestrants: in patients taking a bile acid sequestrant, administer pravastatin sodium tablets at least 1 hour before or at least 4 hours after the bile acid sequestrant 7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Pravastatin Pravastatin is a substrate of the transport protein OATP1B1. Pravastatin plasma levels can be significantly increased with concomitant administration of inhibitors of OATP1B1. Table 3 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with pravastatin and instructions for preventing or managing them [see Warnings and Precautions and Clinical Pharmacology ] . Table 3: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Pravastatin Gemfibrozil Clinical Impact: There is an increased risk of myopathy/rhabdomyolysis when pravastatin is administered with gemfibrozil Intervention: Avoid concomitant use of gemfibrozil with pravastatin . Cyclosporine Clinical Impact: The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine with pravastatin. Intervention: Initiate with a dosage of pravastatin sodium 10 mg once daily. Do not exceed pravastatin 20 mg once daily [see Dosage and Administration ]. Select Macrolide Antibiotics Clinical Impact: The risk of myopathy and rhabdomyolysis is increased by concomitant use of clarithromycin or erythromycin with pravastatin. Other macrolides (e.g., azithromycin) have the potential to increase pravastatin exposures and increase the risk of myopathy and rhabdomyolysis when used concomintantly. Intervention: For patients taking erythromycin or clarithromycin, do not exceed 40 mg pravastatin once daily [see Dosage and Administration ]. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of niacin with pravastatin. Intervention: Consider if the benefit of using niacin concomitantly with pravastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with pravastatin. Intervention: Consider if the benefit of using fibrates concomitantly with pravastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with pravastatin. Intervention: Consider if the benefit of using colchicine concomitantly with pravastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. 7.2 Drug Interactions that Decrease the Efficacy of Pravastatin Table 4 presents drug interactions that may decrease the efficacy of pravastatin and instructions for preventing or managing them. Table 4: Drug Interactions that Decrease the Efficacy of Pravastatin Bile Acid Sequestrants Clinical Impact: Concomitant cholestyramine or colestipol administration decreased the mean exposure of pravastatin approximately 51% and 47%, respectively [see Clinical Pharmacology ] . Intervention: In patients taking a bile acid sequestrant, administer pravastatin at least 1 hour before or at least 4 hours after the bile acid sequestrant [see Dosage and Administration ].

Pregnancy: May cause fetal harm Lactation: Breastfeeding not recommended during treatment with pravastatin sodium tablets

Pregnancy Risk Summary Discontinue pravastatin when pregnancy is recognized.

Alternatively, consider the ongoing therapeutic needs of the individual patient. Pravastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, pravastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology ]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with pravastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data) . In animal reproduction studies, no evidence of fetal malformations was seen in pregnant rats or rabbits orally administered pravastatin during the period of organogenesis at doses that resulted in 10 times and 120 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg/day, based on body surface area (mg/m 2 ). An imbalance in some fetal skeletal variations, increased offspring mortality, and developmental delays occurred when pregnant rats were exposed to 10 times to 12 times the MRHD during organogenesis to parturition (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data A Medicaid cohort linkage study of 1,152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential cofounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for cofounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Embryofetal and neonatal mortality was observed in rats given pravastatin during the period of organogenesis or during organogenesis continuing through weaning. In pregnant rats given oral gavage doses of 4 mg/kg/day, 20 mg/kg/day, 100 mg/kg/day, 500 mg/kg/day, and 1,000 mg/kg/day from gestation days 7 through 17 (organogenesis) increased mortality of offspring and increased cervical rib skeletal anomalies were observed at ≥100 mg/kg/day systemic exposure, 10 times the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2 ). In other studies, no teratogenic effects were observed when pravastatin was dosed orally during organogenesis in rabbits (gestation days 6 through 18) up to 50 mg/kg/day or in rats (gestation days 7 through 17) up to 1,000 mg/kg/day. Exposures were 10 times (rabbit) or 120 times (rat) the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2 ). In pregnant rats given oral gavage doses of 10 mg/kg/day, 100 mg/kg/day, and 1,000 mg/kg/day from gestation day 17 through lactation day 21 (weaning), developmental delays were observed at ≥100 mg/kg/day systemic exposure, corresponding to 12 times the human exposure at 80 mg/day MRHD, based on body surface area (mg/m 2 ). In pregnant rats, pravastatin crosses the placenta and is found in fetal tissue at 30% of the maternal plasma levels following administration of a single dose of 20 mg/day orally on gestation day 18, which corresponds to exposure 2 times the MRHD of 80 mg daily based on body surface area (mg/m 2 ). 8.2 Lactation Risk Summary Based on one lactation study in published literature, pravastatin is present in human milk. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Statins, including pravastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with pravastatin [see Use in Specific Populations , Clinical Pharmacology ] . 8.4 Pediatric Use The safety and effectiveness of pravastatin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 8 years of age and older with HeFH. Use of pravastatin for this indication is based on a double-blind, placebo-controlled clinical study in 214 pediatric patients (100 males and 114 females) 8 years of age and older with HeFH. Doses greater than 40 mg daily have not been studied in this population. The safety and effectiveness of pravastatin have not been established in pediatric patients younger than 10 years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH). 8.5 Geriatric Use In clinical studies, 4,797 (36.4%) pravastatin-treated patients were aged 65 and older and 110 (0.8%) were aged 75 and older. No significant differences in efficacy or safety were observed between geriatric patients and younger patients. Mean pravastatin AUCs are 25% to 50% higher in elderly subjects than in healthy young subjects, but mean maximum plasma concentration (C max ), time to maximum plasma concentration (T max ), and half-life (t ½ ) values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly [see Clinical Pharmacology ]. Advanced age (≥65 years) is a risk factor for pravastatin-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving pravastatin for the increased risk of myopathy [see Warnings and Precautions ]. 8.6 Renal Impairment Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. In patients with severe renal impairment, the recommended starting dose is pravastatin sodium 10 mg once daily. The maximum recommended dosage in patients with severe renal impairment is pravastatin 40 mg once daily. The recommended dosage for patients with mild or moderate renal impairment is the same as patients with normal renal function [see Dosage and Administration , Warnings and Precautions , Clinical Pharmacology ]. 8.7 Hepatic Impairment Pravastatin shows a large inter-subject variability in pharmacokinetics in patients with liver cirrhosis [Clinical Pharmacology ]. Pravastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications , Warnings and Precautions ].