1 INDICATIONS AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia.

Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.

Pravastatin sodium is an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to: Reduce the risk of MI, revascularization, and cardiovascular mortality in hypercholesterolemic patients without clinically evident CHD.

( 1.1 ) Reduce the risk of total mortality by reducing coronary death, MI, revascularization, stroke/TIA, and the progression of coronary atherosclerosis in patients with clinically evident CHD.

( 1.1 ) Reduce elevated Total-C, LDL-C, ApoB, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia.

( 1.2 ) Reduce elevated serum TG levels in patients with hypertriglyceridemia.

( 1.2 ) Treat patients with primary dysbetalipoproteinemia who are not responding to diet.

( 1.2 ) Treat children and adolescent patients ages 8 years and older with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy.

( 1.2 ) Limitations of use: Pravastatin sodium has not been studied in Fredrickson Types I and V dyslipidemias.

( 1.3 ) 1.1 Prevention of Cardiovascular Disease In hypercholesterolemic patients without clinically evident coronary heart disease (CHD), pravastatin sodium tablets are indicated to: reduce the risk of myocardial infarction (MI).

reduce the risk of undergoing myocardial revascularization procedures.

reduce the risk of cardiovascular mortality with no increase in death from non-cardiovascular causes.

In patients with clinically evident CHD, pravastatin sodium is indicated to: reduce the risk of total mortality by reducing coronary death.

reduce the risk of MI.

reduce the risk of undergoing myocardial revascularization procedures.

reduce the risk of stroke and stroke/transient ischemic attack (TIA).

slow the progression of coronary atherosclerosis.

1.2 Hyperlipidemia Pravastatin sodium tablets are indicated: as an adjunct to diet to reduce elevated total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and triglyceride (TG) levels and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia and mixed dyslipidemia ( Fredrickson Types IIa and IIb).

1 as an adjunct to diet for the treatment of patients with elevated serum TG levels ( Fredrickson Type IV).

for the treatment of patients with primary dysbetalipoproteinemia ( Fredrickson Type III) who do not respond adequately to diet.

as an adjunct to diet and lifestyle modification for treatment of heterozygous familial hypercholesterolemia (HeFH) in children and adolescent patients ages 8 years and older if after an adequate trial of diet the following findings are present: a.

LDL-C remains ≥190 mg/dL or b.

LDL-C remains ≥160 mg/dL and: • there is a positive family history of premature cardiovascular disease (CVD) or • two or more other CVD risk factors are present in the patient.

1.3 Limitations of Use Pravastatin sodium has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons ( Fredrickson Types I and V).

6 ADVERSE REACTIONS Pravastatin is generally well tolerated; adverse reactions have usually been mild and transient.

In 4-month-long placebo-controlled trials, 1.7% of pravastatin-treated patients and 1.2% of placebo-treated patients were discontinued from treatment because of adverse experiences attributed to study drug therapy; this difference was not statistically significant.

In short-term clinical trials, the most commonly reported adverse reactions (≥2% and > placebo) regardless of causality 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 Adverse Clinical Events Short-Term Controlled Trials In the pravastatin sodium placebo-controlled clinical trials database of 1313 patients (age range 20 to 76 years, 32.4% women, 93.5% Caucasians, 5% Blacks, 0.9% Hispanics, 0.4% Asians, 0.2% Others) with a median treatment duration of 14 weeks, 3.3% of patients on pravastatin sodium and 1.2% patients on placebo discontinued due to adverse events regardless of causality.

The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: liver function test increased, nausea, anxiety/depression, and dizziness.

All adverse clinical events (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 Events in ≥ 2% of Patients Treated with Pravastatin 5 to 40 mg and at an Incidence Greater Than Placebo in Short-Term Placebo-Controlled Trials (% of patients) Body System/Event 5 mg N=10 0 10 mg N=153 20 mg N=478 40 mg N=171 Any Dose N=902 Placebo N=411 Cardiovascular Angina Pectoris 5.0 4.6 4.8 3.5 4.5 3.4 Dermatologic Rash 3.0 2.6 6.7 1.2 4.5 1.4 Gastrointestinal Nausea/Vomiting 4.0 5.9 10.5 2.3 7.4 7.1 Diarrhea 8.0 8.5 6.5 4.7 6.7 5.6 Flatulence 2.0 3.3 4.6 0.0 3.2 4.4 Dyspepsia/Heartburn 0.0 3.3 3.6 0.6 2.5 2.7 Abdominal Distension 2.0 3.3 2.1 0.6 2.0 2.4 General Fatigue 4.0 1.3 5.2 0.0 3.4 3.9 Chest Pain 4.0 1.3 3.3 1.2 2.7 1.9 Influenza 4.0 2.6 1.9 0.6 2.0 0.7 Musculoskeletal Musculoskeletal Pain 13.0 3.9 13.2 5.3 10.1 10.2 Myalgia 1.0 2.6 2.9 1.2 2.3 1.2 Nervous System Headache 5.0 6.5 7.5 3.5 6.3 4.6 Dizziness 4.0 1.3 5.2 0.6 3.5 3.4 Respiratory Pharyngitis 2.0 4.6 1.5 1.2 2.0 2.7 Upper Respiratory Infection 6.0 9.8 5.2 4.1 5.9 5.8 Rhinitis 7.0 5.2 3.8 1.2 3.9 4.9 Cough 4.0 1.3 3.1 1.2 2.5 1.7 Investigation ALT Increased 2.0 2.0 4.0 1.2 2.9 1.2 g-GT Increased 3.0 2.6 2.1 0.6 2.0 1.2 CPK Increased 5.0 1.3 5.2 2.9 4.1 3.6 The safety and tolerability of pravastatin sodium 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 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.

Long-Term Controlled Morbidity and Mortality Trials In the pravastatin sodium placebo-controlled clinical trials database of 21,483 patients (age range 24 to 75 years, 10.3% women, 52.3% Caucasians, 0.8% Blacks, 0.5% Hispanics, 0.1% Asians, 0.1% Others, 46.1% Not Recorded) with a median treatment duration of 261 weeks, 8.1% of patients on pravastatin sodium and 9.3% patients on placebo discontinued due to adverse events regardless of causality.

Adverse event data 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.

The safety and tolerability profile in the pravastatin group was comparable to that of the placebo group.

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.

In these long-term trials, the most common reasons for discontinuation were mild, non-specific gastrointestinal complaints.

Collectively, these 7 trials represent 47,613 patient-years of exposure to pravastatin.

All clinical adverse events (regardless of causality) occurring in ≥2% of patients treated with pravastatin in these studies are identified in Table 2.

Table 2: Adverse Events in ≥2% of Patients Treated with Pravastatin 40 mg and at an Incidence Greater Than Placebo in Long-Term Placebo-Controlled Trials Body System/Event Pravastatin (N = 10,764) % of patients Placebo (N = 10,719) % of patients Dermatologic Rash (including dermatitis) 7.2 7.1 General Edema 3.0 2.7 Fatigue 8.4 7.8 Chest Pain 10.0 9.8 Fever 2.1 1.9 Weight Gain 3.8 3.3 Weight Loss 3.3 2.8 Musculoskeletal Musculoskeletal Pain 24.9 24.4 Muscle Cramp 5.1 4.6 Musculoskeletal Traumatism 10.2 9.6 Nervous System Dizziness 7.3 6.6 Sleep Disturbance 3.0 2.4 Anxiety/Nervousness 4.8 4.7 Paresthesia 3.2 3.0 Renal/Genitourinary Urinary Tract Infection 2.7 2.6 Respiratory Upper Respiratory Tract Infection 21.2 20.2 Cough 8.2 7.4 Influenza 9.2 9.0 Pulmonary Infection 3.8 3.5 Sinus Abnormality 7.0 6.7 Tracheobronchitis 3.4 3.1 Special Senses Vision Disturbance (includes blurred vision, diplopia) 3.4 3.3 Infections Viral Infection 3.2 2.9 In addition to the events listed above in the long-term trials table, events of probable, possible, or uncertain relationship to study drug that occurred in <2.0% of pravastatin-treated patients in the long-term trials included the following: Dermatologic: scalp hair abnormality (including alopecia), urticaria.

Endocrine/Metabolic: sexual dysfunction, libido change.

General: flushing.

Immunologic: allergy, edema head/neck.

Musculoskeletal: muscle weakness.

Nervous System: vertigo, insomnia, memory impairment, neuropathy (including peripheral neuropathy).

Special Senses: taste disturbance.

6.2 Postmarketing Experience In addition to the events reported above, as with other drugs in this class, the following events have been reported during postmarketing experience with pravastatin sodium, regardless of causality assessment: Musculoskeletal: myopathy, rhabdomyolysis, tendon disorder, polymyositis.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions ( 5.2 )].

Nervous System : dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), peripheral nerve palsy.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use.

These cognitive issues have been reported for all statins.

The reports are 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).

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.

6.3 Laboratory Test Abnormalities Increases in ALT, AST values and CPK have been observed [see Warnings and Precautions (5.1, 5.3 ) ].

Transient, asymptomatic eosinophilia has been reported.

Eosinophil counts usually returned to normal despite continued therapy.

Anemia, thrombocytopenia, and leukopenia have been reported with statins.

6.4 Pediatric Patients In a 2-year, double-blind, placebo-controlled study involving 100 boys and 114 girls with HeFH (n=214; age range 8 to 18.5 years, 53% female, 95% Caucasians, <1% Blacks, 3% Asians, 1% Other), the safety and tolerability profile of pravastatin was generally similar to that of placebo [see Warnings and Precautions (5.4) , Use in Specific Populations (8.4) , and Clinical Pharmacology (12.3) ].