PRAVASTATIN SODIUM

Pravastatin sodium is one of a class of lipid-lowering compounds, the HMG-CoA reductase inhibitors, which reduce cholesterol biosynthesis. These agents are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate. Pravastatin sodium is designated chemically as Sodium (3R,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-[[(2S)-methylbutanoyl]oxy]-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]heptanoate. Structural formula: Pravastatin sodium is an odorless, white to off-white, fine or crystalline powder. It is a relatively polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59 at a pH of 7.0. It is soluble in methanol and water (>300 mg/mL), slightly soluble in isopropanol, and practically insoluble in acetone, acetonitrile, chloroform, and ether. Each tablet, for oral administration contains 10 mg, 20 mg, 40 mg or 80 mg of pravastatin sodium. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose. The 10 mg tablet also contains red ferric oxide, the 20 mg tablet also contains yellow ferric oxide, and the 40 mg tablet also contains a blend of yellow ferric oxide and FD&C blue #1, and the 80 mg tablet also contains yellow ferric oxide. Chemical Structure-Pravastatin

Therapy with Pravastatin Sodium Tablets, USP should be considered in those individuals at increased risk for atherosclerosis-related clinical events as a function of cholesterol level, the presence or absence of coronary heart disease, and other risk factors. Primary Prevention of Coronary Events In hypercholesterolemic patients without clinically evident coronary heart disease, Pravastatin Sodium Tablets, USP are indicated to: Reduce the risk of myocardial infarction Reduce the risk of undergoing myocardial revascularization procedures Reduce the risk of cardiovascular mortality with no increase in death from non-cardiovascular causes. Hyperlipidemia Pravastatin Sodium Tablets, USP are indicated as an adjunct to diet to reduce elevated Total-C, LDL-C, ApoB, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and IIb). 8 Pravastatin Sodium Tablets, USP are indicated as adjunctive therapy to diet for the treatment of patients with elevated serum triglyceride levels (Fredrickson Type IV). Pravastatin Sodium Tablets, USP are indicated for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet. Pravastatin Sodium Tablets, USP are indicated as an adjunct to diet and lifestyle modification for treatment of HeFH in children and adolescent patients ages 8 years and older if after an adequate trial of diet the following findings are present: LDL-C remains ≥190 mg/dL or LDL-C remains ≥160 mg/dL and: there is a positive family history of premature cardiovascular disease or two or more other CVD risk factors are present in the patient. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when the response to diet and other nonpharmacological measures alone has been inadequate (see NCEP Guidelines below). Prior to initiating therapy with pravastatin, secondary causes for hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure Total-C, HDL-C, and TG. For patients with triglycerides (TG) <400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the following equation: LDL-C = Total-C - HDL-C - 1 / 5 TG For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. In many hypertriglyceridemic patients, LDL-C may be low or normal despite elevated Total-C. In such cases, HMG-CoA reductase inhibitors are not indicated. Lipid determinations should be performed at intervals of no less than four weeks and dosage adjusted according to the patient's response to therapy. The National Cholesterol Education Program's Treatment Guidelines are summarized below: Table 5: NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes and Drug Therapy in Different Risk Categories Risk Category LDL Goal (mg/dL) LDL Level at Which to Initiate Therapeutic Lifestyle Changes (mg/dL) LDL Level at Which to Consider Drug Therapy (mg/dL) a CHD, coronary heart disease. b Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of <100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgement also may call for deferring drug therapy in this subcategory. c Almost all people with 0-1 risk factor have 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 risk factor is not necessary. CHD a or CHD risk equivalents (10-year risk >20%) <100 ≥100 ≥130 (100-129: drug optional) b 2+ Risk factors (10-year risk ≤20 %) <130 ≥130 10-year risk 10%-20%: ≥130 10-year risk <10%: ≥160 0-1 Risk factor c <160 ≥160 ≥190 (160-189: LDL-lowering drug optional) After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL-C (Total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category. At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge if the LDL-C is ≥130 mg/dL (see NCEP Guidelines, above). Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the Total-C be used to monitor therapy. As with other lipid-lowering therapy, pravastatin sodium tablets are not indicated when hypercholesterolemia is due to hyperalphalipoproteinemia (elevated HDL-C). The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature cardiovascular disease is summarized below: Category Total-C (mg/dL) LDL-C (mg/dL) Acceptable <170 <110 Borderline 170-199 110-129 High ≥200 ≥130

The patient should be placed on a standard cholesterol-lowering diet before receiving pravastatin sodium tablets and should continue on this diet during treatment with pravastatin sodium tablets (see NCEP Treatment Guidelines for details on dietary therapy). Pravastatin sodium tablets can be administered orally as a single dose at any time of the day, with or without food. Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient's response to therapy and established treatment guidelines. Adult Patients The recommended starting dose is 40 mg once daily. If a daily dose of 40 mg does not achieve desired cholesterol levels, 80 mg once daily is recommended. In patients with a history of significant renal or hepatic dysfunction, a starting dose of 10 mg daily is recommended. Pediatric Patients Children (Ages 8 to 13 Years, Inclusive) The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses greater than 20 mg have not been studied in this patient population. Adolescents (Ages 14 to 18 Years) The recommended starting dose is 40 mg once daily in adolescents 14 to 18 years of age. Doses greater than 40 mg have not been studied in this patient population. Children and adolescents treated with pravastatin should be re-evaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C (see INDICATIONS AND USAGE: Hyperlipidemia, NCEP Treatment Guidelines ). In patients taking immunosuppressive drugs such as cyclosporine (see WARNINGS: Skeletal Muscle ) concomitantly with pravastatin, therapy should begin with 10 mg of pravastatin once-a-day at bedtime and titration to higher doses should be done with caution. Most patients treated with this combination received a maximum pravastatin dose of 20 mg/day. Concomitant Therapy The lipid-lowering effects of pravastatin sodium on total and LDL cholesterol are enhanced when combined with a bile-acid-binding resin. When administering a bile-acid-binding resin (e.g., cholestyramine, colestipol) and pravastatin, pravastatin sodium tablets should be given either 1 hour or more before or at least 4 hours following the resin. (See also ADVERSE REACTIONS: Concomitant Therapy .)

Hypersensitivity to any component of this medication. Active liver disease or unexplained, persistent elevations of serum transaminases (see WARNINGS ). Pregnancy and Lactation. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they are contraindicated during pregnancy and in nursing mothers. Pravastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this class of drug, therapy should be discontinued immediately and the patient apprised of the potential hazard to the fetus (see PRECAUTIONS: Pregnancy ).

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. (See also PRECAUTIONS: Geriatric Use .) Adverse Clinical Events Short-Term Controlled Trials All adverse clinical events (regardless of attribution) reported in more than 2% of pravastatin-treated patients in placebo-controlled trials of up to four months duration are identified in Table 6; also shown are the percentages of patients in whom these medical events were believed to be related or possibly related to the drug: Table 6: Adverse Events in >2 Percent of Patients Treated with Pravastatin 10-40 mg in Short-Term Placebo-Controlled Trials All Events Events Attributed to Study Drug Body System/Event Pravastatin (N=900) % of patients Placebo (N=411) % of patients Pravastatin (N=900) % of patients Placebo (N=411) % of patients *Statistically significantly different from placebo. Cardiovascular Cardiac Chest Pain 4.0 3.4 0.1 0.0 Dermatologic Rash 4.0* 1.1 1.3 0.9 Gastrointestinal Nausea/Vomiting Diarrhea Abdominal Pain Constipation Flatulence Heartburn 7.3 6.2 5.4 4.0 3.3 2.9 7.1 5.6 6.9 7.1 3.6 1.9 2.9 2.0 2.0 2.4 2.7 2.0 3.4 1.9 3.9 5.1 3.4 0.7 General Fatigue Chest Pain Influenza 3.8 3.7 2.4* 3.4 1.9 0.7 1.9 0.3 0.0 1.0 0.2 0.0 Musculoskeletal Localized Pain Myalgia 10.0 2.7 9.0 1.0 1.4 0.6 1.5 0.0 Nervous System Headache Dizziness 6.2 3.3 3.9 3.2 1.7* 1.0 0.2 0.5 Renal/Genitourinary Urinary Abnormality 2.4 2.9 0.7 1.2 Respiratory Common Cold Rhinitis Cough 7.0 4.0 2.6 6.3 4.1 1.7 0.0 0.1 0.1 0.0 0.0 0.0 The safety and tolerability of pravastatin at a dose of 80 mg in two 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 >10X ULN compared to 0 out of 115 patients taking 40 mg of pravastatin. Long-Term Controlled Morbidity and Mortality Trials Adverse event data were pooled from seven double-blind, placebo-controlled trials (West of Scotland Coronary Prevention Study [WOS]; 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 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 seven trials represent 47,613 patient-years of exposure to pravastatin. Events believed to be of probable, possible, or uncertain relationship to study drug, occurring in at least 1% of patients treated with pravastatin in these studies are identified in Table 7. Table 7: Adverse Events in ≥1 Percent of Patients Treated with Pravastatin 40 mg in Long-Term Placebo-Controlled Trials Body System/Event Pravastatin (N=10,764) % of patients Placebo (N=10,719) % of patients Cardiovascular Angina Pectoris 3.1 3.4 Dermatologic Rash 2.1 2.2 Gastrointestinal Dyspepsia/Heartburn Abdominal Pain Nausea/Vomiting Flatulence Constipation 3.5 2.4 1.6 1.2 1.2 3.7 2.5 1.6 1.1 1.3 General Fatigue Chest Pain 3.4 2.6 3.3 2.6 Musculoskeletal Musculoskeletal Pain (includes arthralgia) Muscle Cramp Myalgia 6.0 2.0 1.4 5.8 1.8 1.4 Nervous System Dizziness Headache Sleep Disturbance Depression Anxiety/Nervousness 2.2 1.9 1.0 1.0 1.0 2.1 1.8 0.9 1.0 1.2 Renal/Genitourinary Urinary Abnormality (includes dysuria, frequency, nocturia) 1.0 0.8 Respiratory Dyspnea Upper Respiratory Infection Cough 1.6 1.3 1.0 1.6 1.3 1.0 Special Senses Vision Disturbance (includes blurred vision, diplopia) 1.6 1.3 Events of probable, possible, or uncertain relationship to study drug that occurred in <1.0% of pravastatin-treated patients in the long-term trials included the following; frequencies were similar in placebo-treated patients: Dermatologic: pruritus, dermatitis, dryness skin, scalp hair abnormality (including alopecia), urticaria. Endocrine/Metabolic: sexual dysfunction, libido change. Gastrointestinal: decreased appetite. General: fever, flushing. Immunologic: allergy, edema head/neck. Musculoskeletal: muscle weakness. Nervous System: paresthesia, vertigo, insomnia, memory impairment, tremor, neuropathy (including peripheral neuropathy). Special Senses: lens opacity, taste disturbance. Postmarketing Experience In addition to the events reported above, as with other drugs in this class, the following events have been reported rarely during postmarketing experience with pravastatin sodium tablets, regardless of causality assessment: Musculoskeletal: myopathy, rhabdomyolysis. Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), peripheral nerve palsy. 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: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma. Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails). Reproductive: gynecomastia. Laboratory Abnormalities: LFTabnormalities, thyroid function abnormalities. Laboratory Test Abnormalities Increases in serum transaminase (ALT, AST) values and CPK have been observed (see WARNINGS ). Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been reported with HMG-CoA reductase inhibitors. Concomitant Therapy Pravastatin has been administered concurrently with cholestyramine, colestipol, nicotinic acid, probucol and gemfibrozil. Preliminary data suggest that the addition of either probucol or gemfibrozil to therapy with lovastatin or pravastatin is not associated with greater reduction in LDL-cholesterol than that achieved with lovastatin or pravastatin alone. No adverse reactions unique to the combination or in addition to those previously reported for each drug alone have been reported. Myopathy and rhabdomyolysis (with or without acute renal failure) have been reported when another HMG-CoA reductase inhibitor was used in combination with immunosuppressive drugs, gemfibrozil, erythromycin, or lipid-lowering doses of nicotinic acid. Concomitant therapy with HMG-CoA reductase inhibitors and these agents is generally not recommended. (See WARNINGS: Skeletal Muscle and PRECAUTIONS: Drug Interactions .) Pediatric Patients In a two (2) year, double-blind, placebo-controlled study involving 100 boys and 114 girls with HeFH, the safety and tolerability profile of pravastatin was generally similar to that of placebo. (See CLINICAL PHARMACOLOGY: Pediatric Clinical Study and PRECAUTIONS: Pediatric Use .)

Immunosuppressive Drugs, Gemfibrozil, Niacin (Nicotinic Acid), Erythromycin: See WARNINGS: Skeletal Muscle . Cytochrome P450 3A4 Inhibitors: In vitro and in vivo data indicate that pravastatin is not metabolized by cytochrome P450 3A4 to a clinically significant extent. This has been shown in studies with known cytochrome P450 3A4 inhibitors (see Diltiazem and Itraconazole below). Other examples of cytochrome P450 3A4 inhibitors include ketoconazole, mibefradil, and erythromycin. Diltiazem: Steady-state levels of diltiazem (a known, weak inhibitor of P450 3A4) had no effect on the pharmacokinetics of pravastatin. In this study, the AUC and C max of another HMG-CoA reductase inhibitor which is known to be metabolized by cytochrome P450 3A4 increased by factors of 3.6 and 4.3, respectively. Itraconazole: The mean AUC and C max for pravastatin were increased by factors of 1.7 and 2.5, respectively, when given with itraconazole (a potent P450 3A4 inhibitor which also inhibits p-glycoprotein transport) as compared to placebo. The mean t ½ was not affected by itraconazole, suggesting that the relatively small increases in C max and AUC were due solely to increased bioavailability rather than a decrease in clearance, consistent with inhibition of p-glycoprotein transport by itraconazole. This drug transport system is thought to affect bioavailability and excretion of HMG-CoA reductase inhibitors, including pravastatin. The AUC and C max of another HMG-CoA reductase inhibitor which is known to be metabolized by cytochrome P450 3A4 increased by factors of 19 and 17, respectively, when given with itraconazole. Antipyrine: Since concomitant administration of pravastatin had no effect on the clearance of antipyrine, interactions with other drugs metabolized via the same hepatic cytochrome isozymes are not expected. Cholestyramine/Colestipol: Concomitant administration resulted in an approximately 40 to 50% decrease in the mean AUC of pravastatin. However, when pravastatin was administered 1 hour before or 4 hours after cholestyramine or 1 hour before colestipol and a standard meal, there was no clinically significant decrease in bioavailability or therapeutic effect. (See DOSAGE AND ADMINISTRATION: Concomitant Therapy .) Warfarin: Concomitant administration of 40 mg pravastatin had no clinically significant effect on prothrombin time when administered in a study to normal elderly subjects who were stabilized on warfarin. Cimetidine: The AUC 0-12 hr for pravastatin when given with cimetidine was not significantly different from the AUC for pravastatin when given alone. A significant difference was observed between the AUC's for pravastatin when given with cimetidine compared to when administered with antacid. Digoxin: In a crossover trial involving 18 healthy male subjects given 20 mg pravastatin and 0.2 mg digoxin concurrently for 9 days, the bioavailability parameters of digoxin were not affected. The AUC of pravastatin tended to increase, but the overall bioavailability of pravastatin plus its metabolites SQ 31,906 and SQ 31,945 was not altered. Cyclosporine: Some investigators have measured cyclosporine levels in patients on pravastatin (up to 20 mg), and to date, these results indicate no clinically meaningful elevations in cyclosporine levels. In one single-dose study, pravastatin levels were found to be increased in cardiac transplant patients receiving cyclosporine. Gemfibrozil: In a crossover study in 20 healthy male volunteers given concomitant single doses of pravastatin and gemfibrozil, there was a significant decrease in urinary excretion and protein binding of pravastatin. In addition, there was a significant increase in AUC, C max , and T max for the pravastatin metabolite SQ 31,906. Combination therapy with pravastatin and gemfibrozil is generally not recommended. (See WARNINGS: Skeletal Muscle .) In interaction studies with aspirin , antacids (1 hour prior to pravastatin sodium), cimetidine, nicotinic acid, or probucol, no statistically significant differences in bioavailability were seen when pravastatin sodium was administered.

Storage 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]. Dispense in a tight, light-resistant container [see USP]. Protect from light and moisture.