Pravastatin Sodium 40 mg Tablet, 30-count — NDC 35356-125-30 (Billing 35356-0125-30)

WARNINGS Liver Enzymes HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. In placebo-controlled clinical trials (see CLINICAL PHARMACOLOGY: Clinical Studies ), subjects were exposed to pravastatin or placebo. In an analysis of serum transaminase values (ALT, AST), incidences of marked abnormalities were compared between the pravastatin and placebo treatment groups; a marked abnormality was defined as a post-treatment test value greater than three times the upper limit of normal for subjects with pretreatment values less than or equal to the upper limit of normal, or four times the pretreatment value for subjects with pretreatment values greater than the upper limit of normal but less than 1.5 times the upper limit of normal.

Marked abnormalities of ALT or AST occurred with similar low frequency (≤1.2%) in both treatment groups. Overall, clinical trial experience showed that liver function test abnormalities observed during pravastatin therapy were usually asymptomatic, not associated with cholestasis, and did not appear to be related to treatment duration. In a 320-patient placebo-controlled clinical trial, subjects with chronic (>6 months) stable liver disease, due primarily to hepatitis C or non-alcoholic fatty liver disease, were treated with 80 mg pravastatin or placebo for up to 9 months.

The primary safety endpoint was the proportion of subjects with at least one ALT ≥2 times the upper limit of normal for those with normal ALT (≤ the upper limit of normal) at baseline or a doubling of the baseline ALT for those with elevated ALT (> the upper limit of normal) at baseline. By Week 36, 12 out of 160 (7.5%) subjects treated with pravastatin met the prespecified safety ALT endpoint compared to 20 out of 160 (12.5%) subjects receiving placebo. Conclusions regarding liver safety are limited since the study was not large enough to establish similarity between groups (with 95% confidence) in the rates of ALT elevation.

It is recommended that liver function tests be performed prior to the initiation of therapy, prior to the elevation of the dose, and when otherwise clinically indicated. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of pravastatin (see CONTRAINDICATIONS ). Caution should be exercised when pravastatin is administered to patients who have a recent history of liver disease, have signs that may suggest liver disease (e.g., unexplained aminotransferase elevations, jaundice), or are heavy users of alcohol (see CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism ).

Such patients should be closely monitored, started at the lower end of the recommended dosing range, and titrated to the desired therapeutic effect. Patients who develop increased transaminase levels or signs and symptoms of liver disease should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of three times the upper limit of normal or greater persist, withdrawal of pravastatin therapy is recommended.

Skeletal Muscle Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with pravastatin and other drugs in this class. Uncomplicated myalgia has also been reported in pravastatin-treated patients (see ADVERSE REACTIONS ). Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of normal, was rare (<0.1%) in pravastatin clinical trials.

Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or feve… [Excerpted — this section continues on DailyMed.]

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. (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

0.0Dermatologic Rash 4.0* 1.1 1.3

0.9Gastrointestinal 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

0.7General 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

0.0Musculoskeletal Localized Pain Myalgia 10.0 2.7 9.0 1.0 1.4 0.6 1.5

0.0Nervous System Headache Dizziness 6.2 3.3 3.9 3.2 1.7* 1.0 0.2

0.5Renal/Genitourinary Urinary Abnormality 2.4 2.9 0.7

1.2Respiratory 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

0.0The 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

3.4Dermatologic Rash 2.1

2.2Gastrointestinal 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

1.3General Fatigue Chest Pain 3.4 2.6 3.3

2.6Musculoskeletal Musculoskeletal Pain (includes arthralgia) Muscle Cramp Myalgia 6.0 2.0 1.4 5.8 1.8

1.4Nervous System Dizziness Headache Sleep Disturbance Depression Anxiety/Nervousness 2.2 1.9 1.0 1.0 1.0 2.1 1… [Excerpted — this section continues on DailyMed.]

Drug Interactions 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 aci… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS General Pravastatin sodium may elevate creatine phosphokinase and transaminase levels (see ADVERSE REACTIONS ). This should be considered in the differential diagnosis of chest pain in a patient on therapy with pravastatin. Homozygous Familial Hypercholesterolemia.

Pravastatin has not been evaluated in patients with rare homozygous familial hypercholesterolemia. In this group of patients, it has been reported that HMG-CoA reductase inhibitors are less effective because the patients lack functional LDL receptors. Renal Insufficiency.

A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite (SQ 31,906). A small increase was seen in mean AUC values and half-life (t ½ ) for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945).

Given this small sample size, the dosage administered, and the degree of individual variability, patients with renal impairment who are receiving pravastatin should be closely monitored. Information for Patients Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever (see WARNINGS: Skeletal Muscle ). Drug Interactions 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 observe… [Excerpted — this section continues on DailyMed.]