FDA label 328139c5-d039-5806-e054-00144ff8d46c

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 trials (see CLINICAL PHARMACOLOGY: Clinical Studiesin 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 ALTtimes 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 and when 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 (< 6 months) 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 (see DOSAGE AND ADMINISTRATION: Adult Patients ), and titrated to the desired therapeutic effect. Patients who develop increased transaminase levels or signs and symptoms of active liver disease while taking pravastatin should be evaluated 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 fever. Pravastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. The risk of myopathy during treatment with another HMG-CoA reductase inhibitor is increased with concurrent therapy with either erythromycin, cyclosporine, niacin, or fibrates. However, neither myopathy nor significant increases in CPK levels have been observed in three reports involving a total of 100 post-transplant patients (24 renal and 76 cardiac) treated for up to two years concurrently with pravastatin 10-40 mg and cyclosporine. Some of these patients also received other concomitant immunosuppressive therapies. Further, in clinical trials involving small numbers of patients who were treated concurrently with pravastatin and niacin, there were no reports of myopathy. Also, myopathy was not reported in a trial of combination pravastatin (40 mg/day) and gemfibrozil (1200 mg/day), although 4 of 75 patients on the combination showed marked CPK elevations versus one of 73 patients receiving placebo. There was a trend toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared with the groups receiving placebo, gemfibrozil, or pravastatin monotherapy (see PRECAUTIONS: Drug interactions ). The use of fibrates alone may occasionally be associated with myopathy. The combined use of pravastatin and fibrates should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination.

ADVERSE REACTIONS Pravastatin is generally well tolerated; adverse reactions have usually been mild and transient. In a 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 * Statistically significantly different from placebo.10-40 mg in Short-Term Placebo-Controlled TrialsAll EventsEvents Attributed to Study DrugBody System/EventPravastatin (N=900) % of patientsPlacebo (N=411) % of patientsPravastatin (N=900) % of patientsPlacebo (N=411) % of patientsCardiovascularCardiac Chest Pain4.03.40.10.0DermatologicRash4.0*1.11.30.9GastrointestinalNausea/Vomiting7.37.12.93.4Diarrhea6.25.62.01.9Abdominal Pain5.46.92.03.9Constipation4.07.12.45.1Flatulence3.33.62.73.4Heartburn2.91.92.00.7GeneralFatigue3.83.41.91.0Chest Pain3.71.90.30.2Influenza2.4 * 0.70.00.0MusculoskeletalLocalized Pain10.09.01.41.5Myalgia2.71.00.60.0Nervous SystemHeadache6.23.91.7*0.2Dizziness3.33.21.00.5Renal/GenitourinaryUrinary Abnormality2.42.90.71.2RespiratoryCommon Cold7.06.30.00.0Rhinitis4.04.10.10.0Cough2.61.70.10.0The safety and tolerability of pravastatin sodium at a dose of 80 mg in two 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 >10X ULN compared to 0 out of 115 patients taking 40 mg of pravastatin. Long-Term Controlled Morbidity and Mortality Trials Table 7: Adverse Events inPercent of Patients Treated with Pravastatin 40 mg in Long-Term Placebo-Controlled TrialsBody System/EventPravastatin (N=10,764) % of patientsPlacebo (N=10,719) % of patientsCardiovascularAngina Pectoris3.13.4DermatologicRash2.12.2GastrointestinalDyspepsia/Heartburn3.53.7Abdominal Pain2.42.5Nausea/Vomiting1.61.6Flatulence1.21.1Constipation1.21.3GeneralFatigue3.43.3Chest Pain2.62.6MusculoskeletalMusculoskeletal Pain (includes arthralgia)6.05.8Muscle Cramp2.01.8Myalgia1.41.4Nervous SystemDizziness2.22.1Headache1.91.8Sleep Disturbance1.00.9Depression1.01.0Anxiety/Nervousness1.01.2Renal/GenitourinaryUrinary Abnormality (includes dysuria, frequency, nocturia)1.00.8RespiratoryDyspnea1.61.6Upper Respiratory Infection1.31.3Cough1.01.0Special SensesVision Disturbance (includes blurred vision, diplopia)1.61.3 Dermatologic: pruritus, dermatitis, dryness of 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, regardless of causality assessment: Musculoskeletal: myopathy, rhabdomyolysis. Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular 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: Liver Function Test abnormalities, 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-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 .)