Pravachol Warnings

HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Increases of serum transaminase (ALT, AST) values to more than 3 times the upper limit of normal occurring on 2 or more (not necessarily sequential) occasions have been reported in 1.3% of patients treated with Pravachol in the U.S. over an average period of 18 months. These abnormalities were not associated with cholestasis and did not appear to be related to treatment duration. In those patients in whom these abnormalities were believed to be related to Pravachol and who were discontinued from therapy, the transaminase levels usually fell slowly to pretreatment levels. These biochemical findings are usually asymptomatic although worldwide experience indicates that anorexia, weakness, and/or abdominal pain may also be present in rare patients.

In the largest long-term placebo-controlled clinical trial with pravastatin, the overall incidence of AST and/or ALT elevations to greater than three times the upper limit of normal was 1.05% in the Pravachol group as compared to 0.75% in the placebo group. One (0.03%) Pravachol-treated patient and 2 (0.06%) placebo-treated patients were discontinued because of transaminase elevations. Of the patients with normal liver function at week 12, three of 2875 treated with Pravachol (0.10%) and one of the 2919 placebo patients (0.03%) had elevations of AST greater than three times the upper limit of normal on two consecutive measurements and/or discontinued due to elevations in transaminase levels during the 4.8 years (median treatment) of the study.

It is recommended that liver function tests be performed prior to and at 12 weeks following initiation of therapy or elevation in dose. 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.

Active liver disease or unexplained transaminase elevations are contraindications to the use of Pravachol. Caution should be exercised when Pravachol is administered to patients with a history of liver disease or heavy alcohol ingestion. Such patients should be closely monitored, started at the lower end of the recommended dosing range, and titrated to the desired therapeutic effect.

Skeletal Muscle

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with Pravachol and other drugs in this class. Uncomplicated myalgia has also been reported in Pravachol-treated patients. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper normal limit, was rare (<0.1%) in Pravachol 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. Pravachol therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Pravastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

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 Pravachol 10-40 mg of cyclosporine. Some of these patients also received other concomitant immunosuppressive therapies. In one single-dose study, Pravachol levels were found to be increased in cardiac transplant patients receiving cyclosporine. Further, in clinical trials involving small numbers of patients who were treated concurrently with Pravachol and niacin, there were no reports of myopathy. Also, myopathy was not reported in a trial of combination Pravachol (40 mg/day) and gemfibrozil (1200 mg/day), although 4 of 75 patients on the combination showed marked CPK elevations versus one of 73 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 Pravachol monotherapy. The use of fibrates alone may occasionally be associated with myopathy. The combined use of Pravachol 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.

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