Apo-Pravastatin Warnings

Liver Dysfunction: HMG-CoA reductase inhibitors have been associated with biochemical abnormalities of liver function. As with other lipid-lowering agents, including non-absorbable bile acid-binding resins, increases in liver enzymes to less than three times the upper limit of normal have occurred during therapy with pravastatin. The significance of these changes, which usually appear during the first few months of treatment initiation, is not known. In the majority of patients treated with pravastatin in clinical trials, these increased values declined to pretreatment levels despite continuation of therapy at the same dose.
Marked persistent increases (greater than three times the upper limit of normal) in serum transaminases were seen in 6 out of 1,142 (0.5%) patients treated with pravastatin in clinical trials (see ADVERSE REACTIONS). The increases usually appeared 3 to 12 months after the start of therapy with pravastatin. These elevations were not associated with clinical signs and symptoms of liver disease and usually declined to pretreatment levels upon discontinuation of therapy. Patients rarely had persistent marked abnormalities possibly attributable to therapy. In the largest long-term placebo-controlled trial with pravastatin (Pravastatin Primary Prevention Study/WOSCOPS), no patient with normal liver function after 12 weeks of treatment (N=2875 pravastatin-treated patients) had subsequent ALT elevations greater than three times the upper limit of normal on two consecutive measurements. Two of these 2875 patients treated with pravastatin (0.07%) and one of 2919 placebo patients (0.03%) had elevations of AST greater than three times the upper limit of normal on two consecutive measurements during the 4.8 years (median treatment) of the study.
Liver function tests should be performed at baseline and at 12 weeks following initiation of therapy or the elevation of dose: Special attention should be given to patients who develop increased transaminase levels.
Liver function tests should be repeated to confirm an elevation and subsequently monitored at more frequent intervals. If increases in alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) equal or exceed three times the upper limit of normal and persist, therapy should be discontinued.
Caution should be exercised when pravastatin is administered to patients with a history of liver disease or heavy alcohol ingestion. Active liver disease or unexplained serum transaminase elevations are contraindications to the use of APO-PRAVASTATIN (pravastatin sodium); if such condition develops during therapy, the drug should be discontinued.
Muscle Effects: Elevations of creatinine phosphokinase levels (CPK [MM fraction]), myalgia, myopathy and rhabdomyolysis have been reported with the use of HMG-CoA reductase inhibitors, including pravastatin.
Muscle weakness and rhabdomyolysis have been reported in patients receiving other HMG-CoA reductase inhibitors concomitantly with itraconazole and cyclosporine.
The benefits and risks of using HMG-CoA Reductase Inhibitors concomitantly with immunosuppressive drugs, fibrates, erythromycin, systemic azole derivative antifungal agents or lipid-lowering doses of niacin should be carefully considered.
Myalgia has been associated with pravastatin therapy. Rare cases of rhabdomyolysis associated with pravastatin (and macrocreatine kinase in one case) have been reported.
Myopathy (markedly elevated CPK of greater than 10 times the upper limit of normal with myalgia) was very rarely reported in pravastatin-treated patients in clinical trials. Rhabdomyolysis with renal dysfunction secondary to myoglobinuria has also very rarely been reported with pravastatin. However, myopathy should be considered in any patients with diffuse myalgia, muscle tenderness or weakness, and/or marked elevation of CPK.
As with other statins, the risk of myopathy including rhabdomyolysis may be substantially increased by concomitant immunosuppressive therapy including cyclosporine, and by concomitant therapy with gemfibrozil, erythromycin or niacin (see also PRECAUTIONS).
Myopathy has not been observed in clinical trials involving small numbers of patients who were treated with pravastatin together with immunosuppressants, fibric acid derivatives or niacin.
The use of fibrates alone is occasionally associated with myopathy. In a limited size clinical trial of combined therapy with pravastatin (40 mg/day) and gemfibrozil (1200 mg/day), myopathy was not reported, although a trend towards CPK elevations and musculoskeletal symptoms was seen. The combined use of pravastatin and fibrates should generally be avoided.
No information is available on the combined therapy of pravastatin with erythromycin.
APO-PRAVASTAIN therapy should be discontinued if marked elevation of CPK levels occurs or if myopathy is diagnosed or suspected.
Interruption of therapy with APO-PRAVASTATIN should be considered in any patient with an acute, serious condition, suggestive of a myopathy or having a risk factor predisposing to the development of renal failure or rhabdomyolysis, such as severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine or electrolyte disorders and uncontrolled seizures.