Apo-Pravastatin Special Precautions

General: Before instituting therapy with APO-PRAVASTATIN (pravastatin sodium), an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, weight reduction in overweight and obese patients, and to treat other underlying medical problems (see INDICATIONS). The patient should be advised to inform subsequent physicians of the prior use of pravastatin.
Pravastatin may elevate creatine phosphokinase and transaminase levels. This should be considered in the differential diagnosis of chest pain in a patient on therapy with pravastatin.
Effect on the Lens: Current data from clinical trials do not indicate an adverse effect of pravastatin on the human lens.
Homozygous Familial Hypercholesterolemia: Pravastatin has not been evaluated in patients with rare homozygous familial hypercholesterolemia. Most HMG-CoA reductase inhibitors are less or not effective in this subgroup of hypercholesterolemic patients.
Effect on Lipoprotein(a): In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in the Lipoprotein(a)[Lp(a)] level. Further research is ongoing to elucidate the significance of Lp(a) variations. Therefore, until further experience is obtained, where feasible, it is suggested that measurements of serum Lp(a) be followed up in patients placed on pravastatin therapy.
Effect on CoQ10 Levels (Ubiquinone): A significant short-term decrease in plasma CoQ10 levels in patients treated with pravastatin has been observed. Longer clinical trials have also shown reduced serum ubiquinone levels during treatment with pravastatin and other HMG-CoA reductase inhibitors. The clinical significance of a potential long-term statin-induced deficiency of CoQ10 has not yet been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure.
Carcinogenesis: A 21-month oral study in mice, with doses of 10 to 100 mg/kg daily of pravastatin did not demonstrate any carcinogenic potential. In a 2-year oral study in rats, a statistically significant increase in the incidence of hepatocellular carcinoma was observed in male rats given 100 mg/kg daily (125 times the maximum human dose) of pravastatin. This change was not seen in male rats given 40 mg/kg daily (50 times the recommended human dose) or less, or in female rats at any dose level.
Hypersensitivity: With lovastatin, an apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus-like syndrome, polymyalgia rheumatica, thrombocytopenia, leukopenia, hemolytic anemia, positive antinuclear antibody (ANA), erythrocyte sedimentation rate (ESR) increase, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever and malaise.
Although to date hypersensitivity syndrome has not been described as such, in few instances eosinophilia and skin eruptions appear to be associated with pravastatin treatment. If hypersensitivity is suspected, APO-PRAVASTATIN should be discontinued. Patients should be advised to report promptly any signs of hypersensitivity such as angioedema, urticaria, photosensitivity, polyarthralgia, fever, malaise.
Endocrine Function: HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such could theoretically blunt adrenal and/or gonadal steroid production.
In one long-term study investigating the endocrine function in hypercholesterolemic patients, pravastatin exhibited no effect upon basal and stimulated cortisol levels, as well as on aldosterone secretion. Although no change was reported in the testicular function, conflicting results were observed in the analysis of sperm motility after administration of pravastatin. A case of reversible impotence has been reported in a 57-year-old man administered pravastatin 20 mg/day and metoprolol. A causal relationship to therapy with pravastatin has not been established. Further studies are needed to clarify the effects of HMG-CoA reductase inhibitors on male fertility. Furthermore, the effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.
Patients treated with APO-PRAVASTATIN who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g., ketoconazole, spironolactone, or cimetidine) that may decrease the levels of endogenous steroid hormones.
Patients with Severe Hypercholesterolemia: Higher doses (40 mg/day) required for some patients with severe hypercholesterolemia are associated with increased plasma levels of pravastatin. Caution should be exercised in such patients who are also significantly renally impaired or elderly (see WARNINGS).
Use in Patients with Impaired Renal Function: There have been no studies on the use of pravastatin in patients with renal failure. As a precautionary measure, the lowest dose should be used in these patients (see Muscle Effects under WARNINGS).
Use in pregnancy: APO-PRAVASTATIN is contraindicated during pregnancy (see CONTRAINDICATIONS).
Safety in pregnant women has not been established. Although pravastatin was not teratogenic in rats at doses as high as 1000 mg/kg daily nor in rabbits at doses of up to 50 mg/kg daily, APO-PRAVASTATIN should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of potential hazards. If a woman becomes pregnant while taking APO-PRAVASTATIN, APO-PRAVASTATIN should be discontinued and the patient advised again as to the potential hazards to the fetus.
Use in lactation: A negligible amount of pravastatin is excreted in human breast milk. Because of the potential for adverse reactions in nursing infants, if the mother is being treated with APO-PRAVASTATIN, nursing should be discontinued or treatment with APO-PRAVASTATIN stopped.
Use in children: Only limited experience with the use of statins in children is available. There is no experience to date with the use of pravastatin in such patients.
Use in elderly: Pharmacokinetic evaluation of pravastatin in patients over the age of 65 years indicates an increased AUC. There were no reported increases in the incidence of adverse effects in these or other studies involving patients in that age group. As a precautionary measure, the lowest dose should be administered initially.