CONTRAINDICATIONS
Hypersensitivity to any component of this medication.
Active liver disease or unexplained, persistent elevations in liver function tests (see WARNINGS).
Pregnancy and Lactation: Atherosclerosis is a chronic process and discontinuation of
lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy
of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are
essential components for fetal development (including synthesis of steroids and cell membranes).
Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of
other biologically active substances derived from cholesterol, they may cause fetal harm when
administered to pregnant women. Therefore, HMG-CoA reductase inhibitors are contraindicated
during pregnancy and in nursing mothers. Pravastatin should be administered to women of
childbearing age only when such patients are highly unlikely to conceive and have been
informed of the potential hazards. If the patient becomes pregnant while taking this class of
drug, therapy should be discontinued and the patient apprised of the potential hazard to the fetus
(see PRECAUTIONS, Pregnancy Category X).
WARNINGS
Liver Enzymes
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 pravastatin 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 pravastatin 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 (see CLINICAL
PHARMACOLOGY, Pravastatin Primary Prevention Study), the overall incidence of AST and/or
ALT elevations to greater than 3 times the upper limit of normal was 1.05% in the pravastatin group
as compared to 0.75% in the placebo group. One (0.03%) pravastatin-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, 3 of 2875 treated with pravastatin (0.10%) and 1 of the 2919
placebo patients (0.03%) had elevations of AST greater than 3 times the upper limit of normal on 2
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 3 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
pravastatin (see CONTRAINDICATIONS). Caution should be exercised when pravastatin is
administered to patients with a history of liver disease or heavy alcohol ingestion (see CLINICAL
PHARMACOLOGY, Pharmacokinetics and Metabolism). 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 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 normal limit, 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. 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 3 reports involving a total
of 100 post-transplant patients (24 renal and 76 cardiac) treated for up to 2 years concurrently with
pravastatin 10-40 mg of 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 1 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 pravastatin monotherapy. (See 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.
PRECAUTIONS
General
Pravastatin 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 3a-hydroxy isomeric metabolite (SQ 31,906).
A small increase was seen in mean AUC values and half-life (t½) 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 the Patient
Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness,
particularly if accompanied by malaise or fever (see WARNINGS, Skeletal Muscle).
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower circulating cholesterol
levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Results
of clinical trials with pravastatin in males and post-menopausal females were inconsistent with
regard to possible effects of the drug on basal steroid hormone levels. In a study of 21 males, the
mean testosterone response to human chorionic gonadotropin was significantly reduced (p<0.004)
after 16 weeks of treatment with 40 mg of pravastatin. However, the percentage of patients
showing a ³50% rise in plasma testosterone after human chorionic gonadotropin stimulation did not
change significantly after therapy in these patients. The effects of HMG-CoA reductase inhibitors
on spermatogenesis and fertility have not been studied in adequate numbers of patients. The effects,
if any, of pravastatin on the pituitary-gonadal axis in pre-menopausal females are unknown. Patients
treated with pravastatin who display clinical evidence of endocrine dysfunction should be evaluated
appropriately. Caution should also be exercised if an HMG-CoA reductase inhibitor or other agent
used to lower cholesterol levels is administered to patients also receiving other drugs (e.g.,
ketoconazole, spironolactone, cimetidine) they may diminish the levels or activity of steroid
hormones.
CNS Toxicity
CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononuclear cell
infiltration of perivascular spaces, were seen in dogs treated with pravastatin at a dose of 25
mg/kg/day, a dose that produced a plasma drug level about 50 times higher than the mean drug level
in humans taking 40 mg/day. Similar CNS vascular lesions have been observed with several other
drugs in this class.
A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration
of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60
mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug
level in humans taking the highest recommended dose (as measured by total enzyme inhibitory
activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal
ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in
a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
In a 2 year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was an
increased incidence of hepatocellular carcinomas in males at the highest dose (p <0.01). Although
rats were given up to 125 times the human dose (HD) on a mg/kg body weight basis, serum drug
levels were only 6-10 times higher than those measured in humans given 40 mg pravastatin as
measured by AUC.
In a 2 year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an
increased incidence of hepatocellular carcinomas in males and females at both 250 and 500
mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased (p=0.013). Serum
drug levels were 30-40 times (250 mg/kg/day) and 50 times (500 mg/kg/day) that of humans given
40 mg pravastatin, as measured by AUC. In another 2 year study in mice with doses at up to 100
mg/kg/day (producing plasma drug levels up to 5 times human drug levels at 40 mg), there were no
drug-induced tumors.
No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in
the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or
Escherichia coli; a forward mutation assay in L5178Y TK +/- mouse lymphoma cells; a
chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces
cerevisiae. In addition, there was no evidence of mutagenicity in either a dominant lethal test in
mice or a micronucleus test in mice.
In a study in rats, with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects
on fertility or general reproductive performance. However, in a study with another HMG-CoA
reductase inhibitor, there was decreased fertility in male rats treated for 34 weeks at 25 mg/kg body
weight, although this effect was not observed in a subsequent fertility study when this same dose
was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal
maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule
degeneration (necrosis and loss of spermatogenic epithelium) was observed. Although not seen with
pravastatin, 2 similar drugs in this class caused drug-related testicular atrophy, decreased
spermatogenesis, spermatocytic degeneration, and giant cell formation in dogs. The clinical
significance of these findings is unclear.
Pregnancy Category X
See CONTRAINDICATIONS.
Safety in pregnant women has not been established. Pravastatin was not teratogenic in rats at doses
up to 1000 mg/kg daily or in rabbits at doses of up to 50 mg/kg daily. These doses resulted in 20´
(rabbit) or 240´ (rat) the human exposure based on surface area (mg/m2). Rare reports of
congenital anomalies have been received following intrauterine exposure to other HMG-CoA
reductase inhibitors. In a review9 of approximately 100 prospectively followed pregnancies in
women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous
abortions and fetal deaths/stillbirths did not exceed what would be expected in the general
population. The number of cases is adequate only to exclude a 3- to 4-fold increase in congenital
anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug
treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester
when pregnancy was identified. As safety in pregnant women has not been established and there is
no apparent benefit to therapy with pravastatin sodium during pregnancy (see
CONTRAINDICATIONS), treatment should be immediately discontinued as soon as pregnancy is
recognized. Pravastatin sodium should be administered to women of child-bearing potential only
when such patients are highly unlikely to conceive and have been informed of the potential hazards.
Nursing Mothers
A small amount of pravastatin is excreted in human breast milk. Because of the potential for serious
adverse reactions in nursing infants, women taking pravastatin sodium should not nurse (see
CONTRAINDICATIONS).
Pediatric Use
Safety and effectiveness in individuals less than 18 years old have not been established. Hence,
treatment in patients less than 18 years old is not recommended at this time.
Geriatric Use
Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of 6593
subjects treated with pravastatin 40 mg for periods ranging up to 6 years. Across these 2 studies,
36.1% of pravastatin subjects were aged 65 and older and 0.8% were aged 75 and older. The
beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in
modifying lipid profiles was similar to that seen in younger subjects. The adverse event profile in the
elderly was similar to that in the overall population. Other reported clinical experience has not
identified differences in responses to pravastatin between elderly and younger patients.
Mean pravastatin AUCs are slightly (25-50%) higher in elderly subjects than in healthy young
subjects, but mean Cmax, Tmax and t½ values are similar in both age groups and substantial
accumulation of pravastatin would not be expected in the elderly (see CLINICAL
PHARMACOLOGY, Pharmacokinetics and Metabolism).