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PRAVACHOL® Pravastatin Sodium Tablets
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. 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 US
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. It is
recommended that liver function tests be performed before the
initiation of treatment, at 6 and 12 weeks after initiation of
therapy or elevation in dose, and periodically thereafter (e.g.,
semiannually). Patients who develop increased transaminase
levels 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 ASTor ALTof 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 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/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 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. In
one single-dose study, pravastatin 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 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.
PRECAUTIONS: General- Pravastatin may elevate
creatinine 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 3 a-hydroxy
isomeric metabolite (SQ 31,906). A small increase was seen in
mean AUC values and half-life (t1/2 ) 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 Patients- Patients
should be advised to report promptly unexplained muscle pain,
tenderness or weakness, particularly if accompanied by malaise
or fever. Drug Interactions- Immunosuppressive
Drugs, Gemfibrozil, Niacin (Nicotinic Acid), Erythromycin: See
WARNINGS: Skeletal Muscle. Antipyrine: Since concomitant
administration of pravastatin had no effect on the clearance of
antipyrine, interactions with other drugs metabolized via the
same hepatic cytochrome isozymes are not expected. Cholestyramine/Colestipol:
Concomitant administration resulted in an approximately 40 to
50% decrease in the mean AUC of pravastatin. However, when pravastatin
was administered 1 hour before or 4 hours after cholestyramine
or 1 hour before colestipol and a standard meal, there was no
clinically significant decrease in bioavailability or therapeutic
effect. (See DOSAGE AND ADMINISTRATION: Concomitant Therapy.)
Warfarin: In a study involving 10 healthy male subjects
given pravastatin and warfarin concomitantly for 6 days, bioavailability
parameters at steady state for pravastatin (parent compound) were
not altered. Pravastatin did not alter the plasma protein-binding
of warfarin. Concomitant dosing did increase the AUC and Cmax
of warfarin but did not produce any changes in its anticoagulant
action (i.e., no increase was seen in mean prothrombin time after
6 days of concomitant therapy). However, bleeding and extreme
prolongation of prothrombin time has been reported with another
drug in this class. Patients receiving warfarin-type anticoagulants
should have their prothrombin times closely monitored when pravastatin
is initiated or the dosage of pravastatin is changed. Cimetidine:
The AUC0-12 hr for pravastatin when given with cimetidine was
not significantly different from the AUC for pravastatin when
given alone. A significant difference was observed between the
AUCís for pravastatin when given with cimetidine compared
to when administered with antacid. Digoxin: In a crossover
trial involving 18 healthy male subjects given pravastatin and
digoxin concurrently for 9 days, the bioavailability parameters
of digoxin were not affected. The AUC of pravastatin tended to
increase, but the overall bioavailability of pravastatin plus
its metabolites SQ 31,906 and SQ 31,945 was not altered. Cyclosporine:
Some investigators have measured cyclosporine levels in patients
on pravastatin, and to date, these results indicate no clinically
meaningful elevations in cyclosporine levels. In one single-dose
study, pravastatin levels were found to be increased in cardiac
transplant patients receiving cyclosporine. Gemfibrozil:
In a crossover study in 20 healthy male volunteers given concomitant
single doses of pravastatin and gemfibrozil, there was a significant
decrease in urinary excretion and protein binding of pravastatin.
In addition, there was a significant increase in AUC, Cmax, and
Tmax for the pravastatin metabolite SQ 31,906. Combination therapy
with pravastatin and gemfibrozil is generally not recommended.
In interaction studies with aspirin, antacids (1 hour prior
to PRAVACHOL), cimetidine, nicotinic acid, or probucol,
no statistically significant differences in bioavailability were
seen when PRAVACHOL (pravastatin sodium) was administered. Other
Drugs: During clinical trials, no noticeable drug interactions
were reported when PRAVACHOL was added to: diuretics, antihypertensives,
digitalis, ACE inhibitors, calcium channel blockers, beta-blockers,
or nitroglycerin. 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
CAUTION: Federal (USA) law prohibits dispensing
without prescription.
Consult package insert before prescribing
PRAVACHOL® (pravastatin sodium). Revised July 1996 D3-B001-7-96 J4-538D | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
50% 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) that 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, 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 to 10 times higher than those measured in humans given 40 mg
pravastatin as measured by AUC. The oral administration of 10,
30, or 100 mg/kg (producing plasma drug levels approximately 0.5
to 5.0 times the human drug levels at 40 mg) of pravastatin to
mice for 22 months resulted in a statistically significant increase
in the incidence of malignant lymphomas in treated females when
all treatment groups were pooled and compared to controls (p <
0.05). The incidence was not dose-related and male mice were not
affected. A chemically similar drug in this class was administered
to mice for 72 weeks at 25, 100, and 400 mg/kg body weight, which
resulted in mean serum drug levels approximately 3, 15, and 33
times higher than the mean human serum drug concentration (as
total inhibitory activity) after a 40 mg oral dose. Liver carcinomas
were significantly increased in high-dose females and mid- and
high-dose males, with a maximum incidence of 90 percent in males.
The incidence of adenomas of the liver was significantly increased
in mid- and high-dose females. Drug treatment also significantly
increased the incidence of lung adenomas in mid- and high-dose
males and females. Adenomas of the eye Harderian gland (a gland
of the eye of rodents) were significantly higher in high-dose
mice than in controls. 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,
two 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: 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 20x (rabbit)
or 240x (rat) the human exposure based on surface area (mg/meter2 ).
However, in studies with another HMG-CoA reductase inhibitor,
skeletal malformations were observed in rats and mice. There has
been one report of severe congenital bony deformity, tracheo-esophageal
fistula, and anal atresia (Vater association) in a baby born to
a woman who took another HMG-CoA reductase inhibitor with dextroamphetamine
sulfate during the first trimester of pregnancy. PRAVACHOL (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. If the woman becomes pregnant
while taking PRAVACHOL (pravastatin sodium), it should be discontinued
and the patient advised again as to the potential hazards to the
fetus. 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 PRAVACHOL
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. ADVERSE REACTIONS: Pravastatin is generally well
tolerated; adverse reactions have usually been mild and transient.
In 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.
In long-term studies, the most common reasons for discontinuation
were asymptomatic serum transaminase increases and mild, non-specific
gastrointestinal complaints. During clinical trials the overall
incidence of adverse events in the elderly was not different from
the incidence observed in younger patients. Adverse Clinical
Events- All adverse clinical events (regardless of
attribution) reported in more than 2% of pravastatin-treated patients
in the placebo-controlled trials are identified in the table below;
also shown are the percentages of patients in whom these medical
events were believed to be related or possibly related to the
drug:
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