Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2932
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PRAVASTATIN SODIUM (Tablet)
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The patient should be placed on a standard cholesterol-lowering
diet before receiving Pravastatin Sodium Tablets and should continue on this
diet during treatment with Pravastatin Sodium Tablets (see NCEP Treatment
Guidelines for details on dietary therapy). Pravastatin Sodium Tablets can be administered orally as a single
dose at any time of the day, with or without food. Since the maximal effect
of a given dose is seen within 4 weeks, periodic lipid determinations should
be performed at this time and dosage adjusted according to the patient's response
to therapy and established treatment guidelines.<br/>Adult Patients: The recommended starting dose is 40 mg once daily. If a daily dose
of 40 mg does not achieve desired cholesterol levels, 80 mg once daily is
recommended. In patients with a history of significant renal or hepatic dysfunction,
a starting dose of 10 mg daily is recommended.<br/>Pediatric Patients:<br/>Children (Ages 8 to 13 Years, Inclusive): The recommended dose is 20 mg once daily in children 8 to 13 years
of age. Doses greater than 20 mg have not been studied in this patient population.<br/>Adolescents (Ages 14 to 18 Years): The recommended starting dose is 40 mg once daily in adolescents
14 to 18 years of age. Doses greater than 40 mg have not been studied in this
patient population. Children and adolescents treated with pravastatin should be reevaluated
in adulthood and appropriate changes made to their cholesterol-lowering regimen
to achieve adult goals for LDL-C (see INDICATIONS
AND USAGE: Hyperlipidemia: Table 7: NCEP Treatment Guidelines). In patients taking immunosuppressive drugs such as cyclosporine
concomitantly
with pravastatin, therapy should begin with 10 mg of pravastatin sodium once-a-day
at bedtime and titration to higher doses should be done with caution. Most
patients treated with this combination received a maximum pravastatin sodium
dose of 20 mg/day.<br/>Concomitant Therapy: The lipid-lowering effects of Pravastatin Sodium Tablets on Total-
and LDL-cholesterol are enhanced when combined with a bile-acid-binding resin.
When administering a bile-acid-binding resin (e.g., cholestyramine, colestipol)
and pravastatin, Pravastatin Sodium Tablets should be given either 1 hour
or more before or at least 4 hours following the resin.
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Pravastatin Sodium Tablets are one of a class of lipid-lowering
compounds, the HMG-CoA reductase inhibitors, which reduce cholesterol biosynthesis.
These agents are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme
A (HMG-CoA) reductase, the enzyme catalyzing the early rate-limiting step
in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate. Pravastatin sodium is designated chemically as 1-Naphthalene-heptanoic
acid, 1,2,6,7,8,8a-hexahydro-��,��,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-,
monosodium salt, [1S-[1��(��S*,��S*),2��,6��,8��(R*),8a��]]-. Structural formula: Pravastatin sodium is an odorless, white to off-white, fine or
crystalline powder. It is a relatively polar hydrophilic compound with a partition
coefficient (octanol/water) of 0.59 at a pH of 7.0. It is soluble in methanol
and water (>300 mg/mL), slightly soluble in isopropanol, and practically insoluble
in acetone, acetonitrile, chloroform, and ether. Pravastatin Sodium Tablets are available for oral administration
as 10 mg, 20 mg, 40 mg, and 80 mg tablets. Inactive ingredients include: croscarmellose
sodium, lactose, magnesium oxide, magnesium stearate, microcrystalline cellulose,
and povidone. The 10 mg tablet also contains Red Ferric Oxide, the 20 mg and
80 mg tablets also contain Yellow Ferric Oxide, and the 40 mg
tablet also contains Green Lake Blend (mixture of D&C Yellow No. 10-Aluminum
Lake and FD&C Blue No. 1-Aluminum Lake).
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Cholesterol
and triglycerides in the bloodstream circulate as part of lipoprotein complexes.
These complexes can be separated by density ultracentrifugation into high
(HDL), intermediate (IDL), low (LDL), and very low (VLDL) density lipoprotein
fractions. Triglycerides (TG) and cholesterol synthesized in the liver are
incorporated into very low density lipoproteins (VLDLs) and released into
the plasma for delivery to peripheral tissues. In a series of subsequent steps,
VLDLs are transformed into intermediate density lipoproteins (IDLs), and cholesterol-rich
low density lipoproteins (LDLs). High density lipoproteins (HDLs), containing
apolipoprotein A, are hypothesized to participate in the reverse transport
of cholesterol from tissues back to the liver. Pravastatin
Sodium Tablets produce its lipid-lowering effect in two ways. First, as a
consequence of its reversible inhibition of HMG-CoA reductase activity, it
effects modest reductions in intracellular pools of cholesterol. This results
in an increase in the number of LDL-receptors on cell surfaces and enhanced
receptor-mediated catabolism and clearance of circulating LDL. Second, pravastatin
inhibits LDL production by inhibiting hepatic synthesis of VLDL, the LDL precursor. Clinical
and pathologic studies have shown that elevated levels of total cholesterol
(Total-C), low density lipoprotein cholesterol (LDL-C), and apolipoprotein
B (ApoB���a membrane transport complex for LDL) promote human atherosclerosis.
Similarly, decreased levels of HDL-cholesterol (HDL-C) and its transport complex,
apolipoprotein A, are associated with the development of atherosclerosis.
Epidemiologic investigations have established that cardiovascular morbidity
and mortality vary directly with the level of Total-C and LDL-C and inversely
with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich
lipoproteins, including VLDL, IDL, and remnants, can also promote atherosclerosis.
Elevated plasma TG are frequently found in a triad with low HDL-C levels and
small LDL particles, as well as in association with non-lipid metabolic risk
factors for coronary heart disease. As such, total plasma TG has not consistently
been shown to be an independent risk factor for CHD. Furthermore, the independent
effect of raising HDL or lowering TG on the risk of coronary and cardiovascular
morbidity and mortality has not been determined. In both normal volunteers
and patients with hypercholesterolemia, treatment with Pravastatin Sodium
Tablets reduced Total-C, LDL-C, and apolipoprotein B. Pravastatin Sodium Tablets
also reduced VLDL-C and TG and produced increases in HDL-C and apolipoprotein
A. The effects of pravastatin on Lp (a), fibrinogen, and certain other independent
biochemical risk markers for coronary heart disease are unknown. Although
pravastatin is relatively more hydrophilic than other HMG-CoA reductase inhibitors,
the effect of relative hydrophilicity, if any, on either efficacy or safety
has not been established. In one primary (West of Scotland
Coronary Prevention Study - WOS)and two secondary
(Long-term Intervention with Pravastatin in Ischemic Disease - LIPIDand
the Cholesterol and Recurrent Events - CARE) prevention
studies, Pravastatin Sodium Tablets have been shown to reduce cardiovascular
morbidity and mortality across a wide range of cholesterol levels (see Clinical Studies).<br/>Pharmacokinetics/Metabolism: Pravastatin Sodium Tablets are administered orally in the active
form. In clinical pharmacology studies in man, pravastatin is rapidly absorbed,
with peak plasma levels of parent compound attained 1 to 1.5 hours following
ingestion. Based on urinary recovery of radiolabeled drug, the average oral
absorption of pravastatin is 34% and absolute bioavailability is 17%. While
the presence of food in the gastrointestinal tract reduces systemic bioavailability,
the lipid-lowering effects of the drug are similar whether taken with, or
1 hour prior to, meals. Pravastatin undergoes extensive first-pass extraction in the liver
(extraction ratio 0.66), which is its primary site of action, and the primary
site of cholesterol synthesis and of LDL-C clearance. In vitro studies
demonstrated that pravastatin is transported into hepatocytes with substantially
less uptake into other cells. In view of pravastatin's apparently extensive
first-pass hepatic metabolism, plasma levels may not necessarily correlate
perfectly with lipid-lowering efficacy. Pravastatin plasma concentrations
[including: area under the concentration-timecurve (AUC), peak (C),
and steady-state minimum (C)] are directly proportional
to administered dose. Systemic bioavailability of pravastatin administered
following a bedtime dose was decreased 60% compared to that following an AM
dose. Despite this decrease in systemic bioavailability, the efficacy of pravastatin
administered once daily in the evening, although not statistically significant,
was marginally more effective than that after a morning dose. This finding
of lower systemic bioavailability suggests greater hepatic extraction of the
drug following the evening dose. Steady-state AUCs, Cand
Cplasma concentrations showed no evidence of pravastatin
accumulation following once or twice daily administration of Pravastatin Sodium
Tablets. Approximately 50% of the circulating drug is bound to plasma proteins.
Following single dose administration ofC-pravastatin,
the elimination half-life (t) for total radioactivity
(pravastatin plus metabolites) in humans is 77 hours. Pravastatin, like other HMG-CoA reductase inhibitors, has variable
bioavailability. The coefficient of variation (CV), based on between-subject
variability, was 50% to 60% for AUC. Pravastatin 20 mg was administered under
fasting conditions in adults. The geometric means of Cand
AUC ranged from 23.3 to 26.3 ng/mL and from 54.7 to 62.2 ng���hr/mL, respectively. Approximately 20% of a radiolabeled oral dose is excreted in urine
and 70% in the feces. After intravenous administration of radiolabeled pravastatin
to normal volunteers, approximately 47% of total body clearance was via renal
excretion and 53% by non-renal routes (i.e., biliary excretion and biotransformation).
Since there are dual routes of elimination, the potential exists both for
compensatory excretion by the alternate route as well as for accumulation
of drug and/or metabolites in patients with renal or hepatic insufficiency. In a study comparing the kinetics of pravastatin in patients with
biopsy confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied
18-fold in cirrhotic patients and 5-fold in healthy subjects. Similarly, the
peak pravastatin values varied 47-fold for cirrhotic patients compared to
6-fold for healthy subjects. Biotransformation pathways elucidated for pravastatin include:
(a) isomerization to 6-epi pravastatin and the 3��-hydroxyisomer of pravastatin
(SQ 31,906), (b) enzymatic ring hydroxylation to SQ 31,945, (c)��-1 oxidation
of the ester side chain, (d)��-oxidation of the carboxy side chain, (e) ring
oxidation followed by aromatization, (f) oxidation of a hydroxyl group to
a keto group, and (g) conjugation. The major degradation product is the 3��-hydroxy
isomeric metabolite, which has one-tenth to one-fortieth the HMG-CoA reductase
inhibitory activity of the parent compound. In a single oral dose study using pravastatin 20 mg, the mean AUC
for pravastatin was approximately 27% greater and the mean cumulative urinary
excretion (CUE) approximately 19% lower in elderly men (65 to 75 years old)
compared with younger men (19 to 31 years old). In a similar study conducted
in women, the mean AUC for pravastatin was approximately 46% higher and the
mean CUE approximately 18% lower in elderly women (65 to 78 years old) compared
with younger women (18 to 38 years old). In both studies, C,
Tand tvalues were similar
in older and younger subjects. After 2 weeks of once-daily 20 mg oral pravastatin administration,
the geometric means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng���hr/mL for
children (8-11 years, N=14) and adolescents (12-16 years, N=10), respectively.
The corresponding values for Cwere 42.4 (CV 54%)
and 18.6 ng/mL (CV 100%) for children and adolescents, respectively. No conclusion
can be made based on these findings due to the small number of samples and
large variability.<br/>CLINICAL STUDIES:<br/>Prevention of Coronary Heart Disease: In the Pravastatin Primary Prevention Study (West of Scotland Coronary
Prevention Study���WOS), the effect of Pravastatin
Sodium Tablets on fatal and nonfatal coronary heart disease (CHD) was assessed
in 6595 men 45���64 years of age, without a previous myocardial infarction (MI),
and with LDL-C levels between 156���254 mg/dL (4���6.7 mmol/L). In this randomized,
double-blind, placebo-controlled study, patients were treated with standard
care, including dietary advice, and either Pravastatin Sodium Tablets 40 mg
daily (N=3302) or placebo (N=3293) and followed for a median duration of 4.8
years. Median (25, 75percentile)
percent changes from baseline after 6 months of pravastatin treatment in Total-C,
LDL-C, TG, and HDL-C were -20.3 (-26.9, -11.7), -27.7 (-36.0, -16.9), -9.1
(-27.6, 12.5), and 6.7 (-2.1, 15.6), respectively. Pravastatin Sodium Tablets significantly reduced the rate of first
coronary events (either coronary heart disease [CHD] death or nonfatal MI)
by 31% [248 events in the placebo group (CHD death=44, nonfatal MI=204) vs
174 events in the Pravastatin Sodium Tablets group (CHD death=31, nonfatal
MI=143), p=0.0001 (see figure below)]. The risk reduction with Pravastatin
Sodium Tablets was similar and significant throughout the entire range of
baseline LDL cholesterol levels. This reduction was also similar and significant
across the age range studied with a 40% risk reduction for patients younger
than 55 years and a 27% risk reduction for patients 55 years and older. The
Pravastatin Primary Prevention Study included only men, and therefore it is
not clear to what extent these data can be extrapolated to a similar population
of female patients. Pravastatin Sodium Tablets also significantly decreased the risk
for undergoing myocardial revascularization procedures (coronary artery bypass
graft [CABG] surgery or percutaneous transluminal coronary angioplasty [PTCA])
by 37% (80 vs 51 patients, p=0.009) and coronary angiography by 31% (128 vs
90, p=0.007). Cardiovascular deaths were decreased by 32% (73 vs
50, p=0.03) and there was no increase in death from non-cardiovascular causes.<br/>Secondary Prevention of Cardiovascular Events: In the Long-term Intervention with Pravastatin
in Ischemic Disease (LIPID)study, the effect
of Pravastatin Sodium Tablets, 40 mg daily, was assessed in 9014 patients
(7498 men; 1516 women; 3514 elderly patients [age���65 years]; 782 diabetic
patients) who had experienced either an MI (5754 patients) or had been hospitalized
for unstable angina pectoris (3260 patients) in the preceding 3-36 months.
Patients in this multicenter, double-blind, placebo-controlled study participated
for an average of 5.6 years (median of 5.9 years) and at randomization had
total cholesterol between 114 and 563 mg/dL (mean 219 mg/dL), LDL-C between
46 and 274 mg/dL (mean 150 mg/dL), triglycerides between 35 and 2710 mg/dL
(mean 160 mg/dL), and HDL-C between 1 and 103 mg/dL (mean 37 mg/dL). At baseline,
82% of patients were receiving aspirin and 76% were receiving antihypertensive
medication. Treatment with Pravastatin Sodium Tablets significantly reduced
the risk for total mortality by reducing coronary death (see Table 1). The
risk reduction due to treatment with Pravastatin Sodium Tablets on CHD mortality
was consistent regardless of age. Pravastatin Sodium Tablets significantly
reduced the risk for total mortality (by reducing CHD death) and CHD events
(CHD mortality or nonfatal MI) in patients who qualified with a history of
either MI or hospitalization for unstable angina pectoris. In the Cholesterol and Recurrent Events (CARE)study
the effect of Pravastatin Sodium Tablets, 40 mg daily, on coronary heart disease
death and nonfatal MI was assessed in 4159 patients (3583 men and 576 women)
who had experienced a myocardial infarction in the preceding 3-20 months and
who had normal (below the 75percentile of the
general population) plasma total cholesterol levels. Patients in this double-blind,
placebo-controlled study participated for an average of 4.9 years and had
a mean baseline total cholesterol of 209 mg/dL. LDL-cholesterol
levels in this patient population ranged from 101 mg/dL���180 mg/dL
(mean 139 mg/dL). At baseline, 84% of patients were receiving aspirin and
82% were taking antihypertensive medications. Median (25,
75percentile) percent changes from baseline
after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were
-22.0 (-28.4, -14.9), -32.4 (-39.9, -23.7), -11.0 (-26.5, 8.6), and 5.1 (-2.9,
12.7), respectively. Treatment with Pravastatin Sodium Tablets significantly
reduced the rate of first recurrent coronary events (either CHD death or nonfatal
MI), the risk of undergoing revascularization procedures (PTCA, CABG), and
the risk for stroke or transient ischemic attack (TIA) (see Table 2). In the Pravastatin Limitation of Atherosclerosis in the
Coronary Arteries (PLAC I)study, the effect of
pravastatin therapy on coronary atherosclerosis was assessed by coronary angiography
in patients with coronary disease and moderate hyper��cholesterolemia (baseline
LDL-C range: 130-190 mg/dL). In this double-blind, multicenter, controlled
clinical trial, angiograms were evaluated at baseline and at three years in
264 patients. Although the difference between pravastatin and placebo for
the primary endpoint (per-patient change in mean coronary artery diameter)
and one of two secondary endpoints (change in percent lumen diameter stenosis)
didnot reach statistical significance, for the secondary endpoint of change
in minimum lumen diameter, statistically significant slowing of disease was
seen in the pravastatin treatment group (p=0.02). In
the Regression Growth Evaluation Statin Study (REGRESS),
the effect of pravastatin on coronary atherosclerosis was assessed by coronary
angiography in 885 patients with angina pectoris, angiographically documented
coronary artery disease and hypercholesterolemia (baseline total cholesterol
range: 160-310 mg/dL). In this double-blind, multicenter, controlled clinical
trial, angiograms were evaluated at baseline and at two years in 653 patients
(323 treated with pravastatin). Progression of coronary atherosclerosis was
significantly slowed in the pravastatin group as assessed by changes in mean
segment diameter (p=0.037) and minimum obstruction diameter (p=0.001). Analysis
of pooled events from PLAC I, the Pravastatin, Lipids and Atherosclerosis
in the Carotids Study (PLAC II), REGRESS, and
the Kuopio Atherosclerosis Prevention Study (KAPS)(combined
N=1891) showed that treatment with pravastatin was associated with a statistically
significant reduction in the composite event rate of fatal and nonfatal myocardial
infarction (46 events or 6.4% for placebo versus 21 events or 2.4% for pravastatin,
p=0.001). The predominant effect of pravastatin was to reduce the rate of
nonfatal myocardial infarction.<br/>Primary Hypercholesterolemia (Fredrickson Type IIa and IIb): Pravastatin Sodium Tablets are highly
effective in reducing Total-C, LDL-C and triglycerides (TG) in patients with
heterozygous familial, presumed familial combined and non-familial (non-FH)
forms of primary hypercholesterolemia, and mixed dyslipidemia. A therapeutic
response is seen within 1 week, and the maximum response usually is achieved
within 4 weeks. This response is maintained during extended periods of therapy.
In addition, Pravastatin Sodium Tablets are effective in reducing the risk
of acute coronary events in hypercholesterolemic patients with and without
previous myocardial infarction. A single daily dose
is as effective as the same total daily dose given twice a day. In multicenter,
double-blind, placebo-controlled studies of patients with primary hypercholesterolemia,
treatment with pravastatin in daily doses ranging from 10 mg to 40 mg consistently
and significantly decreased Total-C, LDL-C, TG, and Total-C/HDL-C and LDL-C/HDL-C
ratios (see Table 3). In a pooled analysis of two multicenter,
double-blind, placebo-controlled studies of patients with primary hypercholesterolemia,
treatment with pravastatin at a daily dose of 80 mg (N=277) significantly
decreased Total-C, LDL-C, and TG. The 25and
75percentile changes from baseline in LDL-C
for pravastatin 80 mg were -43% and -30%. The efficacy results of the individual
studies were consistent with the pooled data (see Table 3). Treatment
with Pravastatin Sodium Tablets modestly decreased VLDL-C and Pravastatin
Sodium Tablets across all doses produced variable increases in HDL-C (see
Table 3). In another clinical trial, patients treated with pravastatin
in combination with cholestyramine (70% of patients were taking cholestyramine
20 or 24 g per day) had reductions equal to or greater than 50% in LDL-C.
Furthermore, pravastatin attenuated cholestyramine-induced increases in TG
levels (which are themselves of uncertain clinical significance).<br/>Hypertriglyceridemia (Fredrickson Type IV): The response to pravastatin in patients
with Type IV hyperlipidemia (baseline TG>200 mg/dL and LDL-C<160 mg/dL)
was evaluated in a subset of 429 patients from the Cholesterol and Recurrent
Events (CARE) study. For pravastatin-treated subjects, the median (min, max)
baseline triglyceride level was 246.0 (200.5, 349.5) mg/dL. (See Table 4.)<br/>Dysbetalipoproteinemia (Fredrickson Type III): The response to pravastatin in two double-blind
crossover studies of 46 patients with genotype E2/E2 and Fredrickson Type
III dysbetalipoproteinemia is shown in Table 5.<br/>Pediatric Clinical Study: A double-blind, placebo-controlled study
in 214 patients (100 boys and 114 girls) with heterozygous familial hypercholesterolemia
(HeFH), aged 8-18 years was conducted for two (2) years. The children (aged
8-13 years) were randomized to placebo (N=63) or 20 mg of pravastatin daily
(N=65) and the adolescents (aged 14-18 years) were randomized to placebo (N=45)
or 40 mg of pravastatin daily (N=41). Inclusion in the study required an LDL-C
level>95percentile for age and sex and one
parent with either a clinical or molecular diagnosis of familial hypercholesterolemia.
The mean baseline LDL-C value was 239 mg/dL and 237 mg/dL
in the pravastatin (range: 151-405 mg/dL) and placebo (range: 154-375 mg/dL)
groups, respectively. Pravastatin significantly decreased
plasma levels of LDL-C, Total-C, and apolipoprotein B in both children and
adolescents (see Table 6). The effect of pravastatin treatment in the two
age groups was similar. The mean achieved LDL-C was 186 mg/dL (range: 67-363 mg/dL)
in the pravastatin group compared to 236 mg/dL (range: 105-438 mg/dL) in the
placebo group. The safety and efficacy of pravastatin
doses above 40 mg daily have not been studied in children. The long-term efficacy
of pravastatin therapy in childhood to reduce morbidity and mortality in adulthood
has not been established.
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Hypersensitivity to any component of this medication. Active liver disease or unexplained, persistent elevations of serum
transaminases . 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 are contraindicated during pregnancy and in nursing mothers. Pravastatin
should be administered to women of childbearing ageonly 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 immediately and the patient apprised of the potential hazard
to the fetus .
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Pravastatin Sodium Tablets are supplied as: 10 mg tablets: Pink to peach, rounded, rectangular-shaped,
biconvex with a "10" embossed on one side and "0013" engraved on the opposite
side. They are supplied in bottles of 90 (NDC 0591-0013-19). Bottles contain
a desiccant canister. 20 mg tablets: Yellow, rounded, rectangular-shaped,
biconvex with a "20" embossed on one side and "0014" engraved on the opposite
side. They are supplied in bottles of 90 (NDC 0591-0014-19). Bottles contain
a desiccant canister. 40 mg tablets: Green, rounded, rectangular-shaped,
biconvex with a "40" embossed on one side and "0016" engraved on the opposite
side. They are supplied in bottles of 90 (NDC 0591-0016-19). Bottles contain
a desiccant canister. 80 mg tablets: Yellow, oval-shaped tablet with "80"
on one side and "0019" on the other side. They are supplied in bottles of
90 (NDC 0591-0019-19) and bottles of 500 (NDC 0591-0019-05). Bottles contain
a desiccant canister.<br/>Storage: Store at 25��C (77��F); excursions permitted to 15��-30��C (59��-86��F) [see USP Controlled Room Temperature]. Keep tightly closed (protect from
moisture). Protect from light.
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General: Pravastatin Sodium Tablets 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. 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��-hydroxy isomeric metabolite (SQ 31,906). A small
increase was seen in mean AUC values and half-life (t)
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.<br/>Information for Patients: Patients should be advised to report promptly unexplained muscle
pain, tenderness or weakness, particularly if accompanied by malaise or fever
.<br/>Drug Interactions: Immunosuppressive Drugs, Gemfibrozil, Niacin (Nicotinic Acid),
Erythromycin: See WARNINGS: Skeletal Muscle. Cytochrome P450 3A4 Inhibitors: In vitro and in
vivo data indicate that pravastatin is not metabolized by cytochrome
P450 3A4 to a clinically significant extent. This has been shown in studies
with known cytochrome P450 3A4 inhibitors (see Diltiazem and Itraconazole below). Other examples of cytochrome
P450 3A4 inhibitors include ketoconazole, mibefradil, and erythromycin. Diltiazem: Steady-state levels of diltiazem (a known,
weak inhibitor of P450 3A4) had no effect on the pharmacokinetics of pravastatin.
In this study, the AUC and Cof another HMG-CoA
reductase inhibitor which is known to be metabolized by cytochrome P450 3A4
increased by factors of 3.6 and 4.3, respectively. Itraconazole: The mean AUC and Cfor
pravastatin were increased by factors of 1.7 and 2.5, respectively, when given
with itraconazole (a potent P450 3A4 inhibitor which also inhibits p-glycoprotein
transport) as compared to placebo. The mean twas
not affected by itraconazole, suggesting that the relatively small increases
in Cand AUC were due solely to increased bioavailability
rather than a decrease in clearance, consistent with inhibition of p-glycoprotein
transport by itraconazole. This drug transport system is thought to affect
bioavailability and excretion of HMG-CoA reductase inhibitors, including pravastatin.
The AUC and Cof another HMG-CoA reductase inhibitor
which is known to be metabolized by cytochrome P450 3A4 increased by factors
of 19 and 17, respectively, when given with itraconazole. 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. Warfarin: Concomitant administration of 40 mg pravastatin
had no clinically significant effect on prothrombin time when administered
in a study to normal elderly subjects who were stabilized on warfarin. Cimetidine: The AUCfor
pravastatin when given with cimetidine was not significantly different from
the AUC for pravastatin when given alone. A significant difference was observed
between the AUC's for pravastatin when given with cimetidine compared to when
administered with antacid. Digoxin: In a crossover trial involving 18 healthy
male subjects given 20 mg pravastatin and 0.2 mg 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 (up to 20 mg), 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, C,
and Tfor 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 Pravastatin Sodium Tablets), cimetidine, nicotinic acid, or probucol,
no statistically significant differences in bioavailability were seen when
Pravastatin Sodium Tablets were administered.<br/>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���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. In a placebo-controlled
study of 214 pediatric patients with HeFH, of which 106 were treated with
pravastatin (20 mg in the children aged 8-13 years and 40 mg in the adolescents
aged 14-18 years) for two years, there were no detectable differences seen
in any of the endocrine parameters [ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol
(girls) or testosterone (boys)] relative to placebo. There were no detectable
differences seen in height and weight changes, testicular volume changes,
or Tanner score relative to placebo.<br/>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. These effects
in dogs were observed at approximately 59 times the human dose of 80 mg/day,
based on AUC. 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.<br/>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). These effects in rats
were observed at approximately 12 times the human dose (HD) of 80 mg based
on body surface area mg/mand at approximately
4 times the human dose, based on 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). These effects
in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times
(500 mg/kg/day) the human dose of 80 mg, based on AUC. In another 2-year study
in mice with doses up to 100 mg/kg/day (producing drug exposures approximately
2 times the human dose of 80 mg, based on AUC), 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, 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.<br/>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 10X (rabbit) or
120X (rat) the human exposure based on surface area (mg/meter).
Rare reports of congenital anomalies have been received following intrauterine
exposure to other HMG-CoA reductase inhibitors. In a reviewof
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 three-
to four-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 Tablets
during pregnancy ,
treatment should be immediately discontinued as soon as pregnancy is recognized.
Pravastatin Sodium Tablets should be administered to womenof childbearing
potential only when such patients are highly unlikely to conceive and have
been informed of the potential hazards.<br/>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 Tablets should not nurse .<br/>Pediatric Use: The safety and effectiveness of Pravastatin
Sodium Tablets in children and adolescents from 8-18 years of age have been
evaluated in a placebo-controlled study of 2 years duration. Patients treated
with pravastatin had an adverse experience profile generally similar to that
of patients treated with placebo with influenza and headache commonly reported
in both treatment groups. (See ADVERSE REACTIONS:
Pediatric Patients.) Doses greater than 40 mg have not
been studied in this population. Children and adolescent females of
childbearing potential should be counseled on appropriate contraceptive methods
while on pravastatin therapy . For dosing information
see DOSAGE AND ADMINISTRATION: Adult Patients and Pediatric Patients. Double-blind,
placebo-controlled pravastatin studies in children less than 8 years of age
have not been conducted.<br/>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 two 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 inyounger 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 C, Tand
tvalues are similar in both age groups and substantial
accumulation of pravastatin would not be expected in the elderly .
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To date, there has been limited experience with overdosage of pravastatin.
If an overdose occurs, it should be treated symptomatically with laboratory
monitoring and supportive measures should be instituted as required.
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PRAVASTATIN SODIUM
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PRAVASTATIN SODIUM (Tablet)
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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.<br/>Adverse Clinical Events:<br/>Short-Term Controlled Trials: All adverse clinical events (regardless of attribution) reported
in more than 2% of pravastatin-treated patients in placebo-controlled trials
of up to four months duration are identified in Table 8; also shown are the
percentages of patients in whom these medical events were believed to be related
or possibly related to the drug: The safety and tolerability of Pravastatin Sodium Tablets at a
dose of 80 mg in two controlled trials with a mean exposure of 8.6 months
was similar to that of Pravastatin Sodium Tablets at lower doses except that
4 out of 464 patients taking 80 mg of pravastatin had a single elevation of
CK>10X ULN compared to 0 out of 115 patients taking 40 mg of pravastatin.<br/>Long-Term Controlled Morbidity and Mortality Trials: Adverse event data were pooled from seven
double-blind, placebo-controlled trials (West of Scotland Coronary Prevention
Study [WOS]; Cholesterol and Recurrent Events study [CARE]; Long-term Intervention
with Pravastatin in Ischemic Disease study [LIPID]; Pravastatin Limitation
of Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids
and Atherosclerosis in the Carotids study [PLAC II]; Regression Growth Evaluation
Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention Study [KAPS])
involving a total of 10,764 patients treated with pravastatin 40 mg and 10,719
patients treated with placebo. The safety and tolerability profile in the
pravastatin group was comparable to that of the placebo group. Patients were
exposed to pravastatin for a mean of 4.0 to 5.1 years in WOS,CARE, and LIPID
and 1.9 to 2.9 years in PLAC I, PLAC II, KAPS, and REGRESS. In these long-term
trials, the most common reasons for discontinuation were mild, non-specific
gastrointestinal complaints. Collectively, these seven trials represent 47,613
patient-years of exposure to pravastatin. Events believed to be of probable,
possible, or uncertain relationship to study drug, occurring in at least 1%
of patients treated with pravastatin in these studies are identified in Table
9. Events of probable, possible, or uncertain relationship
to study drug that occurred in<1.0% of pravastatin-treated patients in
the long-term trials included the following; frequencies were similar in placebo-treated
patients: Dermatologic: pruritus,
dermatitis, dryness skin, scalp hair abnormality (including alopecia), urticaria. Endocrine/Metabolic: sexual
dysfunction, libido change. Gastrointestinal: decreased
appetite. General: fever, flushing. Immunologic: allergy,
edema head/neck. Musculoskeletal: muscle
weakness. Nervous System: paresthesia,
vertigo, insomnia, memory impairment, tremor, neuropathy (including peripheral
neuropathy). Special Senses: lens
opacity, taste disturbance.<br/>Postmarketing Experience: In addition to the events reported above, as with other drugs in
this class, the following events have been reported rarely during postmarketing
experience with Pravastatin Sodium Tablets, regardless of causality assessment: Musculoskeletal: myopathy, rhabdomyolysis. Nervous System: dysfunction of certain cranial
nerves (including alteration of taste, impairment of extraocular movement,
facial paresis), peripheral nerve palsy. Hypersensitivity: anaphylaxis, angioedema, lupus
erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis,
purpura, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia,
asthenia, photosensitivity, chills, malaise, toxic epidermal necrolysis, erythema
multiforme, including Stevens-Johnson syndrome. Gastrointestinal: pancreatitis, hepatitis, including
chronic active hepatitis, cholestatic jaundice, fatty change in liver, cirrhosis,
fulminant hepatic necrosis, hepatoma. Dermatologic: a variety of skin changes (e.g.,
nodules, discoloration, dryness of mucous membranes, changes to hair/nails). Reproductive: gynecomastia. Laboratory Abnormalities: Liver Function Test
abnormalities, thyroid function abnormalities.<br/>Laboratory Test Abnormalities: Increases in serum transaminase (ALT, AST) values and CPK have
been observed . Transient, asymptomatic eosinophilia has been reported. Eosinophil
counts usually returned to normal despite continued therapy. Anemia, thrombocytopenia,
and leukopenia have been reported with HMG-CoA reductase inhibitors.<br/>Concomitant Therapy: Pravastatin has been administered concurrently with cholestyramine,
colestipol, nicotinic acid, probucol and gemfibrozil. Preliminary data suggest
that the addition of either probucol or gemfibrozil to therapy with lovastatin
or pravastatin is not associated with greater reduction in LDL-cholesterol
than that achieved with lovastatin or pravastatin alone. No adverse reactions
unique to the combination or in addition to those previously reported for
each drug alone have been reported. Myopathy and rhabdomyolysis (with or without
acute renal failure) have been reported when another HMG-CoA reductase inhibitor
was used in combination with immunosuppressive drugs, gemfibrozil, erythromycin,
or lipid-lowering doses ofnicotinic acid. Concomitant therapy with HMG-CoA
reductase inhibitors and these agents is generally not recommended. (See WARNINGS: Skeletal Muscle and PRECAUTIONS:
Drug Interactions.)<br/>Pediatric Patients: In a two-year, double-blind, placebo-controlled study involving
100 boys and 114 girls with HeFH, the safety and tolerability profile of pravastatin
was generally similar to that of placebo. (See CLINICAL
PHARMACOLOGY: Pediatric Clinical Study and PRECAUTIONS:
Pediatric Use.)
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Liver Enzymes: HMG-CoA reductase inhibitors, like some other lipid-lowering therapies,
have been associated with biochemical abnormalities of liver function. In
three long-term (4.8-5.9 years), placebo-controlled clinical trials (WOS,
LIPID, CARE; see CLINICAL PHARMACOLOGY: Clinical
Studies), 19,592 subjects (19,768 randomized), were exposed
to pravastatin or placebo. In an analysis of serum transaminase values (ALT,
AST), incidences of marked abnormalities were compared between the pravastatin
and placebo treatment groups; a marked abnormality was defined as a post-treatment
test value greater than three times the upper limit of normal for subjects
with pretreatment values less than or equal to the upper limit of normal,
or four times the pretreatment value for subjects with pretreatment values
greater than the upper limit of normal but less than 1.5 times the upper limit
of normal. Marked abnormalities of ALT or AST occurred with similar low frequency
(���1.2%) in both treatment groups. Overall, clinical trial experience showed
that liver function test abnormalities observed during pravastatin therapy
were usually asymptomatic, not associated with cholestasis, and did not appear
to be related to treatment duration. In a 320-patient placebo-controlled clinical
trial, subjects with chronic (>6 months) stable liver disease, due primarily
to hepatitis C or non-alcoholic fatty liver disease, were treated with 80
mg pravastatin or placebo for up to 9 months. The primary safety endpoint
was the proportion of subjects with at least one ALT���2 times the upper limit
of normal for those with normal ALT (���the upper limit of normal) at baseline
or a doubling of the baseline ALT for those with elevated ALT (>the upper
limit of normal) at baseline. By Week 36, 12 out of 160 (7.5%) subjects treated
with pravastatin met the prespecified safety ALT endpoint compared to 20 out
of 160 (12.5%) subjects receiving placebo. Conclusions regarding liver safety
are limited since the study was not large enough to establish similarity between
groups (with 95% confidence) in the rates of ALT elevation. It is recommended that liver function tests be performed
prior to the initiation of therapy and when clinically indicated. Active liver disease or unexplained persistent transaminase elevations
are contraindications to the use of pravastatin .
Caution should be exercised when pravastatin is administered to patients who
have a recent (<6 months) history of liver disease, have signs that may
suggest liver disease (e.g., unexplained aminotransferase elevations, jaundice),
or are heavy users of alcohol (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. Patients who develop increased transaminase levels or signs and
symptoms of active liver disease while taking pravastatin should be evaluated
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.<br/>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 . Myopathy,
defined as muscle aching or muscle weakness in conjunction with increases
in creatine phosphokinase (CPK) values to greater than 10 times the upper
limit of normal, 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. 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.
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| dailymed-instance:indicatio... |
Therapy with Pravastatin Sodium Tablets should be considered in
those individuals at increased risk for atherosclerosis-related clinical events
as a function of cholesterol level, the presence or absence of coronary heart
disease, and other risk factors.<br/>Primary Prevention of Coronary Events: In hypercholesterolemic patients without clinically evident coronary
heart disease, Pravastatin Sodium Tablets are indicated to:<br/>Secondary Prevention of Cardiovascular Events: In patients with clinically evident coronary heart disease, Pravastatin
Sodium Tablets are indicated to:<br/>Hyperlipidemia: Pravastatin Sodium Tablets are indicated
as an adjunct to diet to reduce elevated Total-C, LDL-C, ApoB, and TG levels
and to increase HDL-C in patients with primary hypercholesterolemia and mixed
dyslipidemia (Fredrickson Type IIa and IIb). Pravastatin
Sodium Tablets are indicated as adjunctive therapy to diet for the treatment
of patients with elevated serum triglyceride levels (Fredrickson Type IV). Pravastatin
Sodium Tablets are indicated for the treatment of patients with primary dysbetalipoproteinemia
(Fredrickson Type III) who do not respond adequately to diet. Pravastatin
Sodium Tablets are indicated as an adjunct to diet and lifestyle modification
for treatment of HeFH in children and adolescent patients ages 8 years and
older if after an adequate trial of diet the following findings are present: Lipid-altering agents should be used in addition to a diet
restricted in saturated fat and cholesterol when the response to diet and
other nonpharmacological measures alone has been inadequate (see NCEP Guidelines
below). Prior to initiating therapy with pravastatin,
secondary causes for hypercholesterolemia (e.g., poorly controlled diabetes
mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive
liver disease, other drug therapy, alcoholism) should be excluded, and a lipid
profile performed to measure Total-C, HDL-C, and TG. For patients with triglycerides
(TG)<400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the following
equation: LDL-C = Total-C - HDL-C -
1/5 TG For TG levels>400 mg/dL (>4.5 mmol/L), this
equation is less accurate and LDL-C concentrations should be determined by
ultracentrifugation. In many hypertri��glyceridemic patients, LDL-C may be
low or normal despite elevated Total-C. In such cases, HMG-CoA reductase inhibitors
are not indicated. Lipid determinations should be performed
at intervals of no less than four weeks and dosage adjusted according to the
patient's response to therapy. The National Cholesterol
Education Program's Treatment Guidelines are summarized below: After the LDL-C goal has been achieved, if the TG is still���200 mg/dL, non-HDL-C (Total-C minus HDL-C) becomes a secondary target of
therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each
risk category. At the time of hospitalization for
an acute coronary event, consideration can be given to initiating drug therapy
at discharge if the LDL-C is���130 mg/dL (see NCEP Guidelines, above). Since
the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels
be used to initiate and assess treatment response. Only if LDL-C levels are
not available, should the Total-C be used to monitor therapy. As
with other lipid-lowering therapy, Pravastatin Sodium Tablets are not indicated
when hypercholesterolemia is due to hyperalphalipoproteinemia (elevated HDL-C). The
NCEP classification of cholesterol levels in pediatric patients with a familial
history of hypercholesterolemia or premature cardiovascular disease is summarized
below:
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PRAVASTATIN SODIUM
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