Pravastatin sodium is 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-naphthaleneheptanoic acid,
1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-,
monosodium salt, [1S-[1α (βS*,δS*),2α,6α,8β(R*),8aα]]-. It has the following structural formula: C23 H35 NaO7
M.W. 446.52
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 (greater than 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, and 40 mg tablets. Inactive ingredients include: calcium phosphate dibasic,
croscarmellose sodium, crospovidone, lactose, microcrystalline cellulose,
povidone, and sodium stearyl fumarate. The 10 mg tablet also contains ferric
oxide red, the 20 mg tablet also contains ferric oxide yellow, and the 40 mg
tablet also contains Yellow DC No. 10 and FD&C Blue No. 1.
Pravastatin sodium tablets USP are available for oral administration as 80 mg
tablets. Inactive ingredients include: calcium phosphate dibasic, crospovidone,
lactose, magnesium stearate, microcrystalline cellulose, and povidone.
Clinical Pharmacology
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 produces 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 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)1 prevention study, pravastatin has been shown to reduce
cardiovascular morbidity and mortality across a wide range of cholesterol levels
(see Clinical Studies). Pharmacokinetics/Metabolism Pravastatin sodium is 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-time
curve (AUC), peak (Cmax), and steady-state minimum
(Cmin)] 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, Cmax and Cmin plasma 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 of 14C-pravastatin,
the elimination half-life (t½) 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 Cmax
and 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 3α-hydroxyisomer of pravastatin (SQ
31,906), (b) enzymatic ring hydroxylation to SQ 31,945, (c) ω-1 oxidation of the
ester side chain, (d) β-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 3α-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, Cmax, Tmax and t½
values 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 to 11 years, N = 14) and adolescents (12 to 16 years, N = 10),
respectively. The corresponding values for Cmax were 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.
Clinical StudiesPrevention of Coronary Heart Disease In the Pravastatin Primary Prevention Study (West of Scotland
Coronary Prevention Study – WOS)1, the effect of
pravastatin sodium on fatal and nonfatal coronary heart disease (CHD) was
assessed in 6595 men 45 to 64 years of age, without a previous myocardial
infarction (MI), and with LDL-C levels between 156 to 254 mg/dL (4 to 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 40 mg daily (N = 3302) or placebo (N = 3293) and followed for
a median duration of 4.8 years. Median (25th, 75th percentile) 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 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 group (CHD death = 31, nonfatal MI = 143), p = 0.0001 (see
figure below)]. The risk reduction with pravastatin sodium 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 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. Secondary Prevention of Cardiovascular Events In the Pravastatin Limitation of Atherosclerosis in the Coronary
Arteries (PLAC I)2 study, the effect of pravastatin
therapy on coronary atherosclerosis was assessed by coronary angiography in
patients with coronary disease and moderate hypercholesterolemia (baseline LDL-C
range: 130 to 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) did not 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)3, 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 to 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)4,
REGRESS, and the Kuopio Atherosclerosis Prevention Study (KAPS)5 (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. Primary Hypercholesterolemia (Fredrickson Type IIa and
IIb) Pravastatin sodium is 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 is 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
1).
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 25th and 75th
percentile 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 1).
Treatment with pravastatin sodium modestly decreased VLDL-C and pravastatin
sodium across all doses produced variable increases in HDL-C (see Table 1).
Table 1: Primary Hypercholesterolemia Studies: Dose Response of Pravastatin Once Daily Administration
Dose
Total-C
LDL-C
HDL-C
TG
Mean Percent Changes From
Baseline After 8 Weeks*
Placebo (N = 36)
-3%
-4%
+1%
-4%
10 mg (N = 18)
-16%
-22%
+7%
-15%
20 mg (N = 19)
-24%
-32%
+2%
-11%
40 mg (N = 18)
-25%
-34%
+12%
-24%
Mean Percent Changes From
Baseline After 6 Weeks**
Placebo (N = 162)
0%
-1%
-1%
+1%
80 mb (N = 277)
-27%
-37%
+3%
-19%
* a multicenter, double-blind, placebo-controlled study** pooled analysis of 2 multicenter, double-blind, placebo controlled studies
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). Hypertriglyceridemia (Fredrickson Type IV) The response to pravastatin in patients with Type IV
hyperlipidemia (baseline TG greater than 200 mg/dL and LDL-C less than 160 mg/dL) was
evaluated in a subset of 429 patients. For pravastatin-treated subjects, the
median (min, max) baseline triglyceride level was 246.0 (200.5, 349.5) mg/dL.
(See Table 2.)
Table 2: Patients with Fredrickson Type IV Hyperlipidemia: Median
(25th, 75th percentile) Percent
Change from Baseline
Pravastatin 40 mg (N = 429)
Placebo (N = 430)
Triglycerides
-21.1 (-34.8, 1.3)
-6.3 (-23.1, 18.3)
Total-C
-22.1 (-27.1, -14.8)
0.2 (-6.9, 6.8)
LDL-C
-31.7 (-39.6, -21.5)
0.7 (-9.0, 10.0)
HDL-C
7.4 (-1.2, 17.7)
2.8 (-5.7, 11.7)
Non-HDL-C
-27.2 (-34.0, -18.5)
-0.8 (-8.2, 7.0)
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 3.
Table 3: Patients with Fredrickson Type III Dysbetalipoproteinemia: Median (min, max) Percent Change from Baseline
* N = 14
Pediatric Clinical Study A double-blind, placebo-controlled study in 214 patients (100
boys and 114 girls) with heterozygous familial hypercholesterolemia (HeFH), aged
8 to 18 years was conducted for two (2) years. The children (aged 8 to 13 years)
were randomized to placebo (N = 63) or 20 mg of pravastatin daily (N = 65) and
the adolescents (aged 14 to 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
greater than 95th percentile 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 to 405 mg/dL) and placebo (range: 154 to 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
4). The effect of pravastatin treatment in the two age groups was
similar.
Table 4: Lipid-Lowering Effects of Pravastatin in Pediatric Patients with Heterozygous Familial Hypercholesterolemia: Least-Squares Mean Percent Change from Baseline at Month 24 (Last Observation Carried Forward: Intent-to-Treat)*
Pravastatin 20 mg(Ages 8 to 13years) N = 65
Pravastatin 40 mg(Aged 14 to 18years) N = 41
CombinedPravastatin(Aged 8 to 18years) N = 106
CombinedPlacebo (Aged 8to 18 years)N = 108
95% CI of the DifferenceBetween CombinedPravastatin and Placebo
LDL-C
-26.04**
-21.07**
-24.07**
-1.52
(-26.74, -18.86)
TC
-20.75**
-13.08**
-17.72**
-0.65
(-20.40, -13.83)
HDL-C
1.04
13.71
5.97
3.13
(-1.71, 7.43)
TG
-9.58
-0.30
-5.88
-3.27
(-13.95, 10.01)
ApoB (N)
-23.16** (61)
-18.08** (39)
-21.11** (100)
-0.97 (106)
(-24.29, -16.18)
* The above least-swaures mean values were calculated based on log-transformed lipid values.** Significant at p less than or equal to 0.0001 when compared with placebo.
The mean achieved LDL-C was 186 mg/dL (range: 67 to 363 mg/dL) in the
pravastatin group compared to 236 mg/dL (range: 105 to 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.
Indications And Usage
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. Primary Prevention of Coronary Events In hypercholesterolemic patients without clinically evident
coronary heart disease, pravastatin sodium tablets are indicated to:
- Reduce the risk of myocardial infarction
- Reduce the risk of undergoing myocardial revascularization procedures
- Reduce the risk of cardiovascular mortality with no increase in death from
non-cardiovascular causes 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).6
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:
LDL-C remains greater than or equal to 190 mg/dL or
LDL-C remains greater than or equal to 160 mg/dL and:
there is a positive family history of premature cardiovascular disease or
two or more other CVD risk factors are present in the patient.
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
Treatment 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) less than 400
mg/dL (less than 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 greater than 400 mg/dL (greater than 4.5 mmol/L), this equation is less
accurate and LDL-C concentrations should be determined by ultracentrifugation.
In many hypertriglyceridemic 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:
Table 5: NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes and Drug Therapy in Different Risk Categories
Risk Category
LDL Goal (mg/dL)
LDL Level at Which to Initiate Therapeutic Lifestyle Changes (mg/dL)
LDL Level at Which to Consider Drug Therapy (mg/dL)
CHDa or CHD risk
equivalents (10 year risk greater than 20%)
less than 100
greater than or equal to 100
greater than or equal to 130 (100 to 129: drug optional)b
2+ Risk factors (10 year risk less than or equal to 20%)
less than 130
greater than or equal to 130
10 year risk 10% to 20%: greater than 130
10 year risk less than 10%: greater thanor equal to 160
0 to 1 Risk factorc
less than 160
greater than or equal to 160
greater than or equal to 190 (160 to 189: LDL-lowering drug optional)
a CHD, coronary heart disease.b Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C
level of less than 100 mg/dL cannot be achieved by therapeutic lifestyle changes.
Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g.,
nicotinic acid or fibrate. Clinical judgement also may call for deferring drug
therapy in this subcategory.c Almost all people with 0 to 1 risk factor have 10 year risk less than 10%; thus, 10 year
risk assessment in people with 0 to 1 risk factor is not necessary.
After the LDL-C goal has been achieved, if the TG is still greater than or equal to 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 greater than or equal to 130 mg/dL
(see NCEP Treatment 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:
Category
Total-C
(mg/dL)
LDL-C
(mg/dL)
Acceptable
less than 170
less than 110
Borderline
170 to 199
110 to 129
High
greater than or equal to200
greater than or equal to 130
Contraindications
Hypersensitivity to any component of this medication.
Active liver disease or unexplained, persistent elevations of serum
transaminases (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 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 immediately and the patient
apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy).
Warnings
Liver Enzymes HMG-CoA reductase inhibitors, like some other lipid-lowering
therapies, have been associated with biochemical abnormalities of liver
function. In placebo-controlled clinical trials (see CLINICAL
PHARMACOLOGY, Clinical Studies), subjects 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 (less than or equal to 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 (greater than 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 greater than or equal to 2 times the upper limit of
normal for those with normal ALT (less than or equal to the upper limit of normal) at baseline or a
doubling of the baseline ALT for those with elevated ALT (greater than 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 (see CONTRAINDICATIONS). Caution should be exercised when
pravastatin is administered to patients who have a recent (less than 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 (see DOSAGE AND ADMINISTRATION, Adult
Patients), 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. 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 limit of normal, was rare (less than 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 to 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.
Precautions
General Pravastatin sodium 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
3α-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
(see WARNINGS, Skeletal
Muscle). Drug InteractionsImmunosuppressive 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 Cmax of 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 Cmax for 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 t1/2 was not affected by
itraconazole, suggesting that the relatively small increases in Cmax and 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 Cmax of 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. (See DOSAGE AND
ADMINISTRATION, Concomitant Therapy.) 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 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 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, Cmax, and Tmax for the pravastatin metabolite SQ 31,906. Combination
therapy with pravastatin and gemfibrozil is generally not recommended. (See
WARNINGS, Skeletal Muscle).
In interaction studies with aspirin, antacids (1
hour prior to pravastatin), cimetidine, nicotinic acid,
or probucol, no statistically significant
differences in bioavailability were seen when pravastatin sodium was
administered. 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 less than 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 to 13 years and
40 mg in the adolescents aged 14 to 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. 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. 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 less than 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/m2 and 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 less than 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. PregnancyTeratogenic EffectsPregnancy 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/meter2). Rare reports
of congenital anomalies have been received following intrauterine exposure to
other HMG-CoA reductase inhibitors. In a review7 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
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
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 should not nurse (see CONTRAINDICATIONS). Pediatric Use The safety and effectiveness of pravastatin in children and
adolescents from 8 to 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 (see CONTRAINDICATIONS and PRECAUTIONS,
Pregnancy). 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. Geriatric Use 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 to 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/Metabolism).
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. (See also PRECAUTIONS, Geriatric Use). Adverse Clinical EventsShort-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 6;
also shown are the percentages of patients in whom these medical events were
believed to be related or possibly related to the drug:
Table 6: Adverse Events in > 2 Percent of Patients Treated with Pravastatin 10 to 40 mg in Short-Term Placebo-Controlled Trials
All
Events
Events Attributed
to Study Drug
Body System/Event
Pravastatin (N =900) % of patients
Placebo(N = 411)% of patients
Pravastatin(N = 900)% of patients
Placebo(N = 411)% of patients
Cardiovascular
Cardiac Chest Pain
4.0
3.4
0.1
0.0
Dermatologic
Rash
4.0*
1.1
1.3
0.9
Gastrointestinal
Nausea/Vomiting
7.3
7.1
2.9
3.4
Diarrhea
6.2
5.6
2.0
1.9
Abdominal Pain
5.4
6.9
2.0
3.9
Constipation
4.0
7.1
2.4
5.1
Flatulence
3.3
3.6
2.7
3.4
Heartburn
2.9
1.9
2.0
0.7
General
Fatigue
3.8
3.4
1.9
1.0
Chest Pain
3.7
1.9
0.3
0.2
Influenza
2.4*
0.7
0.0
0.0
Musculoskeletal
Localized Pain
10.0
9.0
1.4
1.5
Myalgia
2.7
1.0
0.6
0.0
Nervous System
Headache
6.2
3.9
1.7*
0.2
Dizziness
3.3
3.2
1.0
0.5
Renal/Genitourinary
Urinary Abmornality
2.4
2.9
0.7
1.2
Respiratory
Common Cold
7.0
6.3
0.0
0.0
Rhinitis
4.0
4.1
0.1
0.0
Cough
2.6
1.7
0.1
0.0
* Statistically significantly different from placebo.
The safety and tolerability of pravastatin at a dose of 80 mg in two
controlled trials with a mean exposure of 8.6 months was similar to that of
pravastatin at lower doses except that 4 out of 464 patients taking 80 mg of
pravastatin had a single elevation of CK greater than 10X ULN compared to 0 out of 115
patients taking 40 mg of pravastatin. Long-Term Controlled Morbidity and Mortality Trials Adverse event data were pooled from several double-blind,
placebo-controlled trials (e.g., West of Scotland Coronary Prevention Study
[WOS]; 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, among other trials, WOS 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 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
7.
Table 7: Adverse Events in ≥ 1 Percent of Patients Treated with
Pravastatin 40 mg in Long-Term Placebo-Controlled Trials
Events of probable, possible, or uncertain relationship to study drug that
occurred in less than 1.0% of pravastatin-treated patients in the long-term trials
included the following; frequencies were similar in placebo-treated
patients:
Special Senses: lens opacity, taste
disturbance. 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, 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.
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. Laboratory Test Abnormalities Increases in serum transaminase (ALT, AST) values and CPK have
been observed (see WARNINGS).
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. 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 of
nicotinic acid. Concomitant therapy with HMG-CoA reductase inhibitors and these
agents is generally not recommended. (See WARNINGS, Skeletal Muscle and PRECAUTIONS, Drug Interactions.) 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.)
Overdosage
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. (See WARNINGS).
Dosage And Administration
The patient should be placed on a standard cholesterol-lowering
diet before receiving pravastatin sodium and should continue on this diet during
treatment with pravastatin (see NCEP Treatment
Guidelines for details on dietary therapy).
Pravastatin 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. 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. Pediatric PatientsChildren (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. 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, NCEP
Treatment Guidelines).
In patients taking immunosuppressive drugs such as cyclosporine (see WARNINGS, Skeletal Muscle)
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. Concomitant Therapy The lipid-lowering effects of pravastatin 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 should be given either 1 hour or more before or at
least 4 hours following the resin. (See also ADVERSE
REACTIONS, ConcomitantTherapy.)
How Supplied
Pravastatin sodium tablets are supplied as:
10 mg tablets: Pink, unscored, round tablet, debossed “93” on one side and
“771” on the other side in:
bottles of 30 NDC 54868-5576-0bottles of 90 NDC 54868-5576-1.
20 mg tablets: Light yellow, unscored, round tablet, debossed “93” on one
side and “7201” on the other side in:
bottles of 30 NDC 54868-5577-0bottles of 90 NDC 54868-5577-1.
40 mg tablets: Light green, unscored, round tablet, debossed “93” on one side
and “7202” on the other side in:
bottles of 30 NDC 54868-5578-0bottles of 60 NDC 54868-5578-2bottles of 90 NDC 54868-5578-1. 80 mg tablets: Off-white to mottled grey, oval-shaped, beveled edged tablet,
debossed with “93” on one side and “7270” on the other side in:
bottles of 30 NDC 54868-5579-0bottles of 90 NDC 54868-5579-1.STORAGE Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room
Temperature]. Keep tightly closed (protect from moisture). Protect from
light.
Dispense in a tight, light-resistant container as defined in the USP, with a
child-resistant closure (as required).
References
Shepherd J, et al. Prevention of Coronary Heart Disease with Pravastatin in
Men with Hypercholesterolemia (WOS). N Engl J Med
1995;333:1301-7.
Pitt B, et al. Pravastatin Limitation of Atherosclerosis in the Coronary
Arteries (PLAC I): Reduction in Atherosclerosis Progression and Clinical Events.
J Am Coll
Cardiol
1995;26:1133-9.
Jukema JW, et al. Effects of Lipid Lowering by Pravastatin on Progression
and Regression of Coronary Artery Disease in Symptomatic Man With Normal to
Moderately Elevated Serum Cholesterol Levels. The Regression Growth Evaluation
Statin Study (REGRESS). Circulation 1995;
91:2528-2540.
Crouse JR, et al. Pravastatin, Lipids, and Atherosclerosis in the Carotid
Arteries: Design Features of a Clinical Trial with Carotid Atherosclerosis
Outcome (PLAC II). Controlled Clinical Trials
1992;13:495.
Salonen R, et al. Kuopio Atherosclerosis Prevention Study (KAPS). A
Population-based Primary Preventive Trial of the Effect of LDL Lowering on
Atherosclerotic Progression in Carotid and Femoral Arteries. Research Institute
of Public Health, University of Kuopio, Finland. Circulation 1995;92:1758.
Fredrickson DS, et al. Fat Transport in Lipoproteins-An Integrated Approach
to Mechanisms and Disorders. N Engl J Med 1967;
276:34-42, 94-102, 148-156, 215-224, 273-281.
Manson JM, Freyssinges C, Ducrocq MB, Stephenson WP. Postmarketing
Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy. Reproductive Toxicology 1996;10(6):439-446.
Manufactured In Israel By:
TEVA PHARMACEUTICAL IND. LTD.
Jerusalem, 91010, Israel
Manufactured For:
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Rev. B 12/2007
Principal Display Panel
Pravastatin sodium tablets, 10 mg
Pravastatin sodium tablets, 20 mg
Pravastatin sodium tablets, 40 mg
Pravastatin sodium tablets, 80 mg
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