Pravastatin Sodium 40 MG Oral Tablet

Details

Generic Name: PRAVASTATIN SODIUM

Brand Name: pravastatin sodium

Substance Name(s):
PRAVASTATIN SODIUM

DRUG INTERACTIONS

For the concurrent therapy of either cyclosporine, fibrates, niacin (nicotinic acid), or erythromycin, the risk of myopathy increases [see Warnings and Precautions ( 5.1) and Clinical Pharmacology ( 12.3) ].

Concomitant lipid-lowering therapies: use with fibrates or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects.

Caution should be used when prescribing with pravastatin sodium.

( 7) Cyclosporine: combination increases exposure.

Limit pravastatin to 20 mg once daily.

( 2.5, 7.1) Clarithromycin: combination increases exposure.

Limit pravastatin to 40 mg once daily.

( 2.6, 7.2) 7.1 Cyclosporine The risk of myopathy/rhabdomyolysis is increased with concomitant administration of cyclosporine.

Limit pravastatin to 20 mg once daily for concomitant use with cyclosporine [see Dosage and Administration ( 2.5) , Warnings and Precautions ( 5.1) , and Clinical Pharmacology ( 12.3) ].

7.2 Clarithromycin The risk of myopathy/rhabdomyolysis is increased with concomitant administration of clarithromycin.

Limit pravastatin to 40 mg once daily for concomitant use with clarithromycin [see Dosage and Administration ( 2.6) , Warnings and Precautions ( 5.1) , and Clinical Pharmacology ( 12.3) ].

7.3 Colchicine The risk of myopathy/rhabdomyolysis is increased with concomitant administration of colchicine [see Warnings and Precautions ( 5.1) ].

7.4 Gemfibrozil Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of pravastatin sodium with gemfibrozil should be avoided [see Warnings and Precautions ( 5.1) ].

7.5 Other Fibrates Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, pravastatin sodium should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions ( 5.1) ].

7.6 Niacin The risk of skeletal muscle effects may be enhanced when pravastatin is used in combination with niacin; a reduction in pravastatin sodium dosage should be considered in this setting [see Warnings and Precautions ( 5.1) ].

OVERDOSAGE

10.

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.

DESCRIPTION

11.

Pravastatin sodium is one of a class of lipid-lowering compounds, the statins, which reduce cholesterol biosynthesis.

These agents are competitive inhibitors of 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-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-, monosodium salt, [1S-[1α(βS*,δS*),2α,6α,8β(R*),8aα]]-.

Structural formula: Pravastatin sodium, USP is white to yellowish white powder or crystalline powder, hygroscopic in nature.

It is a relatively polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59 at a pH of 7.

It is freely soluble in water and in methanol.

Soluble in ethanol.

Each pravastatin sodium tablet, USP intended for oral administration contains 10 mg or 20 mg or 40 mg or 80 mg of pravastatin sodium.

In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polyoxyl 35 castor oil and sodium carbonate anhydrous.

Pravastatin Sodium Tablets, USP

CLINICAL STUDIES

14.

14.1 Prevention of Coronary Heart Disease In the Pravastatin Primary Prevention Study (WOS), 3 the effect of pravastatin sodium on fatal and nonfatal CHD was assessed in 6595 men 45 to 64 years of age, without a previous MI, and with LDL-C levels between 156 to 254 mg/dL (4 to 6.7 mmol/L).

In this randomized, doubleblind, 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 (25 th, 75 th 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, −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 CHD death or nonfatal MI) by 31% (248 events in the placebo group [CHD death=44, nonfatal MI=204] versus 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.

Pravastatin Sodium Tablets, USP 14.2 Secondary Prevention of Cardiovascular Events In the LIPID4 study, the effect of pravastatin, 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 to 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-C between 114 and 563 mg/dL (mean 219 mg/dL), LDL-C between 46 and 274 mg/dL (mean 150 mg/dL), TG 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 significantly reduced the risk for total mortality by reducing coronary death (see Table 5).

The risk reduction due to treatment with pravastatin on CHD mortality was consistent regardless of age.

Pravastatin 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.

Table 5 LIPID – Primary and Secondary Endpoints Number (%) of Subjects Event Pravastatin 40 mg (N=4512) Placebo (N=4502) Risk Reduction p-value Primary Endpoint CHD mortality 287 (6.4) 373 (8.3) 24% 0.0004 Secondary Endpoints Total mortality 498 (11.0) 633 (14.1) 23% <0.0001 CHD mortality or nonfatal MI 557 (12.3) 715 (15.9) 24% <0.0001 Myocardial revascularization procedures (CABG or PTCA) 584 (12.9) 706 (15.7) 20% <0.0001 Stroke All-cause 169 (3.7) 204 (4.5) 19% 0.0477 Non-hemorrhagic 154 (3.4) 196 (4.4) 23% 0.0154 Cardiovascular mortality 331 (7.3) 433 (9.6) 25% <0.0001 In the CARE5 study, the effect of pravastatin, 40 mg daily, on CHD death and nonfatal MI was assessed in 4159 patients (3583 men and 576 women) who had experienced a MI in the preceding 3 to 20 months and who had normal (below the 75th percentile 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-C of 209 mg/dL.

LDL-C levels in this patient population ranged from 101 to 180 mg/dL (mean 139 mg/dL).

At baseline, 84% of patients were receiving aspirin and 82% were taking antihypertensive medications.

Median (25th , 75th percentile) 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 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 TIA (see Table 6).

Table 6 CARE – Primary and Secondary Endpoints Number (%) of Subjects Event Pravastatin 40 mg (N=2081) Placebo (N=2078) Risk Reduction p-value Primary Endpoint CHD mortality or nonfatal MI The risk reduction due to treatment with pravastatin was consistent in both sexes.

212 (10.2) 274 (13.2) 24% 0.003 Secondary Endpoints Myocardial revascularization procedures (CABG or PTCA) 294 (14.1) 391 (18.8) 27% <0.001 Stroke or TIA 93 (4.5) 124 (6.0) 26% 0.029 In the PLAC I6 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: 130-190 mg/dL).

In this double-blind, multicenter, controlled clinical trial, angiograms were evaluated at baseline and at 3 years in 264 patients.

Although the difference between pravastatin and placebo for the primary endpoint (per-patient change in mean coronary artery diameter) and 1 of 2 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 REGRESS7 study, 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 2 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, PLAC II,8 REGRESS, and KAPS9 studies (combined N=1891) showed that treatment with pravastatin was associated with a statistically significant reduction in the composite event rate of fatal and nonfatal MI (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 MI.

14.3 Primary Hypercholesterolemia (Fredrickson Types IIa and IIb) Pravastatin sodium is highly effective in reducing Total-C, LDL-C, and 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 MI.

A single daily dose is as effective as the same total daily dose given twice a day.

In multicenter, doubleblind, placebo-controlled studies of patients with primary hypercholesterolemia, treatment with pravastatin in daily doses ranging from 10 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 7).

In a pooled analysis of 2 multicenter, doubleblind, 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 25 th and 75 th 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 7).

Treatment with pravastatin sodium modestly decreased VLDL-C and pravastatin sodium across all doses produced variable increases in HDL-C (see Table 7).

Table 7 Primary Hypercholesterolemia Studies: Dose Response of Pravastatin Sodium Once Daily Administration Dose Total-C LDL-C HDL-C TG Mean Percent Changes From Baseline After 8 Weeks A multicenter, doubleblind, placebo-controlled study.

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 Pooled analysis of 2 multicenter, doubleblind, placebo-controlled studies.

Placebo (N=162) 0% −1% −1% +1% 80 mg (N=277) −27% −37% +3% −19% 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).

14.4 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 CARE study.

For pravastatin-treated subjects, the median (min, max) baseline TG level was 246 (200.5, 349.5) mg/dL (see Table 8.) Table 8 Patients with Fredrickson Type IV Hyperlipidemia Median (25 th, 75 thpercentile) % Change from Baseline Pravastatin 40 mg (N=429) Placebo (N=430) TG −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, 10) HDL-C 7.4 (−1.2, 17.7) 2.8 (−5.7, 11.7) Non-HDL-C −27.2 (−34, −18.5) −0.8 (−8.2, 7) 14.5 Dysbetalipoproteinemia (Fredrickson Type III) The response to pravastatin in two doubleblind crossover studies of 46 patients with genotype E2/E2 and Fredrickson Type III dysbetalipoproteinemia is shown in Table 9.

Table 9 Patients with Fredrickson Type III Dysbetalipoproteinemia Median (min, max) % Change from Baseline Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Pravastatin 40 mg (N=20) Study 1 Total-C 386.5 (245, 672) −32.7 (−58.5, 4.6) TG 443 (275, 1299) −23.7 (−68.5, 44.7) VLDL-C a 206.5 (110, 379) −43.8 (−73.1, −14.3) LDL-C 117.5 (80, 170) −40.8 (−63.7, 4.6) HDL-C 30 (18, 88) 6.4 (−45, 105.6) Non-HDL-C 344.5 (215, 646) −36.7 (−66.3, 5.8) a N=14 Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Pravastatin 40 mg (N=26) Study 2 Total-C 340.3 (230.1, 448.6) −31.4 (−54.5, −13) TG 343.2 (212.6, 845.9) −11.9 (−56.5, 44.8) VLDL-C 145 (71.5, 309.4) −35.7 (−74.7, 19.1) LDL-C 128.6 (63.8, 177.9) −30.3 (−52.2, 13.5) HDL-C 38.7 (27.1, 58) 5 (−17.7, 66.7) Non-HDL-C 295.8 (195.3, 421.5) −35.5 (−81, −13.5) 14.6 Pediatric Clinical Study A doubleblind, placebo-controlled study in 214 patients (100 boys and 114 girls) with heterozygous familial hypercholesterolemia (HeFH), aged 8 to 18 years was conducted for 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 > 95 th 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 ApoB in both children and adolescents (see Table 10).

The effect of pravastatin treatment in the 2 age groups was similar.

Table 10 Lipid-Lowering Effects of Pravastatin in Pediatric Patients with Heterozygous Familial Hypercholesterolemia: Least-Squares Mean % Change from Baseline at Month 24 (Last Observation Carried Forward: Intent-to-Treat) a Pravastatin 20 mg (Aged 8 to 13 years) N=65 Pravastatin 40 mg (Aged 14 to 18 years) N=41 Combined Pravastatin (Aged 8 to 18 years) N=106 Combined Placebo (Aged 8 to 18 years) N=108 95% CI of the Difference Between Combined Pravastatin and Placebo a The above least-squares mean values were calculated based on log-transformed lipid values.

b Significant at p ≤ 0.0001 when compared with placebo.

LDL-C −26.04 b −21.07 b −24.07 b −1.52 (−26.74, −18.86) TC −20.75 b −13.08 b −17.72 b −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 b (61) −18.08 b (39) −21.11 b (100) −0.97 (106) (−24.29, −16.18) 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.

HOW SUPPLIED

16.

/STORAGE AND HANDLING 16.1 How Supplied Pravastatin Sodium Tablets USP, 10 mg are white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of ‘ZC46’ on one side and plain on the other side and are supplied as follows: Unit dose packages of 100 (10 x 10) NDC 68084-500-01 Pravastatin Sodium Tablets USP, 20 mg are white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of ‘ZC45’ on one side and plain on the other side and are supplied as follows: Unit dose packages of 100 (10 x 10) NDC 68084-501-01 Pravastatin Sodium Tablets USP, 40 mg are white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of ‘ZC44’ on one side and plain on the other side and are supplied as follows: Unit dose packages of 100 (10 x 10) NDC 68084-502-01 Pravastatin Sodium Tablets USP, 80 mg are white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of ‘ZC43’ on one side and plain on the other side and are supplied as follows: Unit dose packages of 30 (5 x 6) NDC 68084-746-25 16.2 Storage Store at 20° to 25° C (68° to 77° F) [See USP Controlled Room Temperature].

Protect from light and moisture

GERIATRIC USE

8.5 Geriatric Use Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of 6593 subjects treated with pravastatin 40 mg for periods ranging up to 6 years.

Across these 2 studies, 36.1% of pravastatin subjects were aged 65 and older and 0.8% were aged 75 and older.

The beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in modifying lipid profiles was similar to that seen in younger subjects.

The adverse event profile in the elderly was similar to that in the overall population.

Other reported clinical experience has not identified differences in responses to pravastatin between elderly and younger patients.

Mean pravastatin AUCs are slightly (25% to 50%) higher in elderly subjects than in healthy young subjects, but mean maximum plasma concentration (C max), time to maximum plasma concentration (T max), and half-life (t ½) values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly [see Clinical Pharmacology ( 12.3) ].

Since advanced age (≥ 65 years) is a predisposing factor for myopathy, pravastatin sodium should be prescribed with caution in the elderly [see Warnings and Precautions ( 5.1) and Clinical Pharmacology ( 12.3) ].

DOSAGE FORMS AND STRENGTHS

Pravastatin sodium tablets, USP are supplied as: 10 mg tablets: white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of ‘ZC46’ on one side and plain on the other side.

20 mg tablets: white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of ‘ZC45’ on one side and plain on the other side.

40 mg tablets: white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of ‘ZC44’ on one side and plain on the other side.

80 mg tablets: white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of ‘ZC43’ on one side and plain on the other side.

Tablets: 10 mg, 20 mg, 40 mg and 80 mg.

( 3)

MECHANISM OF ACTION

12.1 Mechanism of Action Pravastatin is a reversible inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol.

In addition, pravastatin reduces VLDL and TG and increases HDL-C.

INDICATIONS AND USAGE

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia.

Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.

Pravastatin sodium tablet, USP is an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to: Reduce the risk of MI, revascularization, and cardiovascular mortality in hypercholesterolemic patients without clinically evident CHD.

( 1.1) Reduce the risk of total mortality by reducing coronary death, MI, revascularization, stroke/TIA, and the progression of coronary atherosclerosis in patients with clinically evident CHD.

( 1.1) Reduce elevated Total-C, LDL-C, ApoB, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia.

( 1.2) Reduce elevated serum TG levels in patients with hypertriglyceridemia.

( 1.2) Treat patients with primary dysbetalipoproteinemia who are not responding to diet.

( 1.2) Treat children and adolescent patients ages 8 years and older with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy.

( 1.2) Limitations of use: Pravastatin sodium tablets, USP have not been studied in Fredrickson Types I and V dyslipidemias.

( 1.3) 1.1 Prevention of Cardiovascular Disease In hypercholesterolemic patients without clinically evident coronary heart disease (CHD), pravastatin sodium tablets, USP are indicated to: reduce the risk of myocardial infarction (MI).

reduce the risk of undergoing myocardial revascularization procedures.

reduce the risk of cardiovascular mortality with no increase in death from non-cardiovascular causes.

In patients with clinically evident CHD, pravastatin sodium tablet is indicated to: reduce the risk of total mortality by reducing coronary death.

reduce the risk of MI.

reduce the risk of undergoing myocardial revascularization procedures.

reduce the risk of stroke and stroke/transient ischemic attack (TIA).

slow the progression of coronary atherosclerosis.

1.2 Hyperlipidemia Pravastatin sodium tablet is indicated: as an adjunct to diet to reduce elevated total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and triglyceride (TG) levels and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia and mixed dyslipidemia ( Fredrickson Types IIa and IIb).

1 as an adjunct to diet for the treatment of patients with elevated serum TG levels ( Fredrickson Type IV).

for the treatment of patients with primary dysbetalipoproteinemia ( Fredrickson Type III) who do not respond adequately to diet.

as an adjunct to diet and lifestyle modification for treatment of heterozygous familial hypercholesterolemia (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 ≥ 190 mg/dL or LDL-C remains ≥ 160 mg/dL and: there is a positive family history of premature cardiovascular disease (CVD) or two or more other CVD risk factors are present in the patient.

1.3 Limitations of Use Pravastatin sodium has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V).

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of pravastatin sodium 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 ( 6.4) .] 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 ( 4.3) and Use in Specific Populations ( 8.1) ].

For dosing information [see Dosage and Administration ( 2.3) .] Doubleblind, placebo-controlled pravastatin studies in children less than 8 years of age have not been conducted.

PREGNANCY

4.3 Pregnancy 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 statins 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 Use in Specific Populations ( 8.1) ].

NUSRING MOTHERS

4.4 Nursing Mothers A small amount of pravastatin is excreted in human breastmilk.

Because statins have the potential for serious adverse reactions in nursing infants, women who require pravastatin sodium treatment should not breastfeed their infants [see Use in Specific Populations ( 8.3) ].

WARNING AND CAUTIONS

WARNINGS AND PRECAUTIONS Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): predisposing factors include advanced age (≥65), uncontrolled hypothyroidism, and renal impairment.

Patients should be advised to promptly report to their physician any unexplained and/or persistent muscle pain, tenderness, or weakness.

Pravastatin therapy should be discontinued if myopathy is diagnosed or suspected.

( 5.1, 8.5) Liver enzyme abnormalities: persistent elevations in hepatic transaminases can occur.

Check liver enzyme tests before initiating therapy and as clinically indicated thereafter.

( 5.2) 5.1 Skeletal Muscle Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with pravastatin and other drugs in this class.

A history of renal impairment may be a risk factor for the development of rhabdomyolysis.

Such patients merit closer monitoring for skeletal muscle effects.

Uncomplicated myalgia has also been reported in pravastatin-treated patients [see Adverse Reactions (6)].

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 (ULN), 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.

Predisposing factors include advanced age (≥ 65), uncontrolled hypothyroidism, and renal impairment.

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use.

IMNM is characterized by: proximal muscle weakness and elevated serum CPK, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation and improvement with immunosuppressive agents.

All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing pravastatin.

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 statins is increased with concurrent therapy with either erythromycin, cyclosporine, niacin, or fibrates.

However, neither myopathy nor significant increases in CPK levels have been observed in 3 reports involving a total of 100 post-transplant patients (24 renal and 76 cardiac) treated for up to 2 years concurrently with pravastatin 10 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 1 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.

The use of fibrates alone may occasionally be associated with myopathy.

The benefit of further alterations in lipid levels by the combined use of pravastatin sodium with fibrates should be carefully weighed against the potential risks of this combination.

Cases of myopathy, including rhabdomyolysis, have been reported with pravastatin coadministered with colchicine, and caution should be exercised when prescribing pravastatin with colchicine [see Drug Interactions (7.3)].

5.2 Liver Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function.

In 3 long-term (4.8 to 5.9 years), placebo-controlled clinical trials (WOS, LIPID, CARE), 19,592 subjects (19,768 randomized) were exposed to pravastatin or placebo [see Clinical Studies ( 14) ].

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 3 times the upper limit of normal for subjects with pretreatment values less than or equal to the upper limit of normal, or 4 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 [see Contraindications ( 4.2) ].

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.

There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pravastatin.

If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with pravastatin sodium, promptly interrupt therapy.

If an alternate etiology is not found do not restart pravastatin sodium.

5.3 Endocrine Function Statins 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 statins 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 a statin 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 2 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.

INFORMATION FOR PATIENTS

17.

PATIENT COUNSELING INFORMATION Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing pravastatin [see Warnings and Precautions ( 5.1) ].

It is recommended that liver enzyme tests be performed before the initiation of pravastatin sodium, and thereafter when clinically indicated.

All patients treated with pravastatin sodium should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions ( 5.2) ].

Call your doctor for medical advice about side effects.

You may report side effects to FDA at 1-800-FDA-1088.

DOSAGE AND ADMINISTRATION

Adults: the recommended starting dose is 40 mg once daily.

Use 80 mg dose only for patients not reaching LDL-C goal with 40 mg.

( 2.2) Significant renal impairment: the recommended starting dose is 10 mg once daily.

( 2.2) Children (ages 8 to 13 years, inclusive): the recommended starting dose is 20 mg once daily.

( 2.3) Adolescents (ages 14 to 18 years): the recommended starting dose is 40 mg once daily.

( 2.3) 2.1 General Dosing Information 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].

2.2 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 significant renal impairment, a starting dose of 10 mg daily is recommended.

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.

2.3 Pediatric Patients 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.

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 ( 1.2) ].

2.4 Concomitant Lipid-Altering Therapy Pravastatin sodium tablets may be used with bile acid resins.

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.

[See Clinical Pharmacology ( 12.3) .] 2.5 Dosage in Patients Taking Cyclosporine 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.

In patients taking cyclosporine, therapy should be limited to 20 mg of pravastatin sodium once daily [see Warnings and Precautions ( 5.1) and Drug Interactions ( 7.1) ].

2.6 Dosage in Patients Taking Clarithromycin In patients taking clarithromycin, therapy should be limited to 40 mg of pravastatin sodium once daily [see Drug Interactions ( 7.2) ].