PRAVASTATIN SODIUM- pravastatin sodium tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
PRAVASTATIN SODIUM (UNII: 3M8608UQ61) (PRAVASTATIN - UNII:KXO2KT9N0G)
Available from:
REMEDYREPACK INC.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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. In hypercholesterolemic patients without clinically evident coronary heart disease (CHD), pravastatin sodium tablets 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 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 strok
Product summary:
Pravastatin Sodium Tablets, USP 10 mg are available for oral administration as light pink, round, unscored tablets, imprinted “APO” on one side and “PRA” over “10” on the other side. They are supplied as follows: Bottles of 90 (NDC 60505-0168-9) Bottles of 100 (NDC 60505-0168-1) Bottles of 500 (NDC 60505-0168-5) Bottles of 1,000 (NDC 60505-0168-7) Pravastatin Sodium Tablets, USP 20 mg are available for oral administration as off-white to light yellow, round, unscored tablets, imprinted “APO” on one side and “PRA” over “20” on the other side. They are supplied as follows: Bottles of 90 (NDC 60505-0169-9) Bottles of 100 (NDC 60505-0169-1) Bottles of 500 (NDC 60505-0169-5) Bottles of 1,000 (NDC 60505-0169-7) Pravastatin Sodium Tablets, USP 40 mg are available for oral administration as light green, round, unscored tablets, imprinted “APO” on one side and “PRA” over “40” on the other side. They are supplied as follows: Bottles of 90 (NDC 60505-0170-9) Bottles of 100 (NDC 60505-0170-1) Bottles of 500 (NDC 60505-0170-5) Bottles of 1,000 (NDC 60505-0170-7) Pravastatin Sodium Tablets, USP 80 mg are available for oral administration as off-white to light yellow, round, unscored tablets, imprinted "APO" on one side and "PRA" over "80" on the other side. They are supplied as follows: Bottles of 90 (NDC 60505-1323-9) Bottles of 100 (NDC 60505-1323-1) Bottles of 500 (NDC 60505-1323-5) Bottles of 1,000 (NDC 60505-1323-7) Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container [see USP]. Protect from light and moisture.
Authorization status:
Abbreviated New Drug Application
Authorization number:
70518-2229-0

PRAVASTATIN SODIUM- pravastatin sodium tablet

REMEDYREPACK INC.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use PRAVASTATIN SODIUM TABLETS safely

and effectively. See full prescribing information for PRAVASTATIN SODIUM TABLETS.

PRAVASTATIN SODIUM tablets, for oral use

Initial U.S. Approval: 1991

RECENT MAJOR CHANGES

Dosage and Administration

Patients with Renal Impairment (2.3) 7/2016

Contraindications

Pregnancy (4.3), Lactation (4.4) 7/2016

INDICATIONS AND USAGE

Pravastatin sodium 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 has not been studied in Fredrickson Types I and V dyslipidemias. ( 1.3)

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 pravastatin 10 mg once daily. ( 2.3)

Children (ages 8 to 13 years, inclusive): the recommended starting dose is 20 mg once daily. ( 2.4)

Adolescents (ages 14 to 18 years): the recommended starting dose is 40 mg once daily. ( 2.4)

DOSAGE FORMS AND STRENGTHS

Tablets: 10 mg, 20 mg, 40 mg, 80 mg. ( 3)

CONTRAINDICATIONS

Hypersensitivity to any component of this medication. ( 4.1, 6.2, 11)

Active liver disease or unexplained, persistent elevations of serum transaminases. ( 4.2, 5.2)

Pregnancy ( 4.3, 8.1, 8.3)

Lactation ( 4.4, 8.2)

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)

ADVERSE REACTIONS

ADVERSE REACTIONS

In short-term clinical trials, the most commonly reported adverse reactions (≥2% and > placebo) regardless of causality

were: musculoskeletal pain, nausea/vomiting, upper respiratory infection, diarrhea, and headache. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Apotex at 1-800-706-5575 or FDA at 1-800-FDA-1088

or www.fda.gov/medwatch.

DRUG INTERACTIONS

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. ( 2.6, 7.1)

Clarithromycin: combination increases exposure. Limit pravastatin to 40 mg once daily. ( 2.7, 7.2)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 7/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Prevention of Cardiovascular Disease

1.2 Hyperlipidemia

1.3 Limitations of Use

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

2.2 Adult Patients

2.3 Patients with Renal Impairment

2.4 Pediatric Patients

2.5 Concomitant Lipid-Altering Therapy

2.6 Dosage in Patients Taking Cyclosporine

2.7 Dosage in Patients Taking Clarithromycin

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Hypersensitivity

4.2 Liver

4.3 Pregnancy

4.4 Lactation

5 WARNINGS AND PRECAUTIONS

5.1 Skeletal Muscle

5.2 Liver

5.3 Endocrine Function

6 ADVERSE REACTIONS

6.1 Adverse Clinical Events

6.2 Postmarketing Experience

6.3 Laboratory Test Abnormalities

6.4 Pediatric Patients

7 DRUG INTERACTIONS

7.1 Cyclosporine

7.2 Clarithromycin and Other Macrolide Antibiotics

7.3 Colchicine

7.4 Gemfibrozil

7.5 Other Fibrates

7.6 Niacin

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Homozygous Familial Hypercholesterolemia

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Prevention of Coronary Heart Disease

14.2 Secondary Prevention of Cardiovascular Events

14.3 Primary Hypercholesterolemia (Fredrickson Types IIa and IIb)

14.4 Hypertriglyceridemia ( Fredrickson Type IV)

14.5 Dysbetalipoproteinemia ( Fredrickson Type III)

14.6 Pediatric Clinical Study

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 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.

1.1 Prevention of Cardiovascular Disease

In hypercholesterolemic patients without clinically evident coronary heart disease (CHD), pravastatin

sodium tablets 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 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).

Sections or subsections omitted from the full prescribing information are not listed.

slow the progression of coronary atherosclerosis.

1.2 Hyperlipidemia

Pravastatin sodium tablets are 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).

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:

a. LDL-C remains ≥190 mg/dL or

b. 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).

2 DOSAGE AND ADMINISTRATION

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. 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 Patients with Renal Impairment

In patients with severe renal impairment, a starting dose of 10 mg pravastatin daily is recommended. In

patients with severe renal impairment, a starting dose of 10 mg pravastatin daily is recommended.

2.4 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)].

2.5 Concomitant Lipid-Altering Therapy

Pravastatin sodium 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)].

2.6 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)].

2.7 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)].

3 DOSAGE FORMS AND STRENGTHS

Pravastatin Sodium Tablets, USP are supplied as:

10 mg tablets: Light pink, round, unscored tablets, imprinted “APO” on one side and “PRA” over “10”

on the other side.

20 mg tablets: Off-white to light yellow, round, unscored tablets, imprinted “APO” on one side and

“PRA” over “20” on the other side.

40 mg tablets: Light green, round, unscored tablets, imprinted “APO” on one side and “PRA” over

“40” on the other side.

80 mg tablets: Off-white to light yellow, round, unscored tablets, imprinted “APO” on one side and

“PRA” over “80” on the other side.

4 CONTRAINDICATIONS

4.1 Hypersensitivity

Hypersensitivity to any component of this medication.

4.2 Liver

Active liver disease or unexplained, persistent elevations of serum transaminases [see Warnings and

Precautions (5.2)].

4.3 Pregnancy

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 ]. 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, 8.3)].

4.4 Lactation

Pravastatin is present in human milk. 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 ( 8.2) ].

5 WARNINGS AND PRECAUTIONS

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 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 (1,200 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 ULN for subjects with

pretreatment values less than or equal to the ULN, or 4 times the pretreatment value for subjects with

pretreatment values greater than the ULN but less than 1.5 times the ULN. 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 ULN for those with normal ALT (≤ ULN) at baseline or a doubling

of the baseline ALT for those with elevated ALT (> ULN) 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, promptly interrupt therapy. If an alternate etiology is

not found do not restart pravastatin.

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.

6 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.

6.1 Adverse Clinical Events

Short-Term Controlled Trials

In the pravastatin sodium placebo-controlled clinical trials database of 1313 patients (age range 20 to 76

years, 32.4% women, 93.5% Caucasians, 5% Blacks, 0.9% Hispanics, 0.4% Asians, 0.2% Others) with

a median treatment duration of 14 weeks, 3.3% of patients on pravastatin sodium and 1.2% patients on

placebo discontinued due to adverse events regardless of causality. The most common adverse

reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were:

liver function test increased, nausea, anxiety/depression, and dizziness.

All adverse clinical events (regardless of causality) reported in ≥2% of pravastatin-treated patients in

placebo-controlled trials of up to 8 months duration are identified in Table 1:

Table 1: Adverse Events in ≥ 2% of Patients Treated with

Pravastatin 5 to 40 mg and at an Incidence Greater Than

Placebo in Short-Term Placebo-Controlled Trials (% of

patients )

Body System/Event

5 mg

N=10

0

10 mg

N=153

20 mg

N=478

40 mg

N=171

Any

Dos e

N=902

Placebo

N=411

Cardiovascular

Angina Pectoris

Dermatologic

Rash

Gastrointestinal

Nausea/Vomiting

10.5

Diarrhea

Flatulence

Flatulence

Dyspepsia/Heartburn

Abdominal

Distension

General

Fatigue

Chest Pain

Influenza

Musculoskeletal

Musculoskeletal

Pain

13.0

13.2

10.1

10.2

Myalgia

Nervous System

Headache

Dizziness

Respiratory

Pharyngitis

Upper Respiratory

Infection

Rhinitis

Cough

Investigation

ALT Increased

g-GT Increased

CPK Increased

The safety and tolerability of pravastatin sodium at a dose of 80 mg in 2 controlled trials with a mean

exposure of 8.6 months was similar to that of pravastatin sodium at lower doses except that 4 out of 464

patients taking 80 mg of pravastatin had a single elevation of CK >10 times ULN compared to 0 out of

115 patients taking 40 mg of pravastatin.

Long-Term Controlled Morbidity and Mortality Trials

In the pravastatin sodium placebo-controlled clinical trials database of 21,483 patients (age range 24 to

75 years, 10.3% women, 52.3% Caucasians, 0.8% Blacks, 0.5% Hispanics, 0.1% Asians, 0.1% Others,

46.1% Not Recorded) with a median treatment duration of 261 weeks, 8.1% of patients on pravastatin

sodium and 9.3% patients on placebo discontinued due to adverse events regardless of causality.

Adverse event data were pooled from 7 double-blind, placebo-controlled trials (West of Scotland

Coronary Prevention Study [WOS]; Cholesterol and Recurrent Events study [CARE]; Long-term

Intervention with Pravastatin in Ischemic Disease study [LIPID] Pravastatin Limitation of

Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids and Atherosclerosis in the

Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and Kuopio

Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated with pravastatin

40 mg and 10,719 patients treated with placebo. The safety and tolerability profile in the pravastatin

group was comparable to that of the placebo group. Patients were exposed to pravastatin for a mean of

4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9 years in PLAC I, PLAC II, KAPS, and

REGRESS. In these long-term trials, the most common reasons for discontinuation were mild, non-

specific gastrointestinal complaints. Collectively, these 7 trials represent 47,613 patient-years of

exposure to pravastatin. All clinical adverse events (regardless of causality) occurring in ≥2% of

patients treated with pravastatin in these studies are identified in Table 2.

Table 2: Adverse Events in ≥2% of Patients Treated with

Pravastatin 40 mg and at an Incidence Greater Than

Placebo in Long-Term Placebo-Controlled Trials

Body System/Event

Pravas tatin

(N =

10,764)

% of

patients

Placebo

(N =

10,719)

% of

patients

Dermatologic

Rash (including dermatitis)

General

Edema

Fatigue

Chest Pain

10.0

Fever

Weight Gain

Weight Loss

Musculoskeletal

Musculoskeletal Pain

24.9

24.4

Muscle Cramp

Musculoskeletal Traumatism

10.2

Nervous System

Dizziness

Sleep Disturbance

Anxiety/Nervousness

Paresthesia

Renal/Genitourinary

Urinary Tract Infection

Respiratory

Upper Respiratory Tract Infection

21.2

20.2

Cough

Influenza

Pulmonary Infection

Sinus Abnormality

Tracheobronchitis

Special Senses

Vision Disturbance (includes

blurred vision, diplopia)

Infections

Viral Infection

In addition to the events listed above in the long-term trials table, events of probable, possible, or

uncertain relationship to study drug that occurred in <2.0% of pravastatin-treated patients in the long-

term trials included the following:

Dermatologic: scalp hair abnormality (including alopecia), urticaria.

Endocrine/Metabolic: sexual dysfunction, libido change.

General: flushing.

Immunologic: allergy, edema head/neck.

Musculoskeletal: muscle weakness.

Nervous System: vertigo, insomnia, memory impairment, neuropathy (including peripheral neuropathy).

Special Senses: taste disturbance.

6.2 Postmarketing Experience

In addition to the events reported above, as with other drugs in this class, the following events have

been reported during postmarketing experience with pravastatin sodium, regardless of causality

assessment:

Musculoskeletal: myopathy, rhabdomyolysis, tendon disorder, polymyositis.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see

Warnings and Precautions ( 5.1)].

Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment of

extraocular movement, facial paresis), peripheral nerve palsy.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness,

amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been

reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation,

with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica,

dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR increase, arthritis,

arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal necrolysis, erythema multiforme

(including Stevens-Johnson syndrome).

Gastrointestinal: abdominal pain, constipation, pancreatitis, hepatitis (including chronic active hepatitis),

cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, fatal and

non-fatal hepatic failure .

Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes,

changes to hair/nails).

Renal: urinary abnormality (including dysuria, frequency, nocturia).

Respiratory: dyspnea, interstitial lung disease.

Psychiatric: nightmare.

Reproductive: gynecomastia.

Laboratory Abnormalities: liver function test abnormalities, thyroid function abnormalities.

6.3 Laboratory Test Abnormalities

Increases in ALT, AST values and CPK have been observed [see Warnings and Precautions (5.1, 5.2)].

Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal

despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been reported with statins.

6.4 Pediatric Patients

In a 2-year, double-blind, placebo-controlled study involving 100 boys and 114 girls with HeFH

(n=214; age range 8 to 18.5 years, 53% female, 95% Caucasians, <1% Blacks, 3% Asians, 1% Other),

the safety and tolerability profile of pravastatin was generally similar to that of placebo [see Warnings

and Precautions (5.3), Use in Specific Populations (8.4), and Clinical Pharmacology (12.3)].

7 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)].

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 (2.6), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

7.2 Clarithromycin and Other Macrolide Antibiotics

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 (2.7), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

Other macrolides (e.g., erythromycin and azithromycin) have the potential to increase statin exposures

while used in combination. Pravastatin should be used cautiously with macrolide antibiotics due to a

potential increased risk of myopathies.

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 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 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 dosage should be considered in this setting [see Warnings and Precautions

(5.1)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Pravastatin sodium is contraindicated for use in pregnant woman because of the potential for fetal harm.

As safety in pregnant women has not been established and there is no apparent benefit to therapy with

pravastatin during pregnancy, pravastatin sodium tablets should be immediately discontinued as soon as

pregnancy is recognized [see Contraindications ( 4.3) ]. Limited published data on the use of pravastatin

sodium in pregnant women are insufficient to determine a drug-associated risk of major congenital

malformations or miscarriage. In animal reproduction studies, no evidence of fetal malformations was

seen in rabbits or rats exposed to 10 times to 120 times, respectively, the maximum recommended human

dose (MRHD) of 80 mg/day. Fetal skeletal abnormalities, offspring mortality, and developmental delays

occurred when pregnant rats were administered 10 times to 12 times the MRHD during organogenesis

to parturition [see Data]. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is

unknown. In the U.S. general population, the estimated background risk of major birth defects and

miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Human Data

Limited published data on pravastatin have not shown an increased risk of major congenital

malformations or miscarriage.

Rare reports of congenital anomalies have been received following intrauterine exposure to other

statins. In a review

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 to exclude a ≥3 to 4-fold increase in congenital anomalies over the background incidence. In

89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and

was discontinued at some point in the first trimester when pregnancy was identified.

Animal Data

Embryofetal and neonatal mortality was observed in rats given pravastatin during the period of

organogenesis or during organogenesis continuing through weaning. In pregnant rats given oral gavage

doses of 4, 20, 100, 500, and 1,000 mg/kg/day from gestation days 7 through 17 (organogenesis)

increased mortality of offspring and increased cervical rib skeletal anomalies were observed at ≥100

mg/kg/day systemic exposure, 10 times the human exposure at 80 mg/day MRHD based on body surface

area (mg/m

In other studies, no teratogenic effects were observed when pravastatin was dosed orally during

organogenesis in rabbits (gestation days 6 through 18) up to 50 mg/kg/day or in rats (gestation days 7

through 17) up to 1,000 mg/kg/day. Exposures were 10 times (rabbit) or 120 times (rat) the human

exposure at 80 mg/day MRHD based on body surface area (mg/m

In pregnant rats given oral gavage doses of 10, 100, and 1,000 mg/kg/day from gestation day 17 through

lactation day 21 (weaning), increased mortality of offspring and developmental delays were observed at

≥100 mg/kg/day systemic exposure, corresponding to 12 times the human exposure at 80 mg/day

MRHD, based on body surface area (mg/m

In pregnant rats, pravastatin crosses the placenta and is found in fetal tissue at 30% of the maternal

plasma levels following administration of a single dose of 20 mg/day orally on gestation day 18, which

corresponds to exposure 2 times the MRHD of 80 mg daily based on body surface area (mg/m

). In

lactating rats, up to 7 times higher levels of pravastatin are present in the breast milk than in the maternal

plasma, which corresponds to exposure 2 times the MRHD of 80 mg/day based on body surface area

(mg/m

8.2 Lactation

Risk Summary

Pravastatin use is contraindicated during breastfeeding [see Contraindications (4.4)]. Based on one

lactation study in published literature, pravastatin is present in human milk. There is no available

information on the effects of the drug on the breastfed infant or the effects of the drug on milk

production. Because of the potential for serious adverse reactions in a breastfed infant, advise patients

that breastfeeding is not recommended during treatment with pravastatin sodium tablets.

8.3 Females and Males of Reproductive Potential

Contraception

Females

Pravastatin sodium tablets may cause fetal harm when administered to a pregnant woman [see Use in

Specific Populations ( 8.1) ]. Advise females of reproductive potential to use effective contraception

during treatment with pravastatin sodium tablets.

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 ( 2.4) ].

Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age have not been

conducted.

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

), time to maximum plasma concentration (T

), and half-life (t

) 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)].

8.6 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 statins are less effective because the patients lack

functional LDL receptors.

10 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.

11 DESCRIPTION

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 Sodium (3R,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-

hydroxy-2-methyl-8-[[(2S)-methylbutanoyl]oxy]-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]heptanoate.

Structural Formula:

Pravastatin sodium is an odorless, white to off-white, fine or crystalline powder. It is a relatively polar

hydrophilic compound with a partition coefficient (octanol/ water) of 0.59 at a pH of 7.0. It is soluble in

methanol and water (>300 mg/mL), slightly soluble in isopropanol, and practically insoluble in acetone,

acetonitrile, chloroform, and ether.

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

addition, each tablet contains the following inactive ingredients: croscarmellose sodium, lactose

monohydrate, magnesium stearate and microcrystalline cellulose. The 10 mg tablet also contains Red

Ferric Oxide, the 20 mg tablet also contains Yellow Ferric Oxide, the 40 mg tablet also contains a blend

of Yellow Ferric Oxide and FD&C Blue #1 Aluminum Lake, and the 80 mg tablet also contains Yellow

Ferric Oxide.

12 CLINICAL PHARMACOLOGY

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.

12.3 Pharmacokinetics

General

Absorption

Pravastatin sodium is administered orally in the active form. In studies in man, peak plasma pravastatin

concentrations occurred 1 to 1.5 hours upon oral administration. Based on urinary recovery of total

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 plasma concentrations, including area under the concentration-time curve (AUC), C

, and

steady-state minimum (C

), are directly proportional to administered dose. Systemic bioavailability of

pravastatin administered following a bedtime dose was decreased 60% compared to that following an

AM dose. Despite this decrease in systemic bioavailability, the efficacy of pravastatin administered

once daily in the evening, although not statistically significant, was marginally more effective than that

after a morning dose.

The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for AUC.

The geometric means of pravastatin C

and AUC following a 20 mg dose in the fasted state were

26.5 ng/mL and 59.8 ng*hr/mL, respectively.

Steady-state AUCs, C

, and C

plasma concentrations showed no evidence of pravastatin

accumulation following once or twice daily administration of pravastatin sodium tablets.

Distribution

Approximately 50% of the circulating drug is bound to plasma proteins.

Metabolism

The major biotransformation pathways for pravastatin are: (a) isomerization to 6-epi pravastatin and the

3α-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. The

3α-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory

activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver

(extraction ratio 0.66).

Excretion

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).

Following single dose oral administration of

C-pravastatin, the radioactive elimination t

pravastatin is 1.8 hours in humans.

Specific Populations

Renal Impairment

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). Compared to healthy subjects with

normal renal function, patients with severe renal impairment had 69% and 37% higher mean AUC and C

values, respectively, and a 0.61 hour shorter t½ for the inactive enzymatic ring hydroxylation

metabolite (SQ 31,945).

Hepatic Impairment

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 [see Warnings and Precautions (5.2)].

Geriatric

In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was approximately

27% greater and the mean cumulative urinary excretion (CUE) approximately 19% lower in elderly men

(65 to 75 years old) compared with younger men (19 to 31 years old). In a similar study conducted in

women, the mean AUC for pravastatin was approximately 46% higher and the mean CUE approximately

18% lower in elderly women (65 to 78 years old) compared with younger women (18 to 38 years old).

In both studies, C

, and t

values were similar in older and younger subjects [see Use in

Specific Populations (8.5)].

Pediatric

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 C

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 [see Use in Specific Populations

(8.4)].

Drug-Drug Interactions

Table 3: Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin

Coadministered Drug and Dosing

Regimen

Pravas tatin

Dose (mg)

Change in AUC

Change in C

Cyclosporine 5 mg/kg single dose

40 mg single dose

↑282%

↑327%

Clarithromycin 500 mg BID for 9 days

40 mg OD for 8

↑110%

↑128%

max

days

Boceprevir 800 mg TID for 6 days

40 mg single dose

↑63%

↑49%

Darunavir 600 mg BID/Ritonavir 100 mg

BID for 7 days

40 mg single dose

↑81%

↑63%

Colestipol 10 g single dose

20 mg single dose

↓47%

↓53%

Cholestyramine 4 g single dose

Administered simultaneously

Administered 1 hour prior to

cholestyramine

Administered 4 hours after cholestyramine

20 mg single dose

↓40%

↑12%

↓12%

↓39%

↑30%

↓6.8%

Cholestyramine 24 g OD for 4 weeks

20 mg BID for 8

weeks

5 mg BID for 8

weeks

10 mg BID for 8

weeks

↓51%

↓38%

↓18%

↑4.9%

↑23%

↓33%

Fluconazole

200 mg IV for 6 days

200 mg PO for 6 days

20 mg PO+10 mg

20 mg PO+10 mg

↓34%

↓16%

↓33%

↓16%

Kaletra 400 mg/100 mg BID for 14 days

20 mg OD for 4

days

↑33%

↑26%

Verapamil IR 120 mg for 1 day and

Verapamil ER 480 mg for 3 days

40 mg single dose

↑31%

↑42%

Cimetidine 300 mg QID for 3 days

20 mg single dose

↑30%

↑9.8%

Antacids 15 mL QID for 3 days

20 mg single dose

↓28%

↓24%

Digoxin 0.2 mg OD for 9 days

20 mg OD for 9

days

↑23%

↑26%

Probucol 500 mg single dose

20 mg single dose

↑14%

↑24%

Warfarin 5 mg OD for 6 days

20 mg BID for 6

days

↓13%

↑6.7%

Itraconazole 200 mg OD for 30 days

40 mg OD for 30

days

↑11% (compared to

Day 1)

↑17% (compared to

Day 1)

Gemfibrozil 600 mg single dose

20 mg single dose

↓7.0%

↓20%

Aspirin 324 mg single dose

20 mg single dose

↑4.7%

↑8.9%

Niacin 1 g single dose

20 mg single dose

↓3.6%

↓8.2%

Diltiazem

20 mg single dose

↑2.7%

↑30%

Grapefruit juice

40 mg single dose

↓1.8%

↑3.7%

BID = twice daily; OD = once daily; QID = four times daily

Table 4: Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs

Pravastatin Dosing

Regimen

Name and Dose

Change in AUC

Change in C

20 mg BID for 6 days

Warfarin 5 mg OD for 6 days

Change in mean prothrombin

time

↑17%↑0.4 sec

↑15%

20 mg OD for 9 days

Digoxin 0.2 mg OD for 9 days

↑4.6%

↑5.3%

20 mg BID for 4 weeks

10 mg BID for 4 weeks

5 mg BID for 4 weeks

Antipyrine 1.2 g single dose

↑3.0%↑1.6%↑Less than

Not Reported

max

20 mg OD for 4 days

Kaletra 400 mg/100 mg

BID for 14 days

No change

No change

BID = twice daily; OD = once daily

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was an

increased incidence of hepatocellular carcinomas in males at the highest dose (p<0.01). These effects

in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on body surface

area (mg/m

) and at approximately 4 times the HD, based on AUC.

In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased

incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/kg/day (p<0.0001).

At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were

observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the HD 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 HD 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 fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse

effects on fertility or general reproductive performance.

13.2 Animal Toxicology and/or Pharmacology

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 HD 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.

When administered to juvenile rats (postnatal days [PND] 4 through 80 at 5 to 45 mg/kg/day), no drug

related changes were observed at 5 mg/kg/day. At 15 and 45 mg/kg/day, altered body-weight gain was

observed during the dosing and 52-day recovery periods as well as slight thinning of the corpus

callosum at the end of the recovery period. This finding was not evident in rats examined at the

completion of the dosing period and was not associated with any inflammatory or degenerative changes

in the brain. The biological relevance of the corpus callosum finding is uncertain due to the absence of

any other microscopic changes in the brain or peripheral nervous tissue and because it occurred at the

end of the recovery period. Neurobehavioral changes (enhanced acoustic startle responses and

increased errors in water-maze learning) combined with evidence of generalized toxicity were noted at

45 mg/kg/day during the later part of the recovery period. Serum pravastatin levels at 15 mg/kg/day are

approximately ≥1 times (AUC) the maximum pediatric dose of 40 mg. No thinning of the corpus

callosum was observed in rats dosed with pravastatin (≥250 mg/kg/day) beginning PND 35 for 3 months

suggesting increased sensitivity in younger rats. PND 35 in a rat is approximately equivalent to an 8- to

12-year-old human child. Juvenile male rats given 90 times (AUC) the 40 mg dose had decreased

fertility (20%) with sperm abnormalities compared to controls.

14 CLINICAL STUDIES

14.1 Prevention of Coronary Heart Disease

In the Pravastatin Primary Prevention Study (WOS),

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, 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 (25

, 75

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 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.

14.2 Secondary Prevention of Cardiovascular Events

In the LIPID

study, the effect of pravastatin sodium tablets, 40 mg daily, was assessed in 9014 patients

(7498 men; 1516 women; 3514 elderly patients [age ≥65 years]; 782 diabetic patients) who had

experienced either an MI (5754 patients) or had been hospitalized for unstable angina pectoris (3260

patients) in the preceding 3 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 sodium tablets significantly reduced the risk for total mortality by

reducing coronary death (see Table 5). The risk reduction due to treatment with pravastatin sodium

tablets on CHD mortality was consistent regardless of age. Pravastatin sodium tablets significantly

reduced the risk for total mortality (by reducing CHD death) and CHD events (CHD mortality or

nonfatal MI) in patients who qualified with a history of either MI or hospitalization for unstable angina

pectoris.

Table 5: LIPID - Primary and Secondary Endpoints Number (%) of Subjects

Event

Pravastatin 40 mg

Placebo

Ris k

p-value

Event

(N=4512)

(N=4502)

Reduction

p-value

Primary Endpoint

CHD mortality

287 (6.4)

373 (8.3)

0.0004

Secondary Endpoints

Total mortality

498 (11.0)

633 (14.1)

<0.0001

CHD mortality or nonfatal MI

557 (12.3)

715 (15.9)

<0.0001

Myocardial revascularization procedures

(CABG or PTCA)

584 (12.9)

706 (15.7)

<0.0001

Stroke

All-cause

169 (3.7)

204 (4.5)

0.0477

Non-hemorrhagic

154 (3.4)

196 (4.4)

0.0154

Cardiovascular mortality

331 (7.3)

433 (9.6)

<0.0001

In the CARE

study, the effect of pravastatin sodium tablets, 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 75

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 (25

, 75

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

sodium tablets significantly reduced the rate of first recurrent coronary events (either CHD death or

nonfatal MI), the risk of undergoing revascularization procedures (PTCA, CABG), and the risk for

stroke or TIA (see Table 6).

Table 6: CARE -Primary and Secondary Endpoints Number (%) of Subjects

Event

Pravastatin 40 mg

(N=2081)

Placebo

(N=2078)

Ris k

Reduction

p-

value

Primary Endpoint

CHD mortality or nonfatal MIa

212 (10.2)

274 (13.2)

0.003

Secondary Endpoints

Myocardial revascularization procedures

(CABG or PTCA)

294 (14.1)

391 (18.8)

<0.001

Stroke or TIA

93 (4.5)

124 (6.0)

0.029

The risk reduction due to treatment with pravastatin sodium was consistent in both sexes.

In the PLAC I

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 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 REGRESS

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 to 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,

REGRESS, and KAPS

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

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,

double-blind, 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, 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 25

and 75

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

Dos e

Total-C

LDL-C

HDL-C

TG

Mean Percent Changes From Baseline After 8

Weeks

Placebo (N = 36)

−3%

−4%

−4%

10 mg (N = 18)

−16%

−22%

−15%

20 mg (N = 19)

−24%

−32%

−11%

40 mg (N = 18)

−25%

−34%

+12%

−24%

Mean Percent Changes From Baseline After 6

Weeks

Placebo (N = 162)

−1%

−1%

80 mg (N = 277)

−27%

−37%

−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).

A multicenter, double-blind, placebo-controlled study.

Pooled analysis of 2 multicenter, double-blind, placebo-controlled

studies.

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 246.0 (200.5, 349.5) mg/dL (see Table 8).

Table 8: Patients with Fredrickson Type IV Hyperlipidemia Median (25

, 75

percentile) % Change from Baseline

Pravastatin 40 mg (N=429)

Placebo (N=430)

-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)

14.5 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 9.

Table 9: Patients with Fredrickson Type III

Dysbetalipoproteinemia Median (min, max) % Change from

Bas eline

Median (min, max) at

Baseline (mg/dL)

Median % Change (min,

max) Pravastatin 40 mg

(N = 20)

Study 1

Total-C

386.5 (245.0, 672.0)

−32.7 (−58.5, 4.6)

443.0 (275.0, 1299.0)

−23.7 (−68.5, 44.7)

VLDL-C

206.5 (110.0, 379.0)

−43.8 (−73.1, −14.3)

LDL-C

117.5 (80.0, 170.0)

−40.8 (−63.7, 4.6)

HDL-C

30.0 (18.0, 88.0)

6.4 (−45.0, 105.6)

Non-HDL-C

344.5 (215.0, 646.0)

−36.7 (−66.3, 5.8)

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, −13.0)

343.2 (212.6, 845.9)

−11.9 (−56.5, 44.8)

VLDL-C

145.0 (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, 58.0)

5.0 (−17.7, 66.7)

Non-HDL-C

295.8 (195.3, 421.5)

−35.5 (−81.0, −13.5)

14.6 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 2 years. The children

th

th

(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

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)

Pravas tatin

20 mg

(Aged 8 to

13 years) N

= 65

Pravas tatin

40 mg

(Aged 14 to

18 years) N

= 41

Combined

Pravas tatin

(Aged 8 to

18 years) N

= 106

Combined

Placebo

(Aged 8

to 18

years) N =

108

95% CI of the

Difference

Between

Combined

Pravas tatin

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-squares mean values were calculated based on log-transformed lipid values.

Significant at p≤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.

15 REFERENCES

1. Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins - An integrated approach to

mechanisms and disorders. N Engl J Med. 1967;276: 34-44, 94-103, 148-156, 215-225, 273-281.

2. Manson JM, Freyssinges C, Ducrocq MB, Stephenson WP. Postmarketing surveillance of lovastatin

and simvastatin exposure during pregnancy. Reprod Toxicol. 1996;10(6):439-446.

3. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group

(WOS). Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N

Engl J Med. 1995;333:1301-1307.

4. The Long-term Intervention with Pravastatin in Ischemic Disease Group (LIPID). Prevention of

cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad

range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357.

5. Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial

Investigators (CARE). The effect of pravastatin on coronary events after myocardial infarction in

a

patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009.

6. Pitt B, Mancini GBJ, Ellis SG, et al, for the PLAC I Investigators. Pravastatin limitation of

atherosclerosis in the coronary arteries (PLAC I): Reduction in atherosclerosis progression and

clinical events. J Am Coll Cardiol. 1995;26:1133-1139.

7. Jukema JW, Bruschke AVG, van Boven AJ, et al, for the Regression Growth Evaluation Statin Study

Group (REGRESS). 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. Circ. 1995;91:2528-2540.

8. Crouse JR, Byington RP, Bond MG, et al. Pravastatin, lipids, and atherosclerosis in the carotid

arteries: Design features of a clinical trial with carotid atherosclerosis outcome (PLAC II). Control

Clin Trials. 1992;13:495-506.

9. Salonen R, Nyyssonen K, Porkkala E, 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. Circ. 1995;92:1758-1764.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Pravastatin Sodium Tablets, USP 10 mg are available for oral administration as light pink, round,

unscored tablets, imprinted “APO” on one side and “PRA” over “10” on the other side. They are

supplied as follows:

Bottles of 90 (NDC 60505-0168-9)

Bottles of 100 (NDC 60505-0168-1)

Bottles of 500 (NDC 60505-0168-5)

Bottles of 1,000 (NDC 60505-0168-7)

Pravastatin Sodium Tablets, USP 20 mg are available for oral administration as off-white to light

yellow, round, unscored tablets, imprinted “APO” on one side and “PRA” over “20” on the other side.

They are supplied as follows:

Bottles of 90 (NDC 60505-0169-9)

Bottles of 100 (NDC 60505-0169-1)

Bottles of 500 (NDC 60505-0169-5)

Bottles of 1,000 (NDC 60505-0169-7)

Pravastatin Sodium Tablets, USP 40 mg are available for oral administration as light green, round,

unscored tablets, imprinted “APO” on one side and “PRA” over “40” on the other side. They are

supplied as follows:

Bottles of 90 (NDC 60505-0170-9)

Bottles of 100 (NDC 60505-0170-1)

Bottles of 500 (NDC 60505-0170-5)

Bottles of 1,000 (NDC 60505-0170-7)

Pravastatin Sodium Tablets, USP 80 mg are available for oral administration as off-white to light

yellow, round, unscored tablets, imprinted "APO" on one side and "PRA" over "80" on the other side.

They are supplied as follows:

Bottles of 90 (NDC 60505-1323-9)

Bottles of 100 (NDC 60505-1323-1)

Bottles of 500 (NDC 60505-1323-5)

Bottles of 1,000 (NDC 60505-1323-7)

16.2 Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F). [See USP

Controlled Room Temperature]. Dispense in a tight, light-resistant container [see USP]. Protect from

light and moisture.

17 PATIENT COUNSELING INFORMATION

Muscle Pain

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)].

Liver Enzymes

It is recommended that liver enzyme tests be performed before the initiation of pravastatin, and

thereafter when clinically indicated. All patients treated with pravastatin 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)].

Embryofetal Toxicity

Advise females of reproductive potential of the risk to a fetus, to use effective contraception during

treatment, and to inform their healthcare provider of a known or suspected pregnancy [see

Contraindications( 4.3) , Use in Specific Populations ( 8.1, 8.3) ].

Lactation

Advise women not to breastfeed during treatment with pravastatin sodium tablets [see Contraindications(

4.4), Use in Specific Populations ( 8.2) ].

APOTEX INC.

PRAVASTATIN SODIUM TABLETS, USP

10 mg, 20 mg, 40 mg and 80 mg

Manufactured by Manufactured for

Apotex Inc. Apotex Corp.

Toronto, Ontario Weston, Florida

Canada M9L 1T9 33326

Revised: July 2016

Rev. 11

DRUG: PRAVASTATIN SODIUM

GENERIC: PRAVASTATIN SODIUM

DOSAGE: TABLET

ADMINSTRATION: ORAL

NDC: 70518-2229-0

COLOR: pink

SHAPE: ROUND

SCORE: No score

SIZE: 6 mm

IMPRINT: APO;PRA;10

PACKAGING: 30 in 1 BLISTER PACK

ACTIVE INGREDIENT(S):

Pravastatin Sodium 10mg in 1

INACTIVE INGREDIENT(S):

CELLULOSE, MICROCRYSTALLINE

CROSCARMELLOSE SODIUM

FERRIC OXIDE RED

LACTOSE MONOHYDRATE

MAGNESIUM STEARATE

PRAVASTATIN SODIUM

pravastatin sodium tablet

Product Information

Product T ype

HUMAN PRESCRIPTION

DRUG

Ite m Code

(S ource )

NDC:70 518 -2229 (NDC:6 0 50 5-

0 16 8 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

PRAVASTATIN SO DIUM (UNII: 3M8 6 0 8 UQ6 1) (PRAVASTATIN - UNII:KXO2KT9 N0 G)

PRAVASTATIN SODIUM

10 mg

REMEDYREPACK INC.

Inactive Ingredients

Ingredient Name

Stre ng th

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

Product Characteristics

Color

pink

S core

no sco re

S hap e

ROUND

S iz e

6 mm

Flavor

Imprint Code

APO;PRA;10

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date Marketing End Date

1

NDC:70 518 -2229 -0

30 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

0 7/23/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 76 341

0 7/23/20 19

Labeler -

REMEDYREPACK INC. (829572556)

Revised: 7/2019

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