INDICATIONS AND USAGE

Therapy with pravastatin sodium tablets should be considered in those individuals at increased risk for atherosclerosis-related clinical events as a function of cholesterol level, the presence or absence of coronary heart disease, and other risk factors.

Primary Prevention of Coronary Events

In hypercholesterolemic patients without clinically evident coronary heart disease, pravastatin sodium tablets are indicated to:

- Reduce the risk of myocardial infarction

- Reduce the risk of undergoing myocardial revascularization procedures

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

Hyperlipidemia

Pravastatin sodium tablets are indicated as an adjunct to diet to reduce elevated Total-C, LDL-C, ApoB, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and IIb).8

Pravastatin sodium tablets are indicated as adjunctive therapy to diet for the treatment of patients with elevated serum triglyceride levels (Fredrickson Type IV).

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

Pravastatin sodium tablets areindicated as an adjunct to diet and lifestyle modification for treatment of HeFH in children and adolescent patients ages 8 years and older if after an adequate trial of diet the following findings are present:

1.LDL-C remains ≥ 190 mg/dL or 2.LDL-C remains ≥ 160 mg/dL and: *there is a positive family history of premature cardiovascular disease or *two or more other CVD risk factors are present in the patient.

Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when the response to diet and other nonpharmacological measures alone has been inadequate (see NCEP guidelines below).

Prior to initiating therapy with pravastatin, secondary causes for hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure Total-C, HDL-C, and TG. For patients with triglycerides (TG) < 400 mg/dL (< 4.5 mmol/L), LDL-C can be estimated using the following equation:

LDL-C = Total-C - HDL-C - 1/5 TG

For TG levels > 400 mg/dL (> 4.5 mmol/L), this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. In many hypertriglyceridemic patients, LDL-C may be low or normal despite elevated Total-C. In such cases, HMG-CoA reductase inhibitors are not indicated.

Lipid determinations should be performed at intervals of no less than four weeks and dosage adjusted according to the patient’s response to therapy.

The National Cholesterol Education Program’s Treatment Guidelines are summarized below:

Table 7: NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes and Drug Therapy in Different Risk Categories

CHD, coronary heart disease † Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of < 100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgement also may call for deferring drug therapy in this subcategory ‡ Almost all people with 0 to 1 risk factor have 10 year risk < 10%; thus, 10 year risk assessment in people with 0 to 1 risk factor is not necessary.
Risk Category	LDL Goal (mg/dL)	LDL Level at Which to Initiate Therapeutic Lifestyle Changes (mg/dL)	LDL Level at Which to Consider Drug Therapy (mg/dL)
CHD * or CHD risk equivalents (10-year risk > 20%)	< 100	≥ 100	≥ 130 (100 to 129: drug optional) †
2+ Risk factors (10-year risk ≤ 20%)	< 130	≥ 130	10 year risk 10% to 20%: ≥ 130
10 year risk < 10%: ≥ 160
0 to 1 Risk factor ‡	< 160	≥ 160	≥ 190 (160-189: LDL-lowering drug optional)

After the LDL-C goal has been achieved, if the TG is still ≥ 200 mg/dL, non- HDL-C (Total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category.

At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge if the LDL-C is ≥ 130 mg/dL (see NCEP Treatment Guidelines, above).

Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the Total-C be used to monitor therapy.

As with other lipid-lowering therapy, pravastatin sodium tablets are not indicated when hypercholesterolemia is due to hyperalphalipoproteinemia (elevated HDL-C).

The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature cardiovascular disease is summarized below:

Category	Total-C (mg/dL)	LDL-C (mg/dL)
Acceptable	< 170	< 110
Borderline	170-199	110-129
High	≥ 200	≥ 130

ADVERSE REACTIONS

Pravastatin is generally well tolerated; adverse reactions have usually been mild and transient. In 4 month-long placebo-controlled trials, 1.7% of pravastatin-treated patients and 1.2% of placebo-treated patients were discontinued from treatment because of adverse experiences attributed to study drug therapy; this difference was not statistically significant. (See also PRECAUTIONS**:**Geriatric Use).

Adverse Clinical Events

Short-Term Controlled Trials

All adverse clinical events (regardless of attribution) reported in more than 2% of pravastatin treated patients in placebo-controlled trials of up to four months duration are identified in Table 8 ; also shown are the percentages of patients in whom these medical events were believed to be related or possibly related to the drug:

Table 8: Adverse Events in > 2 Percent of Patients Treated with Pravastatin 10-40 mg in Short-Term Placebo-Controlled Trials

Statistically significantly different from placebo.
	All Events	Events Attributed****to Study Drug
Body System/Event	Pravastatin**(N = 900) % ofpatients**	Placebo (N = 411) % of patients	Pravastatin (N = 900) % of patients	Placebo****(N = 411) % o****f patients
Cardiovascular
Cardiac Chest Pain	4.0	3.4	0.1	0.0
Dermatologic
Rash	4.0 *	1.1	1.3	0.9
Gastrointestinal
Nausea/Vomiting	7.3	7.1	2.9	3.4
Diarrhea	6.2	5.6	2.0	1.9
Abdominal Pain	5.4	6.9	2.0	3.9
Constipation	4.0	7.1	2.4	5.1
Flatulence	3.3	3.6	2.7	3.4
Heartburn	2.9	1.9	2.0	0.7
General
Fatigue	3.8	3.4	1.9	1.0
Chest Pain	3.7	1.9	0.3	0.2
Influenza	2.4*	0.7	0.0	0.0
Musculoskeletal
Localized Pain	10.0	9.0	1.4	1.5
Myalgia	2.7	1.0	0.6	0.0
Nervous System
Headache	6.2	3.9	1.7 *	0.2
Dizziness	3.3	3.2	1.0	0.5
Renal/Genitourinary
Urinary Abnormality	2.4	2.9	0.7	1.2
Respiratory
Common Cold	7.0	6.3	0.0	0.0
Rhinitis	4.0	4.1	0.1	0.0
Cough	2.6	1.7	0.1	0.0

The safety and tolerability of pravastatin at a dose of 80 mg in two controlled trials with a mean exposure of 8.6 months was similar to that of pravastatin at lower doses except that 4 out of 464 patients taking 80 mg of pravastatin had a single elevation of CK > 10X ULN compared to 0 out of 115 patients taking 40 mg of pravastatin.

Long-Term Controlled Morbidity and Mortality Trials

Adverse event data were pooled from several double-blind, placebo-controlled trials (e.g., West of Scotland Coronary Prevention Study [WOS]; Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids and Atherosclerosis in the Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated with pravastatin 40 mg and 10,719 patients treated with placebo. The safety and tolerability profile in the pravastatin group was comparable to that of the placebo group. Patients were exposed to pravastatin for a mean of 4.0 to 5.1 years in, among other trials, WOS and 1.9 to 2.9 years in PLAC I, PLAC II, KAPS, and REGRESS. In these long-term trials, the most common reasons for discontinuation were mild, non-specific gastrointestinal complaints. Collectively, these seven trials represent 47,613 patient-years of exposure to pravastatin. Events believed to be of probable, possible, or uncertain relationship to study drug, occurring in at least 1% of patients treated with pravastatin in these studies are identified in Table 9.

Table 9: Adverse Events in ≥ 1 Percent of Patients Treated with Pravastatin 40 mg in Long-Term Placebo-Controlled Trials

Body System/Event	Pravastatin**(N = 10,764) %**of patients	Placebo****(N = 10,719) %****of patients
Cardiovascular
Angina Pectoris	3.1	3.4
Dermatologic
Rash	2.1	2.2
Gastrointestinal
Dyspepsia/Heartburn	3.5	3.7
Abdominal Pain	2.4	2.5
Nausea/Vomiting	1.6	1.6
Flatulence	1.2	1.1
Constipation	1.2	1.3
General
Fatigue	3.4	3.3
Chest Pain	2.6	2.6
Musculoskeletal
Musculoskeletal Pain (includes arthralgia)	6.0	5.8
Muscle Cramp	2.0	1.8
Myalgia	1.4	1.4
Nervous System
Dizziness	2.2	2.1
Headache	1.9	1.8
Sleep Disturbance	1.0	0.9
Depression	1.0	1.0
Anxiety/Nervousness	1.0	1.2
Renal/Genitourinary
Urinary Abnormality (includes dysuria, frequency, nocturia)	1.0	0.8
Respiratory
Dyspnea	1.6	1.6
Upper Respiratory Infection	1.3	1.3
Cough	1.0	1.0
Special Senses
Vision Disturbance (includes blurred vision, diplopia)	1.6	1.3

Events of probable, possible, or uncertain relationship to study drug that occurred in < 1.0% of pravastatin-treated patients in the long-term trials included the following; frequencies were similar in placebo-treated patients:

Dermatologic: pruritus, dermatitis, dryness of skin, scalp hair abnormality (including alopecia), urticaria.

Endocrine/Metabolic: sexual dysfunction, libido change.

Gastrointestinal: decreased appetite.

General: fever, flushing.

Immunologic: allergy, edema head/neck.

Musculoskeletal: muscle weakness.

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

Special Senses: lens opacity, taste disturbance.

Postmarketing Experience

In addition to the events reported above, as with other drugs in this class, the following events have been reported rarely during postmarketing experience with pravastatin, regardless of causality assessment:

Musculoskeletal: myopathy, rhabdomyolysis.

Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), peripheral nerve palsy.

Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma.

Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails).

Reproductive: gynecomastia.

Laboratory Abnormalities: Liver Function Test abnormalities, thyroid function abnormalities.

Laboratory Test Abnormalities

Increases in serum transaminase (ALT, AST) values and CPK have been observed (seeWARNINGS).

Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been reported with HMG-CoA reductase inhibitors.

Concomitant Therapy

Pravastatin has been administered concurrently with cholestyramine, colestipol, nicotinic acid, probucol and gemfibrozil. Preliminary data suggest that the addition of either probucol or gemfibrozil to therapy with lovastatin or pravastatin isnot associated with greater reduction in LDL-cholesterol than that achieved with lovastatin or pravastatin alone. No adverse reactions unique to the combination or in addition to those previously reported for each drug alone have been reported. Myopathy and rhabdomyolysis (with or without acute renal failure) have been reported when another HMG-CoA reductase inhibitor was used in combination with immunosuppressive drugs, gemfibrozil, erythromycin, or lipid-lowering doses of nicotinic acid. Concomitant therapy with HMG-CoA reductase inhibitors and these agents is generally not recommended. (SeeWARNINGS,Skeletal Muscleand**PRECAUTIONS****: **Drug Interactions.)

Pediatric Patients

In a two year, double-blind, placebo-controlled study involving 100 boys and 114 girls with HeFH, the safety and tolerability profile of pravastatin was generally similar to that of placebo. (See** CLINICAL PHARMACOLOGY**,** Pediatric Clinical Study** andPRECAUTIONS,Pediatric Use.)

Manufactured By:

COBALT PHARMACEUTICALS INC.

Mississauga, Canada

L5N 2B8

Manufactured For:

COBALT LABORATORIES

Bonita Springs, Florida

U.S.A., 34134

Repackaged by:

REBEL DISTRIBUTORS CORP

Thousand Oaks, CA 91320

OVERDOSAGE

To date, there has been limited experience with overdosage of pravastatin. If an overdose occurs, it should be treated symptomatically with laboratory monitoring and supportive measures should be instituted as required. (See WARNINGS).

REFERENCES

1 Shepherd J, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia (WOS). N Engl J Med 1995;333:1301-7.

4 Pitt B, et al. Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I): Reduction in Atherosclerosis Progression and Clinical Events. J Am Coll Cardiol 1995;26:1133-9.

5 Jukema JW, et al. Effects of Lipid Lowering by Pravastatin on Progression and Regression of Coronary Artery Disease in Symptomatic Man With Normal to Moderately Elevated Serum Cholesterol Levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation 1995; 91:2528-2540.

6 Crouse JR, et al. Pravastatin, lipids, and atherosclerosis in the carotid arteries: design features of a clinical trial with carotid atherosclerosis outcome (PLAC II). Controlled Clinical Trials 1992;13:495.

7 Salonen R, et al. Kuopio Atherosclerosis Prevention Study (KAPS). A population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Research Institute of Public Health, University of Kuopio, Finland. Circulation 1995;92:1758.

8 Fredrickson DS, et al. Fat transport in lipoproteins-an integrated approach to mechanisms and disorders. N Engl J Med 1967; 276:34-42, 94-102, 148-156, 215-224, 273-281.

9 Manson JM, Freyssinges C, Ducrocq MB, Stephenson WP. Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy. Reproductive Toxicology 1996;10(6):439-446.