PRAVIGARD^™ PAC
(Buffered Aspirin and Pravastatin Sodium) tablets

PRAVIGARD^™ PAC (Buffered Aspirin and Pravastatin Sodium) is intended to facilitate the daily administration of its individual components, buffered aspirin and PRAVACHOL^®, when used together for the intended patient population (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION). PRAVIGARD PAC contains individual daily doses of buffered aspirin 81 mg or 325 mg tablets packed with either PRAVACHOL 20 mg, 40 mg, or 80 mg for oral administration.

PRAVACHOL^® (pravastatin sodium) is one of a class of lipid-lowering compounds, the HMG-CoA reductase inhibitors, that reduce cholesterol biosynthesis. These agents are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate.

Pravastatin sodium is designated chemically as 1-Naphthalene-heptanoic acid, 1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-, monosodium salt, [1S-[1α(βS*,δS*),2α,6α,8β(R*),8aα]]-. Structural formula:

Pravastatin sodium is an odorless, white to off-white, fine or crystalline powder. It is a relatively polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59 at a pH of 7.0. It is soluble in methanol and water (>300 mg/mL), slightly soluble in isopropanol, and practically insoluble in acetone, acetonitrile, chloroform, and ether.

Pravastatin is available for oral administration in PRAVIGARD PAC at strengths of 20 mg, 40 mg, and 80 mg. Inactive ingredients include: croscarmellose sodium, lactose, magnesium oxide, magnesium stearate, microcrystalline cellulose, and povidone. The 20 mg and 80 mg tablets also contain Yellow Ferric Oxide, and the 40 mg tablet also contains Green Lake Blend (mixture of D&C Yellow No. 10-Aluminum Lake and FD&C Blue No. 1-Aluminum Lake).

The chemical name for aspirin is acetylsalicylic acid and its structural formula is as follows:

Aspirin is an odorless white, needle-like crystalline or powdery substance. When exposed to moisture, aspirin hydrolyzes into salicylic and acetic acids, and gives off a vinegary odor. It is highly lipid soluble and slightly soluble in water.

Buffered aspirin tablets for oral administration contain 81 mg or 325 mg aspirin as the active ingredient. The formulations are buffered with calcium carbonate, magnesium oxide, and magnesium carbonate. Other ingredients include benzoic acid, citric acid, corn starch, FD&C Blue No. 1, hypromellose, magnesium stearate, mineral oil, polysorbate 20, povidone, propylene glycol, simethicone emulsion, sodium phosphate, sorbitan monolaurate, and titanium dioxide; formulations may also contain carnauba wax and zinc stearate.

PRAVIGARD PAC (Buffered Aspirin and Pravastatin Sodium) is indicated in patients for whom treatment with both PRAVACHOL and buffered aspirin is appropriate. As described in the labeling for PRAVACHOL and buffered aspirin below, the components of PRAVIGARD PAC are both indicated to reduce the occurrence of cardiovascular events, including death, myocardial infarction or stroke, in patients who have clinical evidence of cardiovascular and/or cerebrovascular disease. Patients receiving treatment with PRAVIGARD PAC should also be placed on a standard cholesterol-lowering diet and should continue on this diet during treatment.

Hypersensitivity to any component of this medication.

Active liver disease or unexplained, persistent elevations in liver function tests (see WARNINGS: Pravachol: Liver Enzymes).

PRAVACHOL (pravastatin sodium) may elevate creatine phosphokinase and transaminase levels (see ADVERSE REACTIONS: Pravachol). This should be considered in the differential diagnosis of chest pain in a patient on therapy with pravastatin.

Patients should be made aware that PRAVIGARD PAC (Buffered Aspirin and Pravastatin Sodium) contains the same ingredient that is in PRAVACHOL (pravastatin sodium) tablets and also contains aspirin.

Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever (see WARNINGS: Pravachol:Skeletal Muscle). Patients should also be advised to report to their physician any conditions that may increase the risk of bleeding. (See WARNINGS: Buffered Aspirin: Coagulation Abnormalities and GI Side Effects. See also Patient Information leaflet printed below.)

PRAVIGARD PAC is not appropriate for use in the pediatric population.

Across the five studies included in the meta-analysis (CARE, LIPID, REGRESS, PLAC I, PLAC II) the combined use of aspirin and pravastatin (N=5888) was well tolerated and was not associated with any increases in adverse reactions when compared to either pravastatin (N=1436) or aspirin (N=5833) alone. There were no significant differences in adverse reactions between genders or age groups.

Many adverse reactions due to aspirin ingestion are dose-related. The following is a ul of adverse reactions that have been reported in the literature. (See also WARNINGS: Buffered Aspirin.)

Gastrointestinal: dyspepsia, GI bleeding, ulceration and perforation, nausea, vomiting, transient elevations of hepatic enzymes, hepatitis, Reye’s Syndrome, pancreatitis.

Hematologic: prolongation of the prothrombin time.

Hypersensitivity: acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema, urticaria.

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: Pravachol.)

Salicylate toxicity may result from acute ingestion (overdose) or chronic intoxication. The early signs of salicylic overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma concentrations approaching 200 µg/mL. Plasma concentrations of aspirin above 300 µg/mL are clearly toxic. Severe toxic effects are associated with levels about 400 µg/mL. (See CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism: Buffered Aspirin:Distribution.) A single lethal dose of aspirin in adults is not known with certainty but death may be expected at 30 g. For real or suspected overdose, a Poison Control Center should be contacted immediately. Careful medical management is essential.

The recommended daily dose of PRAVIGARD PAC is 40 mg of PRAVACHOL with either 81 mg or 325 mg of buffered aspirin. If a daily dose of PRAVACHOL 40 mg does not achieve desired cholesterol levels, 80 mg once daily (with 81 mg or 325 mg of buffered aspirin) is recommended. Some people may require lower doses of PRAVACHOL, and PRAVIGARD PAC is also available with PRAVACHOL 20 mg (see Pravachol below). The daily dose can be taken any time of day, with or without food. Because of the aspirin component, the dose should be taken with a full glass of water, unless the patient is fluid restricted.

PRAVIGARD PAC should be avoided in patients with severe hepatic or renal insufficiency (PRECAUTIONS: Buffered Aspirin).

The recommended starting dose is 40 mg once daily. PRAVACHOL can be administered as a single dose at any time of the day, with or without food. The maximal effect of a given dose is seen within 4 weeks. If a daily dose of 40 mg does not achieve desired cholesterol levels, 80 mg once daily is recommended.

Lower doses are recommended in some patients. A starting dose of 10 mg daily is recommended in patients with a history of significant renal or hepatic dysfunction. In patients taking immunosuppressive drugs such as cyclosporine (see WARNINGS: Skeletal Muscle) concomitantly with pravastatin, therapy should begin with 10 mg of pravastatin once-a-day at bedtime and titration to higher doses should be done with caution. The dose of pravastatin generally should not exceed 20 mg/day in those patients receiving concurrent immunosuppressive therapy.

Each dose of aspirin should be taken with a full glass of water unless patient is fluid restricted.

Pravigard^™ PAC (Buffered Aspirin and Pravastatin Sodium) Tablets

PRAVIGARD^™ PAC is available in cartons containing either 30 buffered aspirin 81 mg or 325 mg tablets packed with either 30 PRAVACHOL (pravastatin sodium) 20 mg, 40 mg, or 80 mg tablets. Within the carton, the buffered aspirin tablets and pravastatin sodium tablets are presented side-by-side each in a separate cavity in a cold-form foil buler card. Each cold-form foil card will contain 5 buffered aspirin tablets and 5 pravastatin sodium tablets, and the carton will contain 6 buler cards.

PRAVACHOL 20 mg tablets are yellow, rounded, rectangular-shaped, biconvex with a P embossed on one side and PRAVACHOL 20 engraved on the opposite side.

PRAVACHOL 40 mg tablets are green, rounded, rectangular-shaped, biconvex with a P embossed on one side and PRAVACHOL 40 engraved on the opposite side.

PRAVACHOL 80 mg tablets are yellow, oval-shaped, with BMS on one side and 80 on the other side.

The buffered aspirin 81 mg tablets are white, oval, film-coated tablets embossed with a lower-case b on one side. The buffered aspirin 325 mg tablets are white, round, film-coated tablets embossed with a capital B on one side.

Store at 20° C - 25° C (68° F - 77° F); excursions permitted to 15° C - 30° C (59° F - 86° F). [See USP Controlled Room Temperature.]

¹The Long-term Intervention with Pravastatin in Ischemic Disease Group. Prevention of Cardiovascular Events and Death with Pravastatin in Patients with Coronary Heart Disease and a Broad Range of Initial Cholesterol Levels (LIPID). N Engl J Med 1998; 339:1349-1357.

²Sacks FM, et al. The Effect of Pravastatin on Coronary Events After Myocardial Infarction in Patients with Average Cholesterol Levels (CARE). N Engl J Med 1996; 335:1001-9.

³Pitt 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.

⁴Jukema 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.

⁵Crouse JR 3rd, et al. Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC II), Am J Cardiol 1995; 75:455-459.

US Patent No.: buffered aspirin 4,664,915

US Patent Nos.: PRAVACHOL^® 4,346,227; 5,030,447; 5,180,589; 5,622,985

Read the patient information that comes with PRAVIGARD PAC before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

What is the most important information about PRAVIGARD PAC?

• 1)If you have disease in the blood vessels of your heart (coronary artery disease), PRAVIGARD PAC can lower your chances of dying of heart disease, having a heart attack, or having a stroke. PRAVIGARD PAC will only help you while you take it. If you stop taking PRAVIGARD PAC, it will not help you anymore.
• 2)Rarely, patients taking PRAVACHOL (1 of the medicines in PRAVIGARD PAC) have experienced serious muscle damage. It is important that you know the early signs and symptoms of muscle damage. (See "What are the possible side effects of PRAVIGARD PAC?")

What is PRAVIGARD PAC?

PRAVIGARD PAC has 2 medicines in it, buffered aspirin and pravastatin sodium (PRAVACHOL^®).

Buffered aspirin stops part of the normal blood clotting process and so keeps clots or plugs from forming in your blood vessels. Buffered aspirin has aspirin in it along with other ingredients that may lower your chance of getting an upset stomach.

PRAVACHOL is a prescription medicine that lowers cholesterol in your blood. It lowers your "bad" LDL cholesterol and raises your "good" HDL cholesterol. High cholesterol can lead to plugs or clots in your blood vessels.

PRAVIGARD PAC is for people who may be helped by having their cholesterol lowered and who also have 1 or more of these problems:

• a heart attack in the past
• chest pain from heart problems (also called angina)
• had a bypass operation or angioplasty to open the blood vessels of the heart
• blood flow problems to the brain (such as strokes, near-strokes, or mini-strokes)

You need to follow your doctor’s advice and take PRAVIGARD PAC every day for it to lower your chances of dying from your heart disease, having a heart attack, or having a stroke. PRAVIGARD PAC is part of a treatment program that should also include a low-fat diet and exercise. If you stop taking PRAVIGARD PAC, it will not help you anymore. You must tell your doctor if you stop taking PRAVIGARD PAC.

PRAVIGARD PAC should not be used by:

• children younger than 18 years of age
• pregnant women (see below under “Who should not take PRAVIGARD PAC?”)

Who should not take PRAVIGARD PAC?

Do not take PRAVIGARD PAC if you:
• have certain liver or kidney problems. If you have liver or kidney problems, check with your doctor.
• are pregnant or planning to become pregnant. PRAVIGARD PAC can reach your baby and may harm it. If you are pregnant, stop taking PRAVIGARD PAC right away and tell your doctor.
• are breast feeding. PRAVIGARD PAC can pass into your breast milk and may harm your baby. You may need to choose between breast feeding or taking PRAVIGARD PAC.
• are 18 years of age or younger. Children younger than 18 years should not use any product with aspirin in it. Children can get a rare but very serious medical problem called Reye's Syndrome if they take aspirin when they are sick.
• are allergic to any medicines called "nonsteroidal anti-inflammatory drugs" (NSAIDs) or to any of the ingredients in PRAVIGARD PAC. The active ingredients are PRAVACHOL and buffered aspirin. See the end of this leaflet for a ul of all the ingredients in PRAVIGARD PAC. Ask your doctor or pharmacist if you need a ul of NSAIDs.

PRAVIGARD PAC may not be right for you or you may need extra care while taking PRAVIGARD PAC. Before you start PRAVIGARD PAC, tell your doctor if you:

• have bleeding problems
• have unexplained muscle aches or weakness
• have stomach problems such as heartburn, upset stomach, stomach pain, or ulcers
• drink 3 or more alcoholic drinks every day
• have asthma (wheezing) along with nasal polyps (small growths in your nose)

Tell your doctor about all of your medical problems or conditions such as a serious injury, a serious infection, or major surgery.

Can PRAVIGARD PAC affect my other medicines?

Tell your doctor about all the medicines you take, including other medicines that contain aspirin, prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines, like those uled below, can cause serious side effects if you take them while you are taking PRAVIGARD PAC. Be extra sure to tell your doctor if you take any of the following kinds of medicines:

• blood thinners. Blood thinners can increase your chance of bleeding since the aspirin in PRAVIGARD PAC also blocks normal blood clotting.
• certain medicines for high cholesterol or high triglycerides called fibrates

PRAVIGARD PAC may affect how some of your other medicines work. If you take a high blood pressure medicine called an ACE inhibitor, you may need to have your blood pressure checked more often.

How should I take PRAVIGARD PAC?

• Take PRAVIGARD PAC exactly as your doctor prescribes it.
• The usual dose of PRAVIGARD PAC is 1 aspirin tablet with 1 PRAVACHOL tablet once a day. PRAVIGARD PAC comes in different strengths and your doctor may adjust your dose. Do not change your dose without talking to your doctor.
• If you miss a dose, take it as soon as you remember. Do not take 2 doses in the same day.
• You can take PRAVIGARD PAC with or without food.
• Take PRAVIGARD PAC with a full glass of water, unless your doctor has told you to keep your fluids low.
• If you take too much PRAVIGARD PAC, call your doctor or Poison Control Center right away.

Some people may need to stop taking PRAVIGARD PAC for a short time. Call your doctor if you plan to have any surgery, medical, or dental procedures. You may be told to stop taking PRAVIGARD PAC for a while to lower your chance of bleeding.

Some people may need to stop taking PRAVIGARD PAC completely, or for a long time (see "What are the possible side effects of PRAVIGARD PAC?").

What activities should I avoid while taking PRAVIGARD PAC?

• Do not get pregnant. If you do, tell your doctor right away.
• Do not breast feed your baby.

What are the possible side effects of PRAVIGARD PAC?

PRAVIGARD PAC contains buffered aspirin and PRAVACHOL. You should be aware of the following serious side effects:

• Muscle damage: Rarely, patients taking PRAVACHOL, have experienced serious muscle damage. If you have unexplained muscle pain or weakness while taking PRAVIGARD PAC, tell your doctor right away. The following can be signs of serious muscle damage that can lead to kidney damage:
  • muscle problems like weakness, tenderness, or pain that don’t have a good reason for happening to you
  • a fever or you feel more tired than usual
  • passing brown or dark-colored urine
• Liver damage: Rare cases of liver function abnormalities have been reported with PRAVACHOL. Your doctor may do blood tests to check your liver before you start taking PRAVIGARD PAC, and while you take it.
• Bleeding: Aspirin can make it harder for your blood to clot. Call your doctor if you have any unusual bleeding.
• Stomach problems: Aspirin may cause stomach ulcers or stomach bleeding. Tell your doctor if you get any of the following:
  • heartburn that is new or won't go away
  • nausea or vomiting. Call your doctor right away if you see blood or something that looks like coffee grounds when you vomit.
  • stomach pain that is new or won't go away
  • bowel movements or stools that look like black tar

Allergic reactions: In people who are allergic to aspirin or NSAIDs, aspirin may cause a severe allergic reaction with hives, facial swelling, asthma (wheezing) or shock. Call a doctor or get emergency help right away if you get any of these symptoms.

Common side effects with PRAVIGARD PAC are rash, stomach pain, upset stomach, muscle ache, and headache.

These are not all the possible side effects of PRAVIGARD PAC. For more information, ask your doctor or pharmacist.

Talk to your doctor or pharmacist if you think you have side effects from taking PRAVIGARD PAC.

General information about the safe and effective use of PRAVIGARD PAC.

Do not use PRAVIGARD PAC for a condition for which it was not prescribed. Do not give PRAVIGARD PAC to other people, even if they have the same symptoms that you have. Keep PRAVIGARD PAC and all other medicines out of the reach of children. This leaflet summarizes the most important information about PRAVIGARD PAC. If you would like more information talk with your doctor. You can ask your doctor or pharmacist for information about PRAVIGARD PAC that is written for health professionals.

What are the ingredients of PRAVIGARD PAC?

Active Ingredients:

The active ingredient in buffered aspirin is aspirin. The active ingredient in PRAVACHOL is pravastatin sodium.

Inactive Ingredients:

The inactive ingredients in buffered aspirin are calcium carbonate, magnesium oxide, magnesium carbonate, benzoic acid, citric acid, corn starch, FD&C Blue No. 1, hypromellose, magnesium stearate, mineral oil, polysorbate 20, povidone, propylene glycol, simethicone emulsion, sodium phosphate, sorbitan monolaurate, titanium dioxide, carnauba wax, and zinc stearate. The inactive ingredients in PRAVACHOL are croscarmellose sodium, lactose, magnesium oxide, magnesium stearate, microcrystalline cellulose, and povidone. The 20 mg tablets and the 80 mg tablets have Yellow Ferric Oxide. The 40 mg tablets have Green Lake Blend (D&C Yellow No. 10-Aluminum Lake and FD&C Blue No. 1-Aluminum Lake).

Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA

1148286A3
Issued June 2003