Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3130
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PRAVIGARD PAC (Kit)
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Pravigard PAC: 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 .<br/>Pravachol: 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 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.<br/>Buffered Aspirin: Each dose of aspirin should be taken with a full glass of water unless patient is fluid restricted.<br/>Prevention of Recurrent MI or Treatment of Chronic Stable Angina Pectoris: 81 or 325 mg once a day. Continue therapy indefinitely.<br/>Ischemic Stroke and TIA: 81 or 325 mg once a day. Continue therapy indefinitely.<br/>Revascularization Procedures: The maintenance dose following revascularization procedures (CABG, angioplasty, carotid endarterectomy) is 81-325 mg/day of aspirin. Higher doses (to 650 mg/day) have also been recommended post endarterectomy.
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PRAVIGARDPAC (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 . 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.<br/>Pravachol: 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-��,��,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-, monosodium salt, [1S-[1��(��S*,��S*),2��,6��,8��(R*),8a��]]-. 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).<br/>Buffered Aspirin: 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.
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Mechanism of Action and Pharmacodynamics:<br/>Pravachol: Cholesterol and triglycerides in the bloodstream circulate as part of lipoprotein complexes. These complexes can be separated by density ultracentrifugation into high (HDL), intermediate (IDL), low (LDL), and very low (VLDL) density lipoprotein fractions. Triglycerides (TG) and cholesterol synthesized inthe liver are incorporated into very low density lipoproteins (VLDLs) and released into the plasma for delivery to peripheral tissues. In a series of subsequent steps, VLDLs are transformed into intermediate density lipoproteins (IDLs), and cholesterol-rich low density lipoproteins (LDLs). High density lipoproteins (HDLs), containing apolipoprotein A, are hypothesized to participate in the reverse transport of cholesterol from tissues back to the liver. PRAVACHOL produces its lipid-lowering effect in two ways. First, as a consequence of its reversible inhibition of HMG-CoA reductase activity, it effects modest reductions in intracellular pools of cholesterol. This results in an increase in the number of LDL-receptors on cell surfaces and enhanced receptor-mediated catabolism and clearance of circulating LDL. Second, pravastatin inhibits LDL production by inhibiting hepatic synthesis of VLDL, the LDL precursor. Clinical and pathologic studies have shown that elevated levels of total cholesterol (Total-C), low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B - a membrane transport complex for LDL) promote human atherosclerosis. Similarly, decreased levels of HDL-cholesterol (HDL-C) and its transport complex, apolipoprotein A, are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of Total-C and LDL-C and inversely with the level ofHDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, IDL, and remnants, can also promote atherosclerosis. Elevated plasma TG are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for coronary heart disease (CHD). Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. In both normal volunteers and patients with hypercholesterolemia, treatment with PRAVACHOL reduced Total-C, LDL-C, and apolipoprotein B. PRAVACHOL also reduced VLDL-C and TG and produced increases in HDL-C and apolipoprotein A.<br/>Buffered Aspirin: Aspirin affects platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating factor thromboxane A. Nonacetylated salicylates do not inhibit this enzyme and have no effect on platelet aggregation. At somewhat higher doses, aspirin reversibly inhibits the formation of prostaglandin I(prostacyclin), which is an arterial vasodilator and inhibits platelet aggregation.<br/>Buffered Aspirin and Pravastatin Pharmacodynamic Interactions: There is no evidence of a pharmacodynamic effect of aspirin on the lipid lowering effect of pravastatin (see Table 1). No study of the effect of pravastatin on the pharmacodynamics of aspirin has been performed.<br/>Pharmacokinetics/Metabolism:<br/>Pravachol:<br/>Buffered Aspirin:<br/>Pravachol Co-Administered With Buffered Aspirin: The pharmacokinetic interaction of buffered aspirin (325 mg) and pravastatin (40 mg) were studied in a single-dose crossover study in healthy subjects. Co-administration with buffered aspirin had no significant effect on the Cand AUC of pravastatin. Similarly, co-administration with pravastatin had no significant effect on the Cand AUC of salicylate.<br/>Clinical Studies:<br/>Pravachol:<br/>Buffered Aspirin:<br/>Pravachol Co-Administered With Buffered Aspirin: Five PRAVACHOL secondary prevention studies (LIPID, CARE, REGRESS, PLAC I, and PLAC II) were combined in a meta-analysis to assess the independent effects of the concomitant use of pravastatin and aspirin when compared to pravastatin alone and aspirin alone on cardiovascular outcomes.These studies enrolled a total of 14,617 patients who were randomized to receive pravastatin or placebo. Within each randomized group, approximately 20% were not concurrently receiving aspirin. Patients enrolled into these studies included women (15%) and individuals greater than 65 years of age (35%). The independent effects of aspirin and pravastatin on cardiovascular events were seen when the population was grouped according to age and gender. Consistency of these outcomes according to race could not be determined, since information on race was not uniformly collected across all five studies. Baseline histories included previous MI (72%) and revascularization (43%). Each component of the pravastatin/aspirin combination contributed to the outcome benefits when these benefits were retrospectively defined as: Table 5 compares the cardiovascular events seen in subjects receiving the combination of pravastatin/aspirin and aspirin alone, derived from the randomized cohort in the five studies. Table 6 compares the cardiovascular events seen in subjects receiving the combination of pravastatin/aspirin and pravastatin alone, derived from the non-randomized cohort not receiving aspirin in the five trials. In a supportive analysis, the effects of pravastatin/aspirin were sustained through five years of follow-up.
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Pravachol: Hypersensitivity to any component of this medication. Active liver disease or unexplained, persistent elevations in liver function tests .<br/>Pregnancy and Lactation: Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they are contraindicated during pregnancy and in nursing mothers. Pravastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informedof 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 .<br/>Buffered Aspirin:<br/>Allergy: Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema, or bronchospasm (asthma).<br/>Reye's Syndrome: Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye's Syndrome with concomitant use of aspirin in certain viral illnesses.
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PravigardPAC (Buffered Aspirin and Pravastatin Sodium) Tablets PRAVIGARDPAC 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 blister card. Each cold-form foil card will contain 5 buffered aspirin tablets and 5 pravastatin sodium tablets, and the carton will contain 6 blister 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.<br/>STORAGE: 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.]
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General:<br/>Pravachol: PRAVACHOL (pravastatin sodium) may elevate creatine phosphokinase and transaminase levels . This should be considered in the differential diagnosis of chest pain in a patient on therapy with pravastatin.<br/>Buffered Aspirin:<br/>Information for Patients: Pravachol Co-Administered With Buffered Aspirin: 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 . 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.)<br/>Drug Interactions:<br/>Pravachol:<br/>Buffered Aspirin:<br/>Endocrine Function:<br/>Pravachol: HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Results of clinical trials with pravastatin in males and post-menopausal females were inconsistent with regard to possible effects of the drug on basal steroid hormone levels. In a study of 21 males, the mean testosterone response to human chorionic gonadotropin was significantly reduced (p<0.004) after 16 weeks of treatment with 40 mg of pravastatin. However, the percentage of patients showing a���50% rise in plasma testosterone after human chorionic gonadotropin stimulation did not change significantly after therapy in these patients. The effects of HMG-CoA reductase inhibitors on spermatogenesis and fertility have not been studied in adequate numbers of patients. The effects, if any, of pravastatin on the pituitary-gonadal axis in pre-menopausal females are unknown. Patients treated with pravastatin who display clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may diminish the levels or activity of steroid hormones.<br/>CNS Toxicity:<br/>Pravachol: CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononuclear cell infiltration of perivascular spaces, were seen in dogs treated with pravastatin at a dose of 25 mg/kg/day. These effects in dogs were observed at approximately 59 times the human dose of 80 mg/day, based on AUC. Similar CNS vascular lesions have been observed with several other drugs in this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma druglevel similar to that seen with the 60 mg/kg/day dose.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Pravachol: 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/mand at approximately 4 times the human dose, based on AUC. In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the human dose of 80 mg, based on AUC. In another 2-year study in mice with doses up to 100 mg/kg/day (producing drug exposures approximately 2 times the human dose of 80 mg, based on AUC), there were no drug-induced tumors. No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/- mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae. In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice. In a study in rats, with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance. However, in a study with another HMG-CoA reductase inhibitor, there was decreased fertility in male rats treated for 34 weeks at 25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. Although not seen withpravastatin, two similar drugs in this class caused drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration, and giant cell formation in dogs. The clinical significance of these findings is unclear.<br/>Buffered Aspirin: Administration of aspirin for 68 weeks at 0.5% in the feed of rats was not carcinogenic. In the Ames Salmonella assay, aspirin was not mutagenic; however, aspirin did induce chromosome aberrations in cultured human fibroblasts. Aspirin inhibits ovulation in rats.<br/>Pregnancy:<br/>Pravachol:<br/>Buffered Aspirin:<br/>Labor and Delivery:<br/>Buffered Aspirin: Aspirin should be avoided 1 week prior to and during labor and delivery because it can result in excessive blood loss at delivery. Prolonged gestation and prolonged labor due to prostaglandin inhibition have been reported.<br/>Nursing Mothers:<br/>Pravachol: A small amount of pravastatin is excreted in human breast milk. Because of the potential for serious adverse reactions in nursing infants, women taking PRAVACHOL should not nurse .<br/>Buffered Aspirin: Nursing mothers should avoid using aspirin because salicylate is excreted in breast milk. Use of high doses may lead to rashes, platelet abnormalities, and bleeding in nursing infants.<br/>Pediatric Use: PRAVIGARD PAC is not appropriate for use in the pediatric population.<br/>Geriatric Use:<br/>Pravigard PAC: Across the five studies (CARE, LIPID, REGRESS, PLAC I, PLAC II) used for the meta-analysis, 35% of subjects were aged 65 and older and 0.8% were aged 75 and older. The number of subjects aged 65 and older in each treatment group was: 1982 (34%) in pravastatin/aspirin, 534 (37%) in pravastatin/placebo, 2017 (35%) in placebo/aspirin, and 534 (37%) in placebo/placebo. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
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Pravachol: 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.<br/>Buffered Aspirin: 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��g/mL. Plasma concentrations of aspirin above 300��g/mL are clearly toxic. Severe toxic effects are associated with levels about 400��g/mL. 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.<br/>Signs and Symptoms: In acute overdose, severe acid-base and electrolyte disturbances may occur and are complicated by hyperthermia and dehydration. Respiratory alkalosis occurs early while hyperventilation is present, but is quickly followed by metabolic acidosis.<br/>Treatment: Treatment consists primarily of supporting vital functions, increasing salicylate elimination, and correcting the acid-base disturbance. Gastric emptying and/or lavage is recommended as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal, as a slurry, is beneficial, if less than 3 hours have passed since ingestion. Charcoal adsorption should not be employed prior to emesis and lavage. Severity of aspirin intoxication is determined by measuring the blood salicylate level. Acid-base status should be closely followed with serial blood gas and serum pH measurements. Fluid and electrolyte balance should also be maintained. In severe cases, hyperthermia and hypovolemia are the major immediate threats to life. Children should be sponged with tepid water. Replacement fluid should be administered intravenously and augmented with correction of acidosis. Plasma electrolytes and pH should be monitored to promote alkaline diuresis of salicylate if renal function is normal. Infusion of glucose may be required to control hypoglycemia. Hemodialysis and peritoneal dialysis can be performed to reduce the body drug content. In patients with renal insufficiency or in cases of life-threatening intoxication, dialysis is usually required. Exchange transfusion may be indicated in infants and young children.
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Aspirin and Pravastatin Sodium
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PRAVIGARD PAC (Kit)
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Pravigard PAC: 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.<br/>Pravachol:<br/>Adverse Clinical Events:<br/>Postmarketing Experience: The following events have been reported rarely during postmarketing experience with PRAVACHOL, regardless of causality assessment: Musculoskeletal: myopathy, rhabdomyolysis. Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), peripheral nerve palsy. Hypersensitivity: anaphylaxis, 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. Special Senses: vision disturbance including blurred vision and diplopia. Laboratory Abnormalities: elevated alkaline phosphatase and bilirubin; thyroid function abnormalities.<br/>Laboratory Test Abnormalities: Increases in serum transaminase (ALT, AST) values and CPK have been observed . 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.<br/>Concomitant Therapy: Pravastatin has been administered concurrently with cholestyramine, colestipol, nicotinic acid, probucol and gemfibrozil. Preliminary data suggest that the addition of either probucol or gemfibrozil to therapy with lovastatin or pravastatin is not associated with greater reduction in LDL-C 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.<br/>Buffered Aspirin: Many adverse reactions due to aspirin ingestion are dose-related. The following is a list of adverse reactions that have been reported in the literature. 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.
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Pravachol:<br/>Liver Enzymes: HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. In three long-term (4.8-5.9 years), placebo-controlled clinical trials, 19,592 subjects (19,768 randomized), were exposed to pravastatin or placebo. In an analysis of serum transaminase values (ALT, AST), incidences of marked abnormalities were compared between the pravastatin and placebo treatment groups; a marked abnormality was defined as a post-treatment test value greater than three times the upper limit of normal for subjects with pretreatment values less than or equal to the upper limit of normal, or four times the pretreatment value for subjects with pretreatment values greater than the upper limit of normal but less than 1.5 times the upper limit of normal. Marked abnormalities of ALT or AST occurred with similar low frequency (���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. It is recommended that liver function tests be performed prior to the initiation of therapy, prior to the elevation of the dose, and when otherwise clinically indicated. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of pravastatin . Caution should be exercised when pravastatin is administered to patients who have a recent history of liver disease, have signs that may suggest liver disease (e.g., unexplained transaminase elevations, jaundice), or are heavy users of alcohol . Such patients should be closely monitored, started at the lower end of the recommended dosing range, and titrated to the desired therapeutic effect. Patients who develop increased transaminase levels or signs and symptoms of liver disease should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of three times the upper limit of normal or greater persist, withdrawal of pravastatin therapy is recommended.<br/>Skeletal Muscle: Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with pravastatin and other drugs in this class. Uncomplicated myalgia has also been reported in pravastatin-treated patients . Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper normal limit, 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. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Pravastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Pravastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. The risk of myopathy during treatment with another HMG-CoA reductase inhibitor is increased with concurrent therapy with either erythromycin, cyclosporine, niacin, or fibrates. However, neither myopathy nor significant increases in CPK levels have been observed in three reports involving a total of 100 post-transplant patients (24 renal and 76 cardiac) treated for up to two years concurrently with pravastatin 10-40 mg and cyclosporine. Some of these patients also received other concomitant immunosuppressive therapies. Further, in clinical trials involving small numbers of patients who were treated concurrently with pravastatin and niacin, there were no reports of myopathy. Also, myopathy was not reported in a trial of combination pravastatin (40 mg/day) and gemfibrozil (1200 mg/day), although 4 of 75 patients on the combination showed marked CPK elevations versus 1 of 73 patients receiving placebo. There was a trend toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared with the groups receiving placebo, gemfibrozil, or pravastatin monotherapy . The use of fibrates alone may occasionally be associated with myopathy. The combined use of pravastatin and fibrates should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination.<br/>Buffered Aspirin:<br/>Alcohol Warning: Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin.<br/>Coagulation Abnormalities: Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited (hemophilia) or acquired (liver disease or vitamin K deficiency) bleeding disorders.<br/>GI Side Effects: GI side effects include stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur.<br/>Peptic Ulcer Disease: Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation and bleeding.<br/>Pregnancy: Pregnant women should only take aspirin if clearly needed. Because of the known effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the fetal cardiovascular system (closure of the ductus arteriosus), use during the third trimester of pregnancy should be avoided. Salicylate products have also been associated with alterations in maternal and neonatal hemostasis mechanisms, decreased birth weight, and with perinatal mortality.
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Pravigard PAC: 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 treatmentwith PRAVIGARD PAC should also be placed on a standard cholesterol-lowering diet and should continue on this diet during treatment.<br/>Pravachol:<br/>Secondary Prevention of Cardiovascular Events: In patients with clinically evident coronary heart disease, PRAVACHOL (pravastatin sodium) is indicated to:<br/>Hypercholesterolemia: PRAVACHOL is indicated as an adjunct to diet to reduce elevated Total-C, LDL-C, Apo B, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and IIb). Prior to initiating therapy with PRAVACHOL, 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, LDL-C, HDL-C, and TG. 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 and Education Program (NCEP - see below) recommends an LDL-C goal of<100 mg/dL in patients who have established CHD or CHD risk equivalents (diabetes, peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease, or multiple risk factors conferring a 10-year risk for CHD>20%). 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. In patients with CHD or CHD risk equivalents the non-HDL-C goal is<130 mg/dL. 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 Guidelines, above).<br/>Buffered Aspirin:<br/>Vascular Indications (Ischemic Stroke, TIA, Acute MI, Prevention of Recurrent MI, Unstable Angina Pectoris, and Chronic Stable Angina Pectoris): Aspirin is indicated to: (1) reduce the combined risk of death and nonfatal stroke in patients who have had ischemic stroke or transient ischemia of the brain due to fibrin platelet emboli, (2) reduce the risk of vascular mortality in patients with a suspected acute MI, (3) reduce the combined risk of death and nonfatal MI in patients with a previous MI or unstable angina pectoris, and (4) reduce the combined risk of MI and sudden death in patients with chronic stable angina pectoris.<br/>Revascularization Procedures (Coronary Artery Bypass Graft [CABG], Percutaneous Transluminal Coronary Angioplasty [PTCA], and Carotid Endarterectomy): Aspirin is indicated in patients who have undergone revascularization procedures (i.e., CABG, PTCA, or carotid endarterectomy) when there is a preexisting condition for which aspirin is already indicated.
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PRAVIGARD PAC
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