buffered aspirin and pravastatin Sodium
Dosage Form: tablets
(Patient Information leaflet included)
The individual products contained in this package each have additional indications and usage recommendations. For complete prescribing information, consult the package inserts for each individual product.
Pravigard PAC Description
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
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).
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.
Pravigard PAC - Clinical Pharmacology
Mechanism of Action and Pharmacodynamics
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 in the 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 of HDL-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.
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 A2. 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 I2 (prostacyclin), which is an arterial vasodilator and inhibits platelet aggregation.
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).
| Mean Percent Change from Baseline * | ||||
|---|---|---|---|---|
| Total-C | LDL-C | HDL-C | TG | |
| * On-treatment lipid measures at 3 months from randomization in CARE study. | ||||
| Pravastatin/Aspirin (N=1730) | -22% | -31% | +5% | -11% |
| Pravastatin/Placebo (N=336) | -21% | -30% | +6% | -9% |
| Placebo/Aspirin (N=1717) | 0% | -1% | +1% | +5% |
| Placebo/Placebo (N=336) | -1% | -1% | 0% | +3% |
No study of the effect of pravastatin on the pharmacodynamics of aspirin has been performed.
Pharmacokinetics/Metabolism
Pravachol
Absorption and Distribution
PRAVACHOL (pravastatin sodium) is administered orally in the active form. In clinical pharmacology studies in man, pravastatin is rapidly absorbed, with peak plasma levels of parent compound attained 1 to 1.5 hours following ingestion. Based on urinary recovery of 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 undergoes extensive first-pass extraction in the liver (extraction ratio 0.66), which is its primary site of action, and the primary site of cholesterol synthesis and of LDL-C clearance. In vitro studies demonstrated that pravastatin is transported into hepatocytes with substantially less uptake into other cells. Pravastatin plasma concentrations [including: area under the concentration-time curve (AUC), peak (Cmax), and steady-state minimum (Cmin)] 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. This finding of lower systemic bioavailability suggests greater hepatic extraction of the drug following the evening dose. Steady-state AUCs, Cmax and Cmin plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of PRAVACHOL tablets. Approximately 50% of the circulating drug is bound to plasma proteins.
Pravastatin, like other HMG-CoA reductase inhibitors, has variable bioavailability. The coefficient of variation, based on between-subject variability, was 50% to 60% for AUC.
Metabolism and Elimination
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). Since there are dual routes of elimination, the potential exists both for compensatory excretion by the alternate route as well as for accumulation of drug and/or metabolites in patients with renal or hepatic insufficiency.
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.
Biotransformation pathways elucidated for pravastatin include: (a) isomerization to 6-epi pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906), (b) enzymatic ring hydroxylation to SQ 31,945, (c) ω-1 oxidation of the ester side chain, (d) β-oxidation of the carboxy side chain, (e) ring oxidation followed by aromatization, (f) oxidation of a hydroxyl group to a keto group, and (g) conjugation. The major degradation product is the 3α-hydroxy isomeric metabolite, which has one-tenth to one-fortieth the HMG-CoA reductase inhibitory activity of the parent compound.
Following single dose administration of 14C-pravastatin, the elimination half-life (t½) for total radioactivity (pravastatin plus metabolites) in humans is 77 hours.
Special Populations
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, Cmax, Tmax and t½ values were similar in older and younger subjects.
Buffered Aspirin
Absorption
In general, immediate-release aspirin is well and completely absorbed from the gastrointestinal (GI) tract. Following absorption, aspirin is hydrolyzed to salicylic acid with peak plasma levels of salicylic acid occurring within 1-2 hours of dosing (see Pharmacokinetics/Metabolism: Buffered Aspirin: Metabolism).
Distribution
Salicylic acid is widely distributed to all tissues and fluids in the body including the central nervous system (CNS), breast milk, and fetal tissues. The highest concentrations are found in the plasma, liver, renal cortex, heart, and lungs. The protein binding of salicylate is concentration-dependent, i.e., nonlinear. At low concentrations (<100 micrograms per milliliter [µg/mL]), approximately 90% of plasma salicylate is bound to albumin while at higher concentrations (>400 µg/mL), only about 75% is bound.
Metabolism
Aspirin is rapidly hydrolyzed in the plasma to salicylic acid such that plasma levels of aspirin are essentially undetectable 1-2 hours after dosing. Salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites. Salicylic acid has a plasma half-life of approximately 6 hours. Salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses (10-20 grams [g]), the plasma half-life may be increased to over 20 hours.
Elimination
The elimination of salicylic acid follows zero order pharmacokinetics; (i.e., the rate of drug elimination is constant in relation to plasma concentration). Renal excretion of unchanged drug depends upon urine pH. As urinary pH rises above 6.5, the renal clearance of free salicylate increases from <5% to >80%. Alkalinization of the urine is a key concept in the management of salicylate overdose. (See OVERDOSAGE: Buffered Aspirin.) Following therapeutic doses, approximately 10% is found excreted in the urine as salicylic acid, 75% as salicyluric acid, and 10% phenolic and 5% acyl glucuronides of salicylic acid.
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 Cmax and AUC of pravastatin. Similarly, co-administration with pravastatin had no significant effect on the Cmax and AUC of salicylate.
Clinical Studies
Pravachol
Secondary Prevention of Cardiovascular Events
In the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID)1 study, the effect of PRAVACHOL, 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 myocardial infarction (MI) (5754 patients) or had been hospitalized for unstable angina pectoris (3260 patients) in the preceding 3-36 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), triglycerides 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 PRAVACHOL significantly reduced the risk for total mortality by reducing coronary death (see Table 2). The risk reduction due to treatment with PRAVACHOL on coronary heart disease (CHD) mortality was consistent regardless of age. PRAVACHOL 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.
| Event | Pravastatin 40 mg (N=4512) | Placebo (N=4502) | Risk Reduction (95% CI) | P-value |
|---|---|---|---|---|
| Primary Endpoint | Number (%) of Subjects | |||
| *The risk reduction due to treatment with PRAVACHOL was consistent in both sexes. | ||||
| CHD mortality * | 287 (6.4) | 373 (8.3) | 24% (12, 35) | 0.0004 |
| Secondary Endpoints | Number (%) of Subjects | |||
| Total mortality | 498 (11.0) | 633 (14.1) | 23% (13, 31) | <0.0001 |
| CHD mortality or nonfatal MI | 557 (12.3) | 715 (15.9) | 24% (15, 32) | <0.0001 |
| Myocardial revascularization procedures (CABG or PTCA) | 584 (12.9) | 706 (15.7) | 20% (10, 28) | <0.0001 |
| Stroke All-cause Non-hemorrhagic | 169 (3.7) 154 (3.4) | 204 (4.5) 196 (4.4) | 19% (0, 34) 23% (5, 38) | 0.048 0.015 |
| Cardiovascular mortality | 331 (7.3) | 433 (9.6) | 25% (13, 35) | <0.0001 |
In the Cholesterol and Recurrent Events (CARE)2 study, the effect of PRAVACHOL, 40 mg daily, on coronary heart disease death and nonfatal MI was assessed in 4159 patients (3583 men and 576 women) who had experienced a myocardial infarction in the preceding 3-20 months and who had normal (below the 75th percentile of the general population) plasma Total-C 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 mg/dL–180 mg/dL (mean 139 mg/dL). At baseline, 84% of patients were receiving aspirin and 82% were taking antihypertensive medications. Median (25th, 75th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL 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 PRAVACHOL significantly reduced the rate of first recurrent coronary events (either CHD death or nonfatal MI), the risk of undergoing revascularization procedures (percutaneous transluminal coronary angioplasty [PTCA], coronary artery bypass graft [CABG]), and the risk for stroke or transient ischemic attack (TIA) (see Table 3).
| Event | Pravastatin 40 mg (N=2081) | Placebo (N=2078) | Risk Reduction (95% CI) | P-value |
|---|---|---|---|---|
| Primary Endpoint | Number (%) of Subjects | |||
| *The risk reduction due to treatment with PRAVACHOL was consistent in both sexes. | ||||
| CHD mortality or nonfatal MI * | 212 (10.2) | 274 (13.2) | 24% (9, 36) | 0.003 |
| Secondary Endpoints | Number (%) of Subjects | |||
| Myocardial revascularization procedures (CABG or PTCA) | 294 (14.1) | 391 (18.8) | 27% (15, 37) | <0.001 |
| Stroke or TIA | 93 (4.5) | 124 (6.0) | 26% (4, 44) | 0.029 |
Primary Hypercholesterolemia (Fredrickson Type IIa and IIb)
PRAVACHOL (pravastatin sodium) is highly effective in reducing Total-C, LDL-C and triglycerides (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.
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 mg 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 4).
In a pooled analysis of two 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 25th and 75th 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 4).
Treatment with PRAVACHOL modestly decreased VLDL-C, and PRAVACHOL across all doses produced variable increases in HDL-C (see Table 4).
| Dose | Total-C | LDL-C | HDL-C | TG |
|---|---|---|---|---|
| Mean Percent Changes From Baseline After 8 Weeks* | ||||
| * a multicenter, double-blind, placebo-controlled study | ||||
| **pooled analysis of 2 multicenter, double-blind, placebo-controlled studies | ||||
| Placebo (N=36) | -3% | -4% | +1% | -4% |
| 10 mg (N=18) | -16% | -22% | +7% | -15% |
| 20 mg (N=19) | -24% | -32% | +2% | -11% |
| 40 mg (N=18) | -25% | -34% | +12% | -24% |
| Mean Percent Changes From Baseline After 6 Weeks** | ||||
| Placebo (N=162) | 0% | -1% | -1% | +1% |
| 80 mg (N=277) | -27% | -37% | +3% | -19% |
Ischemic Stroke and Transient Ischemic Attack (TIA)
In clinical trials of subjects with TIAs due to fibrin platelet emboli or ischemic stroke, aspirin has been shown to significantly reduce the risk of the combined endpoint of stroke or death and the combined endpoint of TIA, stroke, or death by about 13-18%.
Prevention of Recurrent MI and Unstable Angina Pectoris
These indications are supported by the results of six large, randomized, multicenter, placebo-controlled trials of predominantly male post-MI subjects and one randomized placebo-controlled study of men with unstable angina pectoris. Aspirin therapy in MI subjects was associated with a significant reduction (about 20%) in the risk of the combination endpoint of subsequent death and/or nonfatal reinfarction in these patients. In aspirin-treated unstable angina patients, the event rate was reduced to 5% from the 10% rate in the placebo group.
Chronic Stable Angina Pectoris
In a randomized, multicenter, double-blind trial designed to assess the role of aspirin for prevention of MI in patients with chronic stable angina pectoris, aspirin significantly reduced the primary combined endpoint of nonfatal MI, fatal MI, and sudden death by 34%. The secondary endpoint for vascular events (first occurrence of MI, stroke, or vascular death) was also significantly reduced (32%).
Revascularization Procedures
Most patients who undergo coronary artery revascularization procedures have already had symptomatic coronary artery disease for which aspirin is indicated. Similarly, patients with lesions of the carotid bifurcation sufficient to require carotid endarterectomy are likely to have had a precedent event. Aspirin is recommended for patients who undergo revascularization procedures if there is a preexisting condition for which aspirin is already indicated.
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.1-5 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:
- the composite endpoint of fatal or nonfatal MI
- the composite outcome of CHD death or nonfatal MI
- ischemic stroke
- the composite outcome of CHD death, nonfatal MI or revascularization procedures
- the composite endpoint of CHD death, nonfatal MI, revascularization procedures or ischemic stroke
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.
| Event | Pravastatin/ Aspirin (N=5888) | Placebo/ Aspirin (N=5833) | Risk Reduction (95% CI) |
|---|---|---|---|
| Number (%) of Subjects | |||
| Fatal or nonfatal MI | 445 (7.6) | 626 (10.7) | 31% (22, 39) |
| CHD death or nonfatal MI | 597 (10.1) | 830 (14.2) | 31% (23, 38) |
| Ischemic stroke | 134 (2.3) | 183 (3.1) | 29% (12, 43) |
| CHD death, nonfatal MI or revascularization procedures | 1218 (20.7) | 1543 (26.5) | 24% (18, 30) |
| CHD death, nonfatal MI, revascularization procedures or ischemic stroke | 1314 (22.3) | 1661 (28.5) | 24% (19, 30) |
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.
| Event | Pravastatin/ Aspirin (N=5888) | Pravastatin/ Placebo (N=1436) | Risk Reduction (95% CI) |
|---|---|---|---|
| Number (%) of Subjects | |||
| Fatal or nonfatal MI | 445 (7.6) | 125 (8.7) | 26% (10, 39) |
| CHD death or nonfatal MI | 597 (10.1) | 196 (13.7) | 37% (25, 46) |
| Ischemic stroke | 134 (2.3) | 44 (3.1) | 31% (3, 51) |
| CHD death, nonfatal MI or revascularization procedures | 1218 (20.7) | 308 (21.5) | 11% (-0.6, 22) |
| CHD death, nonfatal MI, revascularization procedures or ischemic stroke | 1314 (22.3) | 341 (23.8) | 14% (2, 23) |
In a supportive analysis, the effects of pravastatin/aspirin were sustained through five years of follow-up.
Indications and Usage for Pravigard PAC
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 treatment with Pravigard PAC should also be placed on a standard cholesterol-lowering diet and should continue on this diet during treatment.
Pravachol
Secondary Prevention of Cardiovascular Events
In patients with clinically evident coronary heart disease, PRAVACHOL (pravastatin sodium) is indicated to:
- reduce the risk of total mortality by reducing coronary death
- reduce the risk of myocardial infarction
- reduce the risk of undergoing myocardial revascularization procedures
- reduce the risk of stroke and stroke/transient ischemic attack (TIA)
- slow the progression of coronary atherosclerosis
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.
| 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) |
|---|---|---|---|
| a CHD, coronary heart disease. | |||
| b 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. | |||
| c Almost all people with 0-1 risk factor have 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 risk factor is not necessary. | |||
| CHDa or CHD risk equivalents (10-year risk >20%) | <100 | ≥100 | ≥130 (100-129: drug optional)b |
| 2+ Risk factors (10-year risk ≤20%) | <130 | ≥130 | 10-year risk 10%-20%: ≥130 |
| 10-year risk <10%: ≥160 | |||
| 0-1 Risk factorc | <160 | ≥160 | ≥190 (160-189: LDL-lowering drug optional) |
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).
Buffered Aspirin
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.
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.
Contraindications
Pravachol
Hypersensitivity to any component of this medication.
Active liver disease or unexplained, persistent elevations in liver function tests (see WARNINGS: Pravachol: Liver Enzymes).
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 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 PRECAUTIONS: Pregnancy: Pravachol).
Buffered Aspirin
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).
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.
Warnings
Pravachol
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 (see CONTRAINDICATIONS: Pravachol). 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 (see CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism:Pravachol). 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.
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 (see ADVERSE REACTIONS: Pravachol). 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 (see PRECAUTIONS:
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