Amlodipine/Atorvastatin Fixed-Dose Combination
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Amlodipine/atorvastatin (Caduet®) is a once-daily fixed-dose combination of the dihydropyridine calcium channel antagonist amlodipine and the HMG-CoA reductase inhibitor atorvastatin. In Europe, the combination is indicated for the prevention of cardiovascular events in hypertensive patients with three concomitant cardiovascular risk factors and, in the US, it is indicated for the management of hypertension and dyslipidemia in patients for whom treatment with both agents is appropriate.
In clinical trials, the fixed-dose combination of amlodipine/atorvastatin effectively managed two important risk factors simultaneously in hypertensive patients at risk of cardiovascular disease or in those with concomitant hypertension and dyslipidemia. The combination is bioequivalent to amlodipine and atorvastatin given alone and does not modify the efficacy of either single agent. Amlodipine/atorvastatin is generally well tolerated, with a tolerability profile consistent with that of each single agent. Compared with the coadministration of each single agent, the convenience of single-pill amlodipine/atorvastatin has the potential to improve patient adherence and the management of cardiovascular risk in selected patients, thereby improving clinical outcomes.
Amlodipine is a dihydropyndine calcium channel blocker that inhibits extracellular calcium influx into vascular smooth muscle via blockade of L-type calcium channels causing relaxation of vascular smooth muscle leading to a reduction in BP. Atorvastatin is an HMG-CoA reductase inhibitor that impedes mevalonic acid formation, which subsequently reduces cholesterol formation and increases the rate of low-density lipoprotein-cholesterol (LDL-C) clearance from plasma. The combined administration of amlodipine and atorvastatin may have an additive or potentially synergistic beneficial effect on atherosclerotic plaque formation and some molecular markers of endothelial function.
Administration of the fixed-dose combined amlodipine/atorvastatin tablet does not alter the rate or extent of absorption of either agent. Oral amlodipine peak plasma concentrations (Cmax) are achieved in 6–12 hours. Amlodipine undergoes hepatic metabolism with an elimination half-life (t½β) of ≈30–50 hours. Oral atorvastatin is rapidly absorbed, with Cmax occurring within 1–2 hours. Atorvastatin is metabolized to active ortho- and para-hydroxylated derivatives, which are equipotent to the parent drug in vitro. Active metabolites account for about 70% of the lipid-lowering activity in plasma. Cytochrome P450 (CYP) 3A4 is involved in the metabolism of atorvastatin. The parent drug and its metabolites undergo hepatic metabolism, with t½β values of ≈14 hours and 20–30 hours.
In hypertensive patients with average or below-average LDL-C values in ASCOT-LLA, significantly fewer of those randomized to atorvastatin plus an antihypertensive regimen (either amlodipine or atenolol based) experienced a nonfatal myocardial infarction or fatal coronary heart disease (CHD; primary endpoint) than those randomized to placebo plus an antihypertensive regimen. In a prespecified 2×2 factorial analysis of data from ASCOT-LLA, the risk of nonfatal myocardial infarction and fatal CHD was reduced more in patients receiving atorvastatin plus amlodipine-based treatment than in those receiving atorvastatin plus atenolol-based treatment.
Amlodipine plus atorvastatin once daily demonstrated greater antihypertensive efficacy than atorvastatin alone, and better lipid-lowering efficacy than amlodipine alone, in two randomized, double-blind, placebo-controlled, multicenter studies in patients with hypertension and dyslipidemia. In one study, after 8 weeks of therapy, the percentages of patients who achieved both their BP and LDL-C goals in the groups receiving amlodipine 5 mg plus atorvastatin 10 mg, amlodipine 5 mg plus placebo, atorvastatin 10 mg plus placebo, and placebo plus placebo were 45.5%, 8.3%, 28.6%, and 3.5%, respectively. After a further 12 weeks of nonblind, titration-to-goal treatment with varying dosages of combined therapy, the percentage of patients achieving both goals increased to 67.1%.
In titration-to-goal, noncomparative, prospective, multicenter studies in hypertensive patients with dyslipidemia, the percentage of patients achieving both their BP and LDL-C goals after 14–16 weeks’ treatment with any of 8 fixed-dose combination tablets of amlodipine/atorvastatin once daily ranged from 50.6% to 62.9%. In two prospective subgroup analyses, the proportions of patients with diabetes achieving both goals were 28.6% and 43.6%, and those for patients with metabolic syndrome (as defined by the National Cholesterol Education Program Adult Treatment Panel III) were 45.5% and 55.3%.
The fixed-dose combination of amlodipine/atorvastatin is generally well tolerated in patients with hypertension with or without dyslipidemia, with an overall tolerability profile similar to those of each single agent. In clinical trials, the most common treatment-related adverse events associated with amlodipine and atorvastatin administered as a fixed-dose combination or concomitantly as separate agents were peripheral edema, myalgia, and sinusitis. Most adverse events were mild to moderate in severity.
In a large, double-blind trial, the rate of treatment discontinuation for any reason was 7.7% in the amlodipine 5 mg plus atorvastatin 10 mg group, 7.0% in the amlodipine 5 mg group, 7.5% in the atorvastatin 10 mg group, and 9.6% in the placebo group.
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