Ramipril/Felodipine Extended-Release Fixed-Dose Combination

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Abstract
Ramipril/felodipine extended release (ER) [Triapin® and Triapin Mite®, Unimax®] is a once-daily fixed-dose combination of the ACE inhibitor ramipril and the ER formulation of the dihydropyridine calcium channel antagonist felodipine. It is indicated in adult patients with essential hypertension whose blood pressure (BP) is inadequately controlled with ramipril or felodipine monotherapy. In this patient population, commercially available fixed-dose combinations (i.e. 2.5mg/2.5mg and 5mg/5mg) of ramipril and felodipine ER are more effective at controlling hypertension than the individual components used as monotherapy at the same dosages. Likewise, the 5mg/5mg combination is as effective as felodipine ER 10mg, and more effective than ramipril 10mg administered as monotherapy. The addition of low-dose ramipril plus felodipine ER (fixed-dose or combination of individual components) to the existing antihypertensive regimen also appears to provide adequate BP control and renal protection in hypertensive patients with non-diabetic chronic renal disease. In these patients, the low-dose combination of ramipril and felodipine ER was as effective as standard-dose felodipine ER, but more effective than standard-dose ramipril, in providing diastolic BP (DBP) control, and as effective as standard-dose ramipril, but more effective than standard-dose felodipine ER, in slowing the rate of regression of glomerular filtration. The ramipril/felodipine ER combination is as well tolerated as ramipril or felodipine ER monotherapy administered at the same dosages, and is better tolerated than felodipine ER monotherapy given at twice the dosage used in the combination. Overall, ramipril/felodipine ER appears to be an effective option for the treatment of adults with essential hypertension that is poorly controlled with monotherapy. In addition, a fixed, low-dose combination of ramipril/felodipine ER is a potential alternative to monotherapy for the initial management of essential hypertension. Ramipril is a prodrug of the active metabolite ramiprilat, which reduces vasopressor activity and peripheral vascular resistance by inhibiting conversion of angiotensin I into angiotensin II via angiotensin-converting enzyme. Felodipine is a dihydropyridine calcium channel antagonist that inhibits the influx of calcium into vascular smooth muscle cells, causing their relaxation and vasodilation. Felodipine acts selectively on systemic, but not pulmonary arterioles and has no effect on venous vessels, whereas ramiprilat exerts its antihypertensive effects by dilating both arterial and venous blood vessels. Both agents effectively reduce systolic BP (SBP) and DBP over 24 hours in a dose-dependent manner after single-dose administration in patients with essential hypertension. Individual antihypertensive effects of ramipril and felodipine ER are significantly enhanced by their coadministration. Both drugs also exert a cardioprotective effect by causing regression of left ventricular (LV) hypertrophy in patients with essential hypertension, while preserving LV function. Coadministration of ramipril and felodipine ER does not produce clinically relevant pharmacokinetic interactions. Both agents are well absorbed following oral administration and their bioavailabilities (44% and 16% for ramiprilat and felodipine; the bioavailability of felodipine is low because of extensive first-pass hepatic metabolism) are not affected by concurrent food intake. Ramipril is rapidly converted into ramiprilat during first-pass metabolism in the liver. Ramiprilat and felodipine ER are 56% and 99% plasma protein-bound, reach their respective peak plasma concentrations within 3 and 2.5–5 hours and have long elimination half-lives of 13–17 and 25 hours. Both ramiprilat and felodipine undergo inactivation in the liver, and the majority of a dose of each drug is eliminated as inactive metabolites in urine. In three short-term (6–12 weeks), randomised, double-blind, multicentre trials in adult patients with essential hypertension that was not adequately controlled with monotherapy, ramipril/felodipine ER fixed-dose combinations were more effective in reducing mean SBP and DBP from baseline than both ramipril and felodipine ER monotherapies in corresponding dosages, or placebo. The ramipril/felodipine ER 5mg/5mg combination was also as effective as felodipine 10mg, and more effective than ramipril 10mg once daily, in providing SBP and DBP control over 12 weeks in this patient population. In addition, ramipril/felodipine ER 2.5mg/2.5mg once daily has been found effective in reducing SBP and DBP in previously untreated hypertensive patients in a pilot study. A longer-term (12 months), nonblind, noncomparative study in patients with essential hypertension indicated that satisfactory BP control (a supine DBP of ≤90mm Hg or decreased by ≥10mm Hg from baseline) can be achieved in the majority of patients receiving ramipril/felodipine ER 2.5mg/2.5mg or 5mg/5mg once daily either alone (80% response rate) or in combination with one or two other antihypertensive agents (up to 99% response rate). Low-dose combinations of ramipril and felodipine ER were also effective in controlling SBP and DBP in hypertensive patients with non-diabetic chronic renal disease in two randomised, nonblind, multicentre trials. In a trial that evaluated the fixed-dose combination, ramipril/felodipine ER 5mg/5mg once daily was significantly more effective in achieving target DBP (<90mm Hg) than ramipril 10mg once daily (86% vs 60% response rate) after a mean follow-up period of 1.83 and 1.52 years, respectively. In the other trial, which evaluated concomitant administration of ramipril 2.5mg or 5mg with felodipine ER 5mg or 10mg once daily, both the ramipril-based and the ramipril plus felodipine ER-based regimens significantly reduced SBP and DBP from baseline over 19 months’ follow-up. However, the combined regimen was only...