Trandolapril/Verapamil Sustained Release

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Abstract
Trandolapril/verapamil sustained release (SR) [Tarka®] is an oral, fixed-dose combination of the ACE inhibitor trandolapril and the SR formulation of the phenylalkylamine calcium channel antagonist verapamil. It is indicated for the treatment of hypertension in patients who require more than one agent to achieve blood pressure (BP) targets. In the large, randomised, multicentre INVEST (INternational VErapamil SR/trandolapril STudy), a verapamil SR-based treatment strategy that included trandolapril in most patients was as effective as an atenolol-based treatment strategy in reducing the risk of the primary outcome (first occurrence of death [all-cause], nonfatal myocardial infarction [MI] or nonfatal stroke) in patients with hypertension and coronary artery disease (CAD) and was as well tolerated. Trandolapril/verapamil SR is generally more effective at controlling hypertension than either component as monotherapy, and is as effective as a number of other fixed-dose combination therapies. The combination is as well tolerated as trandolapril monotherapy and is at least as well tolerated as verapamil SR monotherapy. In hypertensive patients with type 2 diabetes mellitus in the BENEDICT (BErgamo NEphrologic DIabetes Complications Trial), trandolapril/verapamil SR prolonged the time to the onset of persistent microalbuminuria compared with placebo, as did trandolapril monotherapy. Thus, trandolapril/verapamil SR is an effective option for the treatment of essential hypertension in patients requiring more than one agent to achieve BP targets, including those with compelling indications, such as CAD or type 2 diabetes. Trandolapril, a prodrug of the active metabolite trandolaprilat, reduces vasopressor activity and aldosterone release and provides negative feedback for renin secretion by inhibiting the conversion of angiotensin I to angiotensin II. The phenylalkylamine calcium channel antagonist verapamil causes dilation of peripheral and coronary vasculature, and thus a decrease in BP, by inhibiting the influx of calcium ions through the L-type calcium channels. Trandolapril/verapamil SR improves left ventricular (LV) wall structure and function in patients with hypertension and preserves LV function in patients with heart failure. Cardiac events are less common with trandolapril/verapamil SR than trandolapril monotherapy in patients with heart failure following an acute MI. Peak plasma concentrations (Cmax) of trandolapril and trandolaprilat are achieved 0.5–1.5 and 3–12 hours after a single oral dose of trandolapril 2mg in healthy volunteers. The Cmax of trandolapril at steady state is double that after a single dose. Trandolapril is converted to trandolaprilat by hepatic metabolism. The absolute bioavailability of the parent drug is ≈10% and that of the active metabolite is 70%; both are highly protein-bound. The respective terminal elimination half-lives (t1/2β) of trandolapril and trandolaprilat are 6 and 10 hours, with the majority of a dose excreted in the faeces. Verapamil SR Cmax is achieved in ≈5 hours. Due to extensive first-pass metabolism in the liver, verapamil SR has an oral bioavailability of 10–35%. Verapamil is highly bound to plasma proteins. The primary metabolite of verapamil is the active desmethyl species, norverapamil. The SR formulation has a t1/2β of 8 hours after repeated administration, with the majority of a dose excreted in urine as metabolites. There are no clinically relevant pharmacokinetic interactions between verapamil SR and trandolapril when the two agents are coadministered. A verapamil SR-based treatment strategy in which most patients also received trandolapril was as effective as an atenolol-based treatment strategy at preventing the primary outcome (first occurrence of death [all-cause], nonfatal MI or nonfatal stroke) [9.9% vs 10.2%; mean follow-up 2.7 years] in patients with hypertension and CAD in the large (n = 22 576), randomised, multicentre INVEST. Similar proportions of patients receiving either treatment strategy achieved US Joint National Committee (JNC) VI BP targets (current consensus guidelines when INVEST was conducted) or BP control 100), trandolapril/verapamil SR 1mg/180mg, 2mg/180mg, 2mg/240mg or 4mg/240mg per day was more effective than placebo, and generally more effective than the corresponding dosages of trandolapril or verapamil SR monotherapy, at reducing mean sitting BP from baseline in adult patients with hypertension. The 1mg/180mg or 2mg/180mg dosages of trandolapril/verapamil SR were more effective at reducing mean 24-hour ambulatory systolic BP or diastolic BP than corresponding dosages of monotherapy. Trandolapril/verapamil SR was generally as effective at reducing BP as other fixed-dose combination therapies (metoprolol/hydrochlorothiazide, atenolol/chlortalidone, lisinopril/hydrochlorothiazide, enalapril/hydrochlorothiazide). Trandolapril/verapamil SR was effective at reducing mean sitting BP from baseline in patients unresponsive to either agent administered as monotherapy, and in special patient populations, such as Black or elderly patients or those with type 2 diabetes. Compared with placebo, trandolapril/verapamil SR prolonged the time to onset of persistent microalbuminuria in patients with hypertension and type 2 diabetes in the large, double-blind, multicentre BENEDICT, as did trandolapril monotherapy. Trandolapril/verapamil SR was generally well tolerated in clinical trials in patients with hypertension and had a tolerability profile similar to that of the individual components or respective class of drug. The incidence of adverse events (9–46%) and withdrawal rates due to adverse events (2.0–11.7%) in patients receiving trandolapril/verapamil SR was generally similar to that of comparator treatment arms. In INVEST, the verapamil SR-based and atenolol-based treatment strategies were equally well tolerated. The most common adverse events occurring more frequently with trandolapril/verapamil SR than placebo were cough, first-degree atrioventricular block and constipation. Gastrointestinal tract adverse events and/or constipation were more likely with trandolapril/verapamil SR or verapamil SR than with trandolapril in two studies.