Amlodipine/Valsartan Single-Pill Combination

Summary

Abstract

Single-pill combinations of the dihydropyridine calcium channel blocker (CCB) amlodipine and the angiotensin II receptor blocker valsartan (amlodipine/valsartan) [Exforge®] are available in the US for the treatment of patients with hypertension. Prescribing information for amlodipine/valsartan states that it may be used in patients whose BP is not adequately controlled on either component monotherapy, and as initial therapy in patients who are likely to need multiple drugs to achieve their BP goals.

The antihypertensive efficacy of combinations of once-daily oral amlodipine and valsartan (administered as separate agents or as amlodipine/valsartan) has been demonstrated in several large, randomized, double-blind clinical trials of 8–16 weeks’ duration; BP reductions were maintained for ≈1 year in open-label extensions of some of these studies. Combination therapy was more effective than amlodipine or valsartan monotherapy in reducing BP in patients with mild to moderate hypertension, and more effective than amlodipine monotherapy in reducing BP in patients with moderate to severe (stage 2) hypertension. In addition, switching to amlodipine plus valsartan was more effective than continuation of monotherapy in reducing BP in patients with hypertension uncontrolled on amlodipine or valsartan monotherapy. The BP-lowering effect of amlodipine plus valsartan was not significantly different from that of other combinations of antihypertensive drugs, including amlodipine plus atenolol, lisinopril plus hydrochlorothiazide (HCTZ), and irbesartan plus HCTZ. Combination therapy with amlodipine and valsartan was generally well tolerated. Based on these results, amlodipine/valsartan offers a rational and convenient treatment option for the management of patients with hypertension, the majority of whom will require at least two drugs to reach target BP levels recommended in US (and international) guidelines.

Pharmacologic Properties

Amlodipine/valsartan comprises two effective antihypertensive agents with complementary mechanisms of action. The CCB amlodipine inhibits calcium influx into vascular smooth muscle to cause a reduction in peripheral vascular resistance, while valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively inhibiting the binding of angiotensin II to angiotensin II type 1 receptors in tissues such as vascular smooth muscle and the adrenal gland.

The absorption pharmacokinetics of amlodipine and valsartan after administration of amlodipine/ valsartan are similar to those following administration of each of drug individually. Bioequivalence between the amlodipine/valsartan tablet formulation and components administered in free combination has also been demonstrated. Amlodipine achieves peak plasma concentrations (C_max) 6–8 hours after oral administration of amlodipine/valsartan, has an apparent volume of distribution (V_d) of 21 L/kg, is highly bound to plasma proteins (93.0–97.5%), and has a terminal elimination half-life (t_1/2γ) of 30–50 hours. Amlodipine is extensively (≈90%) metabolized in the liver to inactive metabolites. Valsartan reaches C_max 3 hours after oral administration of amlodipine/valsartan, has a V_d of 17 L/kg, is 94–97% bound to plasma proteins, and has a t_1/2γ of ≈9 hours. Valsartan is primarily eliminated in the feces (≈83% of a dose) and urine (≈13% of a dose), mainly as unchanged drug.

Therapeutic Efficacy

The antihypertensive efficacy of combinations of once-daily oral amlodipine and valsartan (administered as separate agents or as amlodipine/valsartan) has been demonstrated in numerous well designed studies in patients with all grades/stages of hypertension and those with hypertension inadequately controlled by prior monotherapy (including that with amlodipine or valsartan).

Short-term (8 weeks’) treatment with dosages of amlodipine plus valsartan equivalent to those available in US-approved amlodipine/valsartan formulations was more effective than placebo and the respective individual monotherapies in reducing BP in two large, randomized, double-blind trials in patients with mild to moderate hypertension (studies 1 and 2). For each regimen, the reduction in mean sitting DBP (MSDBP) from baseline to study end (primary endpoint) was significantly greater than that with placebo, or amlodipine or valsartan alone; similar results were seen for the corresponding reductions in mean sitting SBP (MSSBP). The antihypertensive effect of amlodipine plus valsartan appeared to increase with increasing dose over the approved range (5–10 mg and 160–320 mg once daily, respectively).

Combination therapy with amlodipine 2.5–5 mg plus valsartan 80–320 mg once daily, with or without the optional addition of HCTZ 12.5 mg once daily, also achieved clinically significant and persistent reductions in MSSBP/MSDBP over a period of 52 or 54 weeks in open-label extensions to studies 1 and 2. Subgroup analyses of studies 1 and 2 and their respective extensions suggested that amlodipine plus valsartan combination therapy was effective, regardless of hypertension severity (stage 1 or 2), age (≥65 or <65 years) or race (Black or White patients).

In randomized, open-label (blinded endpoint) trials, longer-term (24–48 weeks’) treatment with amlodipine 2.5–10 mg plus valsartan 160 mg once daily produced reductions in BP that did not differ significantly from those with a combination of amlodipine 2.5–10 mg plus atenolol 100 mg once daily in patients with mild hypertension, well controlled type 2 diabetes mellitus, and a recent history of atrial fibrillation, and those with a combination of irbesartan 300 mg plus HCTZ 12.5–25 mg once daily in very elderly patients with moderate hypertension. Ambulatory BP monitoring indicated that amlodipine plus valsartan provided a persistent and smooth antihypertensive effect throughout the 24-hour dosing interval.

BP was reduced more rapidly, and to a greater extent, during short-term (4–8 weeks’) treatment with amlodipine 5–10 mg plus valsartan 160–320 mg once daily than with amlodipine 5–10 mg once daily in two randomized, double-blind studies in patients with moderate to severe (stage 2) hypertension. Reductions in MSSBP/MSDBP, as well as BP control rates, significantly favored amlodipine plus valsartan over amlodipine alone both before and after the optional addition of HCTZ 12.5 mg once daily in these trials. The short-term (6-week) BP-lowering efficacy of amlodipine 5–10 mg plus valsartan 160 mg once daily was not significantly different from that of lisinopril 10–20 mg plus HCTZ 12.5 mg in a third randomized, double-blind study in patients with severe (stage 2) hypertension.

In other randomized, double-blind studies, short-term (8–12 weeks’) treatment with amlodipine 5–10 mg plus valsartan 160 mg once daily provided significant additional BP-lowering effects compared with continuing on the same dose of amlodipine or valsartan in patients with mild to moderate hypertension not adequately controlled on amlodipine 10 mg once daily or valsartan 160 mg once daily, and compared with doubling the dose of amlodipine in patients with hypertension not adequately controlled on amlodipine 5 mg once daily. In one of these trials, responder and BP control rates significantly favored combination therapy over amlodipine monotherapy before, but not 4 weeks after, all monotherapy recipients switched to combination therapy.

Switching directly to either amlodipine/valsartan 5 mg/160 mg once daily or amlodipine/valsartan 5 mg/160 mg once daily plus amlodipine 5 mg once daily, with the optional addition of HCTZ 12.5–25 mg once daily, was effective in establishing BP control in around three-quarters of patients with hypertension not controlled with previous monotherapy (various antihypertensive agents). BP control rates were generally similar before and after the optional addition of HCTZ in this randomized, double-blind study; subgroup analyses suggested that the additional antihypertensive efficacy of amlodipine/valsartan (with or without HCTZ) was maintained irrespective of the prior monotherapy, hypertension severity, diabetic status, body mass index, and age.

Tolerability

Combination therapy with amlodipine and valsartan (administered as separate agents or as amlodipine/ valsartan) was generally well tolerated in patients with all grades/stages of hypertension, including those with hypertension not adequately controlled on previous monotherapy. Most adverse events were mild or moderate in severity and transient in nature. The incidences of peripheral edema, headache, and dizziness — the most common suspected drug-related adverse events with amlodipine plus valsartan — did not differ significantly from those with placebo in studies 1 and 2. In contrast, peripheral edema and headache occurred less frequently with combination therapy than with amlodipine alone, whereas peripheral edema occurred more frequently with combination therapy than with valsartan alone. Adverse events leading to drug discontinuation occurred in 2.1% of amlodipine plus valsartan recipients compared with 1.8% of placebo recipients.

Adverse events associated with low BP occurred infrequently (<1%), or not at all, in amlodipine plus valsartan-treated patients. Combination therapy was not associated with clinically significant changes in laboratory parameters. Long-term (52 or 54 weeks’) treatment with amlodipine 2.5–5 mg plus valsartan 80–320 mg once daily, with or without the optional addition of HCTZ 12.5 mg once daily, was well tolerated in the open-label extensions to studies 1 and 2; no signficant new adverse events were reported compared with those observed in the short-term (8-week) core trial.

Amlodipine plus valsartan and other combinations of antihypertensive agents (irbesartan plus HCTZ or lisinopril plus HCTZ) were generally well tolerated in comparative studies. Compared with irbesartan plus HCTZ, amlodipine plus valsartan was associated with less pronounced BP orthostatic changes and a lack of metabolic adverse effects in very elderly patients with moderate hypertension.