Exforge: New combination recently approved by FDA for amlodipine/valsartan

Key Points

A combined formulation of amlodipine, a dihydropyridine calcium-channel blocker, and valsartan, an angiotensin II receptor antagonist, was approved on June 20, 2007, for the treatment of hypertension. This combination therapy is not indicated for the initial treatment of hypertension.

Efficacy. The efficacy of this combination therapy was evaluated in 2 placebo-controlled and 2 active-controlled trials in patients with hypertension. In the first double-blind, placebo-controlled study, 1,018 patients with mild-to-moderate hypertension were treated with 1 of 3 combinations of amlodipine/valsartan (5/80, 5/160, or 5/320 mg), amlodipine alone (5 mg), valsartan alone (80, 160, or 320 mg), or placebo. At Week 8, the various combination dosing regimens demonstrated statistically significant superiority over the monotherapy regimens in reduction of both sitting diastolic blood pressure (DBP) (placebo-subtracted mean change: 5/80 mg, –7.8; 5/160 mg, –7.6; 5/320 mg, –9.3) and sitting systolic blood pressure (SBP) (placebo-subtracted mean change: 5/80 mg, –14.5; 5/160 mg, –13.2; 5/320 mg, –16.2). In the second double-blind, placebo-controlled study, 1,250 patients with mild-to-moderate hypertension were treated with 1 of 2 combinations of amlodipine/ valsartan (10/160 or 10/320 mg), amlodipine alone (10 mg), valsartan alone (160 or 320 mg), or placebo. At Week 8, the combination regimens again demonstrated statistically significant superiority over the monotherapy regimens in reduction of both sitting DBP (placebo-subtracted mean change: 10/160 mg, –9.0; 10/320 mg, –9.9) and sitting SBP (placebo-subtracted mean change: 10/160 mg, –15.5; 10/320 mg, –15.9). In the first double-blind, active-controlled study, 947 patients with mild-to-moderate hypertension inadequately controlled with valsartan 160 mg were treated with 1 of 2 amlodipine/valsartan combination regimens (10/160 or 5/160 mg) or valsartan alone (160 mg). At Week 8, the combination regimens demonstrated statistically significant improvements in the reduction of both sitting DBP and sitting SBP compared with valsartan monotherapy (treatment difference, DBP: 10/160 mg, –4.8; 5/160, –3.1; treatment difference, SBP: 10/160 mg, –5.7; 5/160 mg, –3.9). In the second double-blind, active-controlled trial, 944 patients with mild-to-moderate hypertension inadequately controlled by amlodipine 10 mg were treated with amlodipine/valsartan (10/160 mg) or amlodipine alone (10 mg). At Week 8, the combination therapy demonstrated statistically significant superiority over the monotherapy in both sitting DBP (treatment difference, –1.8) and sitting SBP (treatment difference, –1.9).

Safety. Agents that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered during pregnancy. In clinical trials, excessive hypotension was observed rarely (0.4%) in patients treated with this amlodipine/valsartan combination. In rare cases, patients have developed increased frequency, duration, and/or severity of angina or acute myocardial infarction (MI) after initiation of calcium-channel blocker therapy or when dosages are increased. Amlodipine should be used with caution in patients with severe hepatic impairment; valsartan should be used with caution in patients with mild-to-moderate hepatic impairment. Care should be exercised when administering calcium-channel blockers to patients with heart failure. Some patients with heart failure have developed increases in blood urea nitrogen, serum creatinine, and potassium when taking valsartan. The most common adverse events reported in association with this combination include peripheral edema, nasopharyngitis, upper respiratory tract infection, and dizziness.