This drug is a novel single-entity tablet, combining a dihydropyridine calcium channel blocker and an angiotensin receptor blocker.
Ms. Domenici and Dr. Patel are bothpharmacists at Brigham andWomen's Hospital, Boston, Mass.
Exforge (amlodipine/valsartan tablets)received full FDA approval on June 21,2007, for the treatment of high bloodpressure.1 A tentative approval hadbeen granted to Novartis on December22, 2006, pending the patent expirationof amlodipine, which is found in Pfizer'sNorvasc.2 Valsartan is marketed underthe name Diovan by Novartis.Exforge is a novel single-entity tabletcombining amlodipine, a dihydropyridinecalcium channel blocker, and valsartan,an angiotensin receptor blocker.Exforge approval was based on severalplacebo- and active-controlled trials.
Amlodipine blocks the transmembraneinflux of calcium ions into thevascular smooth and cardiac muscles,causing a reduction in peripheral vascularresistance and blood pressure.3Amlodipine goes through hepaticmetabolism to inactive metabolites.Elimination is biphasic, with a terminalhalf-life of 30 to 50 hours. The doseshould be adjusted in patients withhepatic insufficiency.3
Angiotensin II binds to angiotensintype 1 (AT1) receptors, causing vasoconstriction,vasopressin production,and aldosterone production—all ofwhich cause an increase in blood pressure.Valsartan has a high affinity forAT1 receptors. Blockade of these receptorscauses a decrease in blood pressure.Peak plasma concentrations afteroral administration are reached within2 to 4 hours.
Exposure of valsartan is increased by2-fold in patients with mild-to-moderateliver disease.3 A dosage adjustmentis not recommended, but precautionsshould be exercised in patients withliver disease.
The results following oral administrationof Exforge, in terms of the rate andextent of absorption, are similar tothose following the administration ofthe 2 components as individual tablets.3
A phase 3, double-blind, placebocontrolledtrial enrolled 1250 patientsdiagnosed with mild-to-moderate hypertension,which was defined as diastolicblood pressure of ≥95 and <110mm Hg.4 Average blood pressure was156.7/99.1 mm Hg in patients in alltreatment assignments. Patients wererandomized to receive once-daily treatmentfor 8 weeks with 1 of the following:
At week 8, the 10-mg/320-mg dosagedecreased diastolic blood pressurefrom baseline by 18.6 mm Hg and the10-mg/160-mg dosage by 17.6 mm Hg.Both Exforge doses reduced diastolicblood pressure to a greater extent thanthe monotherapy doses. Median systolicblood pressure reductions wereconsistent from baseline in bothExforge groups.4
The Exforge 10-mg/320-mg armdemonstrated the greatest percentage(73%) of patients achieving a bloodpressure of <140/90 mm Hg. Althoughstage 1 and 2 hypertension were notprespecified subgroups, both Exforgegroups were superior in achieving ablood pressure of <140/90 mm Hg (58%and 75%, respectively) for stage 1hypertension and 25% and 33% forstage 2.4
The higher Exforge dose also wasmore successful in achieving the moreaggressive blood pressure goal of<130/80 mm Hg, compared with monotherapy.4
The most common adverse eventswith Exforge were nasopharyngitis,upper respiratory tract infection, asthenia,and fatigue. Other reported adverseevents due to the amlodipine part ofExforge were peripheral edema andheadache.3
Exforge is indicated for the treatmentof hypertension in patients whohave failed to control their blood pressurewith monotherapy with amlodipineor valsartan, but not for initial therapy.Exforge tablets are available in thefollowing combinations: 5 mg/160 mg, 5mg/320 mg, 10 mg/160 mg, and 10mg/320 mg. The product is not indicatedfor use in pregnancy. If blood pressureis not controlled after 3 to 4weeks of therapy, the dose should betitrated up.