Rx Product News: Profile: A Closer Look at New FDA Actions: Exforge

NOVEMBER 01, 2007
Caryn Domenici, RPh, and Alka Patel, RPh, PharmD

Ms. Domenici and Dr. Patel are both pharmacists at Brigham and Women's Hospital, Boston, Mass.

Novartis' Exforge

Exforge (amlodipine/valsartan tablets) received full FDA approval on June 21, 2007, for the treatment of high blood pressure.1 A tentative approval had been granted to Novartis on December 22, 2006, pending the patent expiration of amlodipine, which is found in Pfizer's Norvasc.2 Valsartan is marketed under the name Diovan by Novartis. Exforge is a novel single-entity tablet combining amlodipine, a dihydropyridine calcium channel blocker, and valsartan, an angiotensin receptor blocker. Exforge approval was based on several placebo- and active-controlled trials.


Amlodipine blocks the transmembrane influx of calcium ions into the vascular smooth and cardiac muscles, causing a reduction in peripheral vascular resistance and blood pressure.3 Amlodipine goes through hepatic metabolism to inactive metabolites. Elimination is biphasic, with a terminal half-life of 30 to 50 hours. The dose should be adjusted in patients with hepatic insufficiency.3

Angiotensin II binds to angiotensin type 1 (AT1) receptors, causing vasoconstriction, vasopressin production, and aldosterone production—all of which cause an increase in blood pressure. Valsartan has a high affinity for AT1 receptors. Blockade of these receptors causes a decrease in blood pressure. Peak plasma concentrations after oral administration are reached within 2 to 4 hours.

Exposure of valsartan is increased by 2-fold in patients with mild-to-moderate liver disease.3 A dosage adjustment is not recommended, but precautions should be exercised in patients with liver disease.

The results following oral administration of Exforge, in terms of the rate and extent of absorption, are similar to those following the administration of the 2 components as individual tablets.3

Clinical Trials

A phase 3, double-blind, placebocontrolled trial enrolled 1250 patients diagnosed with mild-to-moderate hypertension, which was defined as diastolic blood pressure of ≥95 and <110 mm Hg.4 Average blood pressure was 156.7/99.1 mm Hg in patients in all treatment assignments. Patients were randomized to receive once-daily treatment for 8 weeks with 1 of the following:

  • Amlodipine 10 mg
  • Valsartan 160 mg or 320 mg
  • Exforge 10 mg/160 mg
  • Exforge 10 mg/320 mg
  • Placebo

At week 8, the 10-mg/320-mg dosage decreased diastolic blood pressure from baseline by 18.6 mm Hg and the 10-mg/160-mg dosage by 17.6 mm Hg. Both Exforge doses reduced diastolic blood pressure to a greater extent than the monotherapy doses. Median systolic blood pressure reductions were consistent from baseline in both Exforge groups.4

The Exforge 10-mg/320-mg arm demonstrated the greatest percentage (73%) of patients achieving a blood pressure of <140/90 mm Hg. Although stage 1 and 2 hypertension were not prespecified subgroups, both Exforge groups were superior in achieving a blood pressure of <140/90 mm Hg (58% and 75%, respectively) for stage 1 hypertension and 25% and 33% for stage 2.4

The higher Exforge dose also was more successful in achieving the more aggressive blood pressure goal of <130/80 mm Hg, compared with monotherapy.4

Adverse Events

The most common adverse events with Exforge were nasopharyngitis, upper respiratory tract infection, asthenia, and fatigue. Other reported adverse events due to the amlodipine part of Exforge were peripheral edema and headache.3


Exforge is indicated for the treatment of hypertension in patients who have failed to control their blood pressure with monotherapy with amlodipine or valsartan, but not for initial therapy. Exforge tablets are available in the following combinations: 5 mg/160 mg, 5 mg/320 mg, 10 mg/160 mg, and 10 mg/320 mg. The product is not indicated for use in pregnancy. If blood pressure is not controlled after 3 to 4 weeks of therapy, the dose should be titrated up.


  1. www.novartis.com/newsroom/news/index.shtml. Accessed August 15, 2007.
  2. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed August 15, 2007.
  3. Product Information. East Hanover, NJ: Novartis; April 2007.
  4. Dear Healthcare Professional Letter. East Hanover, NJ: Novartis; August 8, 2007.