Merck Hyzaar blood pressure reduction is 50% greater than Cozaar alone; combo approved April 28.

MERCK HYZAAR BLOOD PRESSURE REDUCTION IS 5.5/3.5 mmHg BETTER THAN COZAAR at the starting dose of the combination product, according to labeling approved by FDA April 28. The combination offers the potential for a 50% increase in blood pressure reduction compared to losartan alone, Merck said. The approval comes exactly two weeks after the agency's April 14 approval of Merck's Cozaar (losartan potassium tablets). Hyzaar is a combination of Cozaar and low-dose hydrochlorothiazide indicated for treatment of hypertension. Merck filed the Hyzaar NDA (20-387) on Dec. 10, 1993.

Clinical trials "showed an added antihypertensive response at trough (24 hours post-dosing) of hydrochlorothiazide 12.5 or 25 mg added to losartan 50 mg of 5.5/3.5 and 10/6 mmHg, respectively," labeling states. "Similarly, there was an added antihypertensive response at trough when losartan 50 or 100 mg was added to hydrochlorothiazide 25 mg of 9/5.5 and 12.5/6.5 mmHg, respectively."

Hyzaar is not indicated for initial therapy. Merck plans to position Hyzaar and Cozaar as a dosing system, with Hyzaar recommended for patients requiring stronger therapy than Cozaar. Merck wants to position Cozaar as initial therapy for untreated hypertension.

Merck will begin shipping the product to wholesalers May 10 and will sell Hyzaar at the same price as Cozaar, the company said. Cozaar is being launched at a price of 88› per 50 mg tablet ("The Pink Sheet" April 24, p. 7). Hyzaar is available as a losartan 50 mg/hydrochlorothiazide 12.5 mg tablet.

Hyzaar's low adverse event rate resembles that of Cozaar, which Merck has highlighted as a potential advantage over angiotensin-converting enzyme inhibitors and other anti-hypertensives. "The overall incidence of adverse experiences reported with the combination was comparable to placebo," Hyzaar labeling states. Therapy discontinuation rates were 2.8% and 2.3% of patients receiving Hyzaar and placebo, respectively. Single-agent losartan shows an even cleaner side-effect profile: Cozaar labeling states that the placebo discontinuation rate was higher than the losartan rate ("The Pink Sheet" April 17, p. 22).

Based on clinical trials evaluating a total of 858 patients with essential hypertension, Hyzaar labeling concludes that "no adverse experiences peculiar to this combination drug have been observed." Adverse events "have been limited to those that were reported previously with losartan potassium and/or hydrochlorothiazide." Adverse events cited in product labeling include edema/swelling (1.3% on Hyzaar versus 1.2% on placebo), palpitation (1.4% v. 0%), dizziness (5.7% v. 2.9%), upper respiratory infection (6.1% v. 4.6%) and cough (2.6% v. 2.3%).

"A patient whose blood pressure is not adequately controlled with losartan monotherapy may be switched to Hyzaar once daily," labeling states. "If blood pressure remains uncontrolled after about three weeks of therapy, the dose may be increased to two tablets once daily. A patient whose blood pressure is inadequately controlled by 25 mg once daily of hydrochlorothiazide, or is controlled but who experiences hypokalemia with this regimen, may be switched to Hyzaar once daily, reducing the dose of hydrochlorothiazide without reducing the overall expected antihypertensive response."

"The overall response to the combination was similar for black and non-black patients," although "black patients had a larger response to hydrochlorothiazide than non-black patients and a smaller dose response to losartan," according to labeling. In addition, "there was no difference in response for men and women or in patients over or under 65 years of age."