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Losartan Gains New Indication in Patients With Severe Hypertension

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Aug. 6, 2004--Merck & Co., Inc. announced today that the U.S. Food and Drug Administration has granted a new indication for HYZAAR(R) (losartan potassium-hydrochlorothiazide tablets) for initial use in appropriate patients with severe hypertension. This fixed dose combination is not indicated for initial therapy of hypertension, except when the hypertension is severe enough that the value of achieving prompt blood pressure control exceeds the risk of initiating combination therapy in these patients. This new indication demonstrates the commitment by the company to conduct important research in the field of high blood pressure.

"This indication provides physicians with an effective and timely treatment option for appropriate patients with severe hypertension, and provides these patients with a treatment choice that is more convenient than taking two separate tablets," said George L. Bakris, M.D., F.A.C.P., F.C.P., director, Hypertension/Clinical Research Center, Rush University Medical Center in Chicago.

Severe hypertension affects many in the United States
In the 1999-2000 National Health and Nutrition Examination Survey (NHANES), of the estimated 60 million people in the United States with high blood pressure an estimated two million people had a blood pressure reading equal to or greater than 180 mmHg systolic or equal to or greater than 110 mmHg diastolic. "Many of these people with severely elevated blood pressure may be candidates for initial therapy with HYZAAR once their physician has evaluated the benefit of starting HYZAAR against the risk of initiating combination therapy," said Dr. Bakris.

Widely utilized guidelines for the treatment of hypertension recommend the initial use of two drugs in certain patients with hypertension. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the latest guidelines issued by the International Society on Hypertension in Blacks (ISHIB) inform physicians to consider the option of initiating therapy with two drugs, one of which should usually be a thiazide-type diuretic, either as separate prescriptions or in fixed dose combination when the physician has determined that the patient's blood pressure is highly elevated. Importantly, when evaluating therapy, physicians should bear in mind that the basis of the new indication for HYZAAR was a study of patients whose diastolic blood pressure reading was 110 mmHg or higher.

Nearly 600 patients with severe hypertension studied for new indication
The safety and efficacy of HYZAAR as initial therapy for severe hypertension (defined as mean sitting diastolic BP greater than or equal to110 mmHg confirmed on two separate occasions off all antihypertensive therapy) was studied in a six-week, double-blind, randomized, multicenter study of 585 patients, including 264 (45 percent) females, 124 (21 percent) blacks, and 21 (4 percent) patients 65 years of age or older. The mean age was 53. The mean blood pressure at baseline for the total population was 171/113 mmHg.

The primary endpoint of the study was a comparison at four weeks of patients who achieved goal diastolic blood pressure (trough sitting DBP less than 90 mmHg) on HYZAAR 50-12.5 mg versus patients on COZAAR(R) (losartan potassium tablets) 50 mg titrated to 100 mg as needed to reach goal diastolic blood pressure. Results of the study at week four showed:

-- The average reduction in diastolic blood pressure was 13.6 mmHg for patients taking HYZAAR vs. 10.5 mmHg for those taking COZAAR, a difference of 3.1 mmHg lower for those treated with HYZAAR.

-- The average reduction in systolic blood pressure was 18.0 mmHg for those taking HYZAAR vs. 12.4 mmHg for those on COZAAR, a difference of 5.6 mmHg for those treated with HYZAAR.

As a result, a greater proportion of the patients on HYZAAR reached the target diastolic blood pressure (17.6 percent for HYZAAR, 9.4 percent for COZAAR; p=0.006). Similar trends were seen when the patients were grouped according to gender, race or age (less than 65 and 65 or older).

The secondary endpoint was a comparison at six weeks of patients who achieved goal diastolic blood pressure on HYZAAR 50-12.5 mg titrated as needed to HYZAAR 100-25 mg vs. patients on COZAAR 50 mg titrated to 100 mg and then to 150 mg. Results of the study at week six showed:

-- The average reduction in diastolic blood pressure was 17.8 mmHg for patients taking HYZAAR vs. 11.9 mmHg for those taking COZAAR.

-- The average reduction in systolic blood pressure was 25.1 mmHg for those taking HYZAAR vs. 14.1 mmHg for those on COZAAR.

At six weeks, more patients in the group treated with HYZAAR reached target diastolic blood pressure than those treated with COZAAR (29.8 percent vs. 12.5 percent).

"In the clinical study supporting this new indication, we saw that more patients with severe hypertension reached their diastolic blood pressure lowering goal of less than 90 mmHg at four weeks with HYZAAR as opposed to being titrated to higher doses of COZAAR," said Dr. Bakris.

HYZAAR offers an excellent tolerability profile
In clinical trials, treatment with HYZAAR was generally well tolerated. In the clinical study supporting this new indication, the overall side effect profile for patients with severe hypertension treated with HYZAAR as initial therapy was similar to the side effect profile in patients with severe hypertension treated with COZAAR as initial therapy. During the study period there were no reported cases of syncope in either treatment group. There were two (0.6 percent) cases and no cases of hypotension reported in the groups treated with HYZAAR and COZAAR, respectively. There were three (0.8 percent) cases and two (1.2 percent) cases of increased serum creatinine (greater than 0.5 mg/dL) in the groups treated with HYZAAR and COZAAR, respectively.

In other clinical trials, the overall incidence of adverse events with losartan potassium-hydrochlorothiazide was comparable to placebo. The most common adverse events occurring with various doses of losartan potassium-hydrochlorothiazide (n=858) at a rate of one percent or more above placebo (n=173) were upper respiratory infection (6 percent vs. 5 percent), dizziness (6 percent vs. 3 percent), back pain (2 percent vs. 1 percent), palpitations (1 percent vs. 0 percent) and rash (1 percent vs. 0 percent).

Selected Important information about HYZAAR and COZAAR
When used in pregnancy during the second or third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, COZAAR and HYZAAR should be discontinued as soon as possible.

COZAAR and HYZAAR are contraindicated in patients who are hypersensitive to any component of these products. Because of the hydrochlorothiazide component, HYZAAR is also contraindicated in patients with anuria (absence of urine formation) or hypersensitivity to other sulfonamide-derived drugs. HYZAAR is not recommended for patients with severe renal impairment (creatinine clearance less than or equal to 30mL/min) or as a means of titration for patients with hepatic impairment. HYZAAR is not recommended for use as initial therapy in patients with intravascular volume depletion (e.g., those treated with diuretics). All patients receiving thiazides should be observed for clinical signs of fluid or electrolyte imbalance, including hypokalemia. As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.

The starting dose of HYZAAR for initial treatment of severe hypertension is one tablet of HYZAAR 50-12.5 mg once daily. For patients who do not respond adequately to HYZAAR 50-12.5 mg after two to four weeks of therapy, the dosage may be increased to one tablet of HYZAAR 100-25 mg once daily. The maximum dose is one tablet of HYZAAR 100-25 mg once daily. HYZAAR is not recommended as initial therapy in patients with hepatic impairment because the appropriate 25 mg starting dose of losartan cannot be given.

The usual starting dose of COZAAR in patients with hypertension is COZAAR 50 mg once daily. The maximum daily dose is 100 mg. If the antihypertensive effect measured at trough using once-a-day dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response. The 150 mg dose of COZAAR has not been shown to give a greater effect than 50 mg or 100 mg. In patients who are volume-depleted, symptomatic hypotension may occur after initiation of therapy with COZAAR. This condition should be corrected prior to administration of COZAAR, or a dosage of COZAAR 25 mg should be used. In patients with a history of hepatic impairment, a starting dose of COZAAR 25 mg should be used.

Patients whose blood pressure is not controlled by monotherapy with either COZAAR or hydrochlorothiazide alone can be switched to HYZAAR 50-12.5 mg once daily. If blood pressure remains uncontrolled, physicians can titrate to HYZAAR 100-25 mg once daily.

Source: Merck & Co., Inc.

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