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New Indication Approved for Losartan

WHITEHOUSE STATION, N.J., April 14, 2005 - Merck & Co., Inc. today announced that the U.S. Food and Drug Administration (FDA) has approved another new indication for HYZAAR®, Merck's fixed-dose combination antihypertensive drug (losartan potassium-hydrochlorothiazide tablets). HYZAAR is now indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy (LVH), but there is evidence that this benefit does not apply to black patients.

The new indication for reduction in stroke is based on the landmark LIFE (Losartan Intervention for Endpoint Reduction in Hypertension) study. In March 2003, the FDA approved the same indication for Merck's antihypertensive drug COZAAR® (losartan potassium tablets). HYZAAR and COZAAR are the only angiotensin II receptor blockers (ARBs) to be indicated to reduce the risk of stroke in patients with hypertension and LVH. HYZAAR is the fixed dose combination of COZAAR (losartan potassium) and hydrochlorothiazide. The FDA approved this indication for HYZAAR based on:

1) the utilization of COZAAR and hydrochlorothiazide in the study - the patients in both arms were coadministered hydrochlorothiazide the majority of time they were on study drug (73.9% and 72.4% of days in the COZAAR and atenolol arms, respectively) and;

2) demonstration by Merck that the losartan and hydrochlorothiazide tablets used in the LIFE study were bioequivalent to the marketed HYZAAR tablets.

In the 9,193-patient LIFE study, treatment with a regimen based on losartan (COZAAR) significantly reduced the risk of stroke (fatal and nonfatal) by 25 percent in patients with hypertension and LVH versus treatment with a regimen based on the beta-blocker atenolol (p=0.001). There were 232 fatal and nonfatal strokes in the group treated with losartan, and 309 in the atenolol group. Other findings from the LIFE study showed no significant difference between the treatment groups in the risk of heart attack or cardiovascular death.

"The LIFE study, for the first time, showed that a losartan-based regimen was more effective than an atenolol-based regimen at reducing the risk of stroke in patients with hypertension and LVH, despite similar blood pressure reductions in the treatment groups," said George L. Bakris, M.D., F.A.C.P., F.C.P., director, Hypertension/Clinical Research Center, Rush University Medical Center in Chicago. Blood pressure reduction measured at trough was similar for both treatment groups. At the end of the study or at the last visit before a primary endpoint, the mean blood pressures were 144.1/81.3 mmHg for the losartan-based group and 145.4/80.9 mmHg for the atenolol-based group. The difference in systolic blood pressure of 1.3 mmHg was significant (p The impact of stroke
According to the 2005 update of the American Heart Association's Heart Disease and Stroke Statistics, each year an estimated 700,000 Americans experience a new or recurrent stroke. Stroke is the third leading cause of death and a leading cause of severe, long-term disability in the United States. Left ventricular hypertrophy, a thickening of the heart's main pumping chamber (the left ventricle), is the most common cardiac abnormality associated with longstanding hypertension and is an important predictor of the risk of stroke. Not all patients with stroke have both hypertension and LVH.

"High blood pressure is the most important risk factor for stroke," said Dr. Bakris. "Widely used guidelines state that more than two-thirds of patients with hypertension require two or more therapies to reach their blood pressure goal, one of which should usually be a thiazide-type diuretic. HYZAAR, in addition to effective blood pressure lowering, now also offers physicians an effective treatment for reducing the risk of stroke in those appropriate patients with hypertension and LVH."

New indication for HYZAAR based on LIFE trial
In the LIFE trial, 4,605 patients were randomized to receive once daily losartan 50 mg and 4,588 patients to receive once daily atenolol 50 mg. If goal blood pressure ( The results showed that in patients treated with losartan, the risk of first occurrence of cardiovascular death, nonfatal stroke or nonfatal myocardial infarction (primary endpoint) was reduced by a statistically significant 13 percent (p= 0.021) compared to patients treated with atenolol. This difference was primarily the result of an effect on fatal and nonfatal stroke. At least one of the components ofthe primary composite endpoint occurred in 508 patients in the group taking losartan and in 588 patients in the atenolol arm.

The new label for HYZAAR also states that, in the LIFE trial, black patients with hypertension and LVH taking atenolol had a lower risk of stroke than those taking COZAAR. Given the difficulty in interpreting subset differences in large trials, it cannot be known whether the observed difference is the result of chance. However, the LIFE study does not provide evidence that the benefits of COZAAR on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to black patients.

The label indicates that the usual starting dose for hypertensive patients with LVH is 50 mg of losartan once daily. Hydrochlorothiazide 12.5 mg should be added or HYZAAR 50-12.5 substituted if the blood pressure reduction is inadequate. If additional blood pressure reduction is needed, COZAAR 100 mg and hydrochlorothiazide 12.5 mg may be substituted, followed by COZAAR 100 mg and hydrochlorothiazide 25 mg or HYZAAR 100-25. The maximum dose is one tablet of HYZAAR 100-25 once daily.

HYZAAR offered an excellent tolerability profile in the LIFE study In clinical trials, including the LIFE study, treatment with losartan potassium-hydrochlorothiazide was generally well tolerated. In these trials, adverse experiences have been limited to those that were reported previously with losartan potassium and/or hydrochlorothiazide. Adverse events occurred at about the same rates in men and women. Adverse events were somewhat more frequent in the elderly compared to non-elderly patients and somewhat more frequent in blacks compared to non-blacks for both the losartan-hydrochlorothiazide and the control groups.

HYZAAR for initial use in appropriate patients with severe hypertension In addition to the new indication for HYZAAR to reduce the risk of stroke in patients with hypertension and LVH, HYZAAR is also the only combination antihypertensive product that is indicated for initial use in appropriate patients with severe hypertension. HYZAAR 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 unique indication is based on a six week double-blind, randomized study of the efficacy and safety of HYZAAR as initial therapy for severe hypertension (defined as a mean SiDBP >110mmHg confirmed on two separate occasions off all antihypertensive therapy).

Source: Merck

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