FDA Approves COZAAR as the First and Only Hypertension Medicine to Help Prevent Stroke in Patients with Hypertension and Left Ventricular Hypertrophy

Business Wire, March 25, 2003

Cozaar (R) is a registered trademark of E.I. du Pont de Nemours & Co., Inc, Wilmington, DE, USA.

Prescribing information for Cozaar(R) is below.

COZAAR(R)

(LOSARTAN POTASSIUM TABLETS)

USE IN PREGNANCY

When used in pregnancy during the second and 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 should be discontinued as soon as possible. See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

DESCRIPTION

COZAAR* (losartan potassium) is an angiotensin II receptor (type AT1) antagonist. Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-(p-(o-1H-tetrazol-5-ylphenyl)benzyl)imidazole-5- methanol monopotassium salt.

Its empirical formula is C(22)H(22)ClKN(6)O, and its structural formula is:

(GRAPHIC OMITTED)

Losartan potassium is a white to off-white free-flowing crystalline powder with a molecular weight of 461.01. It is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as acetonitrile and methyl ethyl ketone. Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan.

COZAAR is available as tablets for oral administration containing either 25 mg, 50 mg or 100 mg of losartan potassium and the following inactive ingredients: microcrystalline cellulose, lactose hydrous, pregelatinized starch, magnesium stearate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, titanium dioxide, D&C yellow No. 10 aluminum lake and FD&C blue No. 2 aluminum lake.

COZAAR 25 mg, 50 mg and 100 mg tablets contain potassium in the following amounts: 2.12 mg (0.054 mEq), 4.24 mg (0.108 mEq) and 8.48 mg (0.216 mEq), respectively.

CLINICAL PHARMACOLOGY

Mechanism of Action

Angiotensin II (formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)), is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT(1) receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). There is also an AT(2) receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT(1) receptor and have much greater affinity (about 1000-fold) for the AT(1) receptor than for the AT(2) receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT(1) receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT(1) receptor.