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

Special Populations

Pediatric: Losartan pharmacokinetics have not been investigated in patients Less than 18 years of age.

Geriatric and Gender: Losartan pharmacokinetics have been investigated in the elderly (65-75 years) and in both genders. Plasma concentrations of losartan and its active metabolite are similar in elderly and young hypertensives. Plasma concentrations of losartan were about twice as high in female hypertensives as male hypertensives, but concentrations of the active metabolite were similar in males and females. No dosage adjustment is necessary (see DOSAGE AND ADMINISTRATION).

Race: Pharmacokinetic differences due to race have not been studied. (see also PRECAUTIONS, Race and CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Reduction in the Risk of Stroke, Race).

Renal Insufficiency: Plasma concentrations of losartan are not altered in patients with creatinine clearance above 30 mL/min. In patients with lower creatinine clearance, AUCs are about 50% greater and they are doubled in hemodialysis patients. Plasma concentrations of the active metabolite are not significantly altered in patients with renal impairment or in hemodialysis patients. Neither losartan nor its active metabolite can be removed by hemodialysis. No dosage adjustment is necessary for patients with renal impairment unless they are volume-depleted (see WARNINGS, Hypotension -- Volume-Depleted Patients and DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency: Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-times and about 1.7-times those in young male volunteers. Compared to normal subjects the total plasma clearance of losartan in patients with hepatic insufficiency was about 50% lower and the oral bioavailability was about 2-times higher. A lower starting dose is recommended for patients with a history of hepatic impairment (see DOSAGE AND ADMINISTRATION).

Drug Interactions

Losartan, administered for 12 days, did not affect the pharmacokinetics or pharmacodynamics of a single dose of warfarin. Losartan did not affect the pharmacokinetics of oral or intravenous digoxin. Coadministration of losartan and cimetidine led to an increase of about 18% in AUC of losartan but did not affect the pharmacokinetics of its active metabolite. Coadministration of losartan and phenobarbital led to a reduction of about 20% in the AUC of losartan and that of its active metabolite. Conversion of losartan to its active metabolite after intravenous administration is not affected by ketoconazole, an inhibitor of P450 3A4. There is no pharmacokinetic interaction between losartan and hydrochlorothiazide.

Pharmacodynamics and Clinical Effects

Hypertension: Losartan inhibits the pressor effect of angiotensin II (as well as angiotensin I) infusions. A dose of 100 mg inhibits the pressor effect by about 85% at peak with 25-40% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a 2-3 fold rise in plasma renin activity and consequent rise in angiotensin II plasma concentration in hypertensive patients. Losartan does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations fall following losartan administration. In spite of the effect of losartan on aldosterone secretion, very little effect on serum potassium was observed.