Cozaar

[Losartan]

Liver Function Tests:

Occasional elevations of liver enzymes and/ or serum bilirubin have occurred. In patients with essential hypertension treated with COZAAR alone, one patient (< 0.1%) was discontinued due to these laboratory adverse experiences.

Drug Interactions

Text Continues Below

---

No significant drug-drug pharmacokinetic interactions have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. (See CLINICAL PHARMACOLOGY, Drug Interactions.)

Potent inhibitors of cytochrome P450 3A4 and 2C9 have not been studied clinically but in vitro studies show significant inhibition of the formation of the active metabolite by inhibitors of P450 3A4 (ketoconazole, troleandomycin, gestodene), or P450 2C9 (sulfaphenazole) and nearly complete inhibition by the combination of sulfaphenazole and ketoconazole.

In humans, ketoconazole, an inhibitor of P450 3A4, did not affect the conversion of losartan to the active metabolite after intravenous administration of losartan. Inhibitors of cytochrome P450 2C9 have not been studied clinically. The pharmacodynamic consequences of concomitant use of losartan and inhibitors of P450 2C9 have not been examined. As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e. g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium. As with other antihypertensive agents, the antihypertensive effect of losartan may be blunted by the non-steroidal anti-inflammatory drug indomethacin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Losartan potassium was not carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. Female rats given the highest dose (270 mg/ kg/ day) had a slightly higher incidence of pancreatic acinar adenoma.

The maximally tolerated dosages (270 mg/ kg/ day in rats, 200 mg/ kg/ day in mice) provided systemic exposures for losartan and its pharmacologically active metabolite that were approximately 160-and 90-times (rats) and 30-and 15-times (mice) the exposure of a 50 kg human given 100 mg per day. Losartan potassium was negative in the microbial mutagenesis and V-79 mammalian cell mutagenesis assays and in the in vitro alkaline elution and in vitro and in vivo chromosomal aberration assays. In addition, the active metabolite showed no evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro chromosomal aberration assays.

Fertility and reproductive performance were not affected in studies with male rats given oral doses of losartan potassium up to approximately 150 mg/ kg/ day. The administration of toxic dosage levels in females (300/ 200 mg/ kg/ day) was associated with a significant (p< 0.05) decrease in the number of corpora lutea/ female, implants/ female, and live fetuses/ female at C-section. At 100 mg/ kg/ day only a decrease in the number of corpora lutea/ female was observed. The relationship of these findings to drug-treatment is uncertain since there was no effect at these dosage levels on implants/ pregnant female, percent post-implantation loss, or live animals/ litter at parturition. In nonpregnant rats dosed at 135 mg/ kg/ day for 7 days, systemic exposure (AUCs) for losartan and its active metabolite were approximately 66 and 26 times the exposure achieved in man at the maximum recommended human daily dosage (100 mg).

Pregnancy

Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS,

Fetal/ Neonatal Morbidity and Mortality.

Nursing Mothers

It is not known whether losartan is excreted in human milk, but significant levels of losartan and its active metabolite were shown to be present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Use in the Elderly

Of the total number of patients receiving COZAAR in controlled clinical studies for hypertension, 391 patients (19%) were 65 years and over, while 37 patients (2%) were 75 years and over. In a controlled clinical study for renal protection in type 2 diabetic patients with proteinuria, 248 patients (33%) were 65 years and over. In a controlled clinical study for the reduction in the combined risk of cardiovascular death, stroke and myocardial infarction in hypertensive patients with left ventricular hypertrophy, 2857 patients (62%) were 65 years and over, while 808 patients (18%) were 75 years and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Race

In the LIFE study, Black patients with hypertension and left ventricular hypertrophy had a lower risk of stroke on atenolol than on 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. (See CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects; Reduction in the Risk of Stroke.)

Page:  << Prev | 1 | 2 | 3 | 4 | 5