Race

In the LIFE study, Black patients treated with atenolol were at lower risk of experiencing the primary composite endpoint compared with Black patients treated with losartan. In the subgroup of Black patients (n=533, 6% of the LIFE study patients), there were 29 primary endpoints among 263 patients on atenolol (11%, 26 per 1000 patient-years) and 46 primary endpoints among 270 patients (17%, 42 per 1000 patient-years) on losartan. This finding could not be explained on the basis of differences in the populations other than race or on any imbalances between treatment groups. In addition, blood pressure reductions in both treatment groups were consistent between Black and non-Black patients. 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 provides no evidence that the benefits of losartan on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to Black patients.

Losartan Potassium-Hydrochlorothiazide

The 3 controlled studies of losartan and hydrochlorothiazide included over 1300 patients assessing the antihypertensive efficacy of various doses of losartan (25, 50 and 100 mg) and concomitant hydrochlorothiazide (6.25, 12.5 and 25 mg). A factorial study compared the combination of losartan/hydrochlorothiazide 50/12.5 mg with its components and placebo. The combination of losartan/hydrochlorothiazide 50/12.5 mg resulted in an approximately additive placebo-adjusted systolic/diastolic response (15.5/9.0 mmHg for the combination compared to 8.5/5.0 mmHg for losartan alone and 7.0/3.0 mmHg for hydrochlorothiazide alone). Another study investigated the dose-response relationship of various doses of hydrochlorothiazide (6.25, 12.5 and 25 mg) or placebo on a background of losartan (50 mg) in patients not adequately controlled (sitting diastolic blood pressure [SiDBP] 93-120 mmHg) on losartan (50 mg) alone. The third study investigated the dose-response relationship of various doses of losartan (25, 50 and 100 mg) or placebo on a background of hydrochlorothiazide (25 mg) in patients not adequately controlled (SiDBP 93-120 mmHg) on hydrochlorothiazide (25 mg) alone. These studies showed an added antihypertensive response at trough (24 hours post-dosing) of hydrochlorothiazide 12.5 or 25 mg added to losartan 50 mg of 5.5/3.5 and 10.0/6.0 mmHg, respectively. Similarly, there was an added antihypertensive response at trough when losartan 50 or 100 mg was added to hydrochlorothiazide 25 mg of 9.0/5.5 and 12.5/6.5 mmHg, respectively. There was no significant effect on heart rate.

There was no difference in response for men and women or in patients over or under 65 years of age.

Black patients had a larger response to hydrochlorothiazide than non-Black patients and a smaller response to losartan. The overall response to the combination was similar for Black and non-Black patients.

Severe Hypertension (Sitting Diastolic Blood Pressure [SiDBP]≥110 mmHg)

The safety and efficacy of HYZAAR as initial therapy for severe hypertension (defined as a mean SiDBP ≥110 mmHg confirmed on 2 separate occasions off all antihypertensive therapy) was studied in a 6-week double-blind, randomized, multicenter study. Patients were randomized to either losartan and hydrochlorothiazide (50-12.5 mg, once daily) or to losartan (50 mg, once daily) and followed for blood pressure response. Patients were titrated at 2-week intervals if their SiDBP did not reach goal (<90 mmHg). Patients on combination therapy were titrated from losartan 50 mg/hydrochlorothiazide 12.5 mg to losartan 50 mg/hydrochlorothiazide 12.5 mg (sham titration to maintain the blind) to losartan 100 mg/hydrochlorothiazide 25 mg. Patients on monotherapy were titrated from losartan 50 mg to losartan 100 mg to losartan 150 mg, as needed. The primary endpoint was a comparison at 4 weeks of patients who achieved goal diastolic blood pressure (trough SiDBP <90 mmHg).

The study enrolled 585 patients, including 264 (45%) females, 124 (21%) Blacks, and 21 (4%) ≥65 years of age. The mean blood pressure at baseline for the total population was 171/113 mmHg. The mean age was 53 years. After 4 weeks of therapy, the mean SiDBP was 3.1 mmHg lower and the mean SiSBP was 5.6 mmHg lower in the group treated with HYZAAR. As a result, a greater proportion of the patients on HYZAAR reached the target diastolic blood pressure (17.6% for HYZAAR, 9.4% for losartan; p=0.006). Similar trends were seen when the patients were grouped according to gender, race or age (<, ≥ 65).

After 6 weeks of therapy, more patients who received the combination regimen reached target diastolic blood pressure than those who received the monotherapy regimen (29.8% versus 12.5%).

During the study period, there were no reported cases of syncope in either treatment group. There were 2 (0.6%) and 0 (0.0%) cases of hypotension reported in the group treated with HYZAAR and the group treated with losartan, respectively. The overall pattern of adverse events reported for patients treated with HYZAAR as initial therapy was similar to the adverse event profile for patients treated with losartan as initial therapy. For information on the specific adverse events observed during the study period, see ADVERSE REACTIONS, Severe Hypertension.

INDICATIONS AND USAGE

Hypertension

HYZAAR is indicated for the treatment of 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 (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, and DOSAGE AND ADMINISTRATION).

Hypertensive Patients with Left Ventricular Hypertrophy

HYZAAR is indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to Black patients. (See PRECAUTIONS, Race, CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Losartan Potassium, Reduction in the Risk of Stroke,Race, and DOSAGE AND ADMINISTRATION.)

CONTRAINDICATIONS

HYZAAR is contraindicated in patients who are hypersensitive to any component of this product.

Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

WARNINGS

Fetal/Neonatal Morbidity and Mortality

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, HYZAAR should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.

Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of HYZAAR as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, HYZAAR should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

There was no evidence of teratogenicity in rats or rabbits treated with a maximum losartan potassium dose of 10 mg/kg/day in combination with 2.5 mg/kg/day of hydrochlorothiazide. At these dosages, respective exposures (AUCs) of losartan, its active metabolite, and hydrochlorothiazide in rabbits were approximately 5, 1.5, and 1.0 times those achieved in humans with 100 mg losartan in combination with 25 mg hydrochlorothiazide. AUC values for losartan, its active metabolite and hydrochlorothiazide, extrapolated from data obtained with losartan administered to rats at a dose of 50 mg/kg/day in combination with 12.5 mg/kg/day of hydrochlorothiazide, were approximately 6, 2, and 2 times greater than those achieved in humans with 100 mg of losartan in combination with 25 mg of hydrochlorothiazide. Fetal toxicity in rats, as evidenced by a slight increase in supernumerary ribs, was observed when females were treated prior to and throughout gestation with 10 mg/kg/day losartan in combination with 2.5 mg/kg/day hydrochlorothiazide. As also observed in studies with losartan alone, adverse fetal and neonatal effects, including decreased body weight, renal toxicity, and mortality, occurred when pregnant rats were treated during late gestation and/or lactation with 50 mg/kg/day losartan in combination with 12.5 mg/kg/day hydrochlorothiazide. Respective AUCs for losartan, its active metabolite and hydrochlorothiazide at these dosages in rats were approximately 35, 10 and 10 times greater than those achieved in humans with the administration of 100 mg of losartan in combination with 25 mg hydrochlorothiazide. When hydrochlorothiazide was administered without losartan to pregnant mice and rats during their respective periods of major organogenesis, at doses up to 3000 and 1000 mg/kg/day, respectively, there was no evidence of harm to the fetus.

Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.