Hyzaar

[Losartan/HCTZ]

Fluconazole, an inhibitor of cytochrome P450 2C9, decreased the AUC of the active metabolite by approximately 40%, but increased the AUC of losartan by approximately 70% following multiple doses. Conversion of losartan to its active metabolite after intravenous administration is not affected by ketoconazole, an inhibitor of P450 3A4. The AUC of active metabolite following oral losartan was not affected by erythromycin, another inhibitor of P450 3A4, but the AUC of losartan was increased by 30%.

Hydrochlorothiazide

After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

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Pharmacodynamics and Clinical Effects

Losartan Potassium

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-to 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. In a single-dose study in normal volunteers, losartan had no effects on glomerular filtration rate, renal plasma flow or filtration fraction.

In multiple dose studies in hypertensive patients, there were no notable effects on systemic or renal prostaglandin concentrations, fasting triglycerides, total cholesterol or HDL-cholesterol or fasting glucose concentrations. There was a small uricosuric effect leading to a minimal decrease in serum uric acid (mean decrease <0.4 mg/ dL) during chronic oral administration.

The antihypertensive effects of losartan were demonstrated principally in 4 placebo-controlled, 6-to 12-week trials of dosages from 10 to 150 mg per day in patients with baseline diastolic blood pressures of 95-115. The studies allowed comparisons of two doses (50-100 mg/ day) as once-daily or twice-daily regimens, comparisons of peak and trough effects, and comparisons of response by gender, age, and race. Three additional studies examined the antihypertensive effects of losartan and hydrochlorothiazide in combination.

The 4 studies of losartan monotherapy included a total of 1075 patients randomized to several doses of losartan and 334 to placebo. The 10 and 25 mg doses produced some effect at peak (6 hours after dosing) but small and inconsistent trough (24 hour) responses. Doses of 50, 100, and 150 mg once daily gave statistically significant systolic/ diastolic mean decreases in blood pressure, compared to placebo in the range of 5.5-10.5/ 3.5-7.5 mmHg, with the 150 mg dose giving no greater effect than 50-100 mg. Twice-daily dosing at 50-100 mg/ day gave consistently larger trough responses than once-daily dosing at the same total dose. Peak (6 hour) effects were uniformly, but moderately larger than trough effects, with the trough to peak ratio for systolic and diastolic responses 50-95% and 60-90%, respectively.

Analysis of age, gender, and race subgroups of patients showed that men and women, and patients over and under 65, had generally similar responses. Losartan was effective in reducing blood pressure regardless of race, although the effect was somewhat less in Black patients (usually a low-renin population).

The effect of losartan is substantially present within one week but in some studies the maximal effect occurred in 3-6 weeks. In long-term follow-up studies (without placebo control) the effect of losartan appeared to be maintained for up to a year. There is no apparent rebound effect after abrupt withdrawal of losartan. There was essentially no change in average heart rate in losartan-treated patients in controlled trials. 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 (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.

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