Valsartan and Hydrochlorothiazide (Page 6 of 8)

14 CLINICAL STUDIES

14.1 Hypertension

Valsartan and Hydrochlorothiazide: In controlled clinical trials including over 7600 patients, 4372 patients were exposed to valsartan (80, 160, and 320 mg) and concomitant hydrochlorothiazide (12.5 and 25 mg). Two factorial trials compared various combinations of 80 mg/12.5 mg, 80 mg/25 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg, and 320 mg/25 mg with their respective components and placebo. The combination of valsartan and hydrochlorothiazide resulted in additive placebo-adjusted decreases in systolic and diastolic blood pressure at trough of 14 to 21/8 to 11 mmHg at 80 mg/12.5 mg to 320 mg/25 mg, compared to 7 to 10/4 to 5 mmHg for valsartan 80 mg to 320 mg, and 5 to 11/2 to 5 mmHg for hydrochlorothiazide 12.5 mg to 25 mg alone.

Three other controlled trials investigated the addition of hydrochlorothiazide to patients who did not respond adequately to valsartan 80 mg to valsartan 320 mg, resulted in the additional lowering of systolic and diastolic blood pressure by approximately 4 to 12/2 to 5 mmHg.

The maximal antihypertensive effect was attained 4 weeks after the initiation of therapy, the first time point at which blood pressure was measured in these trials.

In long-term follow-up studies (without placebo control), the effect of the combination of valsartan and hydrochlorothiazide appeared to be maintained for up to 2 years. The antihypertensive effect is independent of age or gender. The overall response to the combination was similar for black and non-black patients.

There was essentially no change in heart rate in patients treated with the combination of valsartan and hydrochlorothiazide in controlled trials.

There are no trials of the valsartan and hydrochlorothiazide combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but the hydrochlorothiazide component and several ARBs, which are the same pharmacological class as the valsartan component, have demonstrated such benefits.

Valsartan: The antihypertensive effects of valsartan were demonstrated principally in 7 placebo-controlled, 4- to 12-week trials (1 in patients over 65 years) of dosages from 10 to 320 mg/day in patients with baseline diastolic blood pressures of 95 to 115 mmHg. The studies allowed comparison of once-daily and twice-daily regimens of 160 mg/day; comparison of peak and trough effects; comparison (in pooled data) of response by gender, age, and race; and evaluation of incremental effects of hydrochlorothiazide.

Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic and diastolic blood pressure, usually with little or no orthostatic change.

In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs at approximately 2 hours, and maximum reduction of blood pressure is achieved within 6 hours. The antihypertensive effect persists for 24 hours after dosing, but there is a decrease from peak effect at lower doses (40 mg) presumably reflecting loss of inhibition of angiotensin II. At higher doses, however (160 mg), there is little difference in peak and trough effect. During repeated dosing, the reduction in blood pressure with any dose is substantially present within 2 weeks, and maximal reduction is generally attained after 4 weeks. In long-term follow-up studies (without placebo control), the effect of valsartan appeared to be maintained for up to 2 years. The antihypertensive effect is independent of age, gender or race. The latter finding regarding race is based on pooled data and should be viewed with caution, because antihypertensive drugs that affect the renin-angiotensin system (that is, ACE inhibitors and angiotensin II blockers) have generally been found to be less effective in low-renin hypertensives (frequently blacks) than in high-renin hypertensives (frequently whites). In pooled, randomized, controlled trials of valsartan that included a total of 140 blacks and 830 whites, valsartan and an ACE-inhibitor control were generally at least as effective in blacks as whites. The explanation for this difference from previous findings is unclear.

Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure.

The 7 studies of valsartan monotherapy included over 2000 patients randomized to various doses of valsartan and about 800 patients randomized to placebo. Doses below 80 mg were not consistently distinguished from those of placebo at trough, but doses of 80, 160 and 320 mg produced dose-related decreases in systolic and diastolic blood pressure, with the difference from placebo of approximately 6 to 9/3 to 5 mmHg at 80 to 160 mg and 9/6 mmHg at 320 mg.

Patients with an inadequate response to 80 mg once daily were titrated to either 160 mg once daily or 80 mg twice daily, which resulted in a similar response in both groups.

In another 4-week study, 1876 patients randomized to valsartan 320 mg once daily had an incremental blood pressure reduction 3/1 mmHg lower than did 1900 patients randomized to valsartan 160 mg once daily.

In controlled trials, the antihypertensive effect of once daily valsartan 80 mg was similar to that of once daily enalapril 20 mg or once daily lisinopril 10 mg.

There was essentially no change in heart rate in valsartan-treated patients in controlled trials.

14.2 Initial Therapy — Hypertension


The safety and efficacy of valsartan and hydrochlorothiazide as initial therapy for patients with severe hypertension (defined as a sitting diastolic blood pressure ≥ 110 mmHg and systolic blood pressure ≥ 140 mmHg off all antihypertensive therapy) were studied in a 6-week multicenter, randomized, double-blind study. Patients were randomized to either valsartan and hydrochlorothiazide (160 mg/12.5 mg once daily) or to valsartan (160 mg once daily) and followed for blood pressure response. Patients were force-titrated at 2-week intervals. Patients on combination therapy were subsequently titrated to 160 mg/25 mg followed by 320 mg/25 mg valsartan and hydrochlorothiazide. Patients on monotherapy were subsequently titrated to 320 mg valsartan followed by a titration to 320 mg valsartan to maintain the blind. The study randomized 608 patients, including 261 (43%) females, 147 (24%) blacks, and 75 (12%) ≥ 65 years of age. The mean blood pressure at baseline for the total population was 168/112 mmHg. The mean age was 52 years. After 4 weeks of therapy, reductions in systolic and diastolic blood pressure were 9/5 mmHg greater in the group treated with valsartan and hydrochlorothiazide compared to valsartan. Similar trends were seen when the patients were grouped according to gender, race, or age.

16 HOW SUPPLIED/STORAGE AND HANDLING

Valsartan and hydrochlorothiazide tablets, USP are available as non-scored tablets containing valsartan and hydrochlorothiazide 80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg, and 320 mg/25 mg. Strengths are available as follows.
Valsartan and Hydrochlorothiazide Tablets USP, 80 mg/12.5 mg are light orange colored, ovaloid, beveled edge, biconvex film-coated tablets debossed with ‘I’ on one side and ’61’ on other side.
Bottles of 90 NDC 65862-547-90
Bottles of 1,000 NDC 65862-547-99
Cartons of 100 (10 x 10) Unit-dose Tablets NDC 65862-547-10
Valsartan and Hydrochlorothiazide Tablets USP, 160 mg/12.5 mg are dark red colored, ovaloid, beveled edge, biconvex film-coated tablets debossed with ‘I’ on one side and ’62’ on other side.
Bottles of 90 NDC 65862-548-90
Bottles of 1,000 NDC 65862-548-99
Cartons of 100 (10 x 10) Unit-dose Tablets NDC 65862-548-10
Valsartan and Hydrochlorothiazide Tablets USP, 160 mg/25 mg are brown-orange colored, ovaloid, beveled edge, biconvex film-coated tablets debossed with ‘I’ on one side and ’63’ on other side.
Bottles of 90 NDC 65862-549-90
Bottles of 1,000 NDC 65862-549-99
Cartons of 100 (10 x 10) Unit-dose Tablets NDC 65862-549-10
Valsartan and Hydrochlorothiazide Tablets USP, 320 mg/12.5 mg are pink colored, oval shaped, beveled edge, biconvex film-coated tablets debossed with ‘I’ on one side and ’64’ on other side.
Bottles of 90 NDC 65862-550-90
Bottles of 500 NDC 65862-550-05
Valsartan and Hydrochlorothiazide Tablets USP, 320 mg/25 mg are yellow colored, oval shaped, beveled edge, biconvex film-coated tablets debossed with ‘I’ on one side and ’65’ on other side.
Bottles of 90 NDC 65862-551-90
Bottles of 500 NDC 65862-551-05
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Protect from moisture and heat. Dispense in tight container (USP).

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