Diovan (valsartan) - 3 indications

Diovan HCT (valsartan and hydrochlorothiazide USP) - 1 indication

Scroll down for information on each indication:

Diovan

• hypertension; approved December 1996
• heart failure (NYHA class II-IV); approved August 2002
• to reduce cardiovascular mortality in post-myocardial infarction patients; approved August 2005

Diovan HCT

• for the treatment of hypertension, to lower blood pressure, in patients not adequately controlled with monotherapy or as initial therapy; approved March 1998.

General Information

Diovan is an angiotensin II receptor blocker (ARB). Diovan HCT is the combination tablet of valsartan (Diovan) and hydrochlorothiazide (HCTZ), a diuretic.

Diovan is specifically indicated for the following conditions:

• hypertension, to lower blood pressure in adults and pediatric patients one year of age and older
• to reduce the risk of hospitalization for heart failure in adult patients with heart failure (NYHA class II-IV)
• in clinically stable adult patients with left ventricular failure or left ventricular dysfunction following myocardial infarction, Diovan is indicated to reduce the risk of cardiovascular mortality

Diovan HCT is specifically indicated for the treatment of hypertension, to lower blood pressure:

• in patients not adequately controlled with monotherapy
• as initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals

Diovan is supplied as tablets and as an oral suspension. Diovan tablets and oral suspension are not substitutable on a milligram-per-milligram basis. Do not combine two dosage forms to achieve the total dose. Use of the oral suspension is recommended for the following: in pediatric patients aged 1 to 5 years; in patients >5 years of age who cannot swallow tablets and in pediatric patients for whom the calculated dose (mg/kg) does not correspond to the available tablet strengths of Diovan. When switching between suspension and tablets, the dose of valsartan may need to be adjusted. Scroll down to see recommended dosing and administration for each therapeutic condition. 

Diovan HCT is supplied as a tablet for oral administration.  Please scroll down for dosing and administration. 

Mechanism of Action

Diovan is an angiotensin II receptor blocker (ARB). Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Diovan (valsartan) blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.

Diovan HCT is the combination tablet of valsartan (Diovan) and hydrochlorothiazide (HCTZ), a diuretic. Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is unknown.

Side Effects

Adverse effects associated with the use of Diovan may include, but are not limited to, the following:

Hypertension:

• headache
• dizziness
• viral infection
• fatigue
• abdominal pain

Heart Failure

• dizziness
• hypotension
• diarrhea
• arthralgia
• back pain
• fatigue
• hyperkalemia

Post-Myocardial Infarction:

• hypotension
• cough
• increased blood creatinine

Adverse effects associated with the use of Diovan HCT may include, but are not limited to, the following:

• headache
• dizziness
• nasopharyngitis

The Diovan and Diovan HCT drug labels come with the following Black Box Warning: When pregnancy is detected, discontinue Diovan/Diovan HCT as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Diovan - Indication 1 - hypertension

approved December 1996

Dosing/Administration

Adults: The recommended starting dose of Diovan is 80 mg or 160 mg once daily when used as monotherapy in patients who are not volume-depleted. Patients requiring greater reductions may be started at the higher dose. Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once a day. The antihypertensive effect is substantially present within 2 weeks and maximal reduction is generally attained after 4 weeks. If additional antihypertensive effect is required over the starting dose range, the dose may be increased to a maximum of 320 mg or a diuretic may be added. Addition of a diuretic has a greater effect than dose increases beyond 80 mg.

Pediatric Hypertension 1 to 16 Years of Age: The usual recommended starting dose is 1 mg/kg once daily (up to 40 mg total). A higher starting dose of 2 mg/kg may be considered in selected cases when a greater reduction of blood pressure is needed. The dosage should be adjusted according to blood pressure response and tolerability, up to a maximum dose of 4 mg/kg once daily (maximum daily dose 160 mg). No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate < 30 mL/min/1.73 m2.

Clinical Trial Results

Adult Hypertension The antihypertensive effects of Diovan (valsartan) were demonstrated 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 95-115 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. The 7 studies of valsartan monotherapy included over 2,000 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 6-9/3-5 mmHg at 80 to 160 mg and 9/6 mmHg at 320 mg. 

Pediatric Hypertension

Children Between 1 to Less Than 6 Years of Age The antihypertensive effect of valsartan in 290 children aged between 1 to less than 6 years of age has been evaluated in three randomized, double-blind clinical studies. In the first study in 90 patients, patients who weighed less than 18 kg received 5, 20 or 40 mg of valsartan daily (low, medium and high doses), and patients who weighed greater than or equal to 18 kg received 10, 40, and 80 mg of valsartan daily (low, medium and high doses). At the end of 2 weeks, the three dose levels of valsartan (low, medium and high) reduced systolic blood pressure from the baseline by 8.4, 8.3, and 8.6 mmHg, respectively, but a dose response could not be demonstrated. In the second study of 74 patients, higher doses (1 mg/kg and 4 mg/kg daily) of valsartan were associated with numerically greater blood pressure reductions than the lowest dose (0.25 mg/kg) at the end of 6-weeks treatment. The third study was a 6 week, randomized double-blind study to evaluate the dose response of valsartan in 126 children 1 to 5 years of age with hypertension, with or without chronic kidney disease (CKD) randomized to receive either valsartan 0.25 mg/kg or 4 mg/kg daily. At the end of 6 weeks, dose dependent reductions in mean systolic blood pressure (MSBP) were observed. The reduction in MSBP was 8.5 mmHg with valsartan 4 mg/kg and 4.1 mmHg with valsartan 0.25 mg/kg. Similarly, the CKD subgroup showed reductions in MSBP with valsartan 4 mg/kg compared to 0.25 mg/kg (9.2 mmHg vs 1.2 mmHg).

Children Between 6 to 16 Years of Age In a clinical study involving 261 hypertensive pediatric patients 6 to 16 years of age, patients who weighed less than 35 kg received 10, 40 or 80 mg of valsartan daily (low, medium and high doses), and patients who weighed greater than or equal to 35 kg received 20, 80, and 160 mg of valsartan daily (low, medium and high doses). Renal and urinary disorders, and essential hypertension with or without obesity were the most common underlying causes of hypertension in children enrolled in this study. At the end of 2 weeks, valsartan reduced both systolic and diastolic blood pressure in a dose dependent manner. Overall, the three dose levels of valsartan (low, medium and high) significantly reduced systolic blood pressure by 8, 10, and 12 mm Hg from the baseline, respectively. Patients were re-randomized to either continue receiving the same dose of valsartan or were switched to placebo. In patients who continued to receive the medium and high doses of valsartan, systolic blood pressure at trough was 4 and 7 mm Hg lower than patients who received the placebo treatment. In patients receiving the low dose of valsartan, systolic blood pressure at trough was similar to that of patients who received the placebo treatment. Overall, the dose-dependent antihypertensive effect of valsartan was consistent across all the demographic subgroups.

Diovan - Indication 2 - heart failure (NYHA class II-IV)

approved August 2002

Dosing/Administration

The recommended starting dose of Diovan is 40 mg twice daily. Uptitrate to 80 mg and 160 mg twice daily or to the highest dose tolerated by the patient. Consider reducing the dose of concomitant diuretics. The maximum daily dose administered in clinical trials is 320 mg in divided doses.

Clinical Trial Results

The Valsartan Heart Failure Trial (Val-HeFT) was a multinational, double-blind study in which 5,010 patients with NYHA class II (62%) to IV (2%) heart failure and LVEF less than 40%, on baseline therapy chosen by their physicians, were randomized to placebo or valsartan (titrated from 40 mg twice daily to the highest tolerated dose or 160 mg twice daily) and followed for a mean of about 2 years.  The primary outcomes were mortality and the combined end point of mortality and morbidity, defined as the incidence of cardiac arrest with resuscitation, hospitalization for heart failure, or receipt of intravenous inotropic or vasodilator therapy for at least four hours. Overall mortality was similar in the two groups. The incidence of the combined end point, however, was 13.2 percent lower with valsartan than with placebo, predominantly because of a lower number of patients hospitalized for heart failure: 455 (18.2 percent) in the placebo group and 346 (13.8 percent) in the valsartan group. Treatment with valsartan also resulted in significant improvements in NYHA class, ejection fraction, signs and symptoms of heart failure, and quality of life as compared with placebo. In a post hoc analysis of the combined end point and mortality in subgroups defined according to base-line treatment with angiotensin-converting–enzyme (ACE) inhibitors or beta-blockers, valsartan had a favorable effect in patients receiving neither or one of these types of drugs but an adverse effect in patients receiving both types of drugs.

Diovan - Indication 3 - to reduce cardiovascular mortality in post-myocardial infarction patients

approved August 2005

Dosing/Administration

Diovan may be initiated as early as 12 hours after a myocardial infarction. The recommended starting dose of Diovan is 20 mg twice daily. Patients may be up-titrated within 7 days to 40 mg twice daily, with subsequent titrations to a target maintenance dose of 160 mg twice daily, as tolerated by the patient. If symptomatic hypotension or renal dysfunction occurs, consider dosage reduction. Diovan may be given with other standard post-myocardial infarction treatment, including thrombolytics, aspirin, beta-blockers, and statins.

Clinical Trial Results

The VALsartan In Acute myocardial iNfarcTion trial (VALIANT) was a randomized, controlled, multinational, double blind study in 14,703 patients with acute myocardial infarction and either heart failure (signs, symptoms or radiological evidence) or left ventricular systolic dysfunction (ejection fraction ≤ 40% by radionuclide ventriculography or ≤ 35% by echocardiography or ventricular contrast angiography). Patients were randomized within 12 hours to 10 days after the onset of myocardial infarction symptoms to one of three treatment groups: valsartan (titrated from 20 or 40 mg twice daily to the highest tolerated dose up to a maximum of 160 mg twice daily), the ACE inhibitor, captopril (titrated from 6.25 mg three times daily to the highest tolerated dose up to a maximum of 50 mg three times daily), or the combination of valsartan plus captopril. In the combination group, the dose of valsartan was titrated from 20 mg twice daily to the highest tolerated dose up to a maximum of 80 mg twice daily; the dose of captopril was the same as for monotherapy. During a median follow-up of 24.7 months, 979 patients in the valsartan group died, as did 941 patients in the valsartan-and-captopril group and 958 patients in the captopril group. The upper limit of the one-sided 97.5 percent confidence interval for the comparison of the valsartan group with the captopril group was within the prespecified margin for noninferiority with regard to mortality and with regard to the composite end point of fatal and nonfatal cardiovascular events.

Diovan HCT - for the treatment of hypertension, to lower blood pressure, in patients not adequately controlled with monotherapy or as initial therapy

approved March 1998 

Dosing/Administration

The usual starting dose is Diovan HCT 160/12.5 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of one 320/25 tablet once daily as needed to control blood pressure. Maximum antihypertensive effects are attained within 2 to 4 weeks after a change in dose.

Clinical Trial Results

Valsartan-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 80/12.5 mg, 80/25 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg, and 320/25 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 14-21/8-11 mmHg at 80/12.5 mg to 320/25 mg, compared to 7-10/4-5 mmHg for valsartan 80 mg to 320 mg, and 5-11/2-5 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 4-12/2-5 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.

Initial Therapy - Hypertension The safety and efficacy of Diovan HCT 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 Diovan HCT (valsartan and hydrochlorothiazide 160/12.5 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 160/25 mg followed by 320/25 mg valsartan/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. 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 Diovan HCT compared to valsartan. Similar trends were seen when the patients were grouped according to gender, race, or age.