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Valsartan

Diovan®

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Diovan Tablet (Tab 40 mg) [1 of 5 - Click here to see more photos]

[ Patient Education ] [ Indications/Dosage ] [ Administration ] [ Contraindications/Precautions ] [ Interactions ] [ Adverse Reactions ] [ Monitoring Parameters ] [ Chemical Structures] Classification: Cardiovascular Agents Antihypertensive Agents Angiotensin II receptor antagonists Description: Valsartan is a specific angiotensin II antagonist which selectively and competitively blocks the AT1 receptor, which mediates the vasopressor and aldosterone effects of angiotensin II. Unlike losartan, valsartan does not have an active metabolite or possess uricosuric effects. Valsartan is used to treatment hypertension in adults and children >= 6 years of age; it is also FDA-approved to treat heart failure in patients who are intolerant to ACE inhibitors. Because valsartan does not inhibit angiotensin converting enzyme (ACE), it does not result in bradykinin accumulation which is theorized to cause the cough and angioedema associated with ACE inhibitors. However, angioedema has been rarely associated with valsartan or other angiotensin II antagonists. Valsartan is effective for hypertension, either alone or in combination with other antihypertensive agents. Because AT1 receptors are nearly saturated at the starting dose for most angiotensin II antagonists, the antihypertensive dose-response curve of these drugs are nonlinear, with proportionally small decreases in blood pressure attained with increased dosage. Greater antihypertensive efficacy is achieved by adding a small dose of a diuretic to the angiotensin II antagonist. Modest reduction in blood pressure is achieved by increasing the dose of valsartan over the dosage range of 80--320 mg. Valsartan reduces left ventricular hypertrophy (LVH), although the clinical benefit associated with reducing LVH is not well established. Limited data show that valsartan also reduces proteinuria in patients with hypertension and renal disease; however, larger clinical trials are needed to evaluate the comparative renoprotective efficacy and long-term benefits of valsartan versus ACE inhibitors in patients with renal disease or nephropathy. In addition to antihypertensive actions, the angiotensin II antagonists have been effective in the treatment of heart failure. Another angiotensin receptor antagonist, losartan, has been shown to lower all-cause mortality and hospitalization to a greater extent than captopril in elderly patients with chronic CHF.[24866] Shortterm hemodynamic benefits of valsartan have been previously documented in patients with NYHA Class II--IV heart failure. The Val-HeFT trial has evaluated the morbidity and mortality outcomes of valsartan in patients with chronic CHF who are already receiving standard heart failure therapy

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(including ACE inhibitors, digoxin, diuretics, beta-blockers), and has yielded complex results.[27090] Valsartan plus standard therapy has significantly reduced hospitalizations, improved combined endpoints of morbidity and mortality, and improved the clinical signs and symptoms in patients with heart failure. However, a post hoc analysis has shown that the combined therapy subgroup (receiving valsartan, an ACE inhibitor, and a beta-blocker) was associated with an increased risk of heart failure morbidity and total mortality.[27090] Based on these findings, the FDA approved valsartan for use in heart failure patients only when an ACE inhibitor is not tolerated (August, 2002). Subsequently, the VALIANT trial has demonstrated comparable efficacy of valsartan versus captopril in myocardial infarction patients with heart failure and/or left ventricular dysfunction.[27767] This is the first clinical trial to demonstrate equivalent efficacy of an angiotensin II antagonist versus an ACE inhibitor for treating patients with heart failure or left ventricular dysfunction. Interestingly, this study has also reported that the combination of valsartan with captopril increased the rate adverse events without improving survival. These findings for combination angiotensin II antagonist and ACE inhibitor therapy are in contrast to the reported benefits of the CHARM-Added trial.[27704] The CHARM-Added trial demonstrated a significant reduction in cardiovascular mortality and CHF hospitalizations by adding an A-II blocker to an ACE inhibitor in patients with heart failure and LVEF <= 40% (see Candesartan monograph).[27704] Valsartan (Diovan®) was initially FDA-approved for treatment of hypertension on December 23, 1996. Mechanism of Action: Valsartan antagonizes angiotensin II at the AT1 receptor subtype. Two angiotensin II receptors, AT1 and AT2, have been identified. While valsartan has about a 20,000-fold greater affinity for the AT1 subtype than the AT2 subtype, the AT2 subtype is not known to mediate cardiovascular homeostasis. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin system and plays an important role in the pathophysiology of hypertension and congestive heart failure. Angiotensin II is a potent vasoconstrictor; which also stimulates the synthesis and release of aldosterone. By selectively blocking the AT1 receptor in tissues such as vascular smooth muscle and the adrenal gland, valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. Thus, by blocking the effects of angiotensin II, valsartan decreases systemic vascular resistance without a marked change in heart rate. Circulating levels of both renin and angiotensin II rise 2- to 3-fold in response to blockade of AT1 receptors. Because valsartan does not inhibit ACE, it also does not inhibit the breakdown of bradykinin. Unlike losartan, valsartan has no effect on serum uric acid. Pharmacokinetics: Valsartan is administered orally. Approximately 95% of valsartan is bound to serum proteins, primarily albumin. In animal studies, valsartan did not readily penetrate the blood brain barrier. Valsartan is not a prodrug. The primary metabolite of valsartan is valeryl-4-hydroxy valsartan, which is inactive and accounts for about 9% of the dose. In vitro studies indicate CYP 2C9 is the isoenzyme responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan is not an inhibitor of CYP 450 isoenzymes at clinically relevant concentrations.[35588] Valsartan is excreted primarily in the feces, most likely via the biliary route of elimination. Only 10% of the dose is excreted unchanged in urine. The elimination half-life (half-life ) of valsartan averages 6 hours. Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure. ·Route-Specific Pharmacokinetics Oral Route Valsartan is rapidly absorbed, with peak plasma concentrations occurring 2--4 hours after oral administration. Absolute bioavailability for the original capsule formulation (now available as tablets) is roughly 25% (range, 10--35%). The bioavailability of the extemporaneous suspension is 1.6 times greater than the bioavailability of the tablet. Administration of the tablet with food decreases the AUC

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by about 40%; therapeutic effect is maintained despite the reduction in bioavailability. AUC and Cpmax of valsartan increase linearly within the dosage range of 80--320 mg; however, the antihypertensive dose-response curve is nonlinear, with proportionally small decreases in blood pressure attained with increased dosage. An oral dose of valsartan 80 mg inhibits the pressor effect of angiotensin II by about 80% at peak serum concentrations, with 30% inhibition persisting for 24 hours. Onset and peak effect of antihypertensive activity is 2 hours and 6 hours, respectively. The duration of antihypertensive activity is approximately 24 hours, allowing for once daily dosing. Maximum reduction in blood pressure is generally achieved after 4 weeks with chronic dosing. ·Special Populations Hepatic Impairment Patients with mild-moderate hepatic disease have a two-fold increase in the AUC of valsartan (see Precautions). Renal Impairment The elimination half-life of valsartan is not significantly affected by mild to moderate renal impairment. Use in adult patients with severe renal impairment (CrCl < 10 ml/min) has not been studied; valsartan should be used with caution. Use in children 6--16 years of age with a CrCl < 30 ml/min/1.73 m2 has not been studied; use is not recommended. Valsartan is not removed by hemodialysis. Pediatrics In pharmacokinetic study, the clearance of single dose valsartan is similar in adult and pediatric (1--16 years of age) subjects. Use in children 6--16 years of age with a CrCl < 30 ml/min/1.73 m2 has not been studied; use is not recommended.

References

24866. Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997;349:747-52. 27090. Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-1675. 27704. McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767-71. 27767. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-906. 35588. Exforge HCT (amlodipine, valsartan, hydrochlorothiazide) tablets package insert. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2009 Apr. [ Revised 2/14/2011 3:55:00 PM ]

Drug Information Provided by Gold Standard Inc. © 2010

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