sanofi-aventis and Bristol-Myers Squibb Company (BMS) announced that the US Food and Drug Administration (FDA) has approved the supplemental new drug application (sNDA) for the hypertension drug Avalide.

The FDA approved the antihypertensive agent for initial use in patients with hypertension who are likely to need multiple drugs to achieve their blood pressure goals.

The approval is based on data from two clinical trials involving more than 1,200 patients with moderate or severe high blood pressure.

In the first double-blind, active-controlled, seven-week trial, patients with severe hypertension (mean baseline 172/113 mm Hg SBP/DBP) were randomly treated with either Avalide 150/12.5 mg or irbesartan 150 mg monotherapy. After one week, all doses were doubled. At five weeks, Avalide (irbesartan-hydrochlorothiazide) 300/25 mg demonstrated mean blood pressure reductions of 30.8/24.0 mm Hg versus 21.1/19.3 mm Hg (SBP/DBP) for irbesartan 300 mg alone.

In the second double-blind, active-controlled, 12-week trial, patients with moderate hypertension (mean baseline 162/98 mm Hg SBP/DBP) were randomly treated with Avalide 150/12.5 mg, irbesartan 150 mg monotherapy, or hydrochlorothiazide 12.5 mg monotherapy. After two weeks, all doses were doubled. The primary endpoint was mean change in SBP from baseline to Week 8. At eight weeks, Avalide 300/25 mg demonstrated mean blood pressure reductions of 27.1/14.6 mm Hg (SBP/DBP), which was significantly greater than irbesartan 300 mg or hydrochlorothiazide 25 mg alone, 22.1/11.6 mm Hg and 15.7/7.3 mm Hg, respectively.

In the severe hypertension study, the incidences of pre-specified adverse events on Avalide vs. irbesartan were: syncope (0 per cent vs. 0 per cent), hypotension (0.6 per cent vs. 0 per cent), dizziness (3.6 per cent vs. 4.0 per cent), headache (4.3 per cent vs. 6.6 per cent), hyperkalemia (0.2 per cent vs. 0 per cent), and hypokalemia (0.6 per cent vs. 0.4 per cent). In the moderate hypertension study, the incidences of pre-specified adverse events on Avalide vs. irbesartan or hydrochlorothiazide monotherapy were: hypotension (0.9 per cent vs. 0 per cent and 0 per cent), dizziness (3.0 per cent vs. 3.8 per cent and 1.0 per cent), headache (5.5 per cent vs. 3.8 per cent and 4.8 per cent), hyperkalemia (1.2 per cent vs. 0 per cent and 1.0 per cent), and hypokalemia (0.9 per cent vs. 0 per cent and 0 per cent).

"Guidelines support initial combination therapy for severe hypertension based on the need to lower BP within weeks rather than months," said Dr. Joel Neutel, Professor of Medicine, University of California in Irvine.

"Now with Avapro (irbesartan) and Avalide physicians have more therapeutic options to treat mild, moderate and severe hypertension," added Dr. Neutel.

Avapro is indicated for the treatment of hypertension and also helps to slow the progression of nephropathy in type 2 diabetic hypertensive patients. Avalide may be used in appropriate patients whose blood pressure is not adequately controlled on monotherapy and now can be used as initial therapy in appropriate patients who are likely to need multiple drugs to achieve their blood pressure goals.

"JNC 7 guidelines recommend that physicians consider starting with combination therapy for most patients with stage 2 hypertension," said Dr. Michael Weber, Professor of Medicine, SUNY Downstate College of Medicine. "In addition, the approval of Avalide (irbesartan-hydrochlorothiazide) as a first-line therapy in patients likely to need multiple drugs to achieve their blood pressure goals provides physicians with an FDA-approved therapeutic option in one tablet."

In the United States, Avapro is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

Avapro is also indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (>300 mg/day) in patients with type 2 diabetes and hypertension. In this population, Avapro reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation).

Avalide is a fixed-dose combination of the angiotensin II receptor blocker (ARB) Avapro and a diuretic (hydrochlorothiazide). It is indicated for the treatment of hypertension. Avalide may be used in patients whose blood pressure is not adequately controlled on monotherapy.

When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetes. Because of the hydrochlorothiazide component, Avalide is contraindicated in patients with anuria or hypersensitivity to sulfonamide-derived drugs

In patients with volume or sodium depletion (eg, patients vigorously treated with diuretics or on dialysis), such depletion should be corrected prior to administration of Avapro (irbesartan) or Avalide (irbesartan-hydrochlorothiazide), or a lower initial dose of Avapro (75 mg) should be used, to avoid possible symptomatic hypotension

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history

Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus
Thiazides should be used with caution in patients with severe renal disease and in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma, informed the company in a recent press release

In placebo-controlled hypertension studies, there were no significant differences in adverse events (AEs) between Avapro and placebo. Adverse events that occurred in at least 1 per cent of patients treated with Avapro and at a higher incidence vs placebo included diarrhoea (3 per cent vs 2 per cent), dyspepsia/heartburn (2 per cent vs 1 per cent) and fatigue (4 per cent vs 3 per cent)

Additionally, in a study of hypertensive type 2 diabetic patients with renal disease (proteinuria greater than or equal to 900 mg/day), the reported AEs for Avapro were similar to those seen in hypertension studies, with the exception of an increased incidence of orthostatic symptoms; Avapro compared to placebo (both groups received adjunctive antihypertensives): dizziness (10.2 per cent vs 6.0 per cent), orthostatic dizziness (5.4 per cent vs 2.7 per cent) and orthostatic hypotension (5.4 per cent vs 3.2 per cent), respectively.

In placebo-controlled hypertension studies, the most common adverse experiences reported with Avalide that occurred in greater than or equal to 1 per cent of patients and at a higher incidence vs placebo included fatigue (7 per cent vs 3 per cent), musculoskeletal pain (7 per cent vs 5 per cent), dizziness (8 per cent vs 4 per cent), and nausea/vomiting (3 per cent vs 0 per cent). Additionally, in studies of moderate and severe hypertensives where Avalide was used as initial therapy, the types and incidences of adverse events reported for Avalide were similar to monotherapy