International Approvals: Diovan, Paromomycin Injection, Virulizin

Yael Waknine

June 20, 2005

June 20, 2005 — The European Commission has approved valsartan for the treatment of symptomatic heart failure when an angiotensin-converting enzyme inhibitor cannot be used or as add-on therapy to angiotensin-converting enzyme inhibitors when beta-blockers cannot be used; orphan drug paromomycin injection for the treatment of visceral leishmaniasis; and orphan drug Virulizin for the treatment of pancreatic cancer.

Valsartan (Diovan) to Reduce Heart Failure Mortality in the European Union

On June 13, the European Commission (EC) approved a new indication for valsartan (Diovan tablets, made by Novartis Pharmaceutical Corp.), allowing its use in 14 member states of the European Union (EU) for the treatment of symptomatic heart failure when an angiotensin-converting enzyme (ACE) inhibitor cannot be used or as add-on therapy to ACE inhibitors when beta-blockers cannot be used.

The approval was based on the results of the international placebo-controlled Valsartan Heart Failure Trial (Val-HeFT) in 5,010 patients with heart failure, showing that valsartan decreased combined morbidity and mortality by 13.2%,and the rate of hospital admissions by 27.5% when added to standard therapy that included ACE inhibitors, beta-blockers, diuretics, or digitalis.

Valsartan add-on therapy also decreased combined morbidity and mortality by 44% and decreased mortality by 33% in patients whose therapy did not include ACE inhibitors.

Patients receiving valsartan demonstrated improvements in signs and symptoms of heart failure, ejection fraction, and New York Heart Association class; and prognostic factors for poor outcomes such as brain natriuretic peptide, aldosterone, and norepinephrine were positively affected.

Substudy results showed that atrial fibrillation was linked to a worsened prognosis in patients with heart failure and that valsartan add-on therapy decreased the incidence of atrial fibrillation by nearly 35% in patients receiving standard treatment (93% ACE inhibitors; 35% beta-blockers).

Valsartan was previously approved by the EC for the firstline treatment of hypertension and to reduce the risk of mortality in survivors of myocardial infarctions. It is approved by the U.S. Food and Drug Administration for use alone or in combination with other agents for the treatment of hypertension and for heart failure in patients who are intolerant of ACE inhibitors.

Low-Cost Orphan Drug (Paromomycin Injection) for Black Fever in the European Union

On March 4, the European Commission approved orphan drug status for an injectable formulation of paromomycin (made by the nonprofit Institute for OneWorld Health) in the treatment of visceral leishmaniasis (VL, also known as kala-azar or black fever).

The approval was based on the results of a phase 3 randomized trial comparing the safety and efficacy of paromomycin intramuscular injection (15 mg/kg/day for 21 days) and amphotericin B intravenous infusion (1 mg/kg every other day for 30 days) in 667 adults and children (aged 5 to 55 years) with confirmed VL.

Preliminary results showed that paromomycin achieved cure rates comparable to that of amphotericin B at one and six months posttreatment in the study population (99.0% and 94.6% vs 98.8% and 98.8%) and in the subset of children aged 5 to 15 years (99.5% and 96.6% vs 100% and 98.6%).

Primary adverse events associated with paromomycin therapy included injection site pain (55%; children, 54.7%) and fever/chills/rigor (61%; children, 60.0%). There were no incidences of nephrotoxicity; reversible ototoxicity occurred in three adult patients (0.6%) and was not associated with clinical hearing loss at any time.

When not considering injection site reactions, paromomycin was associated with a significantly decreased rate of adverse events (9% vs 66%; children, 6.9% vs 64.3%) comparedwith amphotericin B therapy.

According to a company news release, the low cost ($10 vs $200 for amphotericin B) and favorable safety profile of paromomycin injection will enhance its use in poor countries where VL is most rampant, such as India, Bangladesh, Nepal, Sudan, and Brazil.

Paromomycin is a broad-spectrum aminoglycoside antibiotic with antiparasitic activity that was developed in the 1950s by Parke-Davis as an oral therapy (Humatin) for the treatment of intestinal parasites.

Injectable paromomycin was granted orphan drug status for this indication by the U.S. Food and Drug Administration on March 29, 2005. The company will be filing for approval of the drug this year in countries where the need is greatest, such as India.

Orphan Drug Virulizin for Pancreatic Cancer in European Union

On June 7, the European Commission approved orphan drug status for an immunotherapeutic drug (Virulizin, made by Lorus Therapeutics, Inc.) in the treatment of pancreatic cancer.

The approval was based on the results of clinical studies showing that the product has the potential to provide significant benefit in patients with the disease.

According to a company news release, the agent is designed to stimulate the immune system through the activation of macrophages and the infiltration of natural killer cells into tumors.

Phase 3 clinical trials of Virulizin are currently underway in North America, South America, and Europe; results are expected toward the end of the year.

Virulizin was granted approval for rolling submission of a new drug application by the U.S. Food and Drug Administration (FDA) on June 13, 2005. The FDA previously granted fasttrack and orphan drug status for the product in May 2002 and February 2001, respectively.

Reviewed by Gary D. Vogin, MD

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