International Approvals: Alvesco, Plavix, Paromomycin Injection

Yael Waknine

September 18, 2006

September 18, 2006 — Health Canada has approved inhaled ciclesonide for the prophylaxis of steroid-responsive bronchial asthma in patients aged 18 years or older; the European Commission has approved a new indication for clopidogrel bisulfate tablets, allowing their use to reduce the risk for reinfarction, stroke, or death in patients with acute ST-segment elevation myocardial infarction; and India has approved paromomycin intramuscular injection for the treatment of visceral leishmaniasis.

Inhaled Ciclesonide (Alvesco) for the Management of Bronchial Asthma in Canada

On September 12, Health Canada approved the inhaled corticosteroid ciclesonide ( Alvesco, made by Altana AG) for the prophylactic management of steroid-responsive bronchial asthma in patients aged 18 years or older at doses ranging from 100 to 800 µg/day.

According to a company news release, market introduction of the product is being planned for the fourth quarter of 2006. Ciclesonide is currently approved for use in 39 countries worldwide and is under review by the US Food and Drug Administration (FDA). Applications have also been submitted to Health Canada and the FDA for a nasal spray formulation of the drug ( Omnair) in the treatment of allergic rhinitis.

Clopidogrel (Plavix) for Mortality Risk Reduction in STEMI Patients in EU

On September 7, the European Commission approved a new indication for clopidogrel bisulfate ( Plavix 75-mg tablets, made by Sanofi-Aventis, Inc, and comarketed by Bristol-Myers Squibb Company), allowing its use to reduce the rate of death from any cause and the rate of a combined end point of reinfarction, stroke, or death in patients with acute ST-segment elevation myocardial infarction (STEMI).

The recommended regimen of clopidogrel for this indication consists of an optional 300-mg loading dose, followed by a daily dose of 75 mg administered in combination with aspirin and with or without thrombolytics.

Approval of the indication was based on data from 2 clinical trials of more than 48,000 STEMI patients who were randomized to receive either clopidogrel or placebo in addition to aspirin and standard therapy.

Results of the 28-day Chinese ClOpidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT/CCS-2; N = 46,000) showed that use of clopidogrel vs placebo decreased the relative risk for death by 7% (event rate, 7.5% vs 8.1%; P = .03) and the relative risk for myocardial infarction, stroke, or death by 9% (event rate, 9.2% vs 10.1%; P = .002).

Findings from the multinational 30-day Clopidogrel as Adjunctive ReperfusIon TherapY - Thrombolysis In Myocardial Infarction Study (CLARITY-TIMI 28; N = 3500) also showed that the addition of clopidogrel to aspirin and other standard therapy (including thrombolytics) significantly reduced the risk for having another occluded artery, a second myocardial infarction, or death by 36% at day 8 of hospitalization or discharge compared with aspirin and standard therapy alone (event rate, 15.0% vs placebo, 21.7%; 95% confidence interval, 0.53 - 0.76).

In both trials, the rates of major bleeding and intracranial hemorrhage were similar between treatment and placebo groups. The most commonly reported clopidogrel-related adverse events in all clinical trials included pruritus, purpura, diarrhea, and rash; infrequent events were intracranial hemorrhage (0.4%) and severe neutropenia (0.05%).

Clopidogrel was previously approved by the US Food and Drug Administration for this indication on August 17, 2006.

Low-Cost Antibiotic (Paromomycin Injection) for Black Fever in India

On September 11, the Drug-Controller General of India approved paromomycin intramuscular injection (made by the nonprofit Institute for OneWorld Health) for the treatment of visceral leishmaniasis (VL, also known as kala-azar or black fever).

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.

Approval for the injectable formulation was based on data from a phase 3 randomized trial conducted in India to compare the safety and efficacy of paromomycin intramuscular injection (15 mg/kg/day for 21 days) with that of amphotericin B intravenous infusion (1 mg/kg every other day for 30 days) in 667 adults and children aged 5 to 55 years.

Preliminary results showed that paromomycin achieved cure rates comparable to those of amphotericin B at 1 and 6 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 3 adult patients (0.6%) and was not associated with clinical hearing loss at any time.

Injection-site reactions aside, paromomycin therapy was associated with a significantly decreased rate of adverse events (9% vs 66%; children, 6.9% vs 64.3%) compared with amphotericin B.

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 injection was granted orphan drug status for this indication by the European Commission and the US Food and Drug Administration in March 2005.


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