International Approvals: Yaz, Soliris, Glucomed/Flexove

Yael Waknine

July 23, 2007

July 23, 2007 — The Dutch regulatory authorities have approved a 24-day active-hormone regimen of drospirenone/ethinyl estradiol tablets for contraceptive use and the treatment of acne in women wishing to use oral contraceptives, and the European Commission has approved eculizumab injection for the treatment of paroxysmal nocturnal hemoglobinuria. The Agençe Française de Sécurité Sanitaire des Produits de Santé and the United Kingdom's Medicines and Healthcare Products Regulatory Agency have both granted marketing approval for a glucosamine HCl product in the treatment of osteoarthritis.

Drospirenone/Ethinyl Estradiol 24-Day Regimen (
Yaz) for Contraception and Acne in the Netherlands

On July 12, Dutch regulatory authorities approved a 24-day active-hormone regimen of drospirenone/ethinyl estradiol 3-mg/24-µg tablets (Yaz, Bayer Pharma AG), allowing its use in the Netherlands for contraception and for the treatment of moderate acne in women who choose to use an oral contraceptive for birth control.

The decision marks the first approval for the product in the European Union. "The Netherlands will serve as the Reference Member State for the upcoming Mutual Recognition Procedure to gain European-wide marketing approval for the product," the company says in a news release.

In contrast with other combination contraceptives, the progestin used in the product is drospirenone, which exhibits antiandrogenic properties that make it useful for the treatment of acne. However, because 3 mg of drospirenone also has antimineralocorticoid activity similar to that of a 25-mg dose of spironolactone, the product should not be used in patients with conditions that predispose to hyperkalemia, such as renal insufficiency, hepatic dysfunction, or adrenal insufficiency.

Serum potassium levels should be checked during the first treatment cycle in women receiving long-term treatment with other medications that can cause hyperkalemia, such as angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and nonsteroidal anti-inflammatory drugs.

Oral contraceptives are generally linked to increased risks for venous and arterial thrombotic and thromboembolic events (eg, myocardial infarction, thromboembolism, and stroke), hepatic neoplasia, gallbladder disease, and hypertension. Although the risk for serious morbidity and mortality remains low in healthy women, it increases significantly in the presence of underlying conditions such as hypertension, hyperlipidemias, obesity, and diabetes.

Because cigarette smoking further increases the risk for cardiovascular events, particularly in women older than 35 years, it should be strongly discouraged.

Drospirenone/ethinyl estradiol 3-mg/24-µg tablets previously were approved for these indications and for the treatment of emotional and physical symptoms of premenstrual dysphoric disorder by the US Food and Drug Administration.

Eculizumab (
Soliris) to Treat Paroxysmal Nocturnal Hemoglobinuria in EU

On June 22, the European Commission approved eculizumab injection (Soliris, Alexion Pharmaceuticals, Inc), allowing its use in the European Union (EU) for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria to reduce hemolysis. Eculizumab also was granted orphan drug status for this indication.

"Alexion is prepared to begin reimbursement discussions with healthcare systems in major European countries immediately, and it expects to introduce [eculizumab] in one ormore major European markets by the end of 2007, with additional countries to follow in 2008," the company says in a news release.

Paroxysmal nocturnal hemoglobinuria is an acquired disorder that often strikes people in the prime of their lives, with an average age of onset in the early 30s and an estimated median survival of 10 to 15 years from the time of diagnosis. It affects an estimated 8000 to 10,000 individuals in North America and Europe and produces symptoms such as severe anemia, disabling fatigue, and recurrent pain, shortness of breath, pulmonary hypertension, intermittent hemoglobinuria, kidney disease, impaired quality of life, and thromboses. Paroxysmal nocturnal hemoglobinuria often goes unrecognized — its diagnosis may be delayed for more than 10 years.

Eculizumab represents a new class of drugs known as complement inhibitors and prevents hemolysis by selectively blocking terminal complement. Its approval was based on data from 3 multinational clinical studies: a placebo-controlled 26-week, phase 3 study (n = 87, TRIUMPH); an open-label, 52-week, phase 3 study (n = 97, SHEPHARD); and a long-term extension study (E05-001).

Results from the first study showed that eculizumab effectively reduced hemolysis in 100% of patients, as determined by decreases in the median level of the marker lactate dehydrogenase from baseline at 26 weeks (2032 – 239 U/L; P < .001).

The significant decrease in hemolysis yielded improvements in anemia, as indicated by increased hemoglobin stabilization (49% vs placebo, 0%; P < .001) and reduced need for red blood cell transfusions (0 vs placebo, 10; P < .001).

The decreases in lactate dehydrogenase were observed within 1 week of treatment initiation; at 3 weeks, patients reported less fatigue and improved quality of life. Results of the open-label study and its long-term extension showed that patients sustained a reduction in hemolysis for up to 54 months with continued therapy.

The most commonly reported adverse events associated with eculizumab therapy vs placebo included headache (44% vs 27%), nasopharyngitis (23% vs 18%), back pain (19% vs 9%), nausea (16% vs 11%), fatigue (12% vs 2%), and cough (12% vs 9%).

The recommended regimen for eculizumab consists of 600 mg given every 7 days for the first 4 weeks, 900 mg for the fifth dose 7 days later, and then 900 mg every 14 days thereafter. Eculizumab should be administered by intravenous infusion for a 35-minute period via gravity feed, a syringe-type pump, or an infusion pump. Admixed solutions are stable for 24 hours at 2°C to 8°C (36°F – 46°F) and at room temperature.

Because eculizumab has been linked to an increased risk for meningococcal infection, patients must be vaccinated at least 2 weeks before treatment initiation and then revaccinated according to current medical guidelines for vaccine use. Patients should be monitored for early signs of meningococcal infections; potential symptoms should be evaluated immediately and treated with antibiotics if necessary. In clinical trials, 2 of 196 vaccinated patients treated with eculizumab developed serious meningococcal infection.

If adverse reactions occur, the infusion may be slowed or stopped as necessary. If slowed, total infusion time should not exceed 2 hours. Patients should be monitored for signs and symptoms of infusion reactions for at least 1 hour following its administration. The company notes that treatment with eculizumab should not alter anticoagulant management because the effect of its withdrawal has not been established.

Eculizumab injection previously was approved by the US Food and Drug Administration on March 16, 2006.

Fluvoxamine Product (Glucomed) for Osteoarthritis in France and the UK

On June 4 and 18, the French regulatory authority Agence Française de Sécurité Sanitaire des Produits de Santé and the United Kingdom's (UK) Medicines and Healthcare Products Regulatory Agency, respectively, granted marketing authorization (MA) for a fluvoxamine HCl product (Glucomed tablets [also marketed as Flexove in France], Navamedic ASA) for the symptomatic relief of mild to moderate osteoarthritis.

Glucomed is the only glucosamine product to date to receive an MA in the UK and France, the company said in a news release. The formulation contains 625 mg of glucosamine (750 mg of glucosamine HCl) that is derived from chitin in shrimp shells

Although the product was originally approved by Sweden's Medicinal Products Agency in August 2005 and extended to 19 European Union countries in January 2006 via the mutual recognition procedure, MAs were initially refused in 5 countries (including the France and the UK) because of outstanding issues mainly related to efficacy documentation for glucosamine.

The glucosamine product previously was granted MAs in Spain, Germany, Sweden, Denmark, Iceland, Norway, Poland, Portugal, Austria, Slovakia, Czech Republic, and the Netherlands. It has not been approved by the US Food and Drug Administration.


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