International Approvals: Exelon, Aclasta, Celsentri

Yael Waknine

October 15, 2007

October 15, 2007 — The European Commission (EC) has approved a rivastigmine transdermal system for the treatment of mild to moderate Alzheimer's disease; zoledronic acid 5-mg injection for the once-yearly treatment of postmenopausal osteoporosis; and maraviroc 150- and 300-mg tablets for combination antiretroviral treatment of treatment-experienced adults infected with chemokine receptor 5–tropic HIV-1.

Rivastigmine ( Exelon) Patch for Alzheimer's Disease in EU

On September 24, the European Commission (EC) approved a new indication for rivastigmine transdermal system (Exelon Patch, Novartis Pharmaceuticals Corp), allowing its use for the treatment of mild to moderate Alzheimer's disease (AD). Rivastigmine patches are available in 2 sizes: 5 cm2 (4.6-mg/24-hour dosage) and 10 cm2 (9.5-mg/24-hour dose).

"The patch has been shown to increase compliance, reduce side effects, and allow medication to be delivered through the skin into the bloodstream smoothly and continuously over 24 hours, helping to achieve optimal dosing. All these benefits offer the potential for improved outcomes in patients," says James Shannon, MD, Global Head of Development at Novartis Pharma AG in a company news release.

Approval of the new drug delivery system was based on data from the 24-week international Investigation of transDermal Exelon in ALzheimer's disease (IDEAL) clinical study (N = 1195), which showed that use of the rivastigmine 9.5-mg/day once-daily patch and twice-daily oral administration of a 6-mg capsule both yielded similarly significant mean improvements vs placebo in cognitive function, as evaluated using the AD Assessment Scale–Cognition (ADAS-cog; 1.8 and 1.9, respectively; P < .05 vs placebo).

Patients in the active treatment groups also had equal improvements in overall functioning vs placebo, as demonstrated via the AD Cooperative Study–Clinician's Global Impression of Change scale (ADCS-CGIC, 0.2 units; P < .05 vs placebo).

Although its efficacy was similar to that of the highest doses of rivastigmine capsules, the 9.5-mg/24-hour rivastigmine patch yielded significantly reduced rates of nausea (7% vs 23%) and vomiting (6% vs 17%).

As with Parkinson's disease, treatment for AD should be initiated with a 4.6-mg/day patch applied once daily to the back, chest, or upper arm once every 24 hours. Uptitration to the 9.5-mg/day dosage may be considered after 4 weeks of treatment and good tolerability. To minimize the risk for skin irritation, application sites should be rotated; the same site should not be used within 14 days.

Rivastigmine patches previously were approved by the EC for the symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson's disease. Both indications are also approved by the US Food and Drug Administration.

Zoledronic Acid 5-mg Injection ( Aclasta) for Once-Yearly Treatment of Postmenopausal Osteoporosis in EU

On October 11, the European Commission approved a new indication for zoledronic acid 5-mg injection (Aclasta, Novartis Pharmaceuticals Corp), allowing its use for the once-yearly treatment of postmenopausal osteoporosis. The decision applies to all 27 member states of the European Union (EU), Norway, and Iceland.

In contrast with oral bisphosphonate therapies that must be taken daily, weekly, or monthly, the product is administered as a once-yearly 15-minute intravenous infusion. "The convenience of a once-yearly dose should improve compliance and bone protection among patients while reducing fracture-related hospitalization and healthcare costs," the company notes in a news release.

The approval was based on data from the double-blind, placebo-controlled, randomized, 3-year PivotalFracture Trial (N = 7736; mean age, 73 years), showing that once-yearly treatment with zoledronic acid decreased the risk for morphometric vertebral fractures by 70% (P < .0001) and the risk for hip fractures by 41% (P = .0032).

The study data also showed that the reduction in spine fracture risk was sustained during the 3-year period and that bone mineral density increased significantly, by 6.7% and 6% in the spine and hip, respectively.

Treatment with zoledronic acid was generally well tolerated. The most commonly reported adverse events were postdose symptoms such as fever and muscle pain, which generally resolved within 3 days and could be reduced by paracetamol (acetaminophen) or ibuprofen taken shortly after the infusion.

Although zoledronic acid was linked to an increased incidence of serious atrial fibrillation relative to placebo (1.3% vs 0.6%), the company noted that the finding has not been observed in other clinical studies or in the postmarketing experience of the more than 1.5 million patients receiving the product for oncology indications. No spontaneous cases of osteonecrosis of the jaw were observed in the study.

The osteoporosis indication for zoledronic acid 5-mg infusion (marketed as Reclast) previously was approved by the US Food and Drug Administration in August 2007; in the United States and EU, it also is indicated for the treatment of Paget's bone disease.

Maraviroc Tablets ( Celsentri) for Treatment-Resistant CCR5-Tropic HIV-1 in EU

On September 24, the European Commission approved maraviroc 150- and 300-mg tablets (Celsentri, Pfizer, Inc) for combination antiretroviral treatment of treatment-experienced adults infected with chemokine (C-C motif) receptor 5 (CCR5)-tropic HIV-1 (also known as R5 virus).

Maraviroc is the first in a class of drugs called CCR5 coreceptor antagonists that are designed to interfere with its interaction with HIV, which uses CCR5 or another protein (CXCR4) to enter white blood cells. Although several chemokine receptors can function as viral coreceptors, CCR5 is likely the most physiologically important coreceptor during natural infection, and at least 50% to 60% of treatment-experienced infected patients harbor CCR5-using viruses.

The approval was based on 48-week data from 2 ongoing studies (Maraviroc Plus Optimized Therapy In Viremic Antiretroviral Treatment-Experienced Patients; MOTIVATE-1 and -2) showing that the addition of maraviroc to optimized background therapy yielded significantly greater viral load reductions vs optimized background therapy alone, with more than twice as many patients achieving undetectable levels. Patients receiving maraviroc also achieved significantly greater increases in CD4+ cell counts.

The most frequently reported adverse events occurred with similar frequency in both groups and included diarrhea, nausea, and headache.

Maraviroc (marketed as Selzentry) previously was granted accelerated approval based on 24-week data by the US Food and Drug Administration in August 2007.


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