International Approvals: Remicade, Fodosine, Sprycel

Yael Waknine

April 13, 2007

April 13, 2007 — The European Commission has approved a label extension for infliximab injection to allow higher or more frequent dosing in rheumatoid arthritis patients who have an incomplete response to initial therapy; the Committee for Orphan Medicinal Products of the European Medicines Evaluation Agency has granted orphan drug status for fodosine in the treatment of cutaneous T-cell lymphoma; and Health Canada has granted conditional approval for dasatinib tablets in the treatment of adult patients with chronic myeloid leukemia who are resistant or intolerant to prior therapy.


Stepwise Uptitration of Infliximab (Remicade) for Rheumatoid Arthritis in EU

On March 30, the European Commission (EC) approved a label extension for infliximab injection (Remicade; Centocor, Inc [marketed by Schering-Plough Corp]) that allows greater dosing flexibility in the treatment of rheumatoid arthritis (RA).

The extension allows stepwise dose uptitration to 7.5 mg/kg in 1.5 mg/kg increments every 8 weeks, or use of the 3-mg/kg dose every 4 weeks in patients who have had an incomplete response to initial treatment with 3 mg/kg of infliximab and methotrexate (MTX).

Approval of the dose titration strategy was based on data from the randomized, multicenter, double-blind, 3-arm, parallel-group study known as the S afety T rial for Rheumatoid A rthritis with R emicade T herapy (START; n = 1082). In one study group, patients who met predefined criteria for lack or loss of therapeutic response to 3 mg/kg of infliximab at week 22 were allowed to dose titrate in 1.5 mg/kg increments every 8 weeks from 3 mg/kg to 9 mg/kg.

Results among patients requiring dose titration (33%) showed that 80% achieved clinical response with the strategy, and the majority (64%) required only 1 adjustment of 1.5 mg/kg.

Compared with patients who continued to receive 3 mg/kg of infliximab, those receiving uptitrated doses experienced an increased rate of serious adverse events (4% vs 6%) and serious infections (0% vs 0.5%) during weeks 22 through 54.

The infliximab dosing regimen for RA previously approved by the EC and the US Food and Drug Administration consists of an initial 3-mg/kg dose followed by additional similar doses at weeks 2 and 6, and then repeated every 8 weeks thereafter (all given with MTX). The US label advises that adjusting the dose up to 10 mg/kg or treating as often as every 4 weeks may be considered in patients who demonstrate an incomplete response, while bearing in mind the dose-related increased risk for infection.


Orphan Drug Status for Fodosine in Cutaneous T-Cell Lymphoma in EU

On February 6, the Committee for Orphan Medicinal Products of the European Medicines Evaluation Agency (EMEA) granted orphan drug status for Fodosine (BioCryst Pharmaceuticals, Inc) in the treatment of cutaneous T-cell lymphoma (CTCL).

T-cell lymphoma results when a T lymphocyte undergoes a malignant change and begins to multiply, crowding out healthy cells and creating tumors that enlarge lymph nodes and invade other sites in the body. CTCL is a primary skin neoplasm and accounts for nearly 50% of all T-cell malignancies.

According to company information, the product is a transition-state analog inhibitor of the target enzyme purine nucleoside phosphorylase (PNP). Inhibiting PNP appears to produce selective suppression of T lymphocytes without significantly impairing the function of other cells.

Fodosine was previously granted orphan drug status by the EMEA in the treatment of T-cell acute lymphoblastic leukemia. Orphan drug indications approved by the US Food and Drug Administration (FDA) include T-cell non-Hodgkin's lymphoma (including CTCL); chronic lymphocytic leukemia and related leukemias including prolymphocytic leukemia, adult leukemia, and hairy cell leukemia; and the treatment of B-cell acute lymphoblastic leukemia. The FDA has also granted fast-track status for the drug in the treatment of relapsed or refractory T-cell leukemia.


Dasatinib Tablets (Sprycel) for the Treatment of Resistant CML in Canada


On March 26, Health Canada granted a notice of compliance with conditions for dasatinib tablets ( Sprycel, Bristol-Myers Squibb Canada) in the treatment of adults with chronic, accelerated, or blast-phase chronic myeloid leukemia (CML) who have failed or are intolerant to prior therapy, including imatinib ( Gleevec, Novartis Pharmaceuticals Corp).

According to a company news release, the approval reflects the promising nature of the drug's clinical safety and efficacy in CML patients and the need for further follow-up to verify clinical benefit. The approval was based on rates of hematologic and cytogenetic response in 1 dose escalation study and 5 phase 2 multicenter trials.

"Early clinical data show that patients achieved hematologic and cytogenetic responses across all phases of CML," notes Jeff Lipton, MD, an oncologist and associate professor of medicine at the University of Toronto in Ontario, in a news release. "Through its unique mode of action, [dasatinib] shuts down the cancer cell and ultimately the CML. Since cytogenetic response is associated with a survival benefit, it is reasonable to expect that this treatment will allow patients to keep their condition under control for a very long period of time."

The tablets are available in 20-, 50-, and 70-mg strengths. The recommended dose is 70 mg given twice daily (morning and evening), with adjustments to be made in 20-mg increments per dose based on individual safety and tolerability.

The most commonly reported adverse events in clinical studies included fluid retention events, such as pleural effusion; gastrointestinal events, such as diarrhea, nausea, abdominal pain, and vomiting; and bleeding events. The most frequently reported serious adverse events (incidence ≥ 2%) included pyrexia, pleural effusion, febrile neutropenia, gastrointestinal bleeding, pneumonia, thrombocytopenia, dyspnea, anemia, cardiac failure, and diarrhea.

Dasatinib was previously approved by the US Food and Drug Administration on June 28, 2006, for the CML indication, and for the treatment of adults with Philadelphia chromosome–positive acute lymphoblastic leukemia who are resistant to or intolerant of prior therapy.

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