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Amgen's Neulastsa approved for neutropenia after chemotherapy
In late January, the Food & Drug Administration approved Neulasta (pegfilgrastim, Amgen), a long-acting form of Neupogen (filgrastim, Amgen), for decreasing the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive chemotherapy.
As its name suggests, pegfilgrastim is essentially filgrastim, or recombinant human granulocyte-colony stimulating factor (G-CSF), with a large polyethylene glycol (PEG) molecule covalently bound to it. Since the PEG tail is too large to fit through kidney pores, said Frankie Ann Holmes, M.D., associate director of breast cancer research at US Oncology in Houston, "the only way for this molecule to be cleared is by going to the site where it is most needed," the white blood cell.
As a self-regulating drug, whose blood concentrations fall as the neutrophil count rebounds, pegfilgrastim needs to be administered only once in each chemotherapy cycle. Filgrastim must be administered daily for up to 14 days, until absolute neutrophil count (ANC) reaches 10,000/mm3.
In double-blind clinical trials, pegfilgrastim was compared with filgrastim in patients with breast cancer, lung cancer, and lymphoma. Duration of severe neutropenia was shown to be equal, within a few hours, for both treatment groups. In studies in which Holmes was involved, patients in both groups required an average of 11 days of injections (filgrastim or placebo), with daily blood counts, until target ANC was achieved. While for patients on filgrastim, the counts rose and fell following each injection, ANC in pegfilgrastim-treated patients rose smoothly and "just coasted right in" without overshooting, she reported. In fact, the incidence of neutropenic infections was 50% lower in the pegfilgrastim arm, at 9% as compared with 18% in the filgrastim group.
Pegfilgrastim's once-per-cycle dosing offers several advantages, including "fewer office visits, less time missed from work and family, and fewer reminders of the disease," said George Jaresko, Pharm.D., assistant professor, department of pharmacy, University of Southern California in Los Angeles.
About half of the patients taking filgrastim inject themselves, said Jaresko, an infectious disease pharmacist who has served as a consultant to Amgen on filgrastim; the rest of the patients have someone else administer the drug or go to a physician's office or an infusion center. Holmes noted that going to a clinic might be the only option for patients insured by Medicare, which covers only injectable drugs administered by healthcare professionals. Patients may miss doses when clinics are closed, Jaresko said, putting them "at increased risk for unnecessary neutropenia" and, hence, for potentially life-threatening infections, which can lead to hospitalizations and disrupt chemotherapy regimens.
Unlike filgrastim, for which dosing is based on patient weight, pegfilgrastim was shown to be effective in a fixed dosage and will be supplied in prefilled syringes for subcutaneous injection. This minimizes the risk of medication error, Holmes said.
About half of patients on chemotherapy are at risk for infections due to neutropenia, Jaresko said, but, historically, less than 10% of them have received prophylaxis. Often, he said, physicians wait until neutropenic infections develop to give filgrastim. Pegfilgrastim's convenience may increase preventive therapy.
It is still too early to relegate filgrastim to the back shelves. Filgrastim remains the only G-CSF product approved for inpatients with acute myeloid leukemia (AML) undergoing induction or consolidation therapy, bone marrow transplant (BMT) patients, patients undergoing peripheral blood progenitor cell (PBPC) collection and therapy, and patients with severe chronic neutropenia.
And because pegfilgrastim's fixed-dose formulation makes it inappropriate for patients weighing less than 45 kg, filgrastim is the only product available to treat pediatric chemotherapy-induced neutropenia. Amgen has made postmarketing commitments to the FDA to study pegfilgrastim in children and develop a pediatric dosing form, said Ken Keller, senior director of marketing at Amgen. There are also plans to look at AML, PBPC mobilization, and BMT patients in the future.
In clinical trials, bone pain was the most common side effect attributed to the drug in both filgrastim and pegfilgrastim groups. Pegfilgrastim labeling carries warnings about splenic rupture, adult respiratory distress syndrome, allergic reactions, and sickle cell crises, all of which have been reported following filgrastim administration but none of which has been observed in patients treated with pegfilgrastim.
Pegfilgrastim should be refrigerated, with syringes kept in the carton until time of use. The drug may be kept at room temperature for 48 hours but should be protected from light. Pegfilgrastim will be available April 1.
Tzipora Lieder. New G-CSF product treats neutropenia following chemo.