Managed Care - January 2009 - (Page Cover2b)

References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen. Drug Interaction No formal drug interaction studies between Neulasta® and other drugs have been performed. Drugs such as lithium may potentiate the release of neutrophils; patients receiving lithium and Neulasta® should have more frequent monitoring of neutrophil counts. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. Carcinogenesis, Mutagenesis, and Impairment of Fertility No mutagenesis studies were conducted with pegfilgrastim. The carcinogenic potential of pegfilgrastim has not been evaluated in long-term animal studies. In a toxicity study of 6 months duration in rats given once weekly subcutaneous injections of up to 1000 mcg/kg of pegfilgrastim (approximately 23-fold higher than the recommended human dose), no precancerous or cancerous lesions were noted. When administered once weekly via subcutaneous injections to male and female rats at doses up to 1000 mcg/kg prior to, and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected. Pregnancy Category C Pegfilgrastim has been shown to have adverse effects in pregnant rabbits when administered subcutaneously every other day during gestation at doses as low as 50 mcg/kg/dose (approximately 4-fold higher than the recommended human dose). Decreased maternal food consumption, accompanied by a decreased maternal body weight gain and decreased fetal body weights were observed at 50 to 1000 mcg/kg/dose. Pegfilgrastim doses of 200 and 250 mcg/kg/dose resulted in an increased incidence of abortions. Increased post-implantation loss due to early resorptions was observed at doses of 200 to 1000 mcg/kg/dose, and decreased numbers of live rabbit fetuses were observed at pegfilgrastim doses of 200 to 1000 mcg/kg/dose, given every other day. Subcutaneous injections of pegfilgrastim of up to 1000 mcg/kg/dose every other day during the period of organogenesis in rats were not associated with an embryotoxic or fetotoxic outcome. However, an increased incidence (compared to historical controls) of wavy ribs was observed in rat fetuses at 1000 mcg/kg/dose every other day. Very low levels ( 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta®. Leukocytosis was not associated with any adverse effects. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Neulasta® with the incidence of antibodies to other products may be misleading. Cytopenias resulting from a neutralizing antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors. There is a theoretical possibility that an antibody directed against pegfilgrastim may cross-react with endogenous G-CSF, resulting in immune-mediated neutropenia. This has not been observed in clinical studies of Neulasta®. Postmarketing Experience The following adverse reactions have been identified during postapproval of Neulasta®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • splenic rupture (see WARNINGS: Splenic Rupture) • acute respiratory distress syndrome (ARDS) (see WARNINGS: Acute Respiratory Distress Syndrome) • allergic reactions (including anaphylaxis, skin rash, urticaria, erythema/flushing) (see WARNINGS: Allergic Reactions) • sickle cell crisis (see WARNINGS: Sickle Cell Disorders) • injection site pain • Sweet’s syndrome (acute febrile dermatosis) OVERDOSAGE The maximum amount of Neulasta® that can be safely administered in single or multiple doses has not been determined. Single subcutaneous doses of 300 mcg/kg have been administered to 8 healthy volunteers and 3 patients with non-small cell lung cancer without serious adverse effects. These patients experienced a mean maximum ANC of 55 x 109/L, with a corresponding mean maximum WBC of 67 x 109/L. The absolute maximum ANC observed was 96 x 109/L with a corresponding absolute maximum WBC observed of 120 x 109/L. The duration of leukocytosis ranged from 6 to 13 days. Leukapheresis should be considered in the management of symptomatic individuals. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta® is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle. Neulasta® should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy (see PRECAUTIONS). The 6 mg fixed-dose formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg. No dosing adjustment is necessary for renal dysfunction. Neulasta® should be visually inspected for discoloration and particulate matter before administration. Neulasta® should not be administered if discoloration or particulates are observed. Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 4,810,643; 4,999,291; 5,582,823; 5,580,755, as well as other patents or patents pending. REFERENCE *Heil G, Hoelzer D, Sanz MA, et al. A randomized, double-blind, placebocontrolled, phase III study of Filgrastim in remission induction and consolidation therapy for adults with de novo Acute Myeloid Leukemia. Blood. 1997;90:4710-4718. v.8 Issue Date: 10/2007 as compared to placebo-treated patients Bone pain is limited to the specified adverse event term “bone pain” Manufactured by: Amgen Manufacturing, Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 © 2002–2007 Amgen Inc. All rights reserved. MC40421

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Managed Care - January 2009 Editor's Memo Contents Legislation & Regulation News and Commentary Medication Management Compensation Monitor Health Care's Disruptive Innovations Q&A With Clayton Christensen 'Disruption' May Be Plans' Best Bet Avoid the PBM Rebate Trap HealthPartners Puts Diabetes on Notice Formulary Files Plan Watch Tomorrow's Medicine Ad Index Outlook Unmet Needs in the Management of Plaque Psoriasis Impact of RSV: Implications for Managed Care

Managed Care - January 2009

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