Pharmacy & Therapeutics - November 2008 - (Page 671)

Pharmaceutical Approval Update Mar vin M. Goldenberg, PhD, RPh, MS Romiplostim (Nplate) Manufacturer: Amgen Oncology, Thousand Oaks, Calif. Indication: Romiplostim is indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. It should be used only in patients with ITP whose degree of thrombocytopenia increases the risk for bleeding. It should not be used to normalize platelet counts. Drug Class: As a member of the thrombopoietin (TPO) mimetic class, romiplostim is produced by recombinant DNA technology in Escherichia coli. It is an Fc-peptide fusion protein (peptibody) that activates intracellular transcriptional pathways, leading to increased platelet production via the TPO receptor (cMpl). The peptibody molecule contains two identical single-chain subunits, each consisting of human immunoglobulin (IgG1) Fc domain, covalently linked at the C-terminus to a peptide containing two thrombopoietin receptor-binding domains. Romiplostim has no amino-acid sequence homology to endogenous TPO. Uniqueness of Drug: Romiplostim increases platelet production through binding and activation of the TPO receptor, a mechanism analogous to endogenous TPO. Warnings and Precautions: Bone marrow reticulin formation and risk of bone marrow fibrosis: Romiplostim increases the risk of development or progression of reticulin fiber deposition within bone marrow. In clinical studies, four of 271 patients discontinued romiplostim because of this event. Upon bone marrow biopsy, reticulin was obser ved in six additional patients. All 10 patients with bone marrow reticulin deposition had received doses of 5 mcg/kg or more, and six received doses of 10 mcg/kg or more. In the controlled clinical studies, progression to marrow fibrosis with cytopenia was not reported. In the extension study, marrow fibrosis with collagen developed in one patient with ITP and hemolytic anemia during romiplostim therapy. Clinical studies have not excluded a risk of bone marrow fibrosis with cytopenia. Before romiplostim therapy begins, the peripheral blood smear should be examined to establish a baseline level of cellular morphological abnormalities. After a stable romiplostim dose is identified, peripheral blood smears and a complete blood count (CBC) should be assessed monthly to look for cytopenia or new or worsening morphological abnormalities, such as teardrop and nucleated red blood cells or immature white blood cells. If such abnormalities or cytopenias develop, romiplostim should be discontinued and a bone marrow The author is President of Pharmaceutical and Scientific Services at Marvin M. Goldenberg, LLC, in Westfield, N.J. His e-mail address is marvinmgoldenberg@verizon.net. biopsy, including staining for fibrosis, should be considered. Worsening thrombocytopenia after cessation of therapy: Discontinuation of romiplostim may result in thrombocytopenia more severe than that which was present before therapy. The worsened thrombocytopenia may increase the risk of bleeding, particularly if the agent is discontinued while the patient had been taking anticoagulant or antiplatelet agents. In studies of patients with chronic ITP who discontinued romiplostim, four of 57 patients developed thrombocytopenia of a greater severity than before therapy. This worsened thrombocytopenia resolved within 14 days. After romiplostim is discontinued, weekly CBCs, including platelet counts, should be obtained for at least two weeks, and alternative therapy for worsening thrombocytopenia should be considered, according to treatment guidelines. Thrombotic and thromboembolic complications: Complications may result from an increased platelet count. Excessive doses of romiplostim, or medication errors that result in excessive romiplostim doses, may increase platelet counts to a level that produces thrombotic or thromboembolic sequelae. In controlled trials, the incidence of these complications was similar for both romiplostim and placebo. To minimize the risk of these complications, clinicians should not use romiplostim in an attempt to normalize the platelet count. Doseadjustment guidelines should be followed to achieve and maintain a platelet count of 50 × 109/L or higher. Lack or loss of response to therapy: A weak response or a failure to maintain a platelet response with romiplostim should prompt a search for a cause, including neutralizing antibodies to romiplostim or bone marrow fibrosis. To detect antibody formation, clinicians should submit blood samples to Amgen to assay these samples for antibodies to romiplostim and TPO. Romiplostim should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after four weeks at the highest weekly dose of 10 mcg/kg. Malignancy: Stimulation of the TPO receptor on the surface of hematopoietic cells may increase the risk of hematological malignancies. In controlled studies of chronic ITP, the incidence of hematological malignancy was low and was similar for romiplostim and placebo. In a separate single-arm clinical study of 44 patients with myelodysplastic syndrome (MDS), 11 patients experienced possible disease progression; four of these patients had acute myelogenous leukemia during followup. Romiplostim is not indicated for treating thrombocytopenia attributable to MDS or to any cause of thrombocytopenia other than chronic ITP. Monitoring: The CBC, including platelet counts and peripheral blood smears, should be monitored before, during, and after discontinuation of romiplostim therapy. Before romiplostim is initiated, the peripheral blood differential should be examined to establish the baseline extent of red blood cell Vol. 33 No. 11 • November 2008 • P&T® 671

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Pharmacy & Therapeutics - November 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Heparin-Induced Thrombocytopenia Medication Utilization Patterns and Hypertension-Related Expenditures among Patients Who Were Switched From Fixed-Dose to Free-Combination Antihypertensive Therapy European Society for Medical Oncology and Association for the Study of Bone and Mineral Research Pharmaceutical Approval Update

Pharmacy & Therapeutics - November 2008

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