ASH News Daily 2012 - Sunday, December 9, 2012 - (Page C-15)

BRIEF SUMMARY OF PRESCRIBING INFORMATION Nplate (romiplostim), for subcutaneous injection ® WARNINGS AND PRECAUTIONS Risk of Progression of Myelodysplastic Syndromes to Acute Myelogenous Leukemia Progression from myelodysplastic syndromes (MDS) to acute myelogenous leukemia (AML) has been observed in clinical studies with Nplate®. A randomized, doubleblind, placebo-controlled study enrolling patients with severe thrombocytopenia and International Prognostic Scoring System (IPSS) low or intermediate-1 risk MDS was terminated due to more cases of AML observed in the Nplate® treatment arm. At the time of an interim analysis, among 219 MDS patients randomized 2:1 to treatment with Nplate® or placebo (147 Nplate®: 72 placebo), 11 patients showed progression to AML, including nine on the Nplate® arm versus two on the placebo arm. In addition, in peripheral blood counts, the percentage of circulating myeloblasts increased to greater than 10% in 28 patients, 25 of whom were in the romiplostim treatment arm. Of the 28 patients who had an increase in circulating myeloblasts to greater than 10%, eight of these patients were diagnosed to have AML, and 20 patients had not progressed to AML. In four patients, increased peripheral blood blast cell counts decreased to baseline after discontinuation of Nplate®. In a single-arm study of Nplate® given to 72 patients with thrombocytopenia related to MDS, eight (11%) patients were reported as having possible disease progression, and three patients had confirmation of AML during follow-up. In addition, in three patients, increased peripheral blood blast cell counts decreased to baseline after discontinuation of Nplate®. Nplate® is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP. Thrombotic/Thromboembolic Complications Thrombotic/thromboembolic complications may result from increases in platelet counts with Nplate® use. Portal vein thrombosis has been reported in patients with chronic liver disease receiving Nplate®. Nplate® should be used with caution in patients with ITP and chronic liver disease. To minimize the risk for thrombotic/thromboembolic complications, do not use Nplate® in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain a platelet count of 50 x 109/L [see Dosage and Administration]. Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis Nplate® administration may increase the risk for development or progression of reticulin fiber formation within the bone marrow. This formation may improve upon discontinuation of Nplate®. In a clinical study, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Nplate® therapy. Clinical studies are in progress to assess the risk of bone marrow fibrosis and clinical consequences with cytopenias. If new or worsening morphological abnormalities or cytopenia(s) occurs, consider a bone marrow biopsy to include staining for fibrosis [see Adverse Reactions]. Worsened Thrombocytopenia after Cessation of Nplate® In clinical studies of patients with chronic ITP who had Nplate® discontinued, four of 57 patients developed thrombocytopenia of greater severity than was present prior to Nplate® therapy. This worsened thrombocytopenia resolved within 14 days. Following discontinuation of Nplate®, obtain weekly CBCs, including platelet counts, for at least 2 weeks and consider alternative treatments for worsening thrombocytopenia, according to current treatment guidelines [see Adverse Reactions]. Lack or Loss of Response to Nplate® Hyporesponsiveness or failure to maintain a platelet response with Nplate® should prompt a search for causative factors, including neutralizing antibodies to Nplate® [see Adverse Reactions]. To detect antibody formation, submit blood samples to Amgen (1-800-772-6436). Amgen will assay these samples for antibodies to Nplate® and thrombopoietin (TPO). Discontinue Nplate® if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the highest weekly dose of 10 mcg/kg. Laboratory Monitoring Obtain CBCs, including platelet counts, weekly during the dose adjustment phase of Nplate® therapy and then monthly following establishment of a stable Nplate® dose. Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of Nplate® [see Dosage and Administration and Warnings and Precautions]. ADVERSE REACTIONS Clinical Studies Experience Serious adverse reactions associated with Nplate® in ITP clinical studies were bone marrow reticulin deposition and worsening thrombocytopenia after Nplate® discontinuation [see Warnings and Precautions]. The data described below reflect Nplate® exposure to 271 patients with chronic ITP, aged 18 to 88, of whom 62% were female. Nplate® was studied in two randomized, placebo-controlled, double-blind studies that were identical in design, with the exception that Study 1 evaluated nonsplenectomized patients with ITP and Study 2 evaluated splenectomized patients with ITP. Data are also reported from an open-label, single-arm study in which patients received Nplate® over an extended period of time. Overall, Nplate® was administered to 114 patients for at least 52 weeks and 53 patients for at least 96 weeks. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction, occurring in 35% of patients receiving Nplate® and 32% of patients receiving placebo. Headaches were usually of mild or moderate severity. Table 2 presents adverse drug reactions from Studies 1 and 2 with a 5% higher patient incidence in Nplate® versus placebo. The majority of these adverse drug reactions were mild to moderate in severity. Table 2. Adverse Drug Reactions Identified in Two Placebo-Controlled Studies Preferred Term Arthralgia Dizziness Insomnia Myalgia Abdominal Pain Shoulder Pain Dyspepsia Paresthesia Nplate® (n = 84) 26% 17% 16% 14% 13% 11% 8% 7% 6% Placebo (n = 41) 20% 0% 7% 2% 5% 0% 0% 0% 0% DRUG INTERACTIONS No formal drug interaction studies of Nplate® have been performed. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Nplate® use in pregnant women. In animal reproduction and developmental toxicity studies, romiplostim crossed the placenta, and adverse fetal effects included thrombocytosis, postimplantation loss, and an increase in pup mortality. Nplate® should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Pregnancy Registry : A pregnancy registry has been established to collect information about the effects of Nplate® use during pregnancy. Physicians are encouraged to register pregnant patients, or pregnant women may enroll themselves in the Nplate® pregnancy registry by calling In rat and rabbit developmental toxicity studies no evidence of fetal harm was observed at romiplostim doses up to 11 times (rats) and 82 times (rabbits) the maximum human dose (MHD) based on systemic exposure. In mice at doses 5 times the MHD, reductions in maternal body weight and increased postimplantation loss occurred. In a prenatal and postnatal development study in rats, at doses 11 times the MHD, there was an increase in perinatal pup mortality. Romiplostim crossed the placental barrier in rats and increased fetal platelet counts at clinically equivalent and higher doses. Nursing Mothers It is not known whether Nplate® is excreted in human milk; however, human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Nplate®, a decision should be made whether to discontinue nursing or to discontinue Nplate®, taking into account the importance of Nplate® to the mother and the known benefits of nursing. Pediatric Use The safety and effectiveness in pediatric patients (< 18 years) have not been established. Geriatric Use Of the 271 patients who received Nplate® in ITP clinical studies, 55 (20%) were age 65 and over, and 27 (10%) were 75 and over. No overall differences in safety or efficacy have been observed between older and younger patients in the placebo-controlled studies, but greater sensitivity of some older individuals cannot be ruled out. In general, dose adjustment for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Renal Impairment No clinical studies were conducted in patients with renal impairment. Use Nplate® with caution in this population. Hepatic Impairment No clinical studies were conducted in patients with hepatic impairment. Use Nplate® with caution in this population. OVERDOSAGE In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In this case, discontinue Nplate® and monitor platelet counts. Reinitiate treatment with Nplate® in accordance with dosing and administration recommendations [see Dosage and Administration]. Rx Only. Consult package insert for complete Prescribing Information. Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 This product, its production, and/or its use may be covered by one or more U.S. Patents, including U.S. Patent Nos. 6,835,809, 7,189,827, 7,994,117 and 8,044,174, as well as other patents or patents pending. © 2008-2012 Amgen Inc. All rights reserved. www.nplate.com v5 64256-R2-V1 Trim: 10” Among 142 patients with chronic ITP who received Nplate® in the single-arm extension study, the incidence rates of the adverse reactions occurred in a pattern similar to those reported in the placebo-controlled clinical studies. Postmarketing Experience The following adverse reactions have been identified during post approval use of Nplate®. 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. Immunogenicity As with all therapeutic proteins, patients may develop antibodies to the therapeutic protein. Patients were screened for immunogenicity to romiplostim using a BIAcore-based biosensor immunoassay. This assay is capable of detecting both high- and low-affinity binding antibodies that bind to romiplostim and cross-react with TPO. The samples from patients that tested positive for binding antibodies were further evaluated for neutralizing capacity using a cell-based bioassay. In clinical studies, the incidence of preexisting antibodies to romiplostim was 8% (43/537) and the incidence of binding antibody development during Nplate® treatment was 6% (31/537). The incidence of preexisting antibodies to endogenous TPO was 5% (29/537) and the incidence of binding antibody development to endogenous TPO during Nplate® treatment was 4% (21/537). Of the patients with positive binding antibodies that developed to romiplostim or to TPO, two (0.4%) patients had neutralizing activity to romiplostim and none had neutralizing activity to TPO. No correlation was observed between antibody activity and clinical effectiveness or safety. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection and may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to romiplostim with the incidence of antibodies to other products may be misleading. 

Table of Contents for the Digital Edition of ASH News Daily 2012 - Sunday, December 9, 2012

ASH News Daily 2012 - Sunday, December 9, 2012

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