BRIEF SUMMARY OF PRESCRIBING INFORMATION NPLATE ® (romiplostim) for injection, for subcutaneous use 1 INDICATIONS AND USAGE Nplate ® is indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Limitations of Use: • Nplate ® is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP [see Warnings and Precautions (5.1)]. • Nplate ® should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding [see Warnings and Precautions (5.2)]. • Nplate ® should not be used in an attempt to normalize platelet counts [see Warnings and Precautions (5.2)]. 4 CONTRAINDICATIONS 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. on Nplate ® or a non-US approved romiplostim product was conducted to assess the long-term consequences of the anti-romiplostim antibodies. Patients who lacked response or lost response to Nplate ® or a non-US approved romiplostim product were enrolled. The incidence of new binding antibody development was 3% (5/186) to romiplostim and 1% (2/186) to TPO. One patient was positive for binding antibodies to both romiplostim and TPO. Of the five patients with positive binding antibodies to romiplostim, two (1%) were positive for neutralizing antibodies to romiplostim only. 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. 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 2. Adverse Drug Reactions Identified in Two Placebo Controlled Studies Preferred Term Nplate ® (n = 84) Placebo (n = 41) None. Arthralgia 26% 20% 5 WARNINGS AND PRECAUTIONS Dizziness 17% 0% 5.1 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 trials with Nplate ® . A randomized, double-blind, placebo-controlled trial 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. This trial consisted of a 58-week study period with a 5-year long-term follow-up phase. The subjects were randomized 2:1 to treatment with Nplate or placebo (167 Nplate, 83 placebo). During the 58-week study period, progression to AML occurred in 10 (6.0%) subjects in the Nplate arm and 4 (4.8%) subjects in the placebo arm (hazard ratio [95%CI] = 1.20 [0.38, 3.84]). Of the 250 subjects, 210 (84.0%) entered the long-term follow-up phase of this study. With 5-years of follow-up, 29 (11.6%) subjects showed progression to AML, including 20/168 (11.9%) subjects in the Nplate arm versus 9/82 (11.0%) subjects in the placebo arm (HR [95% CI] = 1.06 [0.48, 2.33]). The incidence of death (overall survival) was 55.7% (93/167) in the Nplate arm versus 54.2% (45/83) in the placebo arm (HR [95% CI] = 1.03 [0.72, 1.47]). In the baseline low IPSS group, there was a higher incidence of death in the Nplate arm [41.3% (19/46)] compared to the placebo arm [30.4% (7/23)] [HR (95% CI) = 1.59 (0.67, 3.80)]. In a single-arm trial of Nplate given to 72 subjects with thrombocytopenia-related MDS, 8 (11.1%) subjects were reported as having possible disease progression, of which 3 (4.2%) had confirmation of AML during follow-up. In addition, in 3 (4.2%) subjects, increased peripheral blood blast cell counts decreased to baseline after discontinuation of Nplate. Insomnia 16% 7% 2% Nplate ® is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP. 5.2 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 ® . To minimize the risk for thrombotic/thromboembolic complications, do not use Nplate ® in an attempt to normalize platelet counts. Follow the dose adjustment guidelines [see Dosage and Administration (2.1)]. 5.3 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 (6.3)]. 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. 5.4 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 (2.1)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections: • Progression of Myelodysplastic Syndromes [see Warnings and Precautions (5.1)] • Thrombotic/Thromboembolic Complications [see Warnings and Precautions (5.2)] • Loss of Response to Nplate ® [see Warnings and Precautions (5.3)] • Laboratory Monitoring [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Myalgia 14% Pain in Extremity 13% 5% Abdominal Pain 11% 0% Shoulder Pain 8% 0% Dyspepsia 7% 0% Paresthesia 6% 0% 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. Bone Marrow Reticulin Formation and Collagen 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 trial, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Nplate ® therapy. An open-label clinical trial prospectively evaluated changes in bone marrow reticulin formation and collagen fibrosis in adult patients with ITP treated with Nplate ® or a non-US approved romiplostim product. Patients were administered romiplostim by SC injection once weekly for up to 3 years. Based on cohort assignment at time of study enrollment, patients were evaluated for bone marrow reticulin and collagen at year 1 (cohort 1), year 2 (cohort 2), or year 3 (cohort 3) in comparison to the baseline bone marrow at start of the trial. Patients were evaluated for bone marrow reticulin formation and collagen fibrosis using the modified Bauermeister grading scale. From the total of 169 patients enrolled in the 3 cohorts, 132 (78%) patients were evaluable for bone marrow collagen fibrosis and 131 (78%) patients were evaluable for bone marrow reticulin formation. Two percent (2/132) of patients (both from cohort 3) developed Grade 4 findings (presence of collagen). There was no detectable bone marrow collagen in one patient on repeat testing 12 weeks after discontinuation of romiplostim. Progression of bone marrow reticulin formation (increase greater than or equal to 2 grades or more) or an increase to Grade 4 (presence of collagen) was reported in 7% (9/131) of patients. 6.2 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. • Erythromelalgia • Hypersensitivity • Angioedema 6.3 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 in patients with ITP, the incidence of preexisting antibodies to romiplostim was 5% (53/1112) and the incidence of binding antibody development during treatment with Nplate ® or a non- US approved romiplostim product was 4% (50/1112). The incidence of preexisting antibodies to endogenous TPO was 4% (40/1112) and the incidence of binding antibody development to endogenous TPO during treatment was 3% (38/1112). Of the patients with positive binding antibodies that developed to romiplostim or to TPO, five patients had neutralizing activity to romiplostim and none had neutralizing activity to TPO. No apparent correlation was observed between antibody activity and clinical effectiveness or safety. A postmarketing registry study involving patients with thrombocytopenia 7 DRUG INTERACTIONS No formal drug interaction studies of Nplate ® have been performed. 8 USE IN SPECIFIC POPULATIONS 8.1 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. 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. Women who become pregnant during Nplate ® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. 8.3 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. 8.4 Pediatric Use The safety and effectiveness in pediatric patients (< 18 years) have not been established. 8.5 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. 8.6 Renal Impairment No clinical studies were conducted in patients with renal impairment. 8.7 Hepatic Impairment No clinical studies were conducted in patients with hepatic impairment. 10 OVERDOSAGE Overdoses due to medication errors have been reported in patients receiving Nplate ® . 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 (2.1, 2.2)]. This Brief Summary using USPIv11 06/2017 Nplate ® (romiplostim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 U.S. License No. 1080 Patent: http://pat.amgen.com/nplate/ © 2008–2017 Amgen Inc. All rights reserved.