Nplate

1 INDICATIONS AND USAGE Nplate is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in: Adult patients with immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. ( 1.1 ) Pediatric patients 1 year of age and older with ITP for at least 6 months who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. ( 1.1 ) Nplate is indicated to increase survival in adults and in pediatric patients (including term neonates) acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [HS-ARS]). ( 1.2 ) Limitations of Use: Nplate is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than ITP. Nplate should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding. Nplate should not be used in an attempt to normalize platelet counts. ( 1 ) 1.1 Patients with Immune Thrombocytopenia (ITP) Nplate is indicated for the treatment of thrombocytopenia in: Adult patients with immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Pediatric patients 1 year of age and older with ITP for at least 6 months who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. 1.2 Patients with Hematopoietic Syndrome of Acute Radiation Syndrome Nplate is indicated to increase survival in adults and in pediatric patients (including term neonates) acutely exposed to myelosuppressive doses of radiation [see Clinical Studies (14.3) ] . Limitations of Use: Nplate is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than 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. Nplate should not be used in an attempt to normalize platelet counts [see Warnings and Precautions ( 5.2 )] .

2 DOSAGE AND ADMINISTRATION Patients with Immune Thrombocytopenia (ITP) Recommended Initial Dose: 1 mcg/kg once weekly as a subcutaneous injection. Adjust dose based on platelet response. ( 2.1 ) Patients acutely exposed to myelosuppressive doses of radiation Recommended Dose: 10 mcg/kg administered once as a subcutaneous injection. Administer the dose as soon as possible after suspected or confirmed exposure to myelosuppressive doses of radiation. ( 2.2 ) See Full Prescribing Information for instructions on reconstitution, preparation, and administration. ( 2.3 ) Reconstitution and Dilution of Nplate Single Dose Vials 2.1 Patients with Immune Thrombocytopenia (ITP) Use the lowest dose of Nplate to achieve and maintain a platelet count ≥ 50 × 10 9 /L as necessary to reduce the risk for bleeding. Administer Nplate as a weekly subcutaneous injection with dose adjustments based upon the platelet count response. The prescribed Nplate dose may consist of a very small volume (e.g., 0.15 mL). Administer Nplate only with a syringe that contains 0.01 mL graduations. Discontinue Nplate if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of Nplate therapy at the maximum weekly dose of 10 mcg/kg [see Warnings and Precautions ( 5.3 )] . Obtain complete blood counts (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. For Adult Patients with ITP The initial dose of Nplate is 1 mcg/kg. Actual body weight at initiation of treatment should always be used when calculating the initial dose. In adults, future dose adjustments are based on changes in platelet counts only. Adjust the weekly dose of Nplate by increments of 1 mcg/kg until the patient achieves a platelet count ≥ 50 × 10 9 /L as necessary to reduce the risk for bleeding; do not exceed a maximum weekly dose of 10 mcg/kg. In clinical studies, most adult patients who responded to Nplate achieved and maintained platelet counts ≥ 50 × 10 9 /L with a median dose of 2-3 mcg/kg. Adjust the dose as follows for adult patients: If the platelet count is < 50 × 10 9 /L, increase the dose by 1 mcg/kg. If platelet count is > 200 × 10 9 /L and ≤ 400 × 10 9 /L for 2 consecutive weeks, reduce the dose by 1 mcg/kg. If platelet count is > 400 × 10 9 /L, do not dose. Continue to assess the platelet count weekly. After the platelet count has fallen to < 200 × 10 9 /L, resume Nplate at a dose reduced by 1 mcg/kg. For Pediatric Patients with ITP The initial dose of Nplate is 1 mcg/kg. Actual body weight at initiation of treatment should always be used when calculating initial dose. In pediatric patients, future dose adjustments are based on changes in platelet counts and changes in body weight. Reassessment of body weight is recommended every 12 weeks. Adjust the weekly dose of Nplate by increments of 1 mcg/kg until the patient achieves a platelet count ≥ 50 × 10 9 /L as necessary to reduce the risk for bleeding; do not exceed a maximum weekly dose of 10 mcg/kg. In a pediatric placebo-controlled clinical study, the median of the most frequent dose of Nplate received by patients during weeks 17 through 24 was 5.5 mcg/kg. Adjust the dose as follows for pediatric patients: If the platelet count is < 50 × 10 9 /L, increase the dose by 1 mcg/kg. If platelet count is > 200 × 10 9 /L and ≤ 400 × 10 9 /L for 2 consecutive weeks, reduce the dose by 1 mcg/kg. If platelet count is > 400 × 10 9 /L, do not dose. Continue to assess the platelet count weekly. After the platelet count has fallen to < 200 × 10 9 /L, resume Nplate at a dose reduced by 1 mcg/kg. 2.2 Patients with Hematopoietic Syndrome of Acute Radiation Syndrome For Adult and Pediatric Patients (including term neonates) The recommended dose of Nplate is 10 mcg/kg administered once as a subcu…

5 WARNINGS AND PRECAUTIONS In some patients with MDS, Nplate increases blast cell counts and increases the risk of progression to acute myelogenous leukemia. ( 5.1 ) Thrombotic/thromboembolic complications have resulted from increases in platelet counts with Nplate use. Portal vein thrombosis has been reported in patients with chronic liver disease receiving Nplate. ( 5.2 ) Severe thrombocytopenia may persist during Nplate treatment due to neutralizing antibodies or other causes. ( 5.3 ) 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 adult clinical trials with Nplate. A randomized, double-blind, placebo-controlled trial enrolling adult 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 arm. This trial consisted of a 58-week study period with a 5-year long-term follow-up phase. The patients 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%) patients in the Nplate arm and 4 (4.8%) patients in the placebo arm (hazard ratio [95%CI] = 1.20 [0.38, 3.84]). Of the 250 patients, 210 (84.0%) entered the long-term follow-up phase of this study. With 5 years of follow-up, 29 (11.6%) patients showed progression to AML, including 20/168 (11.9%) patients in the Nplate arm versus 9/82 (11.0%) patients 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 patients with thrombocytopenia-related MDS, 8 (11.1%) patients 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%) 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 ITP. 5.2 Thrombotic/Thromboembolic Complications Thrombotic/thromboembolic complications have resulted from increases in platelet counts with Nplate use secondary to drug-induced thrombocytosis, regardless of the underlying disease. Thrombotic/ thromboembolic events including deep vein thrombosis (1.4%), pulmonary embolism (1.2%) and myocardial infarction (0.8%) have been observed with the use of Nplate in the ITP population. Other thrombotic events including transient ischemic attack have been reported. These events have occurred regardless of platelet counts. Portal vein thrombosis has been reported in patients with and without chronic liver disease receiving Nplate. In patients with ITP, 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 )] . In the absence of myelosuppression induced by acute exposure to radiation, Nplate administration might cause excessive increases in platelet counts and may cause thrombotic and thromboembolic complications [see Clinical Pharmacology (12.2) ]. 5.3 Loss of Response to Nplate Hyporesponsiveness or failure to maintain a platelet response with Nplate may occur due to neutralizing antibodies or other causes [see Adverse Reactions ( 6.3 )] . 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.

4 CONTRAINDICATIONS None. None ( 4 )

7 DRUG INTERACTIONS Nplate may be used with other medical ITP therapies, such as corticosteroids, danazol, azathioprine, intravenous immunoglobulin (IVIG), and anti-D immunoglobulin [see Clinical Studies ( 14.1 )] .

8.1 Pregnancy Risk Summary Based on findings from animal reproduction studies, Nplate may cause fetal harm when administered to a pregnant woman. Available data with Nplate use in pregnant women are insufficient to draw conclusions about any drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. 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 (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In rat and rabbit embryo-fetal development 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 (AUC). 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.

6 ADVERSE REACTIONS The following clinically significant 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 )] In adult patients, the most common adverse reactions (≥ 5% higher patient incidence in Nplate versus placebo) are arthralgia, dizziness, insomnia, myalgia, pain in extremity, abdominal pain, shoulder pain, dyspepsia, and paresthesia. Headache was the most commonly reported adverse reaction that did not occur at ≥ 5% higher patient incidence in Nplate versus placebo. ( 6.1 ) In pediatric patients, the most common adverse reactions (≥ 25%) are: contusion, upper respiratory tract infection, and oropharyngeal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Adults The data described below reflect Nplate exposure to 271 adult patients with 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 non-splenectomized 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. 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. For those patients receiving Nplate, 14 (48%) of headaches were mild, 9 (31%) were moderate, and 6 (21%) were severe. Table 3 presents adverse drug reactions from Studies 1 and 2 with a ≥ 5% higher patient incidence in Nplate versus placebo. Table 3. Adverse Reactions Identified in Two Placebo-Controlled Studies Adverse Reactions by Body System Nplate (%) (n = 84) Placebo (%) (n = 41) Musculoskeletal and Connective Tissue Disorders Arthralgia 22 (26%) 8 (20%) Myalgia 12 (14%) 1 (2%) Pain in Extremity 11 (13%) 2 (5%) Shoulder Pain 7 (8%) 0 Nervous System Disorders Dizziness 14 (17%) 0 Paresthesia 5 (6%) 0 Psychiatric Disorders Insomnia 13 (16%) 3 (7%) Gastrointestinal Disorders Abdominal pain 9 (11%) 0 Dyspepsia 6 (7%) 0 MedDRA version 9 is used. Among 291 adult patients with 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. The safety profile of Nplate was similar across patients, regardless of ITP duration. The following adverse reactions (at least 5% incidence and at least 5% more frequent with Nplate compared with placebo or standard of care) occurred in Nplate patients with ITP duration up to 12 months: bronchitis, sinusitis, vomiting, arthralgia, myalgia, headache, dizziness, diarrhea, upper respiratory tract infection, cough, nausea and oropharyngeal pain. The adverse reaction of thrombocytosis occurred with an incidence of 2% in adults with ITP duration up to 12 months. 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 dur…