NPLATE

Romiplostim is a thrombopoietin receptor agonist (TPO-RA). Romiplostim, a member of the TPO mimetic class, is an Fc-peptide fusion protein (peptibody). 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. Romiplostim is produced by recombinant DNA technology in Escherichia coli (E . coli) . Nplate (romiplostim) for injection is supplied as a sterile, preservative-free, lyophilized, solid white powder for subcutaneous use. Nplate is supplied as either 125 mcg per vial, 250 mcg per vial or 500 mcg per vial of romiplostim and requires reconstitution with Sterile Water for Injection to obtain a concentration of 500 mcg/mL. Each single-dose 125 mcg vial of Nplate contains the following: 125 mcg of romiplostim, L-histidine (0.7 mg), mannitol (18 mg), polysorbate 20 (0.02 mg), sucrose (9 mg), and sufficient HCl to adjust the pH to a target of 5. Reconstitution with 0.44 mL of Sterile Water for Injection provides a resulting concentration of 125 mcg/0.25 mL. Each single-dose 250 mcg vial of Nplate contains the following: 250 mcg romiplostim, L-histidine (1.2 mg), mannitol (30 mg), polysorbate 20 (0.03 mg), sucrose (15 mg), and sufficient HCl to adjust the pH to a target of 5. Reconstitution with 0.72 mL of Sterile Water for Injection provides a resulting concentration of 250 mcg/0.5 mL. Each single-dose 500 mcg vial of Nplate contains the following: 500 mcg romiplostim, L-histidine (1.9 mg), mannitol (50 mg), polysorbate 20 (0.05 mg), sucrose (25 mg), and sufficient HCl to adjust the pH to a target of 5. Reconstitution with 1.2 mL of Sterile Water for Injection provides a resulting concentration of 500 mcg/mL.

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 )] .

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 subcutaneous injection. Administer the dose as soon as possible after suspected or confirmed exposure to radiation levels greater than 2 gray (Gy). Administer Nplate regardless of whether a complete blood count (CBC) can be obtained. Estimate a patient's absorbed whole body radiation dose (i.e., level of radiation exposure) based on information from public health authorities, biodosimetry if available, or clinical findings such as time to onset of vomiting or lymphocyte depletion kinetics. 2.3 Preparation and Administration To mitigate against medication errors (both overdose and underdose), ensure that these preparation and administration instructions are followed. Use aseptic technique. Only administer subcutaneously [see Overdosage ( 10 )] . Nplate is supplied in single-dose vials as a sterile, preservative-free, white lyophilized powder that must be reconstituted as outlined in Table 1 and administered using a syringe with 0.01 mL graduations. Calculation of Patient Dose Multiply the patient’s weight (kg) by the prescribed dose to obtain the Calculated Patient Dose. Calculated Patient Dose (mcg) = Weight (kg) × Prescribed dose (mcg/kg) Reconstitution and Dilution of Nplate Single - Dose Vials Reconstitute Nplate with Sterile Water for Injection, USP. Do not reconstitute or dilute with Bacteriostatic Water for Injection, USP or dilute with Bacteriostatic Sodium Chloride Injection, USP. If the Calculated Patient Dose is less than 23 mcg, dilution with 0.9% Sodium Chloride Injection, USP is required to reduce the concentration of Nplate (see Table 1 ). This reduced concentration allows for low-doses to be accurately calculated, and consistently measured with a 0.01 mL graduated syringe. Table 1. Reconstitution and Dilution of Nplate Single-Dose Vials Calculated Patient Dose Strength Vial contains overfill to ensure delivery of labeled vial strength. Reconstitute with Sterile Water Add Sterile Water for Injection, USP directly to the vial. Dilute with Normal Saline Add 0.9% Sodium Chloride Injection, USP directly to the vial. Final Concentration Calculated Dose greater than or equal to 23 mcg 125 mcg 0.44 mL Not Required 500 mcg/mL 250 mcg 0.72 mL Not Required 500 mcg 1.2 mL Not Required Calculated Dose less than 23 mcg 125 mcg 0.44 mL 1.38 mL 125 mcg/mL 250 mcg 0.72 mL 2.25 mL 500 mcg 1.2 mL 3.75 mL Gently swirl and invert the vial to reconstitute. Avoid excess or vigorous agitation: DO NOT SHAKE . Generally, dissolution of Nplate takes less than 2 minutes. The reconstituted Nplate solution should be clear and colorless. Visually inspect the reconstituted solution for particulate matter and/or discoloration. Do not administer Nplate if particulate matter and/or discoloration is observed. Calculate Volume to Administer by dividing the Calculated Patient Dose (mcg) by the final concentration of prepared solution. See Table 2 for final concentrations. Table 2. Administration of Prepared Nplate Solution Calculated Patient Dose Final Concentration Volume to Administer (mL) Calculated Dose greater than or equal to 23 mcg 500 mcg/mL = Calculated Patient Dose / 500 mcg/mL Calculated Dose less than 23 mcg 125 mcg/mL = Calculated Patient Dose / 125 mcg/mL Administration of Prepared Nplate Solution Administer Nplate only using a syringe with 0.01 mL graduations for accurate dosage. Round volume to the nearest hundredth mL. Verify that the syringe contains the correct dosage. Discard any unused portion. Do not pool unused portions from the vials. Do not administer more than one dose from a vial. Storage of Reconstituted Solution Reconstituted product with Sterile Water for Injection, USP that has not been further diluted can remain in the original vial at room temperature 25°C (77°F) or be refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours following reconstitution. Reconstituted product with Sterile Water for Injection, USP may be held in a syringe at room temperature 25°C (77°F) for a maximum of 4 hours following reconstitution. Protect product from light. Do not shake. Storage of Diluted solution (after initial reconstitution) Reconstituted and further diluted product with 0.9% Sodium Chloride Injection, USP can be held in a syringe at room temperature 25°C (77°F) or in the original vial refrigerated at 2°C to 8°C (36°F to 46°F) for no longer than 4 hours prior to administration. Protect product from light. Do not shake.

None. None ( 4 )

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 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. Pediatric Patients The data described below reflect median exposure to Nplate of 168 days for 59 pediatric patients (aged 1 to 17 years) with ITP for at least 6 months, of whom 47.5% were female, across the randomized phase of two placebo-controlled trials. Table 4 presents the most common adverse reactions experienced by at least 5% of the pediatric patients (1 year and older) receiving Nplate across the two placebo-controlled trials with at least a 5% higher incidence in patients who received Nplate compared to those who received placebo. Table 4. Common Adverse Reactions (≥ 5% Incidence and ≥ 5% More Frequent on the Nplate Arm) from Two Placebo-Controlled Trials in Pediatric Patients with ITP for at least 6 months MedDRA version 20.1 is used. In pediatric patients of age ≥ 1 year receiving Nplate for ITP, adverse reactions with an incidence of ≥ 25% in the two randomized trials were: contusion (41%), upper respiratory tract infection (31%), and oropharyngeal pain (25%). Adverse Reactions by Body System Nplate (%) (N = 59) Placebo (%) (N = 24) Infections and Infestations Upper Respiratory Tract Infection 18 (31%) 6 (25%) Ear Infection 3 (5%) 0 Gastroenteritis 3 (5%) 0 Sinusitis 3 (5%) 0 Respiratory, Thoracic and Mediastinal Disorders Oropharyngeal Pain 15 (25%) 1 (4%) Gastrointestinal Disorders Diarrhea 12 (20%) 3 (13%) Abdominal Pain Upper 8 (14%) 1 (4%) Skin and Subcutaneous Tissue Disorders Rash 9 (15%) 2 (8%) Purpura 4 (7%) 0 Urticaria 3 (5%) 0 General Disorders and Administration Site Conditions Pyrexia 14 (24%) 2 (8%) Peripheral Swelling 4 (7%) 0 Injury, Poisoning and Procedural Complications Contusion 24 (41%) 8 (33%) Among 203 pediatric patients with ITP who received Nplate in a single arm, open-label, long-term (median duration of 3 years on therapy) study, the incidence rates of the adverse reactions occurred in a pattern similar to those reported in the placebo-controlled clinical studies. In this single arm, open-label, long-term study, headache occurred in 78 patients (38%), 3% (n=6) being severe and 1% (n=2) resulting in discontinuation of drug. Bone Marrow Reticulin Formation and Collagen Fibrosis The open-label long-term study also evaluated changes in bone marrow reticulin and collagen formation. The modified Bauermeister grading scale was used for both assessments. Based on cohort assignment at the time of study enrollment, patients were evaluated for bone marrow reticulin and collagen at year 1 (cohort 1) or year 2 (cohort 2) in comparison to the baseline bone marrow at the start of the study. From the total of 79 patients enrolled in the 2 cohorts, 27 (90%) patients in cohort 1 and 36 (73.5%) patients in cohort 2 had evaluable on-study bone marrow biopsies. Increased reticulin fiber formation was reported for 18.5% (5 of 27) of patients in cohort 1 and 47.2% (17 of 36) of patients in cohort 2, with a maximum grade of 2. No patients in either cohort developed collagen fibrosis (defined as grade 4) or a bone marrow abnormality that was inconsistent with an underlying diagnosis of ITP. 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 reactions including angioedema and anaphylaxis 6.3 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Nplate in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. 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 adult clinical studies in adult patients with ITP, the incidence of pre-existing antibodies to romiplostim was 3.3% (35/1046) and the incidence of binding antibody development during treatment with Nplate or a non-US approved romiplostim product was 5.7% (60/1046). The incidence of pre-existing antibodies to endogenous TPO was 3% (31/1046) and the incidence of binding antibody development to endogenous TPO during treatment was 3.2% (33/1046). Of the patients with positive binding antibodies that developed to romiplostim or to TPO, four 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. In pediatric studies, data on antibody formation was collected from 282 patients (20 from early phase studies, 59 from phase 3 studies with duration of 6 months and 203 from a long-term study with median duration of 3 years). The incidence of binding antibodies to Nplate at any time was 9.6% (27/282), of which 2 patients (0.7%) had pre-existing binding non-neutralizing Nplate antibodies at baseline and 11 patients (3.9%) had persistent binding antibody positivity at end of study. Additionally, 2.8% (8/282) developed neutralizing antibodies to Nplate, with 4 patients (1.4%) having persistent neutralizing antibody positivity at end of study, despite discontinuation of Nplate. The incidence of binding antibodies to TPO at any time was 3.9% (11/282), of which 2 patients (0.7%) had pre-existing binding non-neutralizing antibodies to TPO at baseline and 1 patient (0.4%) had binding persistent antibody positivity at end of study. One patient (0.4%) had a weakly positive postbaseline result for neutralizing antibodies against TPO while on study (with positive non-neutralizing antibodies to Nplate) with a negative result at baseline for both antibodies. The patient showed a transient antibody response for neutralizing antibodies against TPO, with a negative result at the patient's last timepoint tested within the study period after discontinuation of Nplate. A postmarketing registry study involving patients with thrombocytopenia on Nplate or a non-US approved romiplostim product was conducted to assess the long-term consequences of the anti-romiplostim antibodies. Adult 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 3.8% (7/184) to romiplostim and 2.2% (4/184) were positive for binding, non-neutralizing antibodies to TPO; two patients were positive for binding antibodies to both romiplostim and TPO. Of the seven patients with positive binding antibodies to romiplostim, one patient (0.5%; 1/184) was positive for neutralizing antibodies to romiplostim only. Nineteen confirmed pediatric patients were included in the postmarketing registry study. The incidence of binding antibody post treatment was 16% (3/19) to romiplostim, of which 5.3% (1/19) were positive for neutralizing antibodies to romiplostim. There were no antibodies detected to TPO. 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.

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 )] .