N PLATE

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.

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.

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]).

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 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.

Nplate should not be used in an attempt to normalize platelet counts.

Nplate increases platelet production through binding and activation of the TPO receptor, a mechanism analogous to endogenous TPO. 12.2 Pharmacodynamics In clinical studies, treatment with Nplate resulted in dose-dependent increases in platelet counts.

After a single subcutaneous dose of to 10 mcg/kg Nplate in patients with ITP, the peak platelet count was 1.3 to 14.9 times greater than the baseline platelet count over a 2.

• to 3-week period.

The platelet counts were above 50 × 10 9 /L for seven out of eight patients with ITP who received six weekly doses of Nplate at 1 mcg/kg. In a clinical study, peak platelet count increased 4.7 to 7.3 fold (mean: 5.8 fold) above baseline values in healthy adults (n = 4) administered a single 10 mcg/kg IV dose of Nplate.

Results from population modeling and simulation indicate that a single 10 mcg/kg subcutaneous dose of Nplate would result in clinically relevant effects on incidence rate and duration of severe thrombocytopenia in patients acutely exposed to myelosuppressive doses of radiation. 12.3 Pharmacokinetics Patients with Immune Thrombocytopenia (ITP) In the long-term extension study in adult patients with ITP receiving weekly treatment of Nplate subcutaneously, the pharmacokinetics of romiplostim over the dose range of to 15 mcg/kg indicated that peak serum concentrations of romiplostim were observed about to 50 hours post dose (median: 14 hours) with half-life values ranging from to 34 days (median: 3.5 days).

The serum concentrations varied among patients and did not correlate with the dose administered.

The elimination of serum romiplostim is in part dependent on the TPO receptor on platelets.

As a result, for a given dose, patients with high platelet counts are associated with low serum concentrations and vice versa.

In another

ITP clinical study, no accumulation in serum concentrations was observed (n = 4) after six weekly doses of Nplate (3 mcg/kg).

The accumulation at higher doses of romiplostim is unknown.

Patients Acutely Exposed to Myelosuppressive Doses of Radiation The pharmacokinetics of romiplostim is not available in patients acutely exposed to myelosuppressive doses of radiation.

Serum concentrations of romiplostim in pediatric patients with ITP were within the range observed in adult patients with ITP receiving the same dose range of romiplostim.

Similar to adults with

ITP, romiplostim pharmacokinetics are highly variable in pediatric patients with ITP.

The following clinically significant adverse reactions are discussed in greater detail in other sections: Progression of Myelodysplastic Syndromes Thrombotic/Thromboembolic Complications Loss of Response to Nplate 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.

In pediatric patients, the most common adverse reactions (≥ 25%) are: contusion, upper respiratory tract infection, and oropharyngeal pain.

To report SUSPECTED ADVERSE

REACTIONS, contact Amgen Inc.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 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 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 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 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.

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%).

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 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 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.

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 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.

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.

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.

Thrombocytopenia (ITP) Recommended Initial Dose: 1 mcg/kg once weekly as a subcutaneous injection.

Adjust dose based on platelet response.

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.

Information for instructions on reconstitution, preparation, and administration.

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.

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).

Nplate only with a syringe that contains 0.01 mL graduations.

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.

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.

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.

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 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.

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).

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.

Nplate is supplied in single-dose vials as a sterile, preservative-free, white lyophilized powder that must be reconstituted as outlined in Table and administered using a syringe with 0.01 mL graduations.

Multiply the patient’s weight (kg) by the prescribed dose to obtain the Calculated Patient Dose.

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.

Dose is less than 23 mcg, dilution with 0.9% Sodium Chloride Injection, USP is required to reduce the concentration of Nplate.

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.

Add 0.9% Sodium Chloride Injection, USP directly to the vial.

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

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.

Table 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.

Nplate (romiplostim) for injection is supplied as a sterile, preservative-free, solid white lyophilized powder in single-dose vials of 125 mcg (NDC-55513-223-01, NDC-55513-223-21), 250 mcg (NDC 55513-221-01, NDC 55513-221-21) and 500 mcg (NDC 55513-222-01, NDC 55513-222-21) of romiplostim.

Nplate vials in the refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

Do not freeze.

If needed, unopened Nplate vials may be stored in the original carton at room temperature up to a maximum of 25°C (77°F) for a single period of up to 30 days.

The new expiration date must be written in the space provided on the carton.

Once stored at room temperature, do not place back in the refrigerator.

If not used within the 30 days, discard Nplate.

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.

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.

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.

Safety and effectiveness of

Nplate have been established in pediatric patients age 1 year and older with ITP for at least 6 months evaluated in two randomized, placebo-controlled studies.

Long-term safety in the same population using Nplate for a median duration of 3 years was also evaluated in a single arm, open-label study.

The pharmacokinetics of romiplostim have been evaluated in pediatric patients 1 year and older with ITP.

See Dosage and

Administration for dosing recommendations for pediatric patients 1 year and older.

The safety and efficacy of

Nplate in pediatric patients younger than 1 year with ITP have not been established.

Serum concentrations of romiplostim in pediatric patients with ITP were within the range observed in adult patients with ITP receiving the same dose range of romiplostim.

The use of

Nplate to increase survival in pediatric patients (including term neonates) acutely exposed to myelosuppressive doses of radiation is based on efficacy studies conducted in adult animals.

Efficacy studies of

Nplate could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons.

A similar response to

Nplate is expected in the pediatric and adult patients based on the mechanism of action of the drug and pharmacokinetics of Nplate in pediatric patients 1 year and older with ITP.

Of the 271 patients who received Nplate in ITP clinical studies, 55 (20%) were age and over, and 27 (10%) were 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.