N PLATE

Romiplostim is a thrombopoiesis stimulating dimer

Fc-peptide fusion protein (peptibody) to increase platelet production through activation of the thrombopoietin receptor.

The peptibody molecule has two identical single-chain subunits, each one is made up of 269 amino acid residues.

Each subunit consists of an

IgG1 Fc carrier domain that is covalently attached to a polypeptide sequence that contains two binding domains to interact with thrombopoietin receptor c-Mpl.

Each domain consists of 14 amino acids.

Interestingly, romiplostim's amino acid sequence is not similar to that of endogenous thrombopoietin.

Romiplostim is produced by recombinant DNA technology in Escherichia coli.

FDA approved on

August 22, 2008.

Treatment of chronic immune thrombocytopenic purpura.

Responses to platelet increase varies between patients thus indicating a need for individualization of dose.

However, a dose dependent-increase in platelet counts have been observed in clinical trials.

Does not affect platelet destruction.

Cmax, healthy volunteers, subQ = 24-36 hours Cmax, immune thrombocytopenia patients, subQ = 7-50 hours (median = 14 hours).

Not affected by age, weight, or gender.

Accumulation does not occur after six weekly doses of 3 mcg/kg romiplostim.

In healthy volunteers, non-linear decrease in Vd with increase Intravenous dose of romiplostim which indicates saturation of c-Mpl receptors.

Renal clearance (more dominant mode of clearance as dose increases) and binding to c-Mpl receptors (dominant mode of clearance at low doses).

Immune thrombocytopenia patients, subQ = 3.5 days (median) (range 1-34 days).

Improve decision support & research outcomes With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.

View sample adverse effects data in our new Data Library! See the data Improve decision support & research outcomes with our structured adverse effects data.

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.

LD50 = 980 mg/kg.

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.