Nplate
(romiplostim)Dosage & Administration
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Nplate Prescribing Information
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.
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)
Use the lowest dose of Nplate to achieve and maintain a platelet count ≥ 50 × 109/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 × 109/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 × 109/L with a median dose of 2-3 mcg/kg.
Adjust the dose as follows for adult patients:
- If the platelet count is < 50 × 109/L, increase the dose by 1 mcg/kg.
- If platelet count is > 200 × 109/L and ≤ 400 × 109/L for 2 consecutive weeks, reduce the dose by 1 mcg/kg.
- If platelet count is > 400 × 109/L, do not dose. Continue to assess the platelet count weekly. After the platelet count has fallen to < 200 × 109/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 × 109/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 × 109/L, increase the dose by 1 mcg/kg.
- If platelet count is > 200 × 109/L and ≤ 400 × 109/L for 2 consecutive weeks, reduce the dose by 1 mcg/kg.
- If platelet count is > 400 × 109/L, do not dose. Continue to assess the platelet count weekly. After the platelet count has fallen to < 200 × 109/L, resume Nplate at a dose reduced by 1 mcg/kg.
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.
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.
| Calculated Patient Dose | Strength * | Reconstitute with Sterile Water † | Dilute with Normal Saline ‡ | 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.
| 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.
For injection: 125 mcg, 250 mcg or 500 mcg of Nplate as a sterile, lyophilized, solid white powder in single-dose vials.
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.
Lactation
Risk Summary
There is no information regarding the presence of romiplostim in human milk, the effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to romiplostim are unknown. Due to the potential for serious adverse reactions in a breastfed child from Nplate, advise women not to breastfeed during treatment with Nplate.
Pediatric Use
Safety and effectiveness 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 [see Adverse Reactions ( 6.1), Clinical Studies ( 14.2)].
The pharmacokinetics of romiplostim have been evaluated in pediatric patients 1 year and older with ITP [see Clinical Pharmacology ( 12.3)]. See Dosage and Administration ( 2.1) 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 romiplostim is expected in the pediatric and adult patients based on the mechanism of action of the drug and pharmacokinetics of romiplostim in pediatric patients 1 year and older with ITP [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
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.
None.
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.
Thrombotic/Thromboembolic Complications
Thrombotic/thromboembolic complications may result from increases in platelet counts with Nplate use secondary to drug-induced thrombocytosis, regardless of the underlying disease. There is insufficient evidence to establish a relationship between maximum platelet threshold and risk of thrombotic/thromboembolic complications. Portal vein thrombosis has been reported in patients with 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)].
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.