2.1 Recommended Dosage Regimen

Use the lowest dose of Nplate to achieve and maintain a platelet count ≥ 50 x 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 (eg, 0.15 mL). Administer Nplate only with a syringe that contains 0.01 mL graduations.

Initial Dose
The initial dose for Nplate is 1 mcg/kg based on actual body weight.

Dose Adjustments
Use the actual body weight at initiation of therapy, then adjust the weekly dose of Nplate by increments of 1 mcg/kg until the patient achieves a platelet count ≥ 50 x 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 patients who responded to Nplate achieved and maintained platelet counts ≥ 50 x 109/L with a median dose of 2 mcg/kg.

During Nplate therapy, assess CBCs, including platelet counts, weekly until a stable platelet count (≥ 50 x 109/L for at least 4 weeks without dose adjustment) has been achieved. Obtain CBCs, including platelet counts, monthly thereafter.

Adjust the dose as follows:

• If the platelet count is < 50 x 109/L, increase the dose by 1 mcg/kg.
• If platelet count is > 200 x 109/L for 2 consecutive weeks, reduce the dose by 1 mcg/kg.
• If platelet count is > 400 x 109/L, do not dose. Continue to assess the platelet count weekly. After the platelet count has fallen to < 200 x 109/L, resume Nplate at a dose reduced by 1 mcg/kg.

Discontinuation
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 (5.5)]. Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of Nplate [see Warnings and Precautions (5.6)].

2.2 Preparation and Administration

To mitigate against medication errors (both overdose and underdose), ensure that these preparation and administration instructions are followed.

Calculate the dose and reconstitute with the correct volume of sterile water for injection.  Withdraw the appropriate volume of the calculated dose from the vial.  Only administer subcutaneously [see Overdosage (10)].

Nplate is supplied in single-use 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.  Using aseptic technique, reconstitute Nplate with preservative-free Sterile Water for Injection, USP as described in Table 1.  Do not use bacteriostatic water for injection.

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.

Reconstituted Nplate can be kept at room temperature (25°C/77°F) or refrigerated at 2° to 8°C (36° to 46°F) for up to 24 hours prior to administration. Protect the reconstituted product from light.

To determine the injection volume to be administered, first identify the patient’s total dose in micrograms (mcg) using the dosing information in Section 2.1.  For example, a 75 kg patient initiating therapy at 1 mcg/kg will begin with a dose of 75 mcg.  Next, calculate the volume of Nplate solution that is given to the patient by dividing the microgram dose by the concentration of the reconstituted Nplate solution (500 mcg/mL).  For this patient example, the 75 mcg dose is divided by 500 mcg/mL, resulting in an injection volume of 0.15 mL.

As the injection volume may be very small, use a syringe with graduations to 0.01 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.

2.3 Use of Nplate With Concomitant Medical ITP Therapies

Nplate may be used with other medical ITP therapies, such as corticosteroids, danazol, azathioprine, intravenous immunoglobulin (IVIG), and anti-D immunoglobulin. If the patient’s platelet count is ≥ 50 x 109/L, medical ITP therapies may be reduced or discontinued [see Clinical Studies (14.1)].

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 clinical trials with Nplate.  A randomized, double-blind, placebo-controlled trial enrolling 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 treatment arm.  At the time of an interim analysis, among 219 MDS patients randomized 2:1 to treatment with Nplate or placebo (147 Nplate: 72 placebo), 11 patients showed progression to AML, including nine on the Nplate arm versus two on the placebo arm.  In addition, in peripheral blood counts, the percentage of circulating myeloblasts increased to greater than 10% in 28 patients, 25 of whom were in the romiplostim treatment arm.  Of the 28 patients who had an increase in circulating myeloblasts to greater than 10%, eight of these patients were diagnosed to have AML and 20 patients had not progressed to AML. In four patients, increased peripheral blood blast cell counts decreased to baseline after discontinuation of Nplate.  In a single-arm trial of Nplate given to 72 patients with thrombocytopenia related to MDS, eight (11%) patients were reported as having possible disease progression, and three patients had confirmation of AML during follow-up.  In addition, in three 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 chronic ITP.

5.2 Thrombotic/Thromboembolic Complications

Thrombotic/thromboembolic complications may result from increases in platelet counts with Nplate use.  Portal vein thrombosis has been reported in patients with chronic liver disease receiving Nplate.  Nplate should be used with caution in patients with ITP and chronic liver disease.

To minimize the risk for thrombotic/thromboembolic complications, do not use Nplate in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain a platelet count of ≥ 50 x 109/L [see Dosage and Administration (2.1)].

5.3 Bone Marrow Reticulin Formation and Risk for Bone Marrow 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.  Clinical trials are in progress to assess the risk of bone marrow fibrosis and clinical consequences with cytopenias.

If new or worsening morphological abnormalities or cytopenia(s) occur, consider a bone marrow biopsy to include staining for fibrosis [see Adverse Reactions (6.1)].

5.4 Worsened Thrombocytopenia after Cessation of Nplate

In clinical studies of patients with chronic ITP who had Nplate discontinued, four of 57 patients developed thrombocytopenia of greater severity than was present prior to Nplate therapy.  This worsened thrombocytopenia resolved within 14 days.  Following discontinuation of Nplate, obtain weekly CBCs, including platelet counts, for at least 2 weeks and consider alternative treatments for worsening thrombocytopenia, according to current treatment guidelines [see Adverse Reactions (6.1)].

5.5 Lack or 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.

5.6 Laboratory Monitoring

Obtain 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 [see Dosage and Administration (2.1) and Warnings and Precautions (5.3, 5.4)].