"The approval of changes to the Risk Evaluation and Mitigation Strategies (REMS) for both Nplate (romiplostim) and Promacta (eltrombopag) was announced by the U.S. Food and Drug Administration.
An FDA-initiated review of the current in"...
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.
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].
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.
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].
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]. 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.
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].
Medication errors including overdose and underdose have been reported in patients receiving Nplate. Overdose may result in an excessive increase in platelet counts associated with thrombotic/thromboembolic complications. If the platelet counts are excessively increased, discontinue Nplate and monitor platelet counts. Reinitiate treatment with Nplate in accordance with dosing and administration recommendations. Underdose may result in lower than expected platelet counts and potential for bleeding. Platelet counts should be monitored in patients receiving Nplate [see DOSAGE AND ADMINISTRATION and OVERDOSAGE].
Patient Counseling Information
See FDA-Approved Medication Guide.
Information for Patients
Prior to treatment, patients should fully understand the risks and benefits of Nplate. Inform patients that the risks associated with long-term administration of Nplate are unknown.
Inform patients of the following risks and considerations for Nplate:
- Nplate therapy is administered to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding; Nplate is not used to normalize platelet counts.
- Following discontinuation of Nplate, thrombocytopenia and risk of bleeding may develop that is worse than that experienced prior to the Nplate therapy.
- Nplate therapy may increase the risk of reticulin fiber formation within the bone marrow. This formation may improve upon discontinuation. Detection of peripheral blood cell abnormalities may necessitate a bone marrow examination.
- Too much Nplate may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications.
- Nplate stimulates certain bone marrow cells to make platelets and increases the risk of progression to acute myelogenous leukemia in patients with myelodysplastic syndromes.
- Platelet counts and CBCs must be performed weekly until a stable Nplate dose has been achieved; thereafter, platelet counts and CBCs must be performed monthly while taking Nplate.
- Patients must be closely monitored with weekly platelet counts and CBCs for at least 2 weeks following Nplate discontinuation.
- Even with Nplate therapy, patients should continue to avoid situations or medications that may increase the risk for bleeding.
Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of romiplostim has not been evaluated. The mutagenic potential of romiplostim has not been evaluated. Romiplostim had no effect on the fertility of rats at doses up to 37 times the MHD based on systemic exposure.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies of Nplate use in pregnant women. 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. Nplate should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
A pregnancy registry has been established to collect information about the effects of Nplate use during pregnancy. Physicians are encouraged to register pregnant patients, or pregnant women may enroll themselves in the Nplate pregnancy registry by calling 1-800-77-AMGEN (1-800-772-6436).
In rat and rabbit developmental 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. 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.
It is not known whether Nplate is excreted in human milk; however, human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Nplate, a decision should be made whether to discontinue nursing or to discontinue Nplate, taking into account the importance of Nplate to the mother and the known benefits of nursing.
The safety and effectiveness in pediatric patients ( < 18 years) have not been established.
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.
No clinical studies were conducted in patients with renal impairment. Use Nplate with caution in this population.
No clinical studies were conducted in patients with hepatic impairment. Use Nplate with caution in this population.
Last reviewed on RxList: 12/5/2012
This monograph has been modified to include the generic and brand name in many instances.
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