Included as part of the "PRECAUTIONS" Section
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 arm. This trial consisted of a 58-week study period with a 5-year long-term follow-up phase. The subjects 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%) subjects in the Nplate arm and 4 (4.8%) subjects in the placebo arm (hazard ratio [95%CI] = 1.20 [0.38, 3.84]). Of the 250 subjects, 210 (84.0%) entered the long-term follow-up phase of this study. With 5-years of follow-up, 29 (11.6%) subjects showed progression to AML, including 20/168 (11.9%) subjects in the Nplate arm versus 9/82 (11.0%) subjects 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 subjects with thrombocytopenia-related MDS, 8 (11.1%) subjects 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%) subjects, 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.
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].
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].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (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.
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.
Women who become pregnant during Nplate treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.
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.
No clinical studies were conducted in patients with hepatic impairment.