WARNINGS AND PRECAUTIONS
Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis
Nplate administration increases the risk for development or progression of reticulin fiber deposition within the bone marrow. In clinical studies, Nplate was discontinued in four of the 271 patients because of bone marrow reticulin deposition. Six additional patients had reticulin observed upon bone marrow biopsy. All 10 patients with bone marrow reticulin deposition had received Nplate doses ≥ 5 mcg/kg and six received doses ≥ 10 mcg/kg. Progression to marrow fibrosis with cytopenias was not reported in the controlled clinical studies. In the extension study, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Nplate therapy. Clinical studies have not excluded a risk of bone marrow fibrosis with cytopenias.
Prior to initiation of Nplate, examine the peripheral blood smear closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable Nplate dose, examine peripheral blood smears and CBCs monthly for new or worsening morphological abnormalities (eg, teardrop and nucleated red blood cells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), discontinue treatment with Nplate and consider a bone marrow biopsy, including staining for fibrosis [ see Adverse Reactions ].
Worsened Thrombocytopenia After Cessation of Nplate
Discontinuation of Nplate may result in thrombocytopenia of greater severity than was present prior to Nplate therapy. This worsened thrombocytopenia may increase the patient’s risk of bleeding, particularly if Nplate is discontinued while the patient is on anticoagulants or antiplatelet agents. 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 ].
Thrombotic/thromboembolic complications may result from excessive increases in platelet counts. Excessive doses of Nplate or medication errors that result in excessive Nplate doses may increase platelet counts to a level that produces thrombotic/thromboembolic complications. In controlled clinical studies, the incidence of thrombotic/thromboembolic complications was similar between Nplate and placebo. 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 ].
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 or bone marrow fibrosis [ see Warnings and Precautions and 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.
Malignancies and Progression of Malignancies
Nplate stimulation of the TPO receptor on the surface of hematopoietic cells may increase the risk for hematologic malignancies. In controlled clinical studies among patients with chronic ITP, the incidence of hematologic malignancy was low and similar between Nplate and placebo. In a separate single-arm clinical study of 44 patients with myelodysplastic syndrome (MDS), 11 patients were reported as having possible disease progression, among whom four patients had confirmation of acute myelogenous leukemia (AML) during follow-up. Nplate is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP.
Monitor CBCs, including platelet counts and peripheral blood smears, prior to initiation, throughout, and following discontinuation of Nplate therapy. Prior to the initiation of Nplate, examine the peripheral blood differential to establish the baseline extent of red and white blood cell abnormalities. Obtain CBCs, including platelet counts and peripheral blood smears, 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 (5.1, 5.2) ].
Nplate Distribution Program
Nplate is available only through a restricted distribution program called Nplate NEXUS (Network of Experts Understanding and Supporting Nplate and Patients) Program. Under the Nplate NEXUS Program, only prescribers and patients registered with the program are able to prescribe, administer, and receive Nplate. This program provides educational materials and a mechanism for the proper use of Nplate. To enroll in the Nplate NEXUS Program, call 1-877-Nplate1 (1-877-675-2831). Prescribers and patients are required to understand the risks of Nplate therapy. Prescribers are required to understand the information in the prescribing information and be able to:
- Educate patients on the benefits and risks of treatment with Nplate, ensure that the patient receives the Medication Guide, instruct them to read it, and encourage them to ask questions when considering Nplate. Patients may be educated by the enrolled prescriber or a healthcare provider under that prescriber’s direction.
- Review the Nplate NEXUS Program Healthcare Provider Enrollment Form, sign the form, and return the form according to Nplate NEXUS Program instructions.
- Review the Nplate NEXUS Program Patient Enrollment Form, answer all questions, obtain the patient’s signature on the Nplate NEXUS Program Patient Enrollment Form, place the original signed form in the patient’s medical record, send a copy according to Nplate NEXUS Program instructions, and give a copy to the patient.
- Report any serious adverse events associated with the use of Nplate to the Nplate NEXUS Program Call Center at 1-877-Nplate1 (1-877-675-2831) or to the FDA’s MedWatch Program at 1-800-FDA-1088.
- Report serious adverse events observed in patients receiving Nplate, including events actively solicited at 6-month intervals.
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.
Pregnancy Registry: 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 1-877-Nplate1 (1-877-675-2831).
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 (rabbit) 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.