BRIEF SUMMARY OF PRESCRIBING INFORMATION NPLATE ® ( romiplostim ) for injection , for subcutaneous use
1 INDICATIONS AND USAGE
Nplate ® is indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia ( ITP ) who have had an insufficient response to corticosteroids , immunoglobulins , or splenectomy .
Limitations of Use :
• Nplate ® is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome ( MDS ) or any cause of thrombocytopenia other than chronic 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 [ see Warnings and Precautions ( 5.2 )].
• Nplate ® should not be used in an attempt to normalize platelet counts [ see Warnings and Precautions ( 5.2 )].
4 CONTRAINDICATIONS None .
5 WARNINGS AND PRECAUTIONS
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 ® .
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 )].
5.3 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 .
5.4 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 )].
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections :
• Progression of Myelodysplastic Syndromes [ see Warnings and Precautions ( 5.1 )]
• Thrombotic / Thromboembolic Complications [ see Warnings and Precautions ( 5.2 )]
• Loss of Response to Nplate ® [ see Warnings and Precautions ( 5.3 )]
• Laboratory Monitoring [ see Warnings and Precautions ( 5.4 )]
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice .
The data described below reflect Nplate ® exposure to 271 patients with chronic ITP , aged 18 to 88 , of whom 62 % were female . Nplate ® was studied in two randomized , placebo-controlled , double-blind studies that were identical in design , with the exception that Study 1 evaluated nonsplenectomized patients with ITP and Study 2 evaluated splenectomized patients with ITP . Data are also reported from an open-label , single-arm study in which patients received Nplate ® over an extended period of time . Overall , Nplate ® was administered to 114 patients for at least 52 weeks and 53 patients for at least 96 weeks .
In the placebo-controlled studies , headache was the most commonly reported adverse drug reaction , occurring in 35 % of patients receiving Nplate ® and 32 % of patients receiving placebo . Headaches were usually of mild or moderate severity . Table 2 presents adverse drug reactions from Studies 1 and 2 with a ≥ 5 % higher patient incidence in Nplate ® versus placebo . The majority of these adverse drug reactions were mild to moderate in severity .
Table 2 . Adverse Drug Reactions Identified in Two Placebo Controlled Studies
Preferred Term |
Nplate ® ( n = 84 ) |
Placebo ( n = 41 ) |
Arthralgia |
26 % |
20 % |
Dizziness |
17 % |
0 % |
Insomnia |
16 % |
7 % |
Myalgia |
14 % |
2 % |
Pain in Extremity |
13 % |
5 % |
Abdominal Pain |
11 % |
0 % |
Shoulder Pain |
8 % |
0 % |
Dyspepsia |
7 % |
0 % |
Paresthesia |
6 % |
0 % |
Among 142 patients with chronic ITP who received Nplate ® in the single-arm extension study , the incidence rates of the adverse reactions occurred in a pattern similar to those reported in the placebo-controlled clinical studies .
Bone Marrow Reticulin Formation and Collagen 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 .
An open-label clinical trial prospectively evaluated changes in bone marrow reticulin formation and collagen fibrosis in adult patients with ITP treated with Nplate ® or a non-US approved romiplostim product . Patients were administered romiplostim by SC injection once weekly for up to 3 years . Based on cohort assignment at time of study enrollment , patients were evaluated for bone marrow reticulin and collagen at year 1 ( cohort 1 ), year 2 ( cohort 2 ), or year 3 ( cohort 3 ) in comparison to the baseline bone marrow at start of the trial . Patients were evaluated for bone marrow reticulin formation and collagen fibrosis using the modified Bauermeister grading scale . From the total of 169 patients enrolled in the 3 cohorts , 132 ( 78 %) patients were evaluable for bone marrow collagen fibrosis and 131 ( 78 %) patients were evaluable for bone marrow reticulin formation . Two percent ( 2 / 132 ) of patients ( both from cohort 3 ) developed Grade 4 findings ( presence of collagen ). There was no detectable bone marrow collagen in one patient on repeat testing 12 weeks after discontinuation of romiplostim . Progression of bone marrow reticulin formation ( increase greater than or equal to 2 grades or more ) or an increase to Grade 4 ( presence of collagen ) was reported in 7 % ( 9 / 131 ) of patients .
6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Nplate ® . Because these reactions are reported voluntarily from a population of uncertain size , it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure .
• Erythromelalgia
• Hypersensitivity
• Angioedema
6.3 Immunogenicity As with all therapeutic proteins , patients may develop antibodies to the therapeutic protein . Patients were screened for immunogenicity to romiplostim using a BIAcore-based biosensor immunoassay . This assay is capable of detecting both high- and low-affinity binding antibodies that bind to romiplostim and cross-react with TPO . The samples from patients that tested positive for binding antibodies were further evaluated for neutralizing capacity using a cell-based bioassay .
In clinical studies in patients with ITP , the incidence of preexisting antibodies to romiplostim was 5 % ( 53 / 1112 ) and the incidence of binding antibody development during treatment with Nplate ® or a non- US approved romiplostim product was 4 % ( 50 / 1112 ). The incidence of preexisting antibodies to endogenous TPO was 4 % ( 40 / 1112 ) and the incidence of binding antibody development to endogenous TPO during treatment was 3 % ( 38 / 1112 ). Of the patients with positive binding antibodies that developed to romiplostim or to TPO , five patients had neutralizing activity to romiplostim and none had neutralizing activity to TPO . No apparent correlation was observed between antibody activity and clinical effectiveness or safety .
A postmarketing registry study involving patients with thrombocytopenia on Nplate ® or a non-US approved romiplostim product was conducted to assess the long-term consequences of the anti-romiplostim antibodies . Patients who lacked response or lost response to Nplate ® or a non-US approved romiplostim product were enrolled . The incidence of new binding antibody development was 3 % ( 5 / 186 ) to romiplostim and 1 % ( 2 / 186 ) to TPO . One patient was positive for binding antibodies to both romiplostim and TPO . Of the five patients with positive binding antibodies to romiplostim , two ( 1 %) were positive for neutralizing antibodies to romiplostim only .
Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection and may be influenced by several factors , including sample handling , concomitant medications , and underlying disease . For these reasons , comparison of incidence of antibodies to romiplostim with the incidence of antibodies to other products may be misleading .
7 DRUG INTERACTIONS No formal drug interaction studies of Nplate ® have been performed .
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy 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 .
8.3 Nursing Mothers 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 .
8.4 Pediatric Use The safety and effectiveness in pediatric patients (< 18 years ) have not been established .
8.5 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 .
8.6 Renal Impairment No clinical studies were conducted in patients with renal impairment .
8.7 Hepatic Impairment No clinical studies were conducted in patients with hepatic impairment .
10 OVERDOSAGE
Overdoses due to medication errors have been reported in patients receiving Nplate ® . In the event of overdose , platelet counts may increase excessively and result in thrombotic / thromboembolic complications . In this case , discontinue Nplate ® and monitor platelet counts . Reinitiate treatment with Nplate ® in accordance with dosing and administration recommendations [ see Dosage and Administration ( 2.1 , 2.2 )].
This Brief Summary using USPIv10 4 / 22 / 2016 Nplate ® ( romiplostim )
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