bjects with myelodysplastic syndromes (MDS), a numerical increase in cases of MDS disease progression to AML and transient increases in blast cell counts were seen in patients treated with romiplostim compared to placebo. Of the cases of MDS disease progression to AML that were observed, patients with RAEB-1 classification of MDS at baseline were more likely to have disease progression to AML compared to lower risk MDS (see section 4.4). Overall survival and AML free survival were similar to placebo. More hemorrhagic deaths were reported in the placebo arm. A reduction in the risk for clinically significant bleeding events and platelet transfusion events was seen with romiplostim treatment.
Increased bone marrow reticulin
In clinical studies, romiplostim treatment was discontinued in 4 of the 271 patients because of bone marrow reticulin deposition. In 6 additional patients reticulin was observed upon bone marrow biopsy (see section 4.4).
Immunogenicity
Clinical studies in adult ITP patients examined antibodies to romiplostim.
While 5.8% and 3.9% of the subjects were positive for developing binding antibodies to romiplostim and TPO respectively, only 2 subjects (0.4%) were positive for neutralizing antibodies to romiplostim but these antibodies did not cross react with endogenous TPO. Both subjects tested negative for neutralising antibodies to romiplostim at 4 months after the end of dosing. The incidence of pre-existing antibodies to romiplostim and TPO was 8.0% and 5.4%, respectively.
As with all therapeutic proteins, there is a potential for immunogenicity. If formation of neutralising antibodies is suspected, contact the local representative of the Marketing Authorisation Holder (see section 6 of the Package Leaflet) for antibody testing.
Adverse reactions from spontaneous reporting:
The frequency category of the adverse reactions identified from spontaneous reporting that have not been reported in clinical trials cannot be estimated (Frequency: not known). The adverse reactions identified from spontaneous reporting include:
Vascular disorders: Erythromelalgia.
4.9 Overdose
No adverse effects were seen in rats given a single dose of 1000 μg/kg or in monkeys after repeated administration of romiplostim at 500 µg/kg (100 or 50 times the maximum clinical dose of 10 µg/kg, respectively).
In the event of overdose, platelet counts may increase excessively and result in 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 (see section 4.2).
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antihemorrhagics, ATC code: B02BX04
Romiplostim is an Fc-peptide fusion protein (peptibody) that signals and activates intracellular transcriptional pathways via the thrombopoietin (TPO) receptor (also known as cMpl) to increase platelet production. The peptibody molecule is comprised of a human immunoglobulin IgG1 Fc domain, with each single-chain subunit covalently linked at the C-terminus to a peptide chain containing 2 TPO receptor-binding domains.
Romiplostim has no amino acid sequence homology to endogenous TPO. In pre-clinical and clinical studies no anti-romiplostim antibodies cross reacted with endogenous TPO.
