Romiplate Adverse Reactions

Summary of the safety profile: Based on an analysis of all adult ITP patients receiving romiplostim in 4 controlled and 5 uncontrolled clinical studies, the overall subject incidence of all adverse events for romiplostim-treated subjects was 91.5% (248/271). The mean duration of exposure to romiplostim in this study population was 50 weeks.
The most serious adverse reactions that may occur during Romiplate treatment include: reoccurrence of thrombocytopenia and bleeding after cessation of treatment, increased bone marrow reticulin, thrombotic/thromboembolic complications, medication errors and progression of existing MDS to AML. The most common adverse reactions observed include hypersensitivity reactions (including cases of rash, urticaria and angioedema) and headache.
Tabulated list of adverse reactions: Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to >1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each MedDRA system organ class and frequency grouping, undesirable effects are presented in order of decreasing incidence. (See Tables 8a and 8b.)

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Adult population with ITP duration up to 12 months: The safety profile of romiplostim was similar across adult patients, regardless of ITP duration. Specifically in the integrated analysis of ITP ≤12 months duration (n=311), 277 adult patients with ITP ≤12 months duration and who received at least one dose of romiplostim from among those patients in 9 ITP studies were included (see also Pharmacology: Pharmacodynamics under Actions). In this integrated analysis, the following adverse reactions (at least 5% incidence and at least 5% more frequent with Romiplate compared with placebo or standard of care) occurred in romiplostim patients with ITP duration up to 12 months, but were not observed in those adult patients with ITP duration >12 months: bronchitis, sinusitis (reported commonly (≥1/100 to <1/10)).
Description of selected adverse reactions: In addition, the reactions listed as follows have been deemed to be related to romiplostim treatment.
Bleeding events: Across the entire adult ITP clinical programme an inverse relationship between bleeding events and platelet counts was observed. All clinically significant (≥grade 3) bleeding events occurred at platelet counts <30 x 10⁹/L. All bleeding events ≥grade 2 occurred at platelet counts <50 x 10⁹/L. No statistically significant differences in the overall incidence of bleeding events were observed between Romiplate and placebo treated patients.
In the two adult placebo-controlled studies, 9 patients reported a bleeding event that was considered serious (5 [6.0%] romiplostim, 4 [9.8%] placebo; Odds Ratio [romiplostim/placebo]=0.59; 95% Cl=(0.15, 2.31)). Bleeding events that were grade 2 or higher were reported by 15% of patients treated with romiplostim and 34% of patients treated with placebo (Odds Ratio; [romiplostim/placebo]=0.35; 95% Cl=(0.14, 0.85)).
Thrombocytosis: Based on an analysis of all adult ITP patients receiving romiplostim in 4 controlled and 5 uncontrolled clinical trials, 4 events of thrombocytosis were reported, n=271. No clinical sequelae were reported in association with the elevated platelet counts in any of the 3 subjects.
Thrombocytopenia after cessation of treatment: Based on an analysis of all adult ITP patients receiving romiplostim in 4 controlled and 5 uncontrolled clinical trials, 4 events of thrombocytopenia after cessation of treatment were reported, n=271 (see Precautions).
Progression of existing Myelodysplastic Syndromes (MDS): In a randomized placebo-controlled trial in MDS adult subjects with romiplostim was prematurely stopped due to a numerical increase in cases of MDS disease progression to AML and transient increases in blast cell counts 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 (see Precautions). Overall survival was similar to placebo.
Increased bone marrow reticulin: In adult clinical trials, 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 Precautions).
Immunogenicity: Clinical trials in adult ITP patients examined antibodies to romiplostim and TPO. While 5.7% (60/1,046) and 3.2% (33/1,046) of the subjects were positive for developing binding antibodies to romiplostim and TPO respectively, only 4 subjects were positive for neutralising antibodies to romiplostim but these antibodies did not cross react with endogenous TPO. Of the 4 subjects, 2 subjects tested negative for neutralising antibodies to romiplostim at the subject's last timepoint (transient positive) and 2 subjects remained positive at the subject's last timepoint (persistent antibodies). The incidence of pre-existing antibodies to romiplostim and TPO was 3.3% (35/1,046) and 3.0% (31/1,046), respectively.
As with all therapeutic proteins, there is a potential for immunogenicity. If formation of neutralising antibodies is suspected, contact the local product registration holder or Medical Representatives for antibody testing.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system and to the local product registration holder.
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: Erythromelalgia; Hypersensitivity reactions including angioedema. Patients also experienced symptoms consistent with anaphylaxis.