Romiplostim

Corticosteroids, danazol, and azathioprine use may be reduced or discontinued when given in combination with romiplostim. Platelet counts should be monitored when reducing or discontinuing other ITP treatments in order to avoid platelet counts below the recommended range.

No formal clinical trials have been conducted in these patient populations. Romiplostim should be used with caution in these populations.

Romiplostim should not be used in patients with moderate to severe hepatic impairment (Child-Pugh score ≥7) unless the expected benefit outweighs the identified risk of portal venous thrombosis in patients with thrombocytopenia associated to hepatic insufficiency treated with thrombopoietin (TPO) agonists.

If the use of romiplostim is deemed necessary, platelet count should be closely monitored to minimise the risk of thromboembolic complications.

Caution should be used when administering romiplostim to patients with known risk factors for thromboembolism including but not limited to inherited (e.g. Factor V Leiden) or acquired risk factors (e.g. ATIII deficiency, antiphospholipid syndrome), advanced age, patients with prolonged periods of immobilisation, malignancies, contraceptives and hormone replacement therapy, surgery/trauma, obesity and smoking.

There are no or limited amount of data from the use of romiplostim in pregnant women.

Studies in animals have shown that romiplostim crossed the placenta and increased foetal platelet counts. Post implantation loss and a slight increase in peri-natal pup mortality also occurred in animal studies.

Romiplostim is not recommended during pregnancy and in women of childbearing potential not using contraception.

It is unknown whether romiplostim/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from romiplostim therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There is no data available on fertility.

Romiplostim has moderate influence on the ability to drive and use machines. In clinical trials, mild to moderate, transient bouts of dizziness were experienced by some patients.

Summary of the safety profile

Based on an analysis of all adult ITP patients receiving romiplostim in 4 controlled and 5 uncontrolled clinical trials, the overall subject incidence of all adverse reactions 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 romiplostim 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.

^** Hypersensitivity reactions including cases of rash, urticaria, and angioedema
^*** Additional adverse reactions observed in paediatric studies
^**** Additional adverse reactions observed in adult patients with ITP duration up to 12 months

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. In this integrated analysis, the following adverse reactions (at least 5% incidence and at least 5% more frequent with romiplostim 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)).

Paediatric population

In the paediatric studies, 282 paediatric ITP subjects were treated with romiplostim in 2 controlled and 3 uncontrolled clinical trials. The median duration of exposure was 65.4 weeks. The overall safety profile was similar to that seen in adults.

The paediatric adverse reactions are derived from each of the paediatric ITP randomised safety set (2 controlled clinical trials) and paediatric ITP safety set (2 controlled and 3 uncontrolled clinical trials) where the subject incidence was at least 5% higher in the romiplostim arm compared to placebo and at least a 5% subject incidence in romiplostim-treated subjects.

The most common adverse reactions in paediatric ITP patients 1 year and older were upper respiratory tract infection, rhinitis, cough, oropharyngeal pain, upper abdominal pain, diarrhoea, rash, pyrexia, contusion (reported very commonly (≥1/10)), and pharyngitis, conjunctivitis, ear infection, gastroenteritis, sinusitis, purpura, urticaria and peripheral swelling (reported commonly (≥1/100 to <1/10)).

Oropharyngeal pain, upper abdominal pain, rhinitis, pharyngitis, conjunctivitis, ear infection, sinusitis and peripheral swelling were additional adverse reactions observed in paediatric studies compared to those seen in adult studies.

Some of the adverse reactions seen in adults were reported more frequently in paediatric subjects such as cough, diarrhoea, rash, pyrexia and contusion reported very commonly (≥1/10) in paediatric subjects and purpura and urticaria were reported commonly (≥1/100 to <1/10) in paediatric subjects.

Description of selected adverse reactions

In addition, the reactions listed below 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 × 10⁹/L. All bleeding events ≥ grade 2 occurred at platelet counts <50 × 10⁹/L. No statistically significant differences in the overall incidence of bleeding events were observed between romiplostim 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% CI = (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% CI = (0.14, 0.85)).

In the Phase 3 paediatric study, the mean (SD) number of composite bleeding episodes was 1.9 (4.2) for the romiplostim arm and 4.0 (6.9) for the placebo arm.

Thrombocytosis

Based on an analysis of all adult ITP patients receiving romiplostim in 4 controlled and 5 uncontrolled clinical trials, 3 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. Thrombocytosis in paediatric subjects occurred uncommonly (≥1/1 000 to <1/100), with a subject incidence of 1 (0.4%). Subject incidence was 1 (0.4%) for either grade ≥3 or serious thrombocytosis. 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.

Progression of existing Myelodysplastic Syndromes (MDS)

In a randomised placebo-controlled trial in MDS adult subjects treatment 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. 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.

In a paediatric clinical trial, of the subjects with an evaluable on-study bone marrow biopsy, 5 out of 27 subjects (18.5%) developed increased reticulin at year 1 after exposure to romiplostim (cohort 1) and 17 out of 36 subjects (47.2%) developed increased reticulin at year 2 after exposure to romiplostim (cohort 2). However, no subject showed any bone marrow abnormalities that were inconsistent with an underlying diagnosis of ITP at baseline or on-treatment.

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.

In paediatric studies, the incidence of binding antibodies to romiplostim at any time was 9.6% (27/282). Of the 27 subjects, 2 subjects had pre-existing binding non-neutralising romiplostim antibodies at baseline. Additionally, 2.8% (8/282) developed neutralising antibodies to romiplostim. A total of 3.9% (11/282) subjects had binding antibodies to TPO at any time during romiplostim treatment. Of these 11 subjects, 2 subjects had pre-existing binding non-neutralising antibodies to TPO. One subject (0.35%) had a weakly positive postbaseline result for neutralising antibodies against TPO while on study (consistently negative for anti-romiplostim antibodies) with a negative result at baseline. The subject showed a transient antibody response for neutralising antibodies against TPO, with a negative result at the subject’s last timepoint tested within the study period.

In the post-marketing registry study, 19 confirmed paediatric patients were included. The incidence of binding antibody post treatment was 16% (3/19) to romiplostim, of which 5.3% (1/19) were positive for neutralising antibodies to romiplostim. There were no antibodies detected to TPO. A total of 184 confirmed adult patients were included in this study; for these patients, the incidence of binding antibody post treatment was 3.8% (7/184) to romiplostim, of which 0.5% (1/184) was positive for neutralising antibodies to romiplostim. A total of 2.2% (4/184) adult patients developed binding, non-neutralising antibody against TPO.

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 for antibody testing.