Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Amgen Europe B.V., Minervum 7061, 4817 ZK Breda, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to E. coli derived proteins.
Thrombocytopenia is likely to reoccur upon discontinuation of treatment with romiplostim. There is an increased risk of bleeding if romiplostim treatment is discontinued in the presence of anticoagulants or anti-platelet agents. Patients should be closely monitored for a decrease in platelet count and medically managed to avoid bleeding upon discontinuation of treatment with romiplostim. It is recommended that, if treatment with romiplostim is discontinued, ITP treatment be restarted according to current treatment guidelines. Additional medical management may include cessation of anticoagulant and/or antiplatelet therapy, reversal of anticoagulation, or platelet support.
Increased bone marrow reticulin is believed to be a result of TPO receptor stimulation, leading to an increased number of megakaryocytes in the bone marrow, which may subsequently release cytokines. Increased reticulin may be suggested by morphological changes in the peripheral blood cells and can be detected through bone marrow biopsy. Therefore, examinations for cellular morphological abnormalities using peripheral blood smear and complete blood count (CBC) prior to and during treatment with romiplostim are recommended. See section 4.8 for information on the increases of reticulin observed in romiplostim clinical trials.
If a loss of efficacy and abnormal peripheral blood smear is observed in patients, administration of romiplostim should be discontinued, a physical examination should be performed, and a bone marrow biopsy with appropriate staining for reticulin should be considered. If available, comparison to a prior bone marrow biopsy should be made. If efficacy is maintained and abnormal peripheral blood smear is observed in patients, the physician should follow appropriate clinical judgment, including consideration of a bone marrow biopsy, and the risk-benefit of romiplostim and alternative ITP treatment options should be re-assessed.
Platelet counts above the normal range present a risk for thrombotic/thromboembolic complications. The incidence of thrombotic/thromboembolic events observed in clinical trials was 6.0% with romiplostim and 3.6% with placebo. 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.
Cases of thromboembolic events (TEEs), including portal vein thrombosis, have been reported in patients with chronic liver disease receiving romiplostim. Romiplostim should be used with caution in these populations. Dose adjustment guidelines should be followed (see section 4.2).
Medication errors including overdose and underdose have been reported in patients receiving Nplate, dose calculation and dose adjustment guidelines should be followed. In some paediatric patients, accurate dosing relies on an additional dilution step after reconstitution which may increase the risk for medication errors (see section 4.2).
Overdose may result in an excessive increase in platelet counts associated with 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. Underdose may result in lower than expected platelet counts and potential for bleeding. Platelet counts should be monitored in patients receiving Nplate (see sections 4.2, 4.4 and 4.9).
A positive benefit/risk for romiplostim is only established for the treatment of thrombocytopenia associated with chronic ITP and romiplostim must not be used in other clinical conditions associated with thrombocytopenia.
The diagnosis of ITP in adults and elderly patients should have been confirmed by the exclusion of other clinical entities presenting with thrombocytopenia, in particular the diagnosis of MDS must be excluded. A bone marrow aspirate and biopsy should normally have been done over the course of the disease and treatment, particularly in patients over 60 years of age, for those with systemic symptoms or abnormal signs such as increased peripheral blast cells.
In adult clinical studies of treatment with romiplostim in patients with MDS, cases of transient increases in blast cell counts were observed and cases of MDS disease progression to AML were reported. In a randomised placebo-controlled trial in MDS subjects, treatment with romiplostim was prematurely stopped due to a numerical excess of disease progression to AML and an increase in circulating blasts greater than 10% in patients receiving romiplostim. 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.
Romiplostim must not be used for the treatment of thrombocytopenia due to MDS or any other cause of thrombocytopenia other than ITP outside of clinical trials.
A loss of response or failure to maintain a platelet response with romiplostim treatment within the recommended dosing range should prompt a search for causative factors, including immunogenicity (see section 4.8) and increased bone marrow reticulin (see above).
Alterations in red (decrease) and white (increase) blood cell parameters have been observed in non-clinical toxicology studies (rat and monkey) as well as in ITP patients. Concurrent anaemia and leucocytosis (within a 4-week window) may occur in patients regardless of splenectomy status, but have been seen more often in patients who have had a prior splenectomy. Monitoring of these parameters should be considered in patients treated with romiplostim.
No interaction studies have been performed. The potential interactions of romiplostim with co-administered medicinal products due to binding to plasma proteins remain unknown.
Medicinal products used in the treatment of ITP in combination with romiplostim in clinical trials included corticosteroids, danazol, and/or azathioprine, intravenous immunoglobulin (IVIG), and anti-D immunoglobulin. Platelet counts should be monitored when combining romiplostim with other medicinal products for the treatment of ITP in order to avoid platelet counts outside of the recommended range (see section 4.2).
Corticosteroids, danazol, and azathioprine use may be reduced or discontinued when given in combination with romiplostim (see section 5.1). Platelet counts should be monitored when reducing or discontinuing other ITP treatments in order to avoid platelet counts below the recommended range (see section 4.2).
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 (see section 5.3).
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.
There is no data available on fertility.
Nplate 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.
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 Nplate 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.
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.
Very common: Upper respiratory tract infection, Rhinitis***
Common: Gastroenteritis, Pharyngitis***, Conjunctivitis***, Ear infection***, Sinusitis***
Uncommon: Influenza, Localised infection, Nasopharyngitis
Uncommon: Multiple myeloma, Myelofibrosis
Common: Bone marrow disorder*, Thrombocytopenia*, Anaemia
Uncommon: Aplastic anaemia, Bone marrow failure, Leucocytosis, Splenomegaly, Thrombocythaemia, Platelet count increased, Platelet count abnormal
Very common: Hypersensitivity**
Common: Angioedema
Uncommon: Alcohol intolerance, Anorexia, Decreased appetite, Dehydration, Gout
Common: Insomnia
Uncommon: Depression, Abnormal dreams
Very common: Headache
Common: Dizziness, Migraine, Paraesthesia
Uncommon: Clonus, Dysgeusia, Hypoaesthesia, Hypogeusia, Neuropathy peripheral, Transverse sinus, thrombosis
Uncommon: Conjunctival haemorrhage, Accommodation disorder, Blindness, Eye disorder, Eye pruritus, Lacrimation increased, Papilloedema, Visual disturbances
Uncommon: Vertigo
Common: Palpitations
Uncommon: Myocardial infarction, Heart rate increased
Common: Flushing
Uncommon: Deep vein thrombosis, Hypotension, Peripheral embolism, Peripheral ischaemia, Phlebitis, Thrombophlebitis superficial, Thrombosis, Erythromelalgia
Very common: Oropharyngeal pain***
Common: Pulmonary embolism*
Uncommon: Cough, Rhinorrhoea, Dry throat, Dyspnoea, Nasal congestion, Painful respiration
Very common: Upper abdominal pain***
Common: Nausea, Diarrhoea, Abdominal pain, Constipation, Dyspepsia
Uncommon: Vomiting, Rectal haemorrhage, Breath odour, Dysphagia, Gastro-oesophageal reflux disease, Haematochezia, Mouth haemorrhage, Stomach discomfort, Stomatitis, Tooth discolouration
Uncommon: Portal vein thrombosis, Increase in transaminase
Common: Pruritus, Ecchymosis, Rash
Uncommon: Alopecia, Photosensitivity reaction, Acne, Dermatitis contact, Dry skin, Eczema, Erythema, Exfoliative rash, Hair growth abnormal, Prurigo, Purpura, Rash papular, Rash pruritic, Skin nodule, Skin odour abnormal, Urticaria
Common: Arthralgia, Myalgia, Muscle spasms, Pain in extremity, Back pain, Bone pain
Uncommon: Muscle tightness, Muscular weakness, Shoulder pain, Muscle twitching
Uncommon: Protein urine present
Uncommon: Vaginal haemorrhage
Common: Fatigue, Oedema peripheral, Influenza like illness, Pain, Asthenia, Pyrexia, Chills
Uncommon: Injection site reaction, Peripheral swelling***, Injection site haemorrhage, Chest pain, Irritability, Malaise, Face oedema, Feeling hot, Feeling jittery
Uncommon: Blood pressure increased, Blood lactate dehydrogenase increased, Body temperature increased, Weight decreased, Weight increased
Common: Contusion
* see section 4.4
** Hypersensitivity reactions including cases of rash, urticaria, and angioedema
*** Additional adverse reactions observed in paediatric studies
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.
In addition the reactions listed below have been deemed to be related to romiplostim treatment.
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 Nplate 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 (see section 5.1) was 1.9 (4.2) for the romiplostim arm and 4.0 (6.9) for the placebo arm.
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.
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 section 4.4).
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 (see section 4.4). Overall survival was similar to placebo.
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 section 4.4).
In an ongoing paediatric clinical trial, of the subjects with an evaluable on-study bone marrow biopsy, 5 out of 27 subjects (18.5%) developed increased reticulin in cohort 1 and 2 out of 4 subjects (50.0%) developed increased reticulin in cohort 2. However, no subject showed any bone marrow abnormalities that were inconsistent with an underlying diagnosis of ITP at baseline or on-treatment.
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 (see section 6 of the Package Leaflet) for antibody testing.
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 listed in Appendix V.
This medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.
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