1. Name Of The Medicinal Product
Nplate®
Nplate®
2. Qualitative And Quantitative Composition
Each vial contains 250 µg of romiplostim. After reconstitution, a deliverable volume of 0.5 ml solution contains 250 µg of romiplostim (500 µg/ml). An additional overfill is included in each vial to ensure that 250 µg of romiplostim can be delivered.
Each vial contains 500 µg of romiplostim. After reconstitution, a deliverable volume of 1 ml solution contains 500 µg of romiplostim (500 µg/ml). An additional overfill is included in each vial to ensure that 500 µg of romiplostim can be delivered.
Romiplostim is produced by recombinant DNA technology in Escherichia coli (E. coli).
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder and solvent for solution for injection.
The powder is white.
The solvent is a clear colourless liquid.
4. Clinical Particulars
4.1 Therapeutic Indications
Nplate is indicated for adult chronic immune (idiopathic) thrombocytopenic purpura (ITP) splenectomised patients who are refractory to other treatments (e.g. corticosteroids, immunoglobulins).
Nplate may be considered as second line treatment for adult non-splenectomised patients where surgery is contra-indicated.
4.2 Posology And Method Of Administration
Treatment should remain under the supervision of a physician who is experienced in the treatment of haematological diseases.
Posology
Nplate should be administered once weekly as a subcutaneous injection.
Initial dose
The initial dose of romiplostim is 1 µg/kg based on actual body weight.
Dose calculation
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Dose adjustments
A subject's actual body weight at initiation of therapy should be used to calculate dose. The once weekly dose of romiplostim should be increased by increments of 1 μg/kg until the patient achieves a platelet count > 50 x 109/l. Platelet counts should be assessed weekly until a stable platelet count (> 50 x 109/l for at least 4 weeks without dose adjustment) has been achieved. Platelet counts should be assessed monthly thereafter. Do not exceed a maximum once weekly dose of 10 μg/kg.
Adjust the dose as follows:
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Due to the interindividual variable platelet response, in some patients platelet count may abruptly fall below 50 x 109/l after dose reduction or treatment discontinuation. In these cases, if clinically appropriate, higher cut-off levels of platelet count for dose reduction (200 x 109/l) and treatment interruption (400 x 109/l) may be considered according to medical judgement.
A loss of response or failure to maintain a platelet response with romiplostim within the recommended dosing range should prompt a search for causative factors (see section 4.4, loss of response to romiplostim).
Treatment discontinuation
Treatment with romiplostim should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after four weeks of romiplostim therapy at the highest weekly dose of 10 μg/kg.
Patients should be clinically evaluated periodically and continuation of treatment should be decided on an individual basis by the treating physician. The reoccurrence of thrombocytopenia is likely upon discontinuation of treatment (see section 4.4).
Method of administration
For subcutaneous use.
After reconstitution of the powder, Nplate solution for injection is administered subcutaneously. The injection volume may be very small. A syringe with graduations of 0.01 ml should be used.
For instructions on reconstitution of Nplate before administration, see section 6.6.
Elderly patients (
No overall differences in safety or efficacy have been observed in patients < 65 and
Paediatric population
Nplate is not recommended for use in children below age 18 due to insufficient data on safety or efficacy. No recommendation on a posology can be made in this population.
Hepatic Impairment
Romiplostim should not be used in patients with moderate to severe hepatic impairment (Child-Pugh score
If the use of romiplostim is deemed necessary, platelet count should be closely monitored to minimise the risk of thromboembolic complications.
Renal impairment
No formal clinical studies have been conducted in these patient populations. Nplate should be used with caution in these populations.
4.3 Contraindications
Hypersensitivity to the active substance, to any of the excipients or to E. coli derived proteins.
4.4 Special Warnings And Precautions For Use
The following special warnings and precautions have been actually observed or are potential class effects based on the pharmacological mechanism of action of thrombopoietin (TPO) receptor stimulators.
Reoccurrence of thrombocytopenia and bleeding after cessation of treatment
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
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.
Thrombotic/thromboembolic complications
Platelet counts above the normal range present a theoretical risk for thrombotic/thromboembolic complications. The incidence of thrombotic/thromboembolic events observed in clinical trials was similar between romiplostim and placebo, and an association between these events and elevated platelet counts was not observed. 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).
Progression of existing Myelodysplastic Syndromes (MDS)
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 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. Based on available data from a randomized trial, there were numerically more subjects in the romiplostim arm with disease progression to AML (placebo 2/72, romiplostim 9/147) and with an increase in circulating blasts to greater than 10% (placebo 3/72, romiplostim 25/147). 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.
Loss of response to romiplostim
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).
Effects of romiplostim on red and white blood cells
Alterations in red (decrease) and white (increase) blood cell parameters have been observed in non-clinical toxicology studies (rat and monkey) but not in ITP patients. Monitoring of these parameters should be considered in patients treated with romiplostim.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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 studies 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).
4.6 Pregnancy And Lactation
Pregnancy
For romiplostim no clinical data on exposed pregnancies are available.
Studies in animals have shown reproductive toxicity, such as transplacental passage and increased foetal platelet counts in rats (see section 5.3). The potential risk for humans is unknown.
Romiplostim should not be used during pregnancy unless clearly necessary.
Breast-feeding
There are no data on excretion of romiplostim in human milk. However, excretion is likely and a risk to the suckling child cannot be excluded. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with romiplostim should be made taking into account the benefit of breast-feeding to the child and the benefit of romiplostim therapy to the woman.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed. However, patients should be informed that in clinical trials mild to moderate, transient bouts of dizziness were experienced by some patients, which may affect the ability to drive or use machines.
4.8 Undesirable Effects
a. 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 reactions for romiplostim-treated subjects was 91.5% (248/271). The mean duration of exposure to romiplostim in this study population was 50 weeks.
b. Tabulated list of adverse reactions
Frequencies are defined as: Very common (
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* see section 4.4
c. Description of selected adverse reactions
In addition the reactions listed below have been deemed to be related to romiplostim treatment.
Thrombocytosis
Based on an analysis of all adult ITP patients receiving romiplostim in 4 controlled and 5 uncontrolled clinical studies, 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.
Thrombocytopenia after cessation of treatment
Based on an analysis of all adult ITP patients receiving romiplostim in 4 controlled and 5 uncontrolled clinical studies, 4 events of thrombocytopenia after cessation of treatment were reported, n = 271 (see section 4.4).
Progression of existing Myelodysplastic Syndromes (MDS)
Based on available data from a randomized clinical study in subjects 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.
Clinical data
The safety and efficacy of romiplostim have been evaluated for up to 3 years of continuous treatment. In clinical studies, treatment with romiplostim resulted in dose-dependent increases in platelet count. Time to reach the maximum effect on platelet count is approximately 10-14 days, and is independent of the dose. After a single subcutaneous dose of 1 to 10 µg/kg romiplostim in ITP patients, the peak platelet count was 1.3 to 14.9 times greater than the baseline platelet count over a 2 to 3 week period and the response was variable among patients. The platelet counts of ITP patients who received 6 weekly doses of 1 or 3 µg/kg of romiplostim were within the range of 50 to 450 x 109/l for most patients. Of the 271 patients who received romiplostim 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.
Results from pivotal placebo-controlled studies
The safety and efficacy of romiplostim was evaluated in two placebo-controlled, double-blind studies in adults with ITP who had completed at least one treatment prior to study entry and are representative of the entire spectrum of such ITP patients.
Study S1 (212) evaluated patients who were non-splenectomised and had an inadequate response or were intolerant to prior therapies. Patients had been diagnosed with ITP for approximately 2 years at the time of study entry. Patients had a median of 3 (range, 1 to 7) treatments for ITP prior to study entry. Prior treatments included corticosteroids (90% of all patients), immunoglobulins (76%), rituximab (29%), cytotoxic therapies (21%), danazol (11%), and azathioprine (5%). Patients had a median platelet count of 19 x 109/l at study entry.
Study S2 (105) evaluated patients who were splenectomised and continued to have thrombocytopenia. Patients had been diagnosed with ITP for approximately 8 years at the time of study entry. In addition to a splenectomy, patients had a median of 6 (range, 3 to 10) treatments for ITP prior to study entry. Prior treatments included corticosteroids (98% of all patients), immunoglobulins (97%), rituximab (71%), danazol (37%), cytotoxic therapies (68%), and azathioprine (24%). Patients had a median platelet count of 14 x 109/l at study entry.
Both studies were similarly designed. Patients (9/l) platelet counts. In both studies, efficacy was determined by an increase in the proportion of patients who achieved a durable platelet response. The median average weekly dose for splenectomised patients was 3 µg/kg and for non-splenectomised patients was 2 µg/kg.
A significantly higher proportion of patients receiving romiplostim achieved a durable platelet response compared to patients receiving placebo in both studies. Following the first 4-weeks of study romiplostim maintained platelet counts > 50 x 109/l in between 50% to 70% of patients during the 6 month treatment period in the placebo-controlled studies. In the placebo group, 0% to 7% of patients were able achieve a platelet count response during the 6 months of treatment. A summary of the key efficacy endpoints is presented below.
Summary of key efficacy results from placebo-controlled studies
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