1. Name Of The Medicinal Product
Nplate®250 micrograms powder for solution for injection
Nplate®500 micrograms powder for solution for injection
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 for solution for injection.
This powder is white.
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 9/l. Platelet counts should be assessed weekly until a stable platelet count (9/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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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 and 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. Dose adjustment guidelines should be followed (see section 4.2).
Progression of existing haematopoietic malignancies or Myelodysplastic Syndromes (MDS)
TPO receptor stimulators are growth factors that lead to thrombopoietic progenitor cell expansion, differentiation, and platelet production. The TPO receptor is predominantly expressed on the surface of cells of the myeloid lineage. For TPO receptor stimulators there is a theoretical concern that they may stimulate the progression of existing haematopoietic malignancies or MDS.
Romiplostim should not be used for the treatment of thrombocytopenia due to MDS or any other cause of thrombocytopenia other than ITP outside of clinical trials. The risk-benefit profile for romiplostim has not been established in MDS or other non-ITP patient populations. In clinical studies of treatment with romiplostim in patients with MDS, there were reported cases of progression to acute myeloid leukaemia (AML), however this is an expected clinical outcome of MDS and the relationship to romiplostim treatment is unclear.
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.
Breastfeeding
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
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 adverse events listed in the table below are those deemed treatment related by investigators and which occur at a > 1% incidence (n = 271).
Frequencies are defined as: Very common (
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In addition the events 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).
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
In clinical studies, antibodies to romiplostim were examined. Of the 271 adult ITP patients receiving romiplostim in the ITP clinical programme one patient developed antibodies capable of neutralising the activity of romiplostim but these antibodies did not cross react with endogenous TPO. Approximately 4 months later, the patient tested negative for neutralising antibodies to romiplostim.
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.
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. Re-initiate 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 9/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 to 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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Reduction in permitted concurrent ITP medical therapies
In both placebo-controlled, double-blind studies, patients already receiving ITP medical therapies at a constant dosing schedule were allowed to continue receiving these medical treatments throughout the study (corticosteroids, danazol and/or azathioprine). Twenty-one non-splenectomised and 18 splenectomised patients received on-study ITP medical treatments (primarily corticosteroids) at the start of study. All (100%) splenectomised patients who were receiving romiplostim were able to reduce the dose by more than 25% or discontinue the concurrent ITP medical therapies by the end of the treatment period compared to 17% of placebo treated patients. Seventy-three percent of non-splenectomised patients receiving romiplostim were able to reduce the dose by more than 25% or discontinue concurrent ITP medical therapies by the end of the study compared to 50% of placebo treated patients (see section 4.5).
Bleeding events
Across the entire ITP clinical programme an inverse relationship between bleeding events and platelet counts was observed. All clinically significant (9/l. All bleeding events 9/l. No statistically significant differences in the overall incidence of bleeding events were observed between Nplate and placebo treated patients.
In the two 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)).
5.2 Pharmacokinetic Properties
The pharmacokinetics of romiplostim involved target-mediated disposition, which is presumably mediated by TPO receptors on platelets and other cells of the thrombopoietic lineage such as megakaryocytes.
Absorption
After subcutaneous administration of 3 to 15 μg/kg romiplostim, maximum romiplostim serum levels in ITP patients were obtained after 7-50 hours (median 14 hours). The serum concentrations varied among patients and did not correlate with the dose administered. Romiplostim serum levels appear inversely related to platelet counts.
Distribution
The volume of distribution of romiplostim following intravenous administration of romiplostim decreased nonlinearly from 122, 78.8, to 48.2 ml/kg for intravenous doses of 0.3, 1.0 and 10 μg/kg, respectively in healthy subjects. This non-linear decrease in volume of distribution is in line with the (megakaryocyte and platelet) target-mediated binding of romiplostim, which may be saturated at the higher doses applied.
Elimination
Elimination half-life of romiplostim in ITP patients ranged from 1 to 34 days (median, 3.5 days).
The elimination of serum romiplostim is in part dependent on the TPO receptor on platelets. As a result for a given dose, patients with high platelet counts are associated with low serum concentrations and vice versa. In another ITP clinical study, no accumulation in serum concentrations was observed after 6 weekly doses of romiplostim (3 μg/kg).
Special patient populations
Pharmacokinetics of romiplostim in patients with renal and hepatic impairment has not been investigated. Romiplostim pharmacokinetics appear not affected by age, weight and gender to a clinically significant extent.
5.3 Preclinical Safety Data
Multiple dose romiplostim toxicology studies were conducted in rats for 4 weeks and in monkeys for up to 6 months. In general, effects observed during these studies were related to the thrombopoietic activity of romiplostim and were similar regardless of study duration. Injection site reactions were also related to romiplostim administration. Myelofibrosis has been observed in the bone marrow of rats at all tested dose levels. In these studies, myelofibrosis was not observed in animals after a 4-week post-treatment recovery period, indicating reversibility.
In 1-month rat and monkey toxicology studies, a mild decrease in red blood cell count, haematocrit and haemoglobin was observed. There was also a stimulatory effect on leukocyte production, as peripheral blood counts for neutrophils, lymphocytes, monocytes, and eosinophils were mildly increased. In the longer duration chronic monkey study, there was no effect on the erythroid and leukocytic lineages when romiplostim was administered for 6 months where the administration of romiplostim was decreased from thrice weekly to once weekly. Additionally, in the phase 3 pivotal studies, romiplostim did not affect the red blood cell and white blood cells lineages relative to placebo treated subjects.
Due to the formation of neutralising antibodies pharmacodynamic effects of romiplostim in rats were often decreasing at prolonged duration of administration. Toxicokinetic studies showed no interaction of the antibodies with the measured concentrations.
Although high doses were tested in the animal studies, due to differences between the laboratory species and humans with regard to the sensitivity for the pharmacodynamic effect of romiplostim and the effect of neutralising antibodies, safety margins cannot be reliably estimated.
Carcinogenesis: The carcinogenic potential of romiplostim has not been evaluated. Therefore, the risk of potential carcinogenicity of romiplostim in humans remains unknown.
Reproductive toxicology: In all developmental studies neutralising antibodies were formed, which may have inhibited romiplostim effects. In embryo-foetal development studies in mice and rats, reductions in maternal body weight were found only in mice. In mice there was evidence of increased post-implantation loss. In a prenatal and postnatal development study in rats an increase of the duration of gestation and a slight increase in the incidence of peri-natal pup mortality was found. Romiplostim is known to cross the placental barrier in rats and may be transmitted from the mother to the developing foetus and stimulate foetal platelet production. Romiplostim had no observed effect on the fertility of rats.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Mannitol (E421)
Sucrose
L-histidine
Hydrochloric acid (for pH adjustment)
Polysorbate 20
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.
6.3 Shelf Life
3 years.
After reconstitution: Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C and for 24 hours at 2°C – 8°C, when protected from light and kept in the original vial.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 25°C or 24 hours in a refrigerator (2°C – 8°C), protected from light.
6.4 Special Precautions For Storage
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Store in the original carton in order to protect from light.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature And Contents Of Container
5 ml vial (type 1 clear glass) with a stopper (chlorobutyl rubber), seal (aluminium) and a flip-off cap (polypropylene).
Carton containing 1 or 4 vials of either 250 micrograms or 500 micrograms of romiplostim.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
Nplate is a sterile but unpreserved product and is intended for single use only. Nplate should be reconstituted in accordance with good aseptic practice.
Nplate 250 micrograms powder for solution for injection should be reconstituted with 0.72 ml sterile water for injections, yielding a deliverable volume of 0.5 ml. An additional overfill is included in each vial to ensure that 250 µg of romiplostim can be delivered.
Nplate 500 micrograms powder for solution for injection should be reconstituted with 1.2 ml sterile water for injections, yielding a deliverable volume of 1 ml. An additional overfill is included in each vial to ensure that 500 µg of romiplostim can be delivered.
Sodium chloride solutions or bacteriostatic water should not be used when reconstituting the medicinal product.
Water for injections should be injected into the vial. The vial contents may be swirled gently and inverted during dissolution. The vial should not be shaken or vigorously agitated. Generally, dissolution of Nplate takes less than 2 minutes. Visually inspect the solution for particulate matter and discolouration before administration. The reconstituted solution should be clear and colourless and should not be administered if particulate matter and/or discolouration are observed.
For the storage condition of the reconstituted product see section 6.3.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands
8. Marketing Authorisation Number(S)
250 μg (1 pack) – EU/1/08/497/001 250 μg (4 pack) – EU/1/08/497/003
500 μg (1 pack) – EU/1/08/497/002 500 μg (4 pack) – EU/1/08/497/004
