Amgen Ltd

Nplate^® 250 micrograms powder for solution for injection

Nplate^® 500 micrograms powder for solution for injection

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.

Powder for solution for injection.

The powder is white.

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.

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

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:

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 ( 65 years)

No overall differences in safety or efficacy have been observed in patients < 65 and 65 years of age (see section 5.1). Although based on these data no adjustment of the dosing regimen is required for older patients, care is advised considering the small number of elderly patients included in the clinical trials so far.

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 7) unless the expected benefit outweighs the identified risk of portal venous thrombosis in patients with thrombocytopenia associated to hepatic insufficiency treated with TPO agonists (see section 4.4).

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.

Hypersensitivity to the active substance, to any of the excipients or to E. coli derived proteins.

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.

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).

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.

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.

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 ( 1/10), Common ( 1/100 to < 1/10) and Uncommon ( 1/1000 to < 1/100). Within each MedDRA system organ class and frequency grouping, undesirable effects are presented in order of decreasing incidence.

* 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.

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).

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 ( 18 years) were randomised in a 2:1 ratio to receive a starting dose of romiplostim 1 µg/kg or placebo. Patients received single subcutaneous weekly injections for 24 weeks. Doses were adjusted to maintain (50 to 200 x 10⁹/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

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 ( 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 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)).

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.

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.

Mannitol (E421)

Sucrose

L-histidine

Hydrochloric acid (for pH adjustment)

Polysorbate 20

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.

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.

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.

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 250 µg of romiplostim.

Carton containing 1 or 4 vials of 500 µg of romiplostim.

Not all pack sizes may be marketed.

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.

Amgen Europe B.V.

Minervum 7061

4817 ZK Breda

The Netherlands

EU/1/08/497/001

EU/1/08/497/003

EU/1/08/497/002

EU/1/08/497/004

4 February 2009

24 August 2011

Nplate is a registered trademark of Amgen Inc.

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu