Leaflet NPLATE 250mcg powder for injection

Nplate 125 micrograms powder for solution for injection

Nplate 250 micrograms powder for solution for injection

Nplate 500 micrograms powder for solution for injection

Nplate 125 micrograms powder for solution for injection

Each vial contains 125 mcg of romiplostim. After reconstitution, a deliverable volume of 0.25 mLsolution contains 125 mcg of romiplostim (500 mcg/mL). An additional overfill is included in eachvial to ensure that 125 mcg of romiplostim can be delivered.

Nplate 250 micrograms powder for solution for injection

Each vial contains 250 mcg of romiplostim. After reconstitution, a deliverable volume of 0.5 mLsolution contains 250 mcg of romiplostim (500 mcg/mL). An additional overfill is included in eachvial to ensure that 250 mcg of romiplostim can be delivered.

Nplate 500 micrograms powder for solution for injection

Each vial contains 500 mcg of romiplostim. After reconstitution, a deliverable volume of 1 mLsolution contains 500 mcg of romiplostim (500 mcg/mL). An additional overfill is included in eachvial to ensure that 500 mcg of romiplostim can be delivered.

Romiplostim is produced by recombinant DNA technology in Escherichia coli (E. coli).

For the full list of excipients, see section 6.1.

Powder for solution for injection (powder for injection).

The powder is white.

Nplate is indicated for the treatment of primary immune thrombocytopenia (ITP) in adult patients whoare refractory to other treatments (e.g. corticosteroids, immunoglobulins) (see sections 4.2 and 5.1).

Paediatrics:

Nplate is indicated for the treatment of chronic primary immune thrombocytopenia (ITP) in paediatricpatients one year of age and older who are refractory to other treatments (e.g. corticosteroids,immunoglobulins) (see sections 4.2 and 5.1).

Treatment should remain under the supervision of a physician who is experienced in the treatment ofhaematological diseases.

Nplate should be administered once weekly as a subcutaneous injection.

Initial dose

The initial dose of romiplostim is 1 mcg/kg based on actual body weight.

Dose calculation

The volume of romiplostim to administer is calculated based on body weight, dose required, andconcentration of product.

Table 1. Guidelines for calculating individual patient dose and volume of romiplostim toadminister

Individual patient dose Individual patient dose (mcg) = weight (kg) x dose in mcg/kg(mcg)

Actual body weight at initiation of treatment should always be used whencalculating initial dose.

- In adults, future dose adjustments are based on changes in plateletcounts only.

- In paediatric patients, future dose adjustments are based on changesin platelet counts and changes in body weight. Reassessment ofbody weight is recommended every 12 weeks.

If individual patient Reconstitute lyophilised product as described in section 6.6. The resultingdose is ≥ 23 mcg concentration is 500 mcg/mL.

Volume to administer (mL) = Individual patient dose (mcg)/500 mcg/mL(Round volume to the nearest hundredth mL)

If individual patient Dilution is required to ensure accurate dosing. Reconstitute lyophiliseddose is < 23 mcg product and then dilute the product as described in section 6.6. Theresulting concentration is 125 mcg/mL.

Volume to administer (mL) = Individual patient dose (mcg)/125 mcg/mL(Round volume to the nearest hundredth mL)

Example 10 kg patient is initiated at 1 mcg/kg of romiplostim.

Individual patient dose (mcg) = 10 kg x 1 mcg/kg = 10 mcg

Because the dose is < 23 mcg, dilution is required to ensure accuratedosing. Reconstitute lyophilised product and then dilute the product asdescribed in section 6.6. The resulting concentration is 125 mcg/mL.

Volume to administer (mL) = 10 mcg/125 mcg/mL = 0.08 mL

A subject’s actual body weight at initiation of therapy should be used to calculate dose. The onceweekly dose of romiplostim should be increased by increments of 1 mcg/kg until the patient achieves aplatelet 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 shouldbe assessed monthly thereafter and appropriate dose adjustments made as per the dose adjustmenttable (table 2) in order to maintain platelet counts within the recommended range. See table 2 belowfor dose adjustment and monitoring. A maximum once weekly dose of 10 mcg/kg should not beexceeded.

Table 2. Dose adjustment guidance based on platelet count

Platelet count(x 109 Action/L)< 50 Increase once weekly dose by 1 mcg/kg> 150 for two

Decrease once weekly dose by 1 mcg/kgconsecutive weeks

Do not administer, continue to assess the platelet count weekly> 250

After the platelet count has fallen to < 150 x 109/L, resume dosing with onceweekly dose reduced by 1 mcg/kg

Due to the interindividual variable platelet response, in some patients platelet count may abruptly fallbelow 50 x 109/L after dose reduction or treatment discontinuation. In these cases, if clinicallyappropriate, higher cut-off levels of platelet count for dose reduction (200 x 109/L) and treatmentinterruption (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 recommendeddosing range should prompt a search for causative factors (see section 4.4, loss of response toromiplostim).

Treatment with romiplostim should be discontinued if the platelet count does not increase to a levelsufficient to avoid clinically important bleeding after four weeks of romiplostim therapy at the highestweekly dose of 10 mcg/kg.

Patients should be clinically evaluated periodically and continuation of treatment should be decided onan individual basis by the treating physician, and in non-splenectomised patients this should includeevaluation relative to splenectomy. The reoccurrence of thrombocytopenia is likely upondiscontinuation of treatment (see section 4.4).

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 forolder patients, care is advised considering the small number of elderly patients included in the clinicaltrials so far.

The safety and efficacy of romiplostim in children under the age of one year has not been established.

Romiplostim should not be used in patients with moderate to severe hepatic impairment (Child-Pughscore ≥ 7) unless the expected benefit outweighs the identified risk of portal venous thrombosis inpatients with thrombocytopenia associated to hepatic insufficiency treated with thrombopoietin (TPO)agonists (see section 4.4).

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

No formal clinical trials have been conducted in these patient populations. Nplate should be used withcaution in these populations.

For subcutaneous use.

After reconstitution of the powder, Nplate solution for injection is administered subcutaneously. Theinjection volume may be very small. Caution should be used during preparation of Nplate incalculating the dose and reconstitution with the correct volume of sterile water for injection. If thecalculated individual patient dose is less than 23 mcg, dilution with preservative-free, sterile, sodiumchloride 9 mg/mL (0.9%) solution for injection is required to ensure accurate dosing (see section 6.6).

Special care should be taken to ensure that the appropriate volume of Nplate is withdrawn from thevial for subcutaneous administration - a syringe with graduations of 0.01 mL should be used.

Self-administration of Nplate is not allowed for paediatric patients.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to E. coliderived proteins.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Reoccurrence of thrombocytopenia and bleeding after cessation of treatment

Thrombocytopenia is likely to reoccur upon discontinuation of treatment with romiplostim. There isan increased risk of bleeding if romiplostim treatment is discontinued in the presence of anticoagulantsor anti-platelet agents. Patients should be closely monitored for a decrease in platelet count andmedically managed to avoid bleeding upon discontinuation of treatment with romiplostim. It isrecommended that, if treatment with romiplostim is discontinued, ITP treatment be restarted accordingto current treatment guidelines. Additional medical management may include cessation ofanticoagulant 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 anincreased 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 canbe detected through bone marrow biopsy. Therefore, examinations for cellular morphologicalabnormalities using peripheral blood smear and complete blood count (CBC) prior to and duringtreatment with romiplostim are recommended. See section 4.8 for information on the increases ofreticulin observed in romiplostim clinical trials.

If a loss of efficacy and abnormal peripheral blood smear is observed in patients, administration ofromiplostim should be discontinued, a physical examination should be performed, and a bone marrowbiopsy with appropriate staining for reticulin should be considered. If available, comparison to a priorbone marrow biopsy should be made. If efficacy is maintained and abnormal peripheral blood smear isobserved in patients, the physician should follow appropriate clinical judgment, includingconsideration of a bone marrow biopsy, and the risk-benefit of romiplostim and alternative ITPtreatment options should be re-assessed.

Thrombotic/thromboembolic complications

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% withromiplostim and 3.6% with placebo. Caution should be used when administering romiplostim topatients 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 andhormone replacement therapy, surgery/trauma, obesity and smoking.

Cases of thromboembolic events (TEEs), including portal vein thrombosis, have been reported inpatients with chronic liver disease receiving romiplostim. Romiplostim should be used with caution inthese 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 riskfor medication errors (see section 4.2).

Overdose may result in an excessive increase in platelet counts associated withthrombotic/thromboembolic complications. If the platelet counts are excessively increased,discontinue Nplate and monitor platelet counts. Reinitiate treatment with Nplate in accordance withdosing and administration recommendations. Underdose may result in lower than expected plateletcounts and potential for bleeding. Platelet counts should be monitored in patients receiving Nplate (seesections 4.2, pct. 4.4 and 4.9).

Progression of existing Myelodysplastic Syndromes (MDS)

A positive benefit/risk for romiplostim is only established for the treatment of thrombocytopeniaassociated with ITP (see section 4.1) and romiplostim must not be used in other clinical conditionsassociated with thrombocytopenia.

The diagnosis of ITP in adults and elderly patients should have been confirmed by the exclusion ofother clinical entities presenting with thrombocytopenia, in particular the diagnosis of MDS must beexcluded. A bone marrow aspirate and biopsy should normally have been done over the course of thedisease and treatment, particularly in patients over 60 years of age, for those with systemic symptomsor abnormal signs such as increased peripheral blast cells.

In adult clinical studies of treatment with romiplostim in patients with MDS, cases of transientincreases in blast cell counts were observed and cases of MDS disease progression to AML werereported. In a randomised placebo-controlled trial in MDS subjects, treatment with romiplostim wasprematurely stopped due to a numerical excess of disease progression to AML and an increase incirculating blasts greater than 10% in patients receiving romiplostim. Of the cases of MDS diseaseprogression to AML that were observed, patients with RAEB-1 classification of MDS at baseline weremore 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 causeof 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 therecommended 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 parametres have been observed innon-clinical toxicology studies (rat and monkey) as well as in ITP patients. Concurrent anaemia andleucocytosis (within a 4-week window) may occur in patients regardless of splenectomy status, buthave been seen more often in patients who have had a prior splenectomy. Monitoring of theseparametres should be considered in patients treated with romiplostim.

No interaction studies have been performed. The potential interactions of romiplostim withco-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 trialsincluded corticosteroids, danazol, and/or azathioprine, intravenous immunoglobulin (IVIG), andanti-D immunoglobulin. Platelet counts should be monitored when combining romiplostim with othermedicinal products for the treatment of ITP in order to avoid platelet counts outside of therecommended range (see section 4.2).

Corticosteroids, danazol, and azathioprine use may be reduced or discontinued when given incombination with romiplostim (see section 5.1). Platelet counts should be monitored when reducing ordiscontinuing 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 plateletcounts. Post implantation loss and a slight increase in peri-natal pup mortality also occurred in animalstudies (see section 5.3).

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

It is unknown whether romiplostim/metabolites are excreted in human milk. A risk to thenewborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feedingor to discontinue/abstain from romiplostim therapy taking into account the benefit of breast feeding forthe 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 tomoderate, 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 uncontrolledclinical trials, the overall subject incidence of all adverse reactions for romiplostim-treated subjectswas 91.5% (248/271). The mean duration of exposure to romiplostim in this study population was50 weeks.

The most serious adverse reactions that may occur during Nplate treatment include: reoccurrence ofthrombocytopenia 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 (includingcases 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 notknown (cannot be estimated from the available data). Within each MedDRA system organ class andfrequency grouping, undesirable effects are presented in order of decreasing incidence.

MedDRA system Very common Common Uncommonorgan class

Infections and Upper respiratory tract Gastroenteritis Influenzainfestations infection Pharyngitis*** Localised infection

Rhinitis*** Conjunctivitis*** Nasopharyngitis

Ear infection***

Sinusitis***/****

Bronchitis****

Neoplasms benign, Multiple myelomamalignant and Myelofibrosisunspecified (includingcysts and polyps)

Blood and lymphatic Bone marrow Aplastic anaemiasystem disorders disorder* Bone marrow failure

Thrombocytopenia* Leucocytosis

Anaemia Splenomegaly

Thrombocythaemia

Platelet countincreased

Platelet countabnormal

Immune system Hypersensitivity** Angioedemadisorders

Metabolism and Alcohol intolerancenutrition disorders Anorexia

Decreased appetite

Gout

Psychiatric disorders Insomnia Depression

Abnormal dreams

MedDRA system Very common Common Uncommonorgan class

Nervous system Headache Dizziness Clonusdisorders Migraine Dysgeusia

Paraesthesia Hypoaesthesia

Hypogeusia

Neuropathy peripheral

Transverse sinusthrombosis

Eye disorders Conjunctivalhaemorrhage

Accommodationdisorder

Blindness

Eye disorder

Eye pruritus

Lacrimation increased

Papilloedema

Ear and labyrinth Vertigodisorders

Cardiac disorders Palpitations Myocardial infarction

Heart rate increased

Vascular disorders Flushing Deep vein thrombosis

Peripheral embolism

Peripheral ischaemia

Phlebitis

Thrombophlebitissuperficial

Thrombosis

Erythromelalgia

Respiratory, thoracic Oropharyngeal Pulmonary embolism* Coughand mediastinal pain*** Rhinorrhoeadisorders Dry throat

Nasal congestion

Painful respiration

Gastrointestinal Upper abdominal Nausea Vomitingdisorders pain*** Diarrhoea Rectal haemorrhage

Abdominal pain Breath odour

Constipation Dysphagia

Dyspepsia Gastro-oesophagealreflux disease

Haematochezia

Mouth haemorrhage

Stomach discomfort

Stomatitis

Tooth discolouration

Hepatobiliary disorders Portal vein thrombosis

Increase intransaminase

MedDRA system Very common Common Uncommonorgan class

Skin and subcutaneous Pruritus Alopeciatissue disorders Ecchymosis Photosensitivity

Rash 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

Musculoskeletal and Arthralgia Muscle tightnessconnective tissue Myalgia Muscular weaknessdisorders Muscle spasms Shoulder pain

Pain in extremity Muscle twitching

Back pain

Bone pain

Renal and urinary Protein urine presentdisorders

Reproductive system Vaginal haemorrhageand breast disorders

General disorders and Fatigue Injection siteadministration site Oedema peripheral haemorrhageconditions Influenza like illness Chest pain

Pain Irritability

Asthenia Malaise

Pyrexia Face oedema

Chills Feeling hot

Injection site reaction Feeling jittery

Peripheral swelling***

Investigations Blood pressureincreased

Blood lactatedehydrogenaseincreased

Body temperatureincreased

Weight decreased

Weight increased

Injury, poisoning and Contusionproceduralcomplications

* see section 4.4

** Hypersensitivity reactions including cases of rash, urticaria, and angioedema

*** Additional adverse reactions observed in paediatric studies

**** Additional adverse reactions observed in adult patients with ITP duration up to 12 months

Adult population with ITP duration up to 12 months

The safety profile of romiplostim was similar across adult patients, regardless of ITP duration.

Specifically in the integrated analysis of ITP ≤ 12 months duration (n = 311), 277 adult patients with

ITP ≤ 12 months duration and who received at least one dose of romiplostim from among thosepatients in 9 ITP studies were included (see also section 5.1). In this integrated analysis, the followingadverse reactions (at least 5% incidence and at least 5% more frequent with Nplate compared withplacebo or standard of care) occurred in romiplostim patients with ITP duration up to 12 months, butwere not observed in those adult patients with ITP duration > 12 months: bronchitis, sinusitis (reportedcommonly (≥ 1/100 to < 1/10)).

In the paediatric studies, 282 paediatric ITP subjects were treated with romiplostim in 2 controlled and3 uncontrolled clinical trials. The median duration of exposure was 65.4 weeks. The overall safetyprofile 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 clinicaltrials) where the subject incidence was at least 5% higher in the romiplostim arm compared to placeboand 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 respiratorytract 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, sinusitisand peripheral swelling were additional adverse reactions observed in paediatric studies compared tothose seen in adult studies.

Some of the adverse reactions seen in adults were reported more frequently in paediatric subjects suchas cough, diarrhoea, rash, pyrexia and contusion reported very commonly (≥ 1/10) in paediatricsubjects 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.

Bleeding events

Across the entire adult ITP clinical programme an inverse relationship between bleeding events andplatelet counts was observed. All clinically significant (≥ grade 3) bleeding events occurred at plateletcounts < 30 x 109/L. All bleeding events ≥ grade 2 occurred at platelet counts < 50 x 109/L. Nostatistically 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 consideredserious (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 patientstreated 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 (seesection 5.1) was 1.9 (4.2) for the romiplostim arm and 4.0 (6.9) for the placebo arm.

Thrombocytosis

Based on an analysis of all adult ITP patients receiving romiplostim in 4 controlled and 5 uncontrolledclinical trials, 3 events of thrombocytosis were reported, n = 271. No clinical sequelae were reportedin 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 subjectincidence of 1 (0.4%). Subject incidence was 1 (0.4%) for either grade ≥ 3 or serious thrombocytosis.

Thrombocytopenia after cessation of treatment

Based on an analysis of all adult ITP patients receiving romiplostim in 4 controlled and 5 uncontrolledclinical trials, 4 events of thrombocytopenia after cessation of treatment were reported, n = 271 (seesection 4.4).

Progression of existing Myelodysplastic Syndromes (MDS)

In a randomised placebo-controlled trial in MDS adult subjects treatment with romiplostim wasprematurely stopped due to a numerical increase in cases of MDS disease progression to AML andtransient increases in blast cell counts in patients treated with romiplostim compared to placebo. Of thecases 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). Overallsurvival was similar to placebo.

In adult clinical trials, romiplostim treatment was discontinued in 4 of the 271 patients because ofbone marrow reticulin deposition. In 6 additional patients reticulin was observed upon bone marrowbiopsy (see section 4.4).

In a paediatric clinical trial (see section 5.1), of the subjects with an evaluable on-study bone marrowbiopsy, 5 out of 27 subjects (18.5%) developed increased reticulin at year 1 after exposure toromiplostim (cohort 1) and 17 out of 36 subjects (47.2%) developed increased reticulin at year 2 afterexposure to romiplostim (cohort 2). However, no subject showed any bone marrow abnormalities thatwere 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 toromiplostim and TPO respectively, only 4 subjects were positive for neutralising antibodies toromiplostim 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 (persistentantibodies). 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 romiplostimantibodies at baseline. Additionally, 2.8% (8/282) developed neutralising antibodies to romiplostim. Atotal of 3.9% (11/282) subjects had binding antibodies to TPO at any time during romiplostimtreatment. 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 atbaseline. 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 ofbinding antibody post treatment was 16% (3/19) to romiplostim, of which 5.3% (1/19) were positivefor neutralising antibodies to romiplostim. There were no antibodies detected to TPO. A total of184 confirmed adult patients were included in this study; for these patients, the incidence of bindingantibody post treatment was 3.8% (7/184) to romiplostim, of which 0.5% (1/184) was positive forneutralising 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 neutralisingantibodies is suspected, contact the local representative of the Marketing Authorisation Holder (seesection 6 of the Package Leaflet) for antibody testing.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No adverse effects were seen in rats given a single dose of 1,000 mcg/kg or in monkeys after repeatedadministration of romiplostim at 500 mcg/kg (100 or 50 times the maximum clinical dose of10 mcg/kg, respectively).

In the event of overdose, platelet counts may increase excessively and result inthrombotic/thromboembolic complications. If the platelet counts are excessively increased,discontinue Nplate and monitor platelet counts. Reinitiate treatment with Nplate in accordance withdosing and administration recommendations (see sections 4.2 and 4.4).

Pharmacotherapeutic group: Antihaemorrhagics, other systemic haemostatics, ATC code: B02BX04

Romiplostim is an Fc-peptide fusion protein (peptibody) that signals and activates intracellulartranscriptional pathways via the TPO receptor (also known as cMpl) to increase platelet production.

The peptibody molecule is comprised of a human immunoglobulin IgG1 Fc domain, with eachsingle-chain subunit covalently linked at the C-terminus to a peptide chain containing 2 TPOreceptor-binding domains.

Romiplostim has no amino acid sequence homology to endogenous TPO. In pre-clinical and clinicaltrials no anti-romiplostim antibodies cross reacted with endogenous TPO.

The safety and efficacy of romiplostim have been evaluated for up to 3 years of continuous treatment.

In clinical trials, 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 independentof the dose. After a single subcutaneous dose of 1 to 10 mcg/kg romiplostim in ITP patients, the peakplatelet count was 1.3 to 14.9 times greater than the baseline platelet count over a 2 to 3 weeks periodand the response was variable among patients. The platelet counts of ITP patients who received6 weekly doses of 1 or 3 mcg/kg of romiplostim were within the range of 50 to 450 × 109/L for mostpatients. Of the 271 patients who received romiplostim in ITP clinical trials, 55 (20%) were age 65and over, and 27 (10%) were 75 and over. No overall differences in safety or efficacy have beenobserved 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 studiesin adults with ITP who had completed at least one treatment prior to study entry and are representativeof the entire spectrum of such ITP patients.

Study S1 (20030212) evaluated patients who were non-splenectomised and had an inadequateresponse or were intolerant to prior therapies. Patients had been diagnosed with ITP for a median of2.1 years (range 0.1 to 31.6) at the time of study entry. Patients had received a median of 3 (range, 1to 7) treatments for ITP prior to study entry. Prior treatments included corticosteroids (90% of allpatients), immunoglobulins (76%), rituximab (29%), cytotoxic therapies (21%), danazol (11%), andazathioprine (5%). Patients had a median platelet count of 19 x 109/L at study entry.

Study S2 (20030105) evaluated patients who were splenectomised and continued to havethrombocytopenia. Patients had been diagnosed with ITP for a median of 8 years (range 0.6 to 44.8) atthe time of study entry. In addition to a splenectomy, patients had received a median of 6 (range, 3to 10) treatments for ITP prior to study entry. Prior treatments included corticosteroids (98% of allpatients), immunoglobulins (97%), rituximab (71%), danazol (37%), cytotoxic therapies (68%), andazathioprine (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 astarting dose of romiplostim 1 mcg/kg or placebo. Patients received single subcutaneous weeklyinjections for 24 weeks. Doses were adjusted to maintain (50 to 200 x 109/L) platelet counts. In bothstudies, efficacy was determined by an increase in the proportion of patients who achieved a durableplatelet response. The median average weekly dose for splenectomised patients was 3 mcg/kg and fornon-splenectomised patients was 2 mcg/kg.

A significantly higher proportion of patients receiving romiplostim achieved a durable plateletresponse compared to patients receiving placebo in both studies. Following the first 4-weeks of studyromiplostim maintained platelet counts ≥ 50 x 109/L in between 50% to 70% of patients during the6 months treatment period in the placebo-controlled studies. In the placebo group, 0% to 7% ofpatients were able achieve a platelet count response during the 6 months of treatment. A summary ofthe key efficacy endpoints is presented below.

Summary of key efficacy results from placebo-controlled studies

Study 1 Study 2 Combinednon-splenectomised splenectomised patients studies 1 & 2patientsromiplostim Placebo romiplostim Placebo romiplostim Placebo(n = 41) (n = 21) (n = 42) (n = 21) (n = 83) (n = 42)

No. (%)patientswith25 (61%) 1 (5%) 16 (38%) 0 (0%) 41 (50%) 1 (2%)durableplateletresponsea(95% CI) (45%, 76%) (0%, 24%) (24%, 54%) (0%, 16%) (38%, 61%) (0%, 13%)p-value < 0.0001 0.0013 < 0.0001

Study 1 Study 2 Combinednon-splenectomised splenectomised patients studies 1 & 2patientsromiplostim Placebo romiplostim Placebo romiplostim Placebo(n = 41) (n = 21) (n = 42) (n = 21) (n = 83) (n = 42)

No. (%)patientswith36 (88%) 3 (14%) 33 (79%) 0 (0%) 69 (83%) 3 (7%)overallplateletresponseb(95% CI) (74%, 96%) (3%, 36%) (63%, 90%) (0%, 16%) (73%, 91%) (2%, 20%)p-value < 0.0001 < 0.0001 < 0.0001

Mean no.weeks with15 1 12 0 14 1plateletresponsec(SD) 3.5 7.5 7.9 0.5 7.8 2.5p-value < 0.0001 < 0.0001 < 0.0001

No. (%)patientsrequiring 8(20%) 13 (62%) 11 (26%) 12 (57%) 19 (23%) 25 (60%)rescuetherapiesd(95% CI) (9%, 35%) (38%, 82%) (14%, 42%) (34%, 78%) (14%, 33%) (43%, 74%)p-value 0.001 0.0175 < 0.0001

No. (%)patientswithdurable21 (51%) 0 (0%) 13 (31%) 0 (0%) 34 (41%) 0 (0%)plateletresponsewith stabledosee(95% CI) (35%, 67%) (0%, 16%) (18%, 47%) (0%, 16%) (30%, 52%) (0%, 8%)p-value 0.0001 0.0046 < 0.0001a Durable platelet response was defined as weekly platelet count ≥ 50 x 109/L for 6 or more times for studyweeks 18-25 in the absence of rescue therapies any time during the treatment period.b Overall platelet response is defined as achieving durable or transient platelet responses. Transient plateletresponse was defined as weekly platelet count ≥ 50 x 109/L for 4 or more times during study weeks 2-25 butwithout durable platelet response. Patient may not have a weekly response within 8 weeks after receiving anyrescue medicinal products.c Number of weeks with platelet response is defined as number of weeks with platelet counts ≥ 50 x 109/L duringstudy weeks 2-25. Patient may not have a weekly response within 8 weeks after receiving any rescue medicinalproducts.d Rescue therapies defined as any therapy administered to raise platelet counts. Patients requiring rescuemedicinal products were not considered for durable platelet response. Rescue therapies allowed in the study were

IVIG, platelet transfusions, anti-D immunoglobulin, and corticosteroids.e Stable dose defined as dose maintained within ± 1 mcg/kg during the last 8 weeks of treatment.

Results of studies in adult patients with newly diagnosed and persistent ITP

Study S3 (20080435) was a single arm, open label study in adult patients who had an insufficientresponse (platelet count ≤ 30 x 109/L) to first line therapy. The study enrolled 75 patients of whom themedian age was 39 years (range 19 to 85) and 59% were female.

The median time from ITP diagnosis to study enrolment was 2.2 months (range 0.1 to 6.6). Sixtypercent of patients (n = 45) had ITP duration < 3 months and 40% (n = 30) had ITP duration≥ 3 months. The median platelet count at screening was 20 x 109/L. Prior ITP treatments includedcorticosteroids, immunoglobulins and anti D immunoglobulins. Patients already receiving ITP medicaltherapies at a constant dosing schedule were allowed to continue receiving these medical treatmentsthroughout the studies. Rescue therapies (i.e., corticosteroids, IVIG, platelet transfusions, anti Dimmunoglobulin, dapsone, danazol, and azathioprine) were permitted.

Patients received single weekly SC injections of romiplostim over a 12-month treatment period, withindividual dose adjustments to maintain platelet counts (50 x 109/L to 200 x 109/L). During the study,the median weekly romiplostim dose was 3 mcg/kg (25th 75th percentile: 2-4 mcg/kg).

Of the 75 patients enrolled in study 20080435, 70 (93%) had a platelet response ≥ 50 x 109/L duringthe 12-month treatment period. The mean number of months with platelet response during the 12-month treatment period was 9.2 (95% CI: 8.3, 10.1) months; the median was 11 (95% CI: 10, 11)months. The Kaplan Meier estimate of the median time to first platelet response was 2.1 weeks (95%

CI: 1.1, 3.0). Twenty-four (32%) patients had sustained treatment-free remission as defined bymaintaining every platelet count ≥ 50 x 109/L for at least 6 months in the absence of romiplostim andany medication for ITP (concomitant or rescue); the median time to onset of maintaining every plateletcount ≥ 50 x 109/L for at least 6 months was 27 weeks (range 6 to 57).

In an integrated analysis of efficacy, 277 adult patients with ITP duration ≤ 12 months and whoreceived at least one dose of romiplostim from among those patients in 9 ITP studies (inclusive ofstudy S3) were included. Of the 277 romiplostim-treated patients, 140 patients had newly diagnosed

ITP (ITP duration < 3 months) and 137 patients had persistent ITP (ITP duration ≥ 3 to ≤ 12 months).

The percentage of patients achieving a durable platelet response, defined as at least 6 weekly plateletcounts of ≥ 50 x 109/L during weeks 18 through 25 of treatment, was 50% (95% CI: 41.4% to 58.6%)for the 140 patients with newly diagnosed ITP and 55% (95% CI: 46.7% to 64.0%) for the 137patients with persistent ITP. The median (Q1, Q3) percent time with a platelet response ≥ 50 x 109/Lwas 100.0% (70.3%, 100.0%) for patients with newly diagnosed ITP and 93.5% (72.2%, 100.0%) forpatients with persistent ITP, respectively. Also, the percentage of patients requiring rescuemedications was 47.4% for patients with newly diagnosed ITP and 44.9% for patients with persistent

ITP.

Results of studies compared to standard of care (SOC) in non-splenectomised patients

Study S4 (20060131) was an open-label randomised 52 week trial in adult subjects who receivedromiplostim or medical standard of care (SOC) treatment. Patients had been diagnosed with ITP for amedian of 2 years (range 0.01 to 44.2) at the time of study entry. This study evaluatednon-splenectomised patients with ITP and platelet counts < 50 x 109/L. Romiplostim was administeredto 157 subjects by subcutaneous (SC) injection once weekly starting at a dose of 3 mcg/kg, andadjusted throughout the study within a range of 1-10 mcg/kg in order to maintain platelet countsbetween 50 and 200 x 109/L, 77 subjects received SOC treatment according to standard institutionalpractice or therapeutic guidelines.

The overall subject incidence rate of splenectomy was 8.9% (14 of 157 subjects) in the romiplostimgroup compared with 36.4% (28 of 77 subjects) in the SOC group, with an odds ratio (romiplostim vs

SOC) of 0.17 (95% CI: 0.08, 0.35).

The overall subject incidence of treatment failure was 11.5% (18 of 157 subjects) in the romiplostimgroup compared with 29.9% (23 of 77 subjects) in the SOC group, with an odds ratio (romiplostim vs

SOC) of 0.31 (95% CI: 0.15, 0.61).

Of the 157 subjects randomised to the romiplostim group, three subjects did not receive romiplostim.

Among the 154 subjects who received romiplostim, the total median exposure to romiplostim was52.0 weeks and ranged from 2 to 53 weeks. The most frequently used weekly dose was between3-5 mcg/kg (25th-75th percentile respectively; median 3 mcg/kg).

Of the 77 subjects randomised to the SOC group, two subjects did not receive any SOC. Among the75 subjects who received at least one dose of SOC, the total median exposure to SOC was 51 weeksand ranged from 0.4 to 52 weeks.

Reduction in permitted concurrent ITP medical therapies

In both adult placebo-controlled, double-blind studies, patients already receiving ITP medicaltherapies at a constant dosing schedule were allowed to continue receiving these medical treatmentsthroughout the study (corticosteroids, danazol and/or azathioprine). Twenty-one non-splenectomisedand 18 splenectomised patients received on-study ITP medical treatments (primarily corticosteroids) atthe start of study. All (100%) splenectomised patients who were receiving romiplostim were able toreduce the dose by more than 25% or discontinue the concurrent ITP medical therapies by the end ofthe treatment period compared to 17% of placebo treated patients. Seventy-three percent ofnon-splenectomised patients receiving romiplostim were able to reduce the dose by more than 25% ordiscontinue concurrent ITP medical therapies by the end of the study compared to 50% of placebotreated patients (see section 4.5).

Bleeding events

Across the entire adult ITP clinical programme an inverse relationship between bleeding events andplatelet counts was observed. All clinically significant (≥ grade 3) bleeding events occurred at plateletcounts < 30 x 109/L. All bleeding events ≥ grade 2 occurred at platelet counts < 50 x 109/L. Nostatistically significant differences in the overall incidence of bleeding events were observed betweenromiplostim and placebo treated patients.

In the two adult placebo-controlled studies, 9 patients reported a bleeding event that was consideredserious (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 patientstreated with romiplostim and 34% of patients treated with placebo (Odds Ratio;[romiplostim/placebo] = 0.35; 95% CI = (0.14, 0.85)).

The European Medicines Agency has waived the obligation to submit data for children < 1 year.

The safety and efficacy of romiplostim was evaluated in two placebo-controlled, double-blind studies.

Study S5 (20080279) was a phase 3 study with 24 weeks of romiplostim treatment and study S6(20060195) was a phase 1/2 study with 12 weeks of romiplostim treatment (up to 16 weeks for eligibleresponders who enter a 4-week pharmacokinetic assessment period).

Both studies enrolled paediatric subjects (≥ 1 year to < 18 years of age) with thrombocytopenia(defined by a mean of 2 platelet counts ≤ 30 x 109/L with neither count > 35 x 109/L in both studies)with ITP, regardless of splenectomy status.

In study S5, 62 subjects were randomised in a 2:1 ratio to receive romiplostim (n = 42) or placebo(n = 20) and stratified into 1 of 3 age cohorts. The starting dose of romiplostim 1 mcg/kg and doseswere adjusted to maintain (50 to 200 x 109/L) platelet counts. The most frequently used weekly dosewas 3-10 mcg/kg and the maximum allowed dose on study was 10 mcg/kg. Patients received singlesubcutaneous weekly injections for 24 weeks. Of those 62 subjects, 48 subjects had ITP > 12 monthsof duration (32 subjects received romiplostim and 16 subjects received placebo).

The primary endpoint was the incidence of durable response, defined as achieving at least 6 weeklyplatelet counts of ≥ 50 x 109/L during weeks 18 through 25 of treatment. Overall, a significant greaterproportion of subjects in the romiplostim arm achieved the primary endpoint compared with subjectsin the placebo arm (p = 0.0018). A total of 22 subjects (52%) had durable platelet response in theromiplostim arm compared with 2 subjects (10%) in the placebo arm: ≥ 1 to < 6 years 38% versus25%; ≥ 6 to < 12 years 56% versus 11%; ≥ 12 to < 18 years 56% versus 0.

In the subset of subjects with ITP > 12 months of duration, the incidence of durable response was alsosignificantly greater in the romiplostim arm compared with the placebo arm (p = 0.0022). A total of17 subjects (53.1%) had durable platelet response in the romiplostim arm compared with 1 subject(6.3%) in the placebo arm: ≥ 1 to < 6 years 28.6% versus 25%; ≥ 6 to < 12 years 63.6% versus 0%;≥ 12 to < 18 years 57.1% versus 0%.

The composite bleeding episode was defined as clinically significant bleeding events or the use of arescue medication to prevent a clinical significant bleeding event during weeks 2 through 25 of thetreatment period. A clinically significant bleeding event was defined as a Common Terminology

Criteria for Adverse Events (CTCAE) version 3.0 grade ≥ 2 bleeding event. The mean (SD) number ofcomposite bleeding episodes was 1.9 (4.2) for the romiplostim arm and 4.0 (6.9) for the placebo armwith a median (Q1, Q3) number of bleeding events of 0.0 (0, 2) for the romiplostim arm and0.5 (0, 4.5) in the placebo arm. In the subset of subjects with ITP > 12 months of duration, the mean(SD) number of composite bleeding episodes was 2.1 (4.7) for the romiplostim arm and 4.2 (7.5) forthe placebo arm with a median (Q1, Q3) number of bleeding events of 0.0 (0, 2) for the romiplostimarm and 0.0 (0, 4) in the placebo arm. Because the statistical testing for the incidence of rescuemedication use was not significant, no statistical test was done for the number of composite bleedingepisodes endpoint.

In study S6, 22 subjects were randomised in a 3:1 ratio to receive romiplostim (n = 17) or placebo(n = 5). Doses were increased in increments of 2 mcg/kg every 2 weeks and the target platelet countwas ≥ 50 x 109/L. Treatment with romiplostim resulted in statistically significantly greater incidenceof platelet response compared with placebo (p = 0.0008). Of those 22 subjects, 17 subjects had

ITP > 12 months of duration (14 subjects received romiplostim and 3 subjects received placebo).

Treatment with romiplostim resulted in statistically significantly greater incidence of platelet responsecompared with placebo (p = 0.0147).

Paediatric subjects who had completed a prior romiplostim study (including study S5) were allowed toenrol in study S7 (20090340), an open-label extension study evaluating the safety and efficacy oflong-term dosing of romiplostim in thrombocytopenic paediatric subjects with ITP.

A total of 66 subjects were enrolled in this study, including 54 subjects (82%) who had completedstudy S5. Of these, 65 subjects (98.5%) received at least 1 dose of romiplostim. The median (Q1, Q3)duration of treatment was 135.0 weeks (95.0 weeks, 184.0 weeks). The median (Q1, Q3) averageweekly dose was 4.82 mcg/kg (1.88 mcg/kg, 8.79 mcg/kg). The median (Q1, Q3) of most frequentdose received by subjects during the treatment period was 5.0 mcg/kg (1.0 mcg/kg, 10.0 mcg/kg). Ofthe 66 subjects enrolled in the study, 63 subjects had ITP > 12 months of duration. All the 63 subjectsreceived at least 1 dose of romiplostim. The median (Q1, Q3) duration of treatment was 138.0 weeks(91.1 weeks, 186.0 weeks). The median (Q1, Q3) average weekly dose was 4.82 mcg/kg(1.88 mcg/kg, 8.79 mcg/kg). The median (Q1, Q3) of most frequent dose received by subjects duringthe treatment period was 5.0 mcg/kg (1.0 mcg/kg, 10.0 mcg/kg).

Across the study, the overall subject incidence of platelet response (1 or more platelet count≥ 50 x 109/L in the absence of rescue medication) was 93.8% (n = 61) and was similar across agegroups. Across all subjects, the median (Q1, Q3) number of months with platelet response was30.0 months (13.0 months, 43.0 months) and the median (Q1, Q3) time on study was 34.0 months(24.0 months, 46.0 months). Across all subjects, the median (Q1, Q3) percentage of months withplatelet response was 93.33% (67.57%, 100.00%) and was similar across age groups.

In the subset of subjects with ITP > 12 months of duration, the overall subject incidence of plateletresponse was 93.7% (n = 59) and was similar across age groups. Across all subjects, the median (Q1,

Q3) number of months with platelet response was 30.0 months (13.0 months, 43.0 months) and themedian (Q1, Q3) time on study was 35.0 months (23.0 months, 47.0 months). Across all subjects, themedian (Q1, Q3) percentage of months with platelet response was 93.33% (67.57%, 100.00%) andwas similar across age groups.

A total of 31 subjects (47.7%) used concurrent ITP therapy during the study including 23 subjects(35.4%) who used rescue medication and 5 subjects (7.7%) who used concurrent ITP medication atbaseline. The subject prevalence of concurrent ITP medication use showed a trend towards a reductionover the course of the study: from 30.8% (weeks 1 to 12) to < 20.0% (weeks 13 to 240), and then 0%from week 240 to the end of the study.

In the subset of subjects with ITP > 12 months of duration, 29 subjects (46.0%) used concurrent ITPtherapy during the study including 21 subjects (33.3%) who used rescue medication and 5 subjects(7.9%) who used concurrent ITP medication at baseline. The subject prevalence of concurrent ITPmedication use showed a trend towards a reduction over the course of the study: from 31.7% (weeks 1to 12) to < 20.0% (weeks 13 to 240), and then 0% from week 240 to the end of the study.

The subject prevalence of rescue medication use showed a trend towards a reduction over the courseof the study: from 24.6% (weeks 1 to 12) to < 13.0% (weeks 13 to 216), then 0% after week 216 untilthe end of the study. Similar reduction of the subject prevalence of rescue medication over the courseof the study was seen in the subset of subjects with ITP > 12 months of duration: from 25.4% (weeks 1to 12) to ≤ 13.1% (weeks 13 to 216), then 0% after week 216 until the end of the study.

Study S8 (20101221) was a phase 3, long-term, single-arm, open-label, multicentre study conducted in203 paediatric patients with ITP diagnosed for at least 6 months and who received at least 1 prior ITPtherapy (excluding romiplostim) or were ineligible for other ITP therapies. Romiplostim wasadministered weekly by subcutaneous injection starting at a dose of 1 mcg/kg with weekly incrementsto a maximum dose of 10 mcg/kg to reach a target platelet count between 50 x 109/L and 200 x 109/L.

The median age of the patients was 10 years (range 1 to 17 years) and the median duration oftreatment were 155.9 (range, 8.0 to 163.0) weeks.

The mean (SD) and median percentage of time with a platelet response (platelet count ≥ 50 x 109/L)within the first 6 months of initiation of romiplostim without rescue medication use for the past4 weeks was 50.57% (37.01) and 50.0%, respectively. Sixty (29.6%) subjects overall received rescuemedications. Rescue medications (i.e., corticosteroids, platelet transfusions, IVIG, azathioprine, anti-Dimmunoglobulin, and danazol) were permitted.

Study S8 also evaluated bone marrows for reticulin and collagen formation as well as forabnormalities in paediatric patients with ITP receiving romiplostim treatment. The modified

Bauermeister grading scale was used for reticulin and collagen assessments, whereas cytogenetics andfluorescence in situ hybridization (FISH) were used to evidence bone marrow abnormalities. Based oncohort assignment at the time of study enrolment, patients were evaluated for bone marrow reticulinand collagen at year 1 (cohort 1) or year 2 (cohort 2) in comparison to the baseline bone marrow at thestart of the study. From the total of 79 patients enrolled in the 2 cohorts, 27 of 30 (90%) patients incohort 1 and 36 of 49 (73.5%) patients in cohort 2 had evaluable on-study bone marrow biopsies.

Increased reticulin fibre formation was reported for 18.5% (5 of 27) of patients in cohort 1 and 47.2%(17 of 36) of patients in cohort 2. No patients in either cohort developed collagen fibrosis or a bonemarrow abnormality that was inconsistent with an underlying diagnosis of ITP.

The pharmacokinetics of romiplostim involved target-mediated disposition, which is presumablymediated by TPO receptors on platelets and other cells of the thrombopoietic lineage such asmegakaryocytes.

After subcutaneous administration of 3 to 15 mcg/kg romiplostim, maximum romiplostim serumlevels in ITP patients were obtained after 7-50 hours (median 14 hours). The serum concentrationsvaried among patients and did not correlate with the dose administered. Romiplostim serum levelsappear inversely related to platelet counts.

The volume of distribution of romiplostim following intravenous administration of romiplostimdecreased nonlinearly from 122, 78.8, to 48.2 mL/kg for intravenous doses of 0.3, 1.0 and 10 mcg/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 thehigher doses applied.

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 aresult for a given dose, patients with high platelet counts are associated with low serum concentrationsand vice versa. In another ITP clinical trial, no accumulation in serum concentrations was observedafter 6 weekly doses of romiplostim (3 mcg/kg).

Pharmacokinetics of romiplostim in patients with renal and hepatic impairment has not beeninvestigated. Romiplostim pharmacokinetics appear not affected by age, weight and gender to aclinically significant extent.

Pharmacokinetic data of romiplostim were collected from two studies in 21 paediatric subjects with

ITP. In study S6 (20060195), romiplostim concentrations were available from 17 subjects at dosesranging from 1 to 10 mcg/kg. In Study S7 (20090340), intensive romiplostim concentrations wereavailable from 4 subjects (2 at 7 mcg/kg and 2 at 9 mcg/kg). Serum concentrations of romiplostim inpaediatrics with ITP were within the range observed in adult ITP subjects receiving the same doserange of romiplostim. Similar to adults with ITP, romiplostim pharmacokinetics are highly variable inpaediatric subjects with ITP and are not reliable and predictive. However, the data are insufficient todraw any meaningful conclusion relating to the impact of dose and age on the pharmacokinetics ofromiplostim.

Multiple dose romiplostim toxicology studies were conducted in rats for 4 weeks and in monkeys forup to 6 months. In general, effects observed during these studies were related to the thrombopoieticactivity of romiplostim and were similar regardless of study duration. Injection site reactions were alsorelated to romiplostim administration. Myelofibrosis has been observed in the bone marrow of rats atall tested dose levels. In these studies, myelofibrosis was not observed in animals after a 4-weekpost-treatment recovery period, indicating reversibility.

In 1-month rat and monkey toxicology studies, a mild decrease in red blood cell count, haematocritand haemoglobin was observed. There was also a stimulatory effect on leukocyte production, asperipheral blood counts for neutrophils, lymphocytes, monocytes, and eosinophils were mildlyincreased. In the longer duration chronic monkey study, there was no effect on the erythroid andleukocytic lineages when romiplostim was administered for 6 months where the administration ofromiplostim was decreased from thrice weekly to once weekly. Additionally, in the phase 3 pivotalstudies, romiplostim did not affect the red blood cell and white blood cells lineages relative to placebotreated subjects.

Due to the formation of neutralising antibodies pharmacodynamic effects of romiplostim in rats wereoften decreasing at prolonged duration of administration. Toxicokinetic studies showed no interactionof the antibodies with the measured concentrations. Although high doses were tested in the animalstudies, due to differences between the laboratory species and humans with regard to the sensitivity forthe pharmacodynamic effect of romiplostim and the effect of neutralising antibodies, safety marginscannot be reliably estimated.

The carcinogenic potential of romiplostim has not been evaluated. Therefore, the risk of potentialcarcinogenicity of romiplostim in humans remains unknown.

In all developmental studies neutralising antibodies were formed, which may have inhibitedromiplostim effects. In embryo-foetal development studies in mice and rats, reductions in maternalbody 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 aslight increase in the incidence of peri-natal pup mortality was found. Romiplostim is known to crossthe placental barrier in rats and may be transmitted from the mother to the developing foetus andstimulate 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

This medicinal product must not be mixed with other medicinal products, except those mentioned insection 6.6.

5 years.

After reconstitution: Chemical and physical in-use stability has been demonstrated for 24 hours at25°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 medicinal product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 25°C or 24 hours in a refrigerator (2°C - 8°C),protected from light.

After dilution: Chemical and physical in-use stability has been demonstrated for 4 hours at 25°C whenthe diluted product was held in a disposable syringe, or 4 hours in a refrigerator (2°C - 8°C) when thediluted product was held in the original vial.

From a microbiological point of view, the diluted medicinal product should be used immediately. Ifnot used immediately, in-use storage times and conditions prior to use are the responsibility of the userand would normally not be longer than 4 hours at 25°C in disposable syringes, or 4 hours in arefrigerator (2°C - 8°C) in the original vials, 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.

May be removed from the refrigerator for a period of 30 days at room temperature (up to 25°C) whenstored in the original carton.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Single-dose vial (type 1 clear glass) with a stopper (chlorobutyl rubber), seal (aluminium) and aflip-off cap (polypropylene). The 125 mcg vial cap is beige, the 250 mcg vial cap is red and the500 mcg vial cap is blue.

Carton containing 1 or 4 vials of romiplostim.

Not all pack sizes may be marketed.

Nplate is a sterile but unpreserved medicinal product and is intended for single use only. Nplate shouldbe reconstituted in accordance with good aseptic practice.

Nplate 125 micrograms powder for solution for injection

Nplate 125 micrograms powder for solution for injection should be reconstituted with 0.44 mL sterilewater for injections, yielding a deliverable volume of 0.25 mL. An additional overfill is included ineach vial to ensure that 125 mcg of romiplostim can be delivered (see vial content table below).

Nplate 250 micrograms powder for solution for injection

Nplate 250 micrograms powder for solution for injection should be reconstituted with 0.72 mL sterilewater for injections, yielding a deliverable volume of 0.5 mL. An additional overfill is included ineach vial to ensure that 250 mcg of romiplostim can be delivered (see vial content table below).

Nplate 500 micrograms powder for solution for injection

Nplate 500 micrograms powder for solution for injection should be reconstituted with 1.2 mL sterilewater for injections, yielding a deliverable volume of 1 mL. An additional overfill is included in eachvial to ensure that 500 mcg of romiplostim can be delivered (see vial content table below).

Vial Content:

Nplate single- Total vial Volume of Deliverable Finaluse vial content of sterile water product and concentrationromiplostim for injection volume125 mcg 230 mcg + 0.44 mL = 125 mcg in 0.25 mL 500 mcg/mL250 mcg 375 mcg + 0.72 mL = 250 mcg in 0.50 mL 500 mcg/mL500 mcg 625 mcg + 1.20 mL = 500 mcg in 1.00 mL 500 mcg/mL

Sterile water for injections only should be used when reconstituting the medicinal product. Sodiumchloride solutions or bacteriostatic water should not be used when reconstituting the medicinalproduct.

Water for injections should be injected into the vial. The vial contents may be swirled gently andinverted 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 anddiscolouration before administration. The reconstituted solution should be clear and colourless andshould not be administered if particulate matter and/or discolouration are observed.

For the storage condition after reconstitution of the medicinal product see section 6.3.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Dilution (required when the calculated individual patient dose is less than 23 mcg)

Initial reconstitution of romiplostim with designated volumes of sterile water for injections results in aconcentration of 500 mcg/mL in all vial sizes. If the calculated individual patient dose is less than23 mcg (see section 4.2), an additional dilution step to 125 mcg/mL with preservative-free, sterile,sodium chloride 9 mg/mL (0.9%) solution for injection is required to ensure accurate volume (seetable below).

Dilution Guidelines:

Nplate single-use vial Add this volume of preservative-free, sterile, Concentration after dilutionsodium chloride 9 mg/mL (0.9%) solutionfor injection to the reconstituted vial125 mcg 1.38 mL 125 mcg/mL250 mcg 2.25 mL 125 mcg/mL500 mcg 3.75 mL 125 mcg/mL

Preservative-free, sterile, sodium chloride 9 mg/mL (0.9%) solution for injection only must be usedfor dilution. Dextrose (5%) in water or sterile water for injection should not be used for the dilution.

No other diluents have been tested.

For the storage condition after dilution of the reconstituted medicinal product see section 6.3.

Amgen Europe B.V.

Minervum 70614817 ZK Breda

The Netherlands

EU/1/08/497/009

EU/1/08/497/010

EU/1/08/497/001

EU/1/08/497/003

EU/1/08/497/002

EU/1/08/497/004

Date of first authorisation: 4 February 2009

Date of latest renewal: 20 December 2013

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu