MIRCERA 120mcg / 0.3ml injection solution in pre-filled syringe medication leaflet

MIRCERA 30 micrograms/0.3 ml solution for injection in pre-filled syringe

MIRCERA 50 micrograms/0.3 ml solution for injection in pre-filled syringe

MIRCERA 75 micrograms/0.3 ml solution for injection in pre-filled syringe

MIRCERA 100 micrograms/0.3 ml solution for injection in pre-filled syringe

MIRCERA 120 micrograms/0.3 ml solution for injection in pre-filled syringe

MIRCERA 150 micrograms/0.3 ml solution for injection in pre-filled syringe

MIRCERA 200 micrograms/0.3 ml solution for injection in pre-filled syringe

MIRCERA 250 micrograms/0.3 ml solution for injection in pre-filled syringe

MIRCERA 360 micrograms/0.6 ml solution for injection in pre-filled syringe

MIRCERA 30 micrograms/0.3 ml solution for injection in pre-filled syringe

One pre-filled syringe contains 30 micrograms of methoxy polyethylene glycol-epoetin beta* at aconcentration of 100 micrograms/ml

MIRCERA 50 micrograms/0.3 ml solution for injection in pre-filled syringe

One pre-filled syringe contains 50 micrograms of methoxy polyethylene glycol-epoetin beta* at aconcentration of 167 micrograms/ml.

MIRCERA 75 micrograms/0.3 ml solution for injection in pre-filled syringe

One pre-filled syringe contains 75 micrograms of methoxy polyethylene glycol-epoetin beta* at aconcentration of 250 micrograms/ml

MIRCERA 100 micrograms/0.3 ml solution for injection in pre-filled syringe

One pre-filled syringe contains 100 micrograms of methoxy polyethylene glycol-epoetin beta* at aconcentration of 333 micrograms/ml.

MIRCERA 120 micrograms/0.3 ml solution for injection in pre-filled syringe

One pre-filled syringe contains 120 micrograms of methoxy polyethylene glycol-epoetin beta* at aconcentration of 400 micrograms/ml.

MIRCERA 150 micrograms/0.3 ml solution for injection in pre-filled syringe

One pre-filled syringe contains 150 micrograms of methoxy polyethylene glycol-epoetin beta* at aconcentration of 500 micrograms/ml.

MIRCERA 200 micrograms/0.3 ml solution for injection in pre-filled syringe

One pre-filled syringe contains 200 micrograms of methoxy polyethylene glycol-epoetin beta* at aconcentration of 667 micrograms/ml

MIRCERA 250 micrograms/0.3 ml solution for injection in pre-filled syringe

One pre-filled syringe contains 250 micrograms of methoxy polyethylene glycol-epoetin beta* at aconcentration of 833 micrograms/ml.

MIRCERA 360 micrograms/0.6 ml solution for injection in pre-filled syringe

One pre-filled syringe contains 360 micrograms of methoxy polyethylene glycol-epoetin beta* at aconcentration of 600 micrograms/ml.

The strength indicates the quantity of the protein moiety of the methoxy polyethylene glycol-epoetinbeta molecule without consideration of the glycosylation.

*Protein produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells andcovalently conjugated to a linear methoxy-polyethylene glycol (PEG).

The potency of methoxy polyethene glycol-epoetin beta should not be compared to the potency ofanother pegylated or non-pegylated protein of the same therapeutic class. For more information, seesection 5.1.

For the full list of excipients, see section 6.1.

Solution for injection in pre-filled syringe (injection).

The solution is clear and colourless to slightly yellowish.

Treatment of symptomatic anaemia associated with chronic kidney disease (CKD) in adult patients(see section 5.1).

Treatment of symptomatic anaemia associated with chronic kidney disease (CKD) in paediatricpatients from 3 months to less than 18 years of age who are converting from another erythropoiesisstimulating agent (ESA) after their haemoglobin level was stabilised with the previous ESA (seesection 5.1).

Treatment has to be initiated under the supervision of a physician experienced in the management ofpatients with renal impairment.

Treatment of symptomatic anaemia in chronic kidney disease patients

Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; aphysician’s evaluation of the individual patient’s clinical course and condition is necessary. Treatmentshould be administered either subcutaneously or intravenously in order to increase haemoglobin to notgreater than 12 g/dl (7.45 mmol/l). Subcutaneous use is preferable in patients who are not receivinghaemodialysis to avoid puncture of peripheral veins.

Due to intra-patient variability, occasional individual haemoglobin values for a patient above andbelow the desired haemoglobin level may be observed. Haemoglobin variability should be addressedthrough dose management, with consideration for the haemoglobin target range of 10 g/dl(6.21 mmol/l) to 12 g/dl (7.45 mmol/l). A sustained haemoglobin level of greater than 12 g/dl(7.45 mmol/l) should be avoided; guidance for appropriate dose adjustment for when haemoglobinvalues exceeding 12 g/dl (7.45 mmol/l) are observed are described below.

A rise in haemoglobin of greater than 2 g/dl (1.24 mmol/l) in adult patients and 1 g/dl (0.62 mmol/l) inpaediatric patients over a four-week period should be avoided. If it occurs, appropriate doseadjustment should be made as provided.

Patients should be monitored closely to ensure that the lowest approved effective dose of treatment isused to provide adequate control of the symptoms of anaemia whilst maintaining a haemoglobinconcentration below or at 12 g/dl (7.45 mmol/l).

Caution should be exercised with escalation of treatment doses in patients with chronic renal failure.

In patients with a poor haemoglobin response to treatment, alternative explanations for the poorresponse should be considered (see section 4.4 and 5.1).

It is recommended that haemoglobin is monitored every two weeks until stabilised and periodicallythereafter (see section 4.4).

Adult patients not currently treated with an erythropoiesis stimulating agent (ESA):

In order to increase haemoglobin levels to greater than 10 g/dl (6.21 mmol/l), the recommendedstarting dose in patients not on dialysis is 1.2 microgram/kg body weight, administered once everymonth as a single subcutaneous injection.

Alternatively, a starting dose of 0.6 microgram/kg bodyweight may be administered once every twoweeks as a single intravenous or subcutaneous injection in patients on dialysis or not on dialysis.

The dose may be increased by approximately 25% of the previous dose if the rate of rise inhaemoglobin is less than 1.0 g/dl (0.621 mmol/l) over a month. Further increases of approximately25% may be made at monthly intervals until the individual target haemoglobin level is obtained.

If the rate of rise in haemoglobin is greater than 2 g/dl (1.24 mmol/l) in one month or if thehaemoglobin level is increasing and approaching 12 g/dl (7.45 mmol/l), the dose is to be reduced byapproximately 25%. If the haemoglobin level continues to increase, therapy should be interrupted untilthe haemoglobin level begins to decrease, at which point therapy should be restarted at a doseapproximately 25% below the previously administered dose. After dose interruption a haemoglobindecrease of approximately 0.35 g/dl (0.22 mmol/l) per week is expected. Dose adjustments should notbe made more frequently than once a month.

Patients treated once every two weeks whose haemoglobin concentration is above 10 g/dl(6.21 mmol/l) may receive methoxy polyethylene glycol-epoetin beta administered once-monthlyusing the dose equal to twice the previous once-every-two-week dose.

Adult patients currently treated with an ESA:

Patients currently treated with an ESA can be switched to methoxy polyethylene glycol-epoetin betaadministered once a month as a single intravenous or subcutaneous injection. The starting dose ofmethoxy polyethylene glycol-epoetin beta is based on the calculated previous weekly dose ofdarbepoetin alfa or epoetin at the time of substitution as described in Table 1. The first injectionshould start at the next scheduled dose of the previously administered darbepoetin alfa or epoetin.

Table 1: Methoxy polyethylene glycol-epoetin beta starting doses for adult patients currentlyreceiving an ESA

Previous weekly Previous weekly Monthly methoxydarbepoetin alfa epoetin polyethylene glycol-intravenous or intravenous or epoetin betasubcutaneous dose subcutaneous intravenous or(microgram/week) dose (IU/week) subcutaneous dose(microgram/oncemonthly)<40 <8000 12040-80 8000-16000 200>80 >16000 360

If a dose adjustment is required to maintain the target haemoglobin concentration above 10 g/dl(6.21 mmol/l), the monthly dose may be increased by approximately 25%.

If the rate of rise in haemoglobin is greater than 2 g/dl (1.24 mmol/l) over a month or if thehaemoglobin level is increasing and approaching 12 g/dl (7.45 mmol/l), the dose is to be reduced byapproximately 25%. If the haemoglobin level continues to increase, therapy should be interrupted untilthe haemoglobin level begins to decrease, at which point therapy should be restarted at a doseapproximately 25% below the previously administered dose. After dose interruption a haemoglobindecrease of approximately 0.35 g/dl (0.22 mmol/l) per week is expected. Dose adjustments should notbe made more frequently than once a month.

Since the treatment experience is limited in patients on peritoneal dialysis, regular haemoglobinmonitoring and strict adherence to dose adjustment guidance are recommended in these patients.

Paediatric patients from 3 months to less than 18 years of age currently treated with an ESA:

Paediatric patients whose haemoglobin level has been stabilised by treatment with an ESA can beconverted to methoxy polyethylene glycol-epoetin beta administered once every 4 weeks as an IV or

SC injection, but keeping the same administration route. The starting dose of methoxy polyethyleneglycol-epoetin beta is calculated based on the total weekly ESA dose at the time of conversion (Table2).

Table 2. Methoxy polyethylene glycol-epoetin beta starting doses for paediatric patients from 3months to less than 18 years of age currently receiving an ESA

Previous weekly Previous weekly Every 4-week methoxydarbepoetin alfa dose epoetin dose (IU/week) polyethylene glycol-(microgram/week) epoetin beta dose(microgram)9 - <12 2000 - <2700 3012 - <15 2700 - <3500 5015 - <24 3500 - <5500 7524 - <30 5500 - <6500 10030 - <35 6500 - <8000 12035 - <47 8000 - <10000 15047 - <60 10000 - <13000 20060 - <90 13000 - <20000 250≥90 ≥20000 360

Pre-filled syringes are not designed for administration of partial doses. Due to the available dosestrengths of pre-filled syringes, paediatric patients with an ESA dose of <9 microgram/week(darbepoetin alfa) or <2000 IU/week of epoetin, should not be switched to methoxy polyethyleneglycol-epoetin beta.

If a dose adjustment is required to maintain the target haemoglobin concentration above 10 g/dl, the4 weekly dose may be adjusted by approximately 25%.

If the rise in haemoglobin is greater than 1 g/dl (0.62 mmol/l) over 4 weeks or the haemoglobin levelis increasing and approaching 12 g/dl (7.45 mmol/l), the methoxy polyethylene glycol-epoetin betadose is to be reduced by approximately 25%.

If the haemoglobin level continues to increase following dose reduction, therapy is to be interrupteduntil the haemoglobin level begins to decrease, at which point therapy should be restarted at a doseapproximately 25% below the previously administered dose.

Dose adjustments should not be made more often than once every 4 weeks.

Treatment interruption

Treatment is normally long-term. However, it can be interrupted at any time, if necessary.

If one dose of treatment is missed, the missed dose is to be administered as soon as possible andadministration of treatment is to be restarted at the prescribed dosing frequency.

The safety and efficacy of methoxy polyethylene glycol-epoetin beta in paediatric patients less than 3months of age have not been established. No data are available.

No adjustments of the starting dose nor of the dose modification rules are required in patients withhepatic impairment (see section 5.2).

In clinical studies 24% of patients treated with methoxy polyethylene glycol-epoetin beta were aged65 to 74 years, while 20% were aged 75 years and over. No dose adjustment is required in patientsaged 65 years or older.

Treatment should be administered either subcutaneously or intravenously. It can be injectedsubcutaneously in the abdomen, arm or thigh. All three injection sites are equally suitable. Forinstructions on the administration of the medicinal product, see section 6.6.

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

Uncontrolled hypertension.

The safety and efficacy of methoxy polyethylene glycol-epoetin beta therapy in other indications,including anaemia in patients with cancer, has not been established.

Caution should be exercised with escalation of methoxy polyethylene glycol-epoetin beta doses inpatients with chronic renal failure since high cumulative epoetin doses may be associated with anincreased risk of mortality, serious cardiovascular and cerebrovascular events. In patients with a poorhaemoglobin response to epoetins, alternative explanations for the poor response should be considered(see section 4.2 and 5.1).

Paediatric patients, especially children <1 year of age, should be carefully evaluated before switchingfrom another ESA treatment and the haemoglobin level should be stabilised prior to switching.

Following ESA conversion, it is recommended that haemoglobin is monitored every 4 weeks.

If the current ESA dose is <9 microgram/week of darbepoetin alfa or <2000 IU/week of epoetin, thepatient should not be switched to methoxy polyethylene glycol-epoetin beta, as the lowest availablepre-filled syringe dose strength is 30 micrograms. Administration of partial doses with pre-filledsyringes is not recommended.

Supplementary iron therapy is recommended for all patients with serum ferritin values below100 microgram/l or with transferrin saturation below 20%. To ensure effective erythropoiesis, ironstatus has to be evaluated for all patients prior to and during treatment.

Failure to respond to treatment should prompt for a search for causative factors. Deficiencies of iron,folic acid or vitamin B12 reduce the effectiveness of ESAs and should therefore be corrected.

Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, haemolysis, severealuminium toxicity, underlying haematologic diseases, or bone marrow fibrosis may also compromisethe erythropoietic response. A reticulocyte count should be considered as part of the evaluation. If allthe conditions mentioned are excluded and the patient has a sudden drop of haemoglobin associatedwith reticulocytopenia and anti-erythropoietin antibodies, examination of the bone marrow for thediagnosis of Pure Red Cell Aplasia (PRCA) should be considered. In case PRCA is diagnosed,treatment must be discontinued and patients should not be switched to another ESA.

Physicians may request the Marketing Authorisation Holder to test or re-test serum samples in areference laboratory for cases of suspected or confirmed AEAB-mediated PRCA or unexplained lossof effect under treatment (e.g. observed clinically by severe anaemia and low reticulocyte count).

Pure Red Cell Aplasia caused by anti-erythropoietin antibodies has been reported in association withall ESAs, including methoxy polyethylene glycol-epoetin beta. These antibodies have been shown tocross-react with all ESAs, and patients suspected or confirmed to have antibodies to erythropoietinshould not be switched to methoxy polyethylene glycol-epoetin beta (see section 4.8).

PRCA in patients with Hepatitis C: A paradoxical decrease in haemoglobin and development of severeanaemia associated with low reticulocyte counts should prompt to discontinue treatment with epoetinand perform anti-erythropoietin antibody testing. Cases have been reported in patients with hepatitis Ctreated with interferon and ribavirin, when epoetins are used concomitantly. Epoetins are not approvedin the management of anaemia associated with hepatitis C.

Blood pressure monitoring: As with other ESAs, blood pressure may rise during treatment withmethoxy polyethylene glycol-epoetin beta. Blood pressure should be adequately controlled in allpatients before, at initiation of, and during treatment with methoxy polyethylene glycol-epoetin beta. Ifhigh blood pressure is difficult to control by medical treatment or dietary measures, the dose must bereduced or administration discontinued (see section 4.2).

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxicepidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in associationwith epoetin treatment (see section 4.8). More severe cases have been observed with long-actingepoetins. At the time of prescription patients should be advised of the signs and symptoms andmonitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear,methoxy polyethylene glycol-epoetin beta should be withdrawn immediately and an alternativetreatement considered. If the patient has developed a severe cutaneous skin reaction such as SJS or

TEN due to the use of methoxy polyethylene glycol-epoetin beta, treatment with ESA must not berestarted in this patient at any time.

Haemoglobin concentration: In patients with chronic kidney disease, maintenance haemoglobinconcentration should not exceed the upper limit of the target haemoglobin concentration recommendedin section 4.2. In clinical trials, an increased risk of death, serious cardiovascular events includingthrombosis or cerebrovascular events including stroke was observed when ESAs were administered totarget a haemoglobin of greater than 12 g/dl (7.5 mmol/l) (see section 4.8).

Controlled clinical trials have not shown significant benefits attributable to the administration ofepoetins when haemoglobin concentration is increased beyond the level necessary to controlsymptoms of anaemia and to avoid blood transfusion.

The safety and efficacy of treatment has not been established in patients with haemoglobinopathies,seizures, bleeding or a recent history of bleeding requiring transfusions or with platelet levels greaterthan 500 x 109/l. Therefore, caution should be used in these patients.

Effect on tumour growth: Methoxy polyethylene glycol-epoetin beta, like other ESAs, is a growthfactor that primarily stimulates red blood cell production. Erythropoietin receptors may be expressedon the surface of a variety of tumour cells. As with all growth factors, there is a concern that ESAscould stimulate the growth of any type of malignancy. Two controlled clinical studies in whichepoetins were administered to patients with various cancers including head and neck cancers, andbreast cancer, have shown an unexplained excess mortality.

Misuse of methoxy polyethylene glycol-epoetin beta by healthy people may lead to an excessiveincrease in haemoglobin. This may be associated with life-threatening cardiovascular complications.

Traceability: In order to improve the traceability of biological medicinal products, the name and thebatch number of the administered product should be clearly recorded.

This medicinal product contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially‘sodium free’.

No interaction studies have been performed. There is no evidence that methoxy polyethylene glycol-epoetin beta alters the metabolism of other medicinal products.

There are no data from the use of methoxy polyethylene glycol-epoetin beta in pregnant women.

Animal studies do not indicate direct harmful effects with respect to pregnancy, embryofoetaldevelopment, parturition or postnatal development but indicate a class-related reversible reduction infoetal weight (see section 5.3). Caution should be exercised when prescribing to pregnant women.

It is unknown whether methoxy polyethylene glycol-epoetin beta is excreted in human breast milk.

One animal study has shown excretion of methoxy polyethylene glycol-epoetin beta in maternal milk.

A decision on whether to continue or discontinue breast-feeding or to continue or discontinue therapywith methoxy polyethylene glycol-epoetin beta should be made taking into account the benefit ofbreast-feeding to the child and the benefit of methoxy polyethylene glycol-epoetin beta therapy to thewoman.

Studies in animals have shown no evidence of impaired fertility (see section 5.3). The potential riskfor humans is unknown.

Methoxy polyethylene glycol-epoetin beta has no or negligible influence on the ability to drive anduse machines.

(a) Summary of the safety profile

The safety data base from clinical trials comprised 3,042 CKD adult patients, including 1,939 adultpatients treated with methoxy polyethylene glycol-epoetin beta and 1,103 with another ESA.

Approximately 6% of adult patients treated with methoxy polyethylene glycol-epoetin beta areexpected to experience adverse reactions. The most frequent reported adverse reaction washypertension (common).

(b) Tabulated list of adverse reactions

Adverse reactions in Table 3 are listed according to MedDRA system organ class and frequencycategory. Frequency categories are defined using the following convention: 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); not known (cannot be estimated from the available data).

Table 3: Adverse reactions attributed to the treatment with methoxy polyethylene glycol-epoetin beta in CKD adult patients. Adverse reactions observed only during post-marketing aremarked (*).

System organ class Frequency Adverse reaction

Blood and lymphatic system Uncommon Thrombocytopenia*disorders Not known Pure red cell aplasia*

Immune system disorders Rare Hypersensitivity

Not known Anaphylactic reaction*

Nervous system disorders Uncommon Headache

Rare Hypertensive encephalopathy

Common Hypertension

Vascular disorders Uncommon Thrombosis*

Rare Hot flush

Rare Pulmonary embolism*

Skin and subcutaneous Rare Rash, maculopapulardisorders Not known Stevens-Johnson syndrome/toxicepidermal necrolysis*

Injury, poisoning andprocedural complications Uncommon Vascular access site thrombosis(c) Description of selected adverse reactions

Adult population

Cases of thrombocytopenia have been reported from post-marketing setting. A slight decrease inplatelet counts remaining within the normal range was observed in clinical studies.

Platelet counts below 100 x 109/l were observed in 7% of adult patients treated with methoxypolyethylene glycol-epoetin beta and 4% of adult patients treated with other ESAs during clinicaldevelopment. In a post-authorisation safety study with long treatment exposure of up to 8.4 years,baseline platelet counts below 100 x 109/l was present in 2.1% of adult patients in the methoxypolyethylene glycol-epoetin beta group and 2.4% of adult patients in other ESAs group. During thestudy, platelet counts below 100 x 109/l were observed yearly in 1.5% to 3.0% of adult patients treatedwith methoxy polyethylene glycol-epoetin beta and 1.6% to 2.5% of adult patients treated with other

ESAs.

Data from a controlled clinical trial with epoetin alfa or darbepoetin alfa reported an incidence ofstroke as common. A post-authorisation safety study showed similar incidence of stroke betweenmethoxy polyethylene glycol-epoetin beta (6.3%) and reference ESAs groups (epoetin alfa,darbepoetin alfa and epoetin beta) (7%).

As with other ESAs, cases of thrombosis, including pulmonary embolism, have been reported in thepost-marketing setting (see section 4.4).

Neutralising anti-erythropoietin antibody-mediated pure red cell aplasia (PRCA) has been reported,frequency unknown. In case PRCA is diagnosed, therapy with methoxy polyethylene glycol-epoetinbeta must be discontinued, and patients should not be switched to another recombinant erythropoieticprotein (see section 4.4).

In the two paediatric studies, the paediatric population studied comprised a total of 104 patients, ofwhich 12 were less than 5 years of age, 36 were 5 to 11 years of age and 56 were 12 to 17 years ofage. The safety profile of methoxy polyethylene glycol-epoetin beta in the paediatric populationincluded in these two studies was overall consistent with that known for the adult population, based onlow patient exposure in these studies (see section 5.1).

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.

The therapeutic range of methoxy polyethylene glycol-epoetin beta is wide. Individual responsivenessmust be considered when treatment is initiated. Overdose can result in manifestations of anexaggerated pharmacodynamic effect, e.g. excessive erythropoiesis. In case of excessive haemoglobinlevels, treatment with methoxy polyethylene glycol-epoetin beta should be temporarily discontinued(see section 4.2). If clinically indicated, phlebotomy may be performed.

Pharmacotherapeutic group: Other antianemic preparations, ATC code: B03XA03

Methoxy polyethylene glycol-epoetin beta stimulates erythropoiesis by interaction with theerythropoietin receptor on progenitor cells in the bone marrow. Methoxy polyethylene glycol-epoetinbeta, the active substance of MIRCERA, is a continuous erythropoietin receptor activator that shows adifferent activity at the receptor level characterized by a slower association to and faster dissociationfrom the receptor, a reduced specific activity in vitro with an increased activity in vivo, as well as anincreased half-life, in contrast to erythropoietin. The average molecular mass is approximately 60 kDaof which the protein moiety plus the carbohydrate part constitutes approximately 30 kDa.

As primary growth factor for erythroid development, the natural hormone erythropoietin is producedin the kidney and released into the bloodstream in response to hypoxia. In responding to hypoxia, thenatural hormone erythropoietin interacts with erythroid progenitor cells to increase red cell production.

Adult population

Data from correction studies with patients treated once every two weeks and once every four weeksshow that the haemoglobin response rates in the methoxy polyethylene glycol-epoetin beta group atthe end of the correction period were high and comparable to comparators. The median time toresponse was 43 days in the methoxy polyethylene glycol-epoetin beta arm and 29 days in thecomparator arm, with increases of haemoglobin within the first 6 weeks of 0.2 g/dl/week and0.3 g/dl/week, respectively.

Four randomized controlled studies were performed in dialysis patients currently treated withdarbepoetin alfa or epoetin at the time of enrollment. Patients were randomized to stay on theirtreatment at the time of enrollment or to be switched to methoxy polyethylene glycol-epoetin beta inorder to maintain stable haemoglobin levels. At the evaluation period (week 29-36), the mean andmedian level of haemoglobin in patients treated with methoxy polyethylene glycol-epoetin beta wasvirtually identical to their baseline haemoglobin level.

In a randomised, double-blind, placebo-controlled study of 4,038 CRF patients not on dialysis withtype 2 diabetes and haemoglobin levels ≤ 11 g/dl, patients received either treatment with darbepoetinalfa to target haemoglobin levels of 13 g/dl or placebo (see section 4.4). The study did not meet eitherprimary objective of demonstrating a reduction in risk for all-cause mortality, cardiovascularmorbidity, or end stage renal disease (ESRD). Analysis of the individual components of the compositeendpoints showed the following HR (95% CI): death 1.05 (0.92, 1.21), stroke 1.92 (1.38, 2.68),congestive heart failure (CHF) 0.89 (0.74, 1.08), myocardial infarction (MI) 0.96 (0.75, 1.23),hospitalisation for myocardial ischaemia 0.84 (0.55, 1.27), ESRD 1.02 (0.87, 1.18).

Pooled post-hoc analyses of clinical studies of ESAs have been performed in chronic renal failurepatients (on dialysis, not on dialysis, in diabetic and non-diabetic patients). A tendency towardsincreased risk estimates for all-cause mortality, cardiovascular and cerebrovascular events associatedwith higher cumulative ESA doses independent of the diabetes or dialysis status was observed (seesection 4.2 and section 4.4).

Erythropoietin is a growth factor that primarily stimulates red cell production. Erythropoietin receptorsmay be expressed on the surface of a variety of tumour cells.

Survival and tumour progression have been examined in five large controlled studies involving a totalof 2,833 patients, of which four were double-blind placebo-controlled studies and one was an open-label study. Two of the studies recruited patients who were being treated with chemotherapy. Thetarget haemoglobin concentration in two studies was >13 g/dl; in the remaining three studies it was 12-14 g/dl. In the open-label study there was no difference in overall survival between patients treatedwith recombinant human erythropoietin and controls. In the four placebo-controlled studies the hazardratios for overall survival ranged between 1.25 and 2.47 in favour of controls. These studies haveshown a consistent unexplained statistically significant excess mortality in patients who have anaemiaassociated with various common cancers who received recombinant human erythropoietin comparedto controls. Overall survival outcome in the trials could not be satisfactorily explained by differencesin the incidence of thrombosis and related complications between those given recombinant humanerythropoietin and those in the control group.

A patient-level data analysis has also been performed on more than 13,900 cancer patients (chemo-,radia-, chemoradia-, or no therapy) participating in 53 controlled clinical trials involving severalepoetins. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.06 infavour of controls (95% CI: 1.00, 1.12; 53 trials and 13,933 patients) and for the cancer patientsreceiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38 trials and10,441 patients). Meta-analyses also indicate consistently a significantly increased relative risk ofthromboembolic events in cancer patients receiving recombinant human erythropoietin (see section4.4). No patients treated with methoxy polyethylene glycol-epoetin beta were included in this dataanalysis.

Methoxy polyethylene glycol-epoetin beta is not approved for treatment of patients with chemotherapyinduced anaemia (see section 4.1 and 4.4.).

Two studies have been conducted in paediatric patients. One study with intravenous administration(IV) and one study with subcutaneous administration (SC) of methoxy polyethylene glycol-epoetinbeta.

The study using IV administration was a phase II, dose-finding, open-label, single-arm, multicenter,multiple dose study (NH19707) conducted in 64 paediatric patients (aged 5 to 17 years old) with CKDon hemodialysis, to evaluate two conversion factors (group 1 and group 2) in order to switch frommaintenance treatment with IV epoetin alfa/beta or darbepoetin alfa to methoxy polyethylene glycol-epoetin beta, administed IV once every 4 weeks for 20 weeks. Efficacy was assessed based on thechange in haemoglobin concentration (g/dl) between the baseline and evaluation period. The adjustedmean change in haemoglobin from baseline to the evaluation period in group 1 was -0.74 g/dl [95%

CI: -1.32 to -0.16] and in group 2 it was -0.09 g/dl [95% CI: -0.45 to 0.26]. 58% and 75% of patientsmaintained haemoglobin values within ±1 g/dl of baseline and 75% and 81% maintained haemoglobinvalues within 10-12 g/dl in group 1 and group 2 respectively. Subgroup analyses by age groups (5-11years and 12-17 years) were consistent with the observations in the overall population. Patients whocompleted the 20 weeks of core treatment, who adequately maintained haemoglobin levels wereeligible to enter an optional 52-week safety extension period with the same dosing frequency.

The study using SC administration was a second phase II, dose-finding, open-label, single-arm,multicenter study (NH19708) conducted in 40 paediatric patients (aged 3 months to 17 years old) with

CKD on dialysis, or not yet on dialysis, to evaluate the conversion factor used in group 2 in the IVstudy, in order to switch from maintenance treatment with SC epoetin alfa/ beta or darboepoetin alfa tomethoxy polyethylene glycol-epoetin beta, administered SC once every 4 weeks for 20 weeks.

Similarly, in this study, the primary efficacy endpoint was the change in haemoglobin concentration(g/dl) between the baseline and evaluation period. The mean change in haemoglobin concentrationduring the evaluation period was 0.48 g/dl [95% CI: 0.15 to 0.82], which was within the equivalencebounds of -1 to +1g/dl. The results of the mean change in haemoglobin concentration by age group (<5years, 5-11 years, ≥12 years) were consistent with the results of the primary endpoint during theevaluation period. Patients who completed the 20 weeks of core treatment, who adequately maintainedhaemoglobin levels, were eligible to enter an optional 24-week safety extension period with the samedosing frequency.

In both the studies, the mean haemoglobin values remained within 10 to 12 g/dl throughout the entireevaluation period and safety extension period for the majority of patients. The safety profile observedin paediatric patients from both studies was consistent with that found in adults (see section 4.8).

Adult population

The pharmacokinetics of methoxy polyethylene glycol-epoetin beta were studied in healthy volunteersand in anaemic patients with CKD including patients on dialysis and not on dialysis.

Following subcutaneous administration to CKD patients not on dialysis, the maximum serumconcentrations of methoxy polyethylene glycol-epoetin beta were observed 95 hours (median value)after administration. The absolute bioavailability of methoxy polyethylene glycol-epoetin beta aftersubcutaneous administration was 54%. The observed terminal elimination half-life was 142 hours in

CKD patients not on dialysis.

Following subcutaneous administration to CKD patients on dialysis, the maximum serumconcentrations of methoxy polyethylene glycol-epoetin beta were observed 72 hours (median value)after administration. The absolute bioavailability of methoxy polyethylene glycol-epoetin beta aftersubcutaneous administration was 62% and the observed terminal elimination half-life was 139 hoursin CKD patients on dialysis.

Following intravenous administration to CKD patients on dialysis, the total systemic clearance was0.494 ml/h per kg. The elimination half-life after intravenous administration of methoxy polyethyleneglycol-epoetin beta is 134 hours.

A comparison of serum concentrations of methoxy polyethylene glycol-epoetin beta measured beforeand after haemodialysis in 41 CKD patients showed that haemodialysis has no effect on thepharmacokinetics of this medicinal product.

An analysis in 126 CKD patients showed no pharmacokinetic difference between patients on dialysisand patients not on dialysis.

In a single dose study, after intravenous administration, the pharmacokinetics of methoxy polyethyleneglycol-epoetin beta are similar in patients with severe hepatic impairment as compared to healthysubjects (see section 4.2).

A population pharmacokinetic analysis was performed with data from 103 paediatric patients, agedfrom 6 months to 17 years, body weight ranging from 7 to 90 kg, and 524 adult patients. Paediatricpatients received methoxy polyethylene glycol-epoetin beta IV (all on hemodialysis) or SC (onperitoneal dialysis, hemodialysis or not yet on dialysis). Clearance and volume of distribution werefound to increase with body weight and volume of distribution with age. The observed maximum andminimum serum concentrations of methoxy polyethylene glycol-epoetin beta in paediatric patients,collected when their haemoglobin levels were stabilised, were comparable to those observed in adultsfor both routes of administration, IV and SC.

Non-clinical data show no special hazard for humans based on conventional studies of cardiovascularsafety pharmacology, repeat dose toxicity and reproductive toxicity.

The carcinogenic potential of methoxy polyethylene glycol-epoetin beta has not been evaluated inlong-term animal studies. It did not induce a proliferative response in non-haematological tumor celllines in vitro. In a six-month rat toxicity study no tumorigenic or unexpected mitogenic responses wereobserved in non-haematological tissues. In addition, using a panel of human tissues, the in vitrobinding of methoxy polyethylene glycol-epoetin beta was only observed in target cells (bone marrowprogenitor cells).

No significant placental transfer of methoxy polyethylene glycol-epoetin beta was observed in the rat,and studies in animals have not shown any harmful effect on pregnancy, embryofoetal development,parturition or postnatal development. There was however a class-related reversible reduction in foetalweight and a decrease in postnatal body-weight gain of offspring at the doses causing exaggeratedpharmacodynamic effects in mothers. Physical, cognitive, or sexual developments in the offspring ofmothers receiving methoxy polyethylene glycol-epoetin beta during gestation and lactation were notaffected. When methoxy polyethylene glycol-epoetin beta was administered subcutaneously to maleand female rats prior to and during mating, reproductive performance, fertility, and sperm assessmentparameters were not affected.

Sodium dihydrogen phosphate monohydrate

Sodium sulphate

Mannitol (E421)

Methionine

Poloxamer 188

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the pre-filled syringe in the outer carton in order to protect from light.

The end-user may remove the medicinal product from refrigeration for storage at a room temperaturenot above 30°C for one single period of 1 month. Once removed from the refrigerator the medicinalproduct must be used within this period.

Pre-filled syringe (type I glass) with laminated plunger stopper (bromobutyl rubber) and tip cap(bromobutyl rubber) and a needle 27G1/2.

Pre-filled syringes 30, 50, 75, 100, 120, 150, 200 and 250 micrograms contain 0.3 ml solution.

Pre-filled syringe 360 micrograms contains 0.6 ml solution.

Pre-filled syringes 30, 50, 75 micrograms are available in pack size of 1 or 3 pre-filled syringe(s).

Pre-filled syringes 100, 120, 150, 200, 250 and 360 micrograms are available in pack size of 1 pre-filled syringe.

Not all pack sizes may be marketed.

The pre-filled syringe is ready for use. The sterile pre-filled syringe does not contain any preservativeand is to be used for a single injection only. Only one dose should be administered per syringe. Pre-filled syringes are not designed for administration of partial doses. Only solutions which are clear,colourless to slightly yellowish and free of visible particles must be injected.

Do not shake.

Allow the pre-filled syringe to reach room temperature before injecting.

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

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/07/400/008

EU/1/07/400/009

EU/1/07/400/010

EU/1/07/400/011

EU/1/07/400/012

EU/1/07/400/013

EU/1/07/400/017

EU/1/07/400/020

EU/1/07/400/021

EU/1/07/400/022

EU/1/07/400/023

EU/1/07/400/024

Date of first authorisation: 20 July 2007

Date of latest renewal: 15 May 2012

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

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