Treatment of symptomatic renal anemia associated with chronic kidney disease (CKD) in dialyzed
or nondialyzed adult patients.
The safety and efficacy of MIRCERA therapy have not been established in other indications.

Dosage
Treatment with MIRCERA must be initiated under the supervision of a physician experienced in the
management of patients with renal impairment.
Treatment of symptomatic anemia in CKD patients
Patients should be monitored closely to ensure that the lowest approved effective dose of
MIRCERA is used to adequately control the symptoms of anemia while maintaining a hemoglobin
level at or below 12 g/dl (7.5 mmol/l). Caution should be exercised when increasing MIRCERA
doses in patients with chronic renal failure. In patients with a poor hemoglobin response to
MIRCERA, various causes for the poor response should be investigated (see Warnings and
precautions and Properties/Effects).
Anemia symptoms and sequelae may vary with age, gender and overall disease severity; evaluation
of the individual patient’s clinical course and condition by a physician is therefore necessary.
MIRCERA should be administered either subcutaneously or intravenously to increase hemoglobin
to no higher than 12 g/dl (7.45 mmol/l). In patients not receiving hemodialysis, subcutaneous use is
preferable to avoid puncturing peripheral veins.
MIRCERA can be injected subcutaneously in the abdomen, arm or thigh. All three injection sites
are equally suitable for subcutaneous injection of MIRCERA.
Because of intraindividual variations between patients, hemoglobin values above or below the
desired level may occasionally be observed. Such hemoglobin variations can be offset by dose
adjustment, taking account of the hemoglobin target range of 10 g/dl (6.21 mmol/l) to 12 g/dl (7.45
mmol/l). A sustained hemoglobin level of greater than 12 g/dl (7.45 mmol/l) should be avoided;
guidelines for appropriate dose adjustment when hemoglobin values exceed 12 g/dl (7.45 mmol/l)
are described below.
A rise in hemoglobin of greater than 2 g/dl (1.24 mmol/l) over a four-week period should be
avoided. If it occurs, appropriate dose adjustment should be undertaken as specified.
Patients should be monitored closely to ensure use of the lowest approved dose of MIRCERA that
adequately controls the symptoms of anemia.

It is recommended that hemoglobin levels be monitored every two weeks until stabilized and at
regular intervals thereafter.
As recommended in current guidelines, the rate of increase in Hb and the target Hb should be
determined for each patient individually. In CKD patients, the aim of treatment is to reach a target
Hb level of 10-12 g/dl. Patients should be monitored closely to ensure that the lowest effective dose
of Mircera is used to provide adequate control of the symptoms of anaemia.
Initiation of treatment
Patients not currently treated with an erythropoiesis-stimulating agent (ESA):
Patients not on dialysis – The recommended starting dose is 1.2 μg/kg body weight administered
once monthly as a single subcutaneous injection. Alternatively a starting dose of 0.6 μg/kg body
weight may be administered once every two weeks as a single i.v. or s.c. injection.
Patients on dialysis – The recommended starting dose of 0.6 μg/kg body weight may be
administered once every two weeks as a single i.v. or s.c. injection.
Dose adjustment
The MIRCERA dose may be increased by approximately 25% of the previous dose if the rise in
hemoglobin is less than 1.0 g/dl (0.621 mmol/l) over a month. Further dose increases of
approximately 25% may be made every 4 weeks until the individual target hemoglobin level is
achieved.
If the rise in hemoglobin exceeds 2 g/dl (1.24 mmol/l) in one month or if the hemoglobin level
exceeds 12 g/dl, the dose should be reduced by approximately 25%. If the hemoglobin level
continues to increase, therapy should be interrupted until the hemoglobin level begins to decrease,
at which point therapy should be restarted at a dose approximately half the previously administered
dose. After dose interruption a hemoglobin decrease of approximately 0.35 g/dl (0.22 mmol/l) per
week is expected. Dose adjustments should not be made more frecuently than once a month.
In patients treated once every two weeks whose hemoglobin concentration is above the target range,
may receive MIRCERA once monthly at twice the dose previously administered once every two
weeks.
Switching from erythropoiesis stimulating agent (ESA) treatment to Mircera
Patients currently treated with an ESA, can be switched to MIRCERA administered once a month
as a single intravenous or subcutaneous injection. The starting dose of MIRCERA is calculated
from the previous weekly ESA dose at the time of the treatment switch, as described in Table 1. The
first MIRCERA injection should be given at the time of the next scheduled dose of the previously
administered darbepoetin alfa or epoetin.

Table 1. MIRCERA starting doses

If a dose adjustment is required to maintain the target hemoglobin concentration above 10 g/dl (6.21
mmol/l), the dose may be increased by approximately 25%.
If the rise in hemoglobin levels exceeds 2 g/dl (1.24 mmol/l) in one month or if the hemoglobin
level exceeds 12 g/dl, the dose should be reduced by approximately 25%. If the hemoglobin level
continues to increase, therapy should be interrupted until the hemoglobin level begins to decrease,
at which point therapy should be restarted at a dose approximately half the previously administered
dose. After dose interruption a haemoglobin decrease of approximately 0.35 g/dl (0.22 mmol/l) per
week is expected. Dose adjustments should not be made more frequently than once a month.
To ensure the traceability of biological medicinal products, it is recommended that the trade name
and batch number be documented with every treatment.
Special dosage instructions
Patients with hepatic impairment
No adjustments of the starting dose or dose modification rules are required in patients with any
degree of hepatic impairment (see “Kinetics in specific patient groups”).
Elderly patients
In clinical studies, 24% of patients treated with MIRCERA were 65 to 74 years old and 20% were
75 years or older. No dose adjustment is necessary in patients aged ≥65 years.
Children and adolescents
Due to limited safety and efficacy data, no dosage recommendations can be given for use in patients
under 18 years of age.
Delayed administration
If a dose of Mircera is missed, the missed dose should be administered as soon as possible and
treatment with Mircera continued at the prescribed dosing frequency.
Mode of administration
Intravenous and subcutaneous administration.

Hemoglobin target levels above 12 g/dl may be assosiated with an increased risk of cardiovascular
events, including death. Controlled clinical studies have shown no significant benefit attributable to
epoetin use when the hemoglobin level is higher than that necessary to control symptoms of anemia
and avoid blood transfusion.
Patients with chronic renal failure
Caution should be exercised when increasing MIRCERA doses in patients with chronic renal failure
since high cumulative epoetin doses may be associated with an increased risk of mortality and
serious cardiovascular and cerebrovascular events. In patients with a poor hemoglobin response to
epoetins, various causes for the poor response should be investigated (see Dosage/Administration
and Properties/Effects
Iron supplementation
To ensure effective erythropoiesis, iron status should be determined in all patients before and during
treatment. As a rule, supplemental iron therapy should be given in accordance with current
treatment guidelines.
Failure to respond to MIRCERA therapy should prompt an immediate 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,
hemolysis, severe aluminium toxicity, underlying hematological disease or bone marrow fibrosis
may also compromise the erythropoietic response. A reticulocyte count should be considered as part
of the evaluation.
If all the conditions mentioned are excluded and the patient has a sudden drop of hemoglobin
associated with reticulocytopenia and antierythropoietin antibodies, examination of the bone
marrow for the diagnosis of pure red cell aplasia [PRCA] should be considered. If PRCA is
diagnosed, therapy with Mircera must be discontinued and patients must not be switched to another
ESA.
Pure red cell aplasia (PRCA)
Pure red cell aplasia due to antierythropoietin antibodies has been reported during treatment with
ESAs, including MIRCERA. These antibodies cross-react with all ESAs, and patients suspected or
confirmed to have antibodies to erythropoietin must not be switched to Mircera.
Blood pressure monitoring
As with other ESAs, blood pressure may rise during treatment with MIRCERA. Blood pressure
should be adequately monitored in all patients before, at initiation of and during treatment with
MIRCERA. If high blood pressure is difficult to control by medication or diet, MIRCERA must be
reduced in dose or withheld (see Contraindications).
SCAR
Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic
epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in
association with epoetin treatments. More severe cases have been observed with long-acting
epoetins.
At the time of prescription, patients should be advised of the signs and symptoms and monitored
closely for skin reactions. Typical signs include fever, a spreading painful rash that is often
preceded by fever and flu-like symptoms, blistering, and inflammation of the eyes and mucous

membranes. If signs and symptoms suggestive of such hypersensitivity reactions appear, Mircera
should be discontinued immediately.
If a patient has developed a severe skin reaction such as SJS or TEN due to the use of Mircera,
treatment with Mircera must not be restarted in this patient at any time.
Effect on tumor growth
MIRCERA, like other ESAs, is a growth factor that primarily stimulates erythrocyte production.
Erythropoietin receptors may be expressed on the surface of a variety of tumor cells. As with all
growth factors, there is a concern that ESAs could stimulate the growth of certain types of
malignancy. MIRCERA is not approved for the treatment of anemia in cancer patients.
Other
The safety and efficacy of MIRCERA therapy have not been investigated in patients with
hemoglobinopathies, seizure disorders, bleeding or a recent history of bleeding requiring
transfusions or with platelet counts above 500 × 109/l. Caution is therefore required in these
patients.
Misuse
Misuse by non-anaemic persons (e.g. for doping) may lead to an excessive increase in hemoglobin.
This carries a risk of life-threatening cardiovascular complications (risk of thrombosis due to
hemoconcentration in erythrocytosis).
Hemoglobin concentration
In CKD patients the maintenance hemoglobin concentration should not persistently exceed the
upper limit of the target hemoglobin concentration recommended under Dosage/Administration. In
clinical trials an increased risk of death and serious cardiovascular events was observed when
erythropoiesis stimulating agents (ESAs) were administered to achieve a target hemoglobin of
greater than 12 g/dl (7.5 mmol/l).
Controlled clinical trials have not shown significant benefits attributable to the administration of
epoetins when the hemoglobin concentration is increased beyond the level necessary to control
symptoms of anemia and to avoid blood transfusion.
This medicinal product contains less than 1 mmol of sodium (23 mg) per prefilled syringe, i.e. it is
virtually “sodium-free”.

No interaction studies have been performed. Clinical studies have produced no evidence that
MIRCERA interacts with other medicinal products. The effect of other drugs on the MIRCERA
pharmacokinetics and pharmacodynamics was investigated in a population analysis. No evidence
was found of an effect on MIRCERA pharmacokinetics or pharmacodynamics.

Pregnancy
There are insufficient data on use in pregnant women.
Animal studies have shown no direct or indirect toxicity affecting pregnancy, embryonic
development, fetal development, parturition (see Preclinical data) and/or postnatal development.
Caution is required if used during pregnancy.

Lactation
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. In deciding whether to continue or discontinue breastfeeding during treatment with
MIRCERA or to discontinue MIRCERA, the benefit of breastfeeding to the child should be
weighed against the benefit of MIRCERA therapy to the woman.

MIRCERA has no or negligible influence on the ability to drive and use machines.

The MIRCERA safety data from clinical trials are based on 3042 CKD patients, including 1939
patients treated with MIRCERA and 1103 with another ESA. Undesirable effects must be expected
in some 6% of patients treated with MIRCERA. The most frequent reported undesirable effect was
hypertension (common).

Table 2. Undesirable effects attributed to MIRCERA treatment in controlled clinical trials in CKD patients

All other reactions attributed to MIRCERA were rare and in most cases mild to moderate in
severity. These reactions could be explained by comorbidities known in the population.
In clinical studies, the platelet count decreased slightly during treatment with MIRCERA, but
remained within the normal range.
Platelet counts below 100 × 109/l were observed in 7.5% of patients treated with MIRCERA and
4.4% of patients treated with ESAs.
The safety profile in the paediatric population was consistent with that in adults.
Undesirable effects after market launch
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic
epidermal necrolysis (TEN), skin exfoliation and erythema multiforme, have been reported with
Mircera in the post-marketing setting (see “Warnings and precautions”). Frequencies are not
known.

The occurrence of neutralizing antierythropoietin antibody-mediated pure red cell aplasia (AEABPRCA)
has been reported in association with MIRCERA therapy during post-marketing experience
(see Warnings and precautions).
Description of selected adverse reactions
Reporting of suspected adverse reactions after marketing authorisation is very important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals
are asked to report any suspected new or serious adverse reaction.

To report any side effect(s):
• Saudi Arabia:

• Other GCC States:

MIRCERA has a wide therapeutic range. Individual response must be considered when initiating
treatment with MIRCERA.
Signs and symptoms
Overdose can result in an exaggerated pharmacodynamic effect, e.g. excessive erythropoiesis.
Treatment
In case of excessive haemoglobin levels, Mircera should be temporarily withheld (see
“Dosage/Administration”).
If clinically indicated, phlebotomy may be performed.

ATC code: B03XA03

Mechanism of action
Mircera stimulates erythropoiesis by interaction with the erythropoietin receptor on progenitor cells
in the bone marrow. As primary growth factor for erythroid development, the natural hormone
erythropoietin is produced by the kidney and released into the bloodstream according to the level of
tissue oxygen saturation. In response to hypoxia, the natural hormone erythropoietin interacts with
erythroid progenitor cells, increasing their production.
Pharmacodynamics
Methoxy polyethylene glycol-epoetin beta, the active substance of MIRCERA, is a continuous
erythropoietin receptor activator that differs from erythropoietin in its activity at the receptor level,
which is characterized by slower association with and faster dissociation from the receptor, reduced
specific activity in vitro with increased activity in vivo, and an increased half-life. Its average
molecular weight is about 60 kDa, of which the protein portion plus carbohydrate portion accounts
for approximately 30 kDa.
Clinical efficacy
In two randomized controlled studies in patients with chronic renal disease not on dialysis,
BA16738 and NH20052, MIRCERA corrected anemia in 97.5% and 94.1% of the patients,
respectively. In study BA16738, the proportion of patients with a hemoglobin level exceeding
13 g/dl in the first 8 treatment weeks was 11.4% in the MIRCERA group and 34% in the
darbepoetin alfa group. In study NH20052, the proportion of patients with a hemoglobin level
exceeding 12 g/dl was 25.8% in the MIRCERA group and 47.7% in the darbepoetin alfa group. In
the randomized controlled study in chronic renal failure with dialysis, MIRCERA corrected anemia
in 93.3% of patients.
Four randomized controlled studies were performed in dialysis patients currently treated with ESAs.
Patients were randomized to stay on their current treatment or be switched to MIRCERA in order to
achieve stable hemoglobin levels. In the evaluation period (weeks 29–36), mean and median
hemoglobin levels in patients in the MIRCERA group were virtually identical to their baseline
levels.
In a randomized study of epoetin beta in predialysis patients (CREATE), in which 603 patients with
renal anemia were assigned to a group with either high (13–15 g/dl) or low (10.5–11.5 g/dl) target
hemoglobin levels, the frequency of cardiovascular events in the group with higher hemoglobin
levels was 19% vs 16% in the lower target hemoglobin group (58 vs 47 cases; p=0.20). The
frequency of thromboembolic events in this study was 11% in the high target hemoglobin group and
7% in that with a low target hemoglobin as the treatment goal (p=0.06). As reported earlier, the
frequency of vascular-access thrombosis in patients referred for dialysis was likewise higher in
those with a high hemoglobin level as the treatment goal (4% vs 3%; p=0.42).
In a randomized study of epoetin alfa in predialysis patients (CHOIR), in which 1432 patients were
assigned to a study arm with a high target hemoglobin level (13.5 g/dl) or one with a low target
hemoglobin level (11.5 g/dl), there were significantly more cardiovascular events in the high target
hemoglobin group than in the group with low target hemoglobin levels (17% vs 14%; 125 vs 97

cases; p=0.03). The frequency of thromboembolic events in the high-hemoglobin study arm was
18% vs 17% in the low-hemoglobin arm (p=0.65).
In the MIRCERA development program, no study was performed to compare high and low target
hemoglobin levels in a similar patient population.
Safety and efficacy in paediatric patients
A phase II, dose-finding, open-label, repeated-dose, multicentre study was conducted in 64
paediatric haemodialysis patients (5 to 17 years old) with CKD to determine the effective starting
dose of Mircera i.v. when switching from maintenance treatment with another ESA (epoetin
alfa/beta or darbepoetin alfa). The primary efficacy endpoint in this study (change in Hb
concentration [g/dl] between the baseline and evaluation periods) has been met.

The pharmacokinetic and pharmacological properties of MIRCERA make it possible to treat
patients with a once-monthly regimen, thanks to its long elimination half-life. After intravenous
dosing, MIRCERA has an elimination half-life 15 to 20 times longer than that of recombinant
human erythropoietin.
The pharmacokinetics of MIRCERA were studied in healthy volunteers and in anemic dialyzed and
nondialyzed CKD patients.
The clearance and volume of distribution of MIRCERA in the CKD patients were not dosedependent.
MIRCERA pharmacokinetics were studied in CKD patients after the first dose and after dosing in
week 9 and week 19 or 21. Repeated administration had no effects on the clearance, volume of
distribution or bioavailability of MIRCERA. Four-weekly administration in CKD patients led to
virtually no accumulation of MIRCERA, as shown by the accumulation ratio of 1.03. After 2-
weekly administration the accumulation ratio was 1.12.
Comparison of MIRCERA serum concentrations measured before and after hemodialysis in 41
CKD patients showed that hemodialysis had no effect on the drug’s pharmacokinetics.
An analysis in 126 CKD patients showed no pharmacokinetic difference between dialyzed and
nondialyzed patients.
Absorption
Following subcutaneous administration to CKD patients, the maximum serum concentrations of
methoxy polyethylene glycol-epoetin beta were observed 72 hours (median value) after
administration in dialyzed patients and 95 hours after administration in patients not on dialysis.
The absolute bioavailability of methoxy polyethylene glycol-epoetin beta after s.c. administration
was 62% and 54%, in dialysis patients and patients not on dialysis, respectively.
Distribution
A study in 400 CKD patients showed that MIRCERA has a volume of distribution of approximately
5 l.
Metabolism
No information.

Elimination
Following intravenous administration to CKD patients, the half-life of MIRCERA was 134 hours
(5.6 days) and the total systemic clearance was 0.494 ml/h per kg. Following subcutaneous
administration, the terminal half-life was 139 hours (5.8 days) in CKD patients on dialysis and 142
hours in patients not on dialysis.
Kinetics in specific patient groups
Hepatic impairment
Mircera pharmacokinetics in patients with severe liver failure are similar to those in healthy
subjects (see Special dosage instructions).
Renal impairment
Pooled post hoc analyses of clinical studies with erythropoiesis-stimulating agents (ESAs) have
been performed in chronic renal failure patients (dialysis patients, diabetics and nondiabetics). With
higher cumulative ESA doses, a trend towards increased risk event probabilities for all-cause
mortality and cardiovascular and cerebrovascular events was observed, independently of diabetes or
dialysis status (see Dosage/Administration and Warnings and precautions).
Children and adolescents The pharmacokinetics of Mircera were studied in 64 paediatric CKD
patients (5 to 17 years old) receiving haemodialysis. At steady state (after the third dose of
Mircera), a Cmax of 66.1 ng/ml and AUC0 tau of 7170 ng.hr/ml (both geometric means) were
measured as the maximum observed exposure. Subsequently, Mircera serum concentrations
declined with an apparent mean half-life of approximately 121 to 147 hours (geometric mean) in a
manner similar to that in adults.
Other special populations
Population analyses found no evidence that age, gender or ethnicity have a relevant
pharmacokinetic effect. A population-based pharmacokinetic analysis likewise showed no relevant
difference in pharmacokinetics between dialyzed and nondialyzed patients.

Preclinical data based on conventional studies of cardiovascular safety pharmacology, repeateddose
toxicity, reproductive toxicity and carcinogenic potential show no special hazard for humans.
Carcinogenicity
The carcinogenic potential of MIRCERA has not been evaluated in long-term animal studies.
MIRCERA did not induce a proliferative response in nonhematological tumor cell lines in vitro. In
a six-month rat toxicity study, no mitogenic or tumorigenic responses were observed in
nonhematological tissues.
Reproductive toxicity
Animal studies produced no evidence of adverse effects on pregnancy, embryofetal development or
delivery. Peri-postnatal studies showed reduced weight gain in neonates. Subcutaneous
administration of MIRCERA to male and female rats before and during mating had no effect on
reproductive performance, fertility or sperm parameters.

Additional data
In a panel of human tissues, in vitro binding of MIRCERA was only observed in target cells (bone
marrow progenitor cells).

In the absence of compatibility studies, MIRCERA must not be mixed with other medicinal
products.

36 Months
Do not use this medicine after the expiry date (“EXP”) stated on the pack.

The MIRCERA solution for injection in the prefilled syringe is ready for use. The sterile solution
for injection in the prefilled syringe contains no preservatives and is intended for a single injection
only. Only one dose should be administered per syringe. Only solutions that are clear, colorless to
pale yellow and free of visible particles may be injected.
Do not shake.
Allow the prefilled syringe to reach room temperature before injecting.
Dispose of any unused product or waste in accordance with local requirements.

Packs
Prefilled syringe containing 30 μg in 0.3 ml: 1
Prefilled syringe containing 50 μg in 0.3 ml: 1
Prefilled syringe containing 75 μg in 0.3 ml: 1
Prefilled syringe containing 100 μg in 0.3 ml: 1
Prefilled syringe containing 120 μg in 0.3 ml: 1
Prefilled syringe containing 150 μg in 0.3 ml: 1
Prefilled syringe containing 200 μg in 0.3 ml: 1
Prefilled syringe containing 250 μg in 0.3 ml: 1

The MIRCERA prefilled syringe is ready for use. The prefilled syringe contains no preservatives and is intended for a single injection only. Only one dose should be administered per syringe. Only solutions that are clear, colourless to pale yellow and free of visible particles may be injected. Do not shake. Allow the prefilled syringe to reach room temperature before injecting. Dispose of any unused product or waste in accordance with local requirements