ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
MIRCERA 50 micrograms/0.3 ml solution for injection in pre-filled syringe
2.
One pre-filled syringe contains 50 micrograms of methoxy polyethylene glycol-epoetin beta* at a
concentration of 167 micrograms/ml. The strength indicates the quantity of the protein moiety of the
methoxy polyethylene glycol-epoetin beta molecule without consideration of the glycosylation.
*Protein produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells and
covalently conjugated to a linear methoxy-polyethylene glycol (PEG).
The potency of methoxy polyethene glycol-epoetin beta should not be compared to the potency of
another pegylated or non-pegylated protein of the same therapeutic class. For more information, see
section 5.1.
For a full list of excipients, see section 6.1.
3.
Solution for injection (injection).
The solution is clear and colourless to slightly yellowish.
4.
Treatment of
symptomatic
anaemia associated with chronic kidney disease (CKD).
The safety and efficacy of MIRCERA therapy in other indications has not been established.
Treatment of symptomatic anaemia in adult chronic kidney disease patients
Treatment with MIRCERA has to be initiated under the supervision of a physician experienced in the
management of patients with renal impairment.
Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a
physician’s evaluation of the individual patient’s clinical course and condition is necessary.
MIRCERA should be administered either subcutaneously or intravenously in order to increase
haemoglobin to not greater than 12 g/dl (7.45 mmol/l). Subcutaneous use is preferable in patients who
are not receiving haemodialysis to avoid puncture of peripheral veins.
MIRCERA can be injected subcutaneously in the abdomen, arm or thigh. All three injection sites are
equally suitable.
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed
through 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 haemoglobin
values 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) over a four-week period should be avoided.
If it occurs, appropriate dose adjustment should be made as provided.
2
Patients should be monitored closely to ensure that the lowest approved dose of MIRCERA is used to
provide adequate control of the symptoms of anaemia.
It is recommended that haemoglobin is monitored every two weeks until stabilized and periodically
thereafter.
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 recommended
starting dose in patients not on dialysis is 1.2 microgram/kg body weight, administered once every
month as a single subcutaneous injection.
Alternatively, a starting dose of 0.6 microgram/kg bodyweight may be administered once every two
weeks 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 in
haemoglobin is less than 1.0 g/dl (0.621 mmol/l) over a month. Further increases of approximately
25% 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 the
haemoglobin level is increasing and approaching 12 g/dl (7.45 mmol/l), the dose is to be reduced by
approximately 25%. If the haemoglobin level continues to increase, therapy should be interrupted until
the haemoglobin level begins to decrease, at which point therapy should be restarted at a dose
approximately 25% below 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.
Patients treated once every two weeks whose haemoglobin concentration above is 10 g/dl
(6.21 mmol/l) may receive MIRCERA administered once-monthly using the dose equal to twice the
previous once-every–two-weeks dose.
Patients currently treated with an ESA:
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 methoxy polyethylene glycol-
epoetin beta is based on the calculated previous weekly dose of darbepoetin alfa or epoetin at the time
of substitution as described in Table 1. The first injection should start at the next scheduled dose of the
previously administered darbepoetin alfa or epoetin.
Table 1: MIRCERA starting doses
Previous weekly
darbepoetin alfa
intravenous or
subcutaneous dose
(microgram/week)
Previous weekly
epoetin
intravenous or
subcutaneous
dose (IU/week)
Monthly MIRCERA
intravenous or
subcutaneous dose
(microgram/once
monthly)
<40
<8000
120
40-80
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 the
haemoglobin level is increasing and approaching 12 g/dl (7.45 mmol/l), the dose is to be reduced by
approximately 25%. If the haemoglobin level continues to increase, therapy should be interrupted until
the haemoglobin level begins to decrease, at which point therapy should be restarted at a dose
approximately 25% below the previously administered dose. After dose interruption a haemoglobin
3
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.
Since the treatment experience is limited in patients on peritoneal dialysis, regular haemoglobin
monitoring and strict adherence to dose adjustment guidance is recommended in these patients.
Treatment interruption
Treatment with MIRCERA is normally long-term. However, it can be interrupted at any time, if
necessary.
Missed dose
If one dose of MIRCERA is missed, the missed dose is to be administered as soon as possible and
administration of MIRCERA is to be restarted at the prescribed dosing frequency.
Paediatric use
MIRCERA is not recommended for use in children and adolescents below 18 years due to a lack of
safety and efficacy data.
Elderly patients
In clinical studies 24% of patients treated with MIRCERA were aged 65 to 74 years, while 20% were
aged 75 years and over. No dose adjustment is required in patients aged 65 years or older.
Patients with hepatic impairment
No adjustments of the starting dose nor of the dose modification rules are required in patients with
hepatic impairment (see section 5.2).
Hypersensitivity to the active substance or to any of the excipients.
Uncontrolled hypertension.
Supplementary iron therapy
is recommended for all patients with serum ferritin values below
100 microgram/l or with transferrin saturation below 20%. To ensure effective erythropoiesis, iron
status has to be evaluated for all patients prior to and during treatment.
Failure to respond to MIRCERA therapy 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, severe
aluminium toxicity, underlying haematologic diseases, 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 haemoglobin associated
with reticulocytopenia and anti-erythropoietin antibodies, examination of the bone marrow for the
diagnosis of Pure Red Cell Aplasia (PRCA) should be considered. In case PRCA is diagnosed, therapy
with MIRCERA must be discontinued and patients should not be switched to another ESA.
Pure Red Cell Aplasia
caused by anti-erythropoietin antibodies has been reported in association with
ESAs. These antibodies have been shown to cross-react with all ESAs, and patients suspected or
confirmed to have antibodies to erythropoietin should not be switched to MIRCERA.
PRCA in patients with Hepatitis C:
A paradoxical decrease in haemoglobin and development of severe
anaemia associated with low reticulocyte counts should prompt to discontinue treatment with epoetin
and perform anti-erythropoietin antibody testing. Cases have been reported in patients with hepatitis C
treated with interferon and ribavirin, when epoetins are used concomitantly. Epoetins are not approved
in the management of anaemia associated with hepatitis C.
4
Haemoglobin concentration:
In patients with chronic kidney disease, maintenance haemoglobin
concentration should not exceed the upper limit of the target haemoglobin concentration recommended
in section 4.2. In clinical trials, an increased risk of death and serious cardiovascular events was
observed when erythropoiesis stimulating agents (ESAs) were administered to target a haemoglobin 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 haemoglobin concentration is increased beyond the level necessary to control
symptoms of anaemia and to avoid blood transfusion.
Blood pressure monitoring:
As with other ESAs, blood pressure may rise during treatment with
MIRCERA. Blood pressure should be adequately controlled in all patients before, at initiation of, and
during treatment with MIRCERA. If high blood pressure is difficult to control by medical treatment or
dietary measures, the dose must be reduced or administration discontinued (see section 4.2).
Effect on tumour growth:
MIRCERA, like other ESAs, is a growth factor that primarily stimulates red
blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour
cells. As with all growth factors, there is a concern that ESAs could stimulate the growth of any type
of malignancy. Two controlled clinical studies in which epoetins were administered to patients with
various cancers including head and neck cancers, and breast cancer, have shown an unexplained
excess mortality.
MIRCERA is not approved for the treatment of anaemia in patients with cancer.
The safety and efficacy of MIRCERA therapy has not been established in patients with
haemoglobinopathies, seizures, bleeding or a recent history of bleeding requiring transfusions or with
platelet levels greater than 500 x 10
9
/l. Therefore, caution should be used in these patients.
Misuse
of MIRCERA by healthy people may lead to an excessive increase in haemoglobin. This may
be associated with life-threatening cardiovascular complications.
Traceability
of MIRCERA: In order to improve the traceability of erythropoiesis-stimulating agents
(ESAs), the trade name of the administered ESA should be clearly recorded (or stated) in the patient
file.
No interaction studies have been performed. There is no evidence that MIRCERA alters the
metabolism of other medicinal products.
Pregnancy:
There are no data from the use of MIRCERA in pregnant women.
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryofoetal
development, parturition or postnatal development but indicate a class-related reversible reduction in
foetal weight (see section 5.3). Caution should be exercised when prescribing to pregnant women.
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.
A decision on whether to continue or discontinue breast-feeding or to continue or discontinue therapy
with MIRCERA should be made taking into account the benefit of breast-feeding to the child and the
benefit of MIRCERA therapy to the woman.
MIRCERA has no or negligible influence on the ability to drive and use machines.
5
The safety data base from clinical trials comprised 3’042 CKD patients, including 1’939 patients
treated with MIRCERA and 1’103 with another ESA. Approximately 6% of patients treated with
MIRCERA are expected to experience adverse reactions. The most frequent reported adverse reaction
was hypertension (common).
The frequencies are defined as follows:
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 2: Adverse reactions attributed to the treatment with MIRCERA in controlled clinical
trials in CKD patients
System organ class
Frequency
Adverse reaction
Nervous system disorders
Uncommon
Headache
Nervous system disorders
Rare
Hypertensive encephalopathy
Skin and subcutaneous tissue
disorders
Rare
Rash, maculo-papular
Injury, poisoning and
procedural complications
Uncommon
Vascular access thrombosis
Vascular disorders
Common
Hypertension
Vascular disorders
Rare
Hot flush
Immune system disorders
Rare
Hypersensitivity
All other events attributed to MIRCERA were reported with rare frequency and the majority were
mild to moderate in severity. These events were consistent with comorbidities known in the population.
Hypersensitivity reactions, including cases of anaphylactic reaction, have been spontaneously reported,
frequency unknown.
During treatment with MIRCERA, a slight decrease in platelet counts remaining within the normal
range was observed in clinical studies.
Platelet counts below 100 x 10
9
/l were observed in 7% of patients treated with MIRCERA and 4% of
patients treated with other ESAs.
The therapeutic range of MIRCERA is wide. Individual responsiveness must be considered when
effect, e.g. excessive erythropoiesis. In case of excessive haemoglobin levels, treatment with
MIRCERA should be temporarily discontinued (see section 4.2). If clinically indicated, phlebotomy
may be performed.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other antianemic preparations, ATC code: B03XA03
6
Methoxy polyethylene glycol-epoetin beta, the active substance of MIRCERA, is a continuous
erythropoietin receptor activator that shows a different activity at the receptor level characterized by a
slower association to and faster dissociation from the receptor, a reduced specific activity
in vitro
with
an increased activity
in vivo
, as well as an increased half-life, in contrast to erythropoietin. The
average molecular mass is approximately 60 kDa of which the protein moiety plus the carbohydrate
part constitutes approximately 30 kDa.
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 in the kidney and released into the bloodstream in response to hypoxia. In
responding to hypoxia, the natural hormone erythropoietin interacts with erythroid progenitor cells to
increase red cell production.
Data from correction studies with patients treated once every two weeks and once every four weeks
show that the haemoglobin response rates in the MIRCERA group at the end of the correction period
were high and comparable to comparators. The median time to response was 43 days in the MIRCERA
arm and 29 days in the comparator arm, with increases of haemoglobin within the first 6 weeks of
0.2 g/dl/week and 0.3 g/dl/week, respectively.
Four randomized controlled studies were performed in dialysis patients treated with darbepoetin alfa
or epoetin at the time of enrollment. Patients were randomized to stay on their treatment at the time of
enrollment or to be switched to MIRCERA in order to maintain stable haemoglobin levels. At the
evaluation period (week 29-36), the mean and median level of haemoglobin in patients treated with
MIRCERA was virtually identical to their baseline haemoglobin level.
Erythropoietin is a growth factor that primarily stimulates red cell production. Erythropoietin receptors
may 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 total
of 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. The
target 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 treated
with recombinant human erythropoietin and controls. In the four placebo-controlled studies the hazard
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls. These studies have
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia
associated with various common cancers who received recombinant human erythropoietin compared
to controls. Overall survival outcome in the trials could not be satisfactorily explained by differences
in the incidence of thrombosis and related complications between those given recombinant human
erythropoietin 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 several
epoetins. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.06 in
favour of controls (95% CI: 1.00, 1.12; 53 trials and 13933 patients) and for the cancer patients
receiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38 trials and
10,441 patients). Meta-analyses also indicate consistently a significantly increased relative risk of
thromboembolic events in cancer patients receiving recombinant human erythropoietin (see section
4.4). Mircera is not approved for treatment of patients with chemotherapy induced anaemia (see
section 4.1), no patients treated with MIRCERA were part of this data analysis.
5.2 Pharmacokinetic properties
The pharmacokinetics of methoxy polyethylene glycol-epoetin beta were studied in healthy volunteers
and in anaemic patients with CKD including patients on dialysis and not on dialysis.
7
Following subcutaneous administration to CKD patients not on dialysis, the maximum serum
concentrations of methoxy polyethylene glycol-epoetin beta were observed 95 hours (median value)
after administration. The absolute bioavailability of methoxy polyethylene glycol-epoetin beta after
subcutaneous 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 serum
concentrations of methoxy polyethylene glycol-epoetin beta were observed 72 hours (median value)
after administration. The absolute bioavailability of methoxy polyethylene glycol-epoetin beta after
subcutaneous administration was 62% and the observed terminal elimination half-life was 139 hours
in CKD patients on dialysis.
Following intravenous administration to CKD patients on dialysis, the total systemic clearance was
0.494 ml/h per kg. The elimination half-life after intravenous administration of methoxy polyethylene
glycol-epoetin beta is 134 hours.
A comparison of serum concentrations of methoxy polyethylene glycol-epoetin beta measured before
and after haemodialysis in 41 CKD patients showed that haemodialysis has no effect on the
pharmacokinetics of this medicinal product.
An analysis in 126 CKD patients showed no pharmacokinetic difference between patients on dialysis
and patients not on dialysis.
In a single dose study, after intravenous administration, the pharmacokinetics of methoxy polyethylene
glycol-epoetin beta are similar in patients with severe hepatic impairment as compared to healthy
subjects (see section 4.2).
5.3 Preclinical safety data
Non-clinical data show no special hazard for humans based on conventional studies of cardiovascular
safety pharmacology, repeat dose toxicity and reproductive toxicity.
The carcinogenic potential of methoxy polyethylene glycol-epoetin beta has not been evaluated in
long-term animal studies. It did not induce a proliferative response in non-haematological tumor cell
lines
in vitro
. In a six-month rat toxicity study no tumorigenic or unexpected mitogenic responses were
observed in non-haematological tissues. In addition, using a panel of human tissues, the
in vitro
binding of methoxy polyethylene glycol-epoetin beta was only observed in target cells (bone marrow
progenitor 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 foetal
weight and a decrease in postnatal body-weight gain of offspring at the doses causing exaggerated
pharmacodynamic effects in mothers. Physical, cognitive, or sexual developments in the offspring of
mothers receiving methoxy polyethylene glycol-epoetin beta during gestation and lactation were not
affected. When methoxy polyethylene glycol-epoetin beta was administered subcutaneously to male
and female rats prior to and during mating, reproductive performance, fertility, and sperm assessment
parameters were not affected.
8
6.
6.1 List of excipients
Sodium dihydrogen phosphate monohydrate
Sodium sulphate
Mannitol (E421)
Methionine
Poloxamer 188
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
3 years
6.4 Special precautions for storage
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 temperature
not above 30°C for one single period of 1 month. Once removed from the refrigerator the medicinal
product must be used within this period.
6.5 Nature and contents of container
Pre-filled syringe (type I glass) with laminated plunger stopper (bromobutyl rubber material) and tip
cap (bromobutyl rubber material) and a needle 27G1/2. Pack size of 1.
6.6 Special precautions for disposal and other handling
The pre-filled syringe is ready for use. The sterile pre-filled syringe does not contain any preservative
and is to be used for a single injection only. Only one dose should be administered per syringe. 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 local
requirements.
7.
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
8.
9
EU/1/07/400/008
9.
20 July 2007
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
10
1.
MIRCERA 75 micrograms/0.3 ml solution for injection in pre-filled syringe.
2.
One pre-filled syringe contains 75 micrograms of methoxy polyethylene glycol-epoetin beta* at a
concentration of 250 micrograms/ml. The strength indicates the quantity of the protein moiety of the
methoxy polyethylene glycol-epoetin beta molecule without consideration of the glycosylation.
*Protein produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells and
covalently conjugated to a linear methoxy-polyethylene glycol (PEG).
The potency of methoxy polyethene glycol-epoetin beta should not be compared to the potency of
another pegylated or non-pegylated protein of the same therapeutic class. For more information, see
section 5.1.
For a full list of excipients, see section 6.1.
3.
Solution for injection (injection).
The solution is clear and colourless to slightly yellowish.
4.
Treatment of symptomatic anaemia associated with chronic kidney disease (CKD).
The safety and efficacy of MIRCERA therapy in other indications has not been established.
Treatment of symptomatic anaemia in adult chronic kidney disease patients
Treatment with MIRCERA has to be initiated under the supervision of a physician experienced in the
management of patients with renal impairment.
Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a
physician’s evaluation of the individual patient’s clinical course and condition is necessary.
MIRCERA should be administered either subcutaneously or intravenously in order to increase
haemoglobin to not greater than 12 g/dl (7.45 mmol/l). Subcutaneous use is preferable in patients who
are not receiving haemodialysis to avoid puncture of peripheral veins.
MIRCERA can be injected subcutaneously in the abdomen, arm or thigh. All three injection sites are
equally suitable.
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed
through 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 haemoglobin
values 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) over a four-week period should be avoided.
If it occurs, appropriate dose adjustment should be made as provided.
11
Patients should be monitored closely to ensure that the lowest approved dose of MIRCERA is used to
provide adequate control of the symptoms of anaemia.
It is recommended that haemoglobin is monitored every two weeks until stabilized and periodically
thereafter.
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 recommended
starting dose in patients not on dialysis is 1.2 microgram/kg body weight, administered once every
month as a single subcutaneous injection.
Alternatively, a starting dose of 0.6 microgram/kg bodyweight may be administered once every two
weeks 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 in
haemoglobin is less than 1.0 g/dl (0.621 mmol/l) over a month. Further increases of approximately
25% 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 the
haemoglobin level is increasing and approaching 12 g/dl (7.45 mmol/l), the dose is to be reduced by
approximately 25%. If the haemoglobin level continues to increase, therapy should be interrupted until
the haemoglobin level begins to decrease, at which point therapy should be restarted at a dose
approximately 25% below 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.
Patients treated once every two weeks whose haemoglobin concentration above is 10 g/dl
(6.21 mmol/l) may receive MIRCERA administered once-monthly using the dose equal to twice the
previous once-every–two-weeks dose.
Patients currently treated with an ESA:
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 methoxy polyethylene glycol-
epoetin beta is based on the calculated previous weekly dose of darbepoetin alfa or epoetin at the time
of substitution as described in Table 1. The first injection should start at the next scheduled dose of the
previously administered darbepoetin alfa or epoetin.
Table 1: MIRCERA starting doses
Previous weekly
darbepoetin alfa
intravenous or
subcutaneous dose
(microgram/week)
Previous weekly
epoetin
intravenous or
subcutaneous
dose (IU/week)
Monthly MIRCERA
intravenous or
subcutaneous dose
(microgram/once
monthly)
<40
<8000
120
40-80
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 the
haemoglobin level is increasing and approaching 12 g/dl (7.45 mmol/l), the dose is to be reduced by
approximately 25%. If the haemoglobin level continues to increase, therapy should be interrupted until
the haemoglobin level begins to decrease, at which point therapy should be restarted at a dose
approximately 25% below the previously administered dose. After dose interruption a haemoglobin
12
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.
Since the treatment experience is limited in patients on peritoneal dialysis, regular haemoglobin
monitoring and strict adherence to dose adjustment guidance is recommended in these patients.
Treatment interruption
Treatment with MIRCERA is normally long-term. However, it can be interrupted at any time, if
necessary.
Missed dose
If one dose of MIRCERA is missed, the missed dose is to be administered as soon as possible and
administration of MIRCERA is to be restarted at the prescribed dosing frequency.
Paediatric use
MIRCERA is not recommended for use in children and adolescents below 18 years due to a lack of
safety and efficacy data.
Elderly patients
In clinical studies 24% of patients treated with MIRCERA were aged 65 to 74 years, while 20% were
aged 75 years and over. No dose adjustment is required in patients aged 65 years or older.
Patients with hepatic impairment
No adjustments of the starting dose nor of the dose modification rules are required in patients with
hepatic impairment (see section 5.2).
Hypersensitivity to the active substance or to any of the excipients.
Uncontrolled hypertension.
Supplementary iron therapy
is recommended for all patients with serum ferritin values below
100 microgram/l or with transferrin saturation below 20%. To ensure effective erythropoiesis, iron
status has to be evaluated for all patients prior to and during treatment.
Failure to respond to MIRCERA therapy 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, severe
aluminium toxicity, underlying haematologic diseases, 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 haemoglobin associated
with reticulocytopenia and anti-erythropoietin antibodies, examination of the bone marrow for the
diagnosis of Pure Red Cell Aplasia (PRCA) should be considered. In case PRCA is diagnosed, therapy
with MIRCERA must be discontinued and patients should not be switched to another ESA.
Pure Red Cell Aplasia
caused by anti-erythropoietin antibodies has been reported in association with
ESAs. These antibodies have been shown to cross-react with all ESAs, and patients suspected or
confirmed to have antibodies to erythropoietin should not be switched to MIRCERA.
PRCA in patients with Hepatitis C:
A paradoxical decrease in haemoglobin and development of severe
anaemia associated with low reticulocyte counts should prompt to discontinue treatment with epoetin
and perform anti-erythropoietin antibody testing. Cases have been reported in patients with hepatitis C
treated with interferon and ribavirin, when epoetins are used concomitantly. Epoetins are not approved
in the management of anaemia associated with hepatitis C.
13
Haemoglobin concentration:
In patients with chronic kidney disease, maintenance haemoglobin
concentration should not exceed the upper limit of the target haemoglobin concentration recommended
in section 4.2. In clinical trials, an increased risk of death and serious cardiovascular events was
observed when erythropoiesis stimulating agents (ESAs) were administered to target a haemoglobin 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 haemoglobin concentration is increased beyond the level necessary to control
symptoms of anaemia and to avoid blood transfusion.
Blood pressure monitoring:
As with other ESAs, blood pressure may rise during treatment with
MIRCERA. Blood pressure should be adequately controlled in all patients before, at initiation of, and
during treatment with MIRCERA. If high blood pressure is difficult to control by medical treatment or
dietary measures, the dose must be reduced or administration discontinued (see section 4.2).
Effect on tumour growth:
MIRCERA, like other ESAs, is a growth factor that primarily stimulates red
blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour
cells. As with all growth factors, there is a concern that ESAs could stimulate the growth of any type
of malignancy. Two controlled clinical studies in which epoetins were administered to patients with
various cancers including head and neck cancers, and breast cancer, have shown an unexplained
excess mortality.
MIRCERA is not approved for the treatment of anaemia in patients with cancer.
The safety and efficacy of MIRCERA therapy has not been established in patients with
haemoglobinopathies, seizures, bleeding or a recent history of bleeding requiring transfusions or with
platelet levels greater than 500 x 10
9
/l. Therefore, caution should be used in these patients.
Misuse
of MIRCERA by healthy people may lead to an excessive increase in haemoglobin. This may
be associated with life-threatening cardiovascular complications.
Traceability
of MIRCERA: In order to improve the traceability of erythropoiesis-stimulating agents
(ESAs), the trade name of the administered ESA should be clearly recorded (or stated) in the patient
file.
No interaction studies have been performed. There is no evidence that MIRCERA alters the
metabolism of other medicinal products.
Pregnancy:
There are no data from the use of MIRCERA in pregnant women.
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryofoetal
development, parturition or postnatal development but indicate a class-related reversible reduction in
foetal weight (see section 5.3). Caution should be exercised when prescribing to pregnant women.
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.
A decision on whether to continue or discontinue breast-feeding or to continue or discontinue therapy
with MIRCERA should be made taking into account the benefit of breast-feeding to the child and the
benefit of MIRCERA therapy to the woman.
MIRCERA has no or negligible influence on the ability to drive and use machines.
14
The safety data base from clinical trials comprised 3’042 CKD patients, including 1’939 patients
treated with MIRCERA and 1’103 with another ESA. Approximately 6% of patients treated with
MIRCERA are expected to experience adverse reactions. The most frequent reported adverse reaction
was hypertension (common).
The frequencies are defined as follows:
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 2: Adverse reactions attributed to the treatment with MIRCERA in controlled clinical
trials in CKD patients
System organ class
Frequency
Adverse reaction
Nervous system disorders
Uncommon
Headache
Nervous system disorders
Rare
Hypertensive encephalopathy
Skin and subcutaneous tissue
disorders
Rare
Rash, maculo-papular
Injury, poisoning and
procedural complications
Uncommon
Vascular access thrombosis
Vascular disorders
Common
Hypertension
Vascular disorders
Rare
Hot flush
Immune system disorders
Rare
Hypersensitivity
All other events attributed to MIRCERA were reported with rare frequency and the majority were
mild to moderate in severity. These events were consistent with comorbidities known in the population.
Hypersensitivity reactions, including cases of anaphylactic reaction, have been spontaneously reported,
frequency unknown.
During treatment with MIRCERA, a slight decrease in platelet counts remaining within the normal
range was observed in clinical studies.
Platelet counts below 100 x 10
9
/l were observed in 7% of patients treated with MIRCERA and 4% of
patients treated with other ESAs.
The therapeutic range of MIRCERA is wide. Individual responsiveness must be considered when
effect, e.g. excessive erythropoiesis. In case of excessive haemoglobin levels, treatment with
MIRCERA should be temporarily discontinued (see section 4.2). If clinically indicated, phlebotomy
may be performed.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other antianemic preparations, ATC code: B03XA03
15
Methoxy polyethylene glycol-epoetin beta, the active substance of MIRCERA, is a continuous
erythropoietin receptor activator that shows a different activity at the receptor level characterized by a
slower association to and faster dissociation from the receptor, a reduced specific activity
in vitro
with
an increased activity
in vivo
, as well as an increased half-life, in contrast to erythropoietin. The
average molecular mass is approximately 60 kDa of which the protein moiety plus the carbohydrate
part constitutes approximately 30 kDa.
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 in the kidney and released into the bloodstream in response to hypoxia. In
responding to hypoxia, the natural hormone erythropoietin interacts with erythroid progenitor cells to
increase red cell production.
Data from correction studies with patients treated once every two weeks and once every four weeks
show that the haemoglobin response rates in the MIRCERA group at the end of the correction period
were high and comparable to comparators. The median time to response was 43 days in the MIRCERA
arm and 29 days in the comparator arm, with increases of haemoglobin within the first 6 weeks of
0.2 g/dl/week and 0.3 g/dl/week, respectively.
Four randomized controlled studies were performed in dialysis patients treated with darbepoetin alfa
or epoetin at the time of enrollment. Patients were randomized to stay on their treatment at the time of
enrollment or to be switched to MIRCERA in order to maintain stable haemoglobin levels. At the
evaluation period (week 29-36), the mean and median level of haemoglobin in patients treated with
MIRCERA was virtually identical to their baseline haemoglobin level.
Erythropoietin is a growth factor that primarily stimulates red cell production. Erythropoietin receptors
may 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 total
of 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. The
target 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 treated
with recombinant human erythropoietin and controls. In the four placebo-controlled studies the hazard
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls. These studies have
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia
associated with various common cancers who received recombinant human erythropoietin compared
to controls. Overall survival outcome in the trials could not be satisfactorily explained by differences
in the incidence of thrombosis and related complications between those given recombinant human
erythropoietin 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 several
epoetins. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.06 in
favour of controls (95% CI: 1.00, 1.12; 53 trials and 13933 patients) and for the cancer patients
receiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38 trials and
10,441 patients). Meta-analyses also indicate consistently a significantly increased relative risk of
thromboembolic events in cancer patients receiving recombinant human erythropoietin (see section
4.4). Mircera is not approved for treatment of patients with chemotherapy induced anaemia (see
section 4.1), no patients treated with MIRCERA were part of this data analysis.
5.2 Pharmacokinetic properties
The pharmacokinetics of methoxy polyethylene glycol-epoetin beta were studied in healthy volunteers
and in anaemic patients with CKD including patients on dialysis and not on dialysis.
16
Following subcutaneous administration to CKD patients not on dialysis, the maximum serum
concentrations of methoxy polyethylene glycol-epoetin beta were observed 95 hours (median value)
after administration. The absolute bioavailability of methoxy polyethylene glycol-epoetin beta after
subcutaneous 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 serum
concentrations of methoxy polyethylene glycol-epoetin beta were observed 72 hours (median value)
after administration. The absolute bioavailability of methoxy polyethylene glycol-epoetin beta after
subcutaneous administration was 62% and the observed terminal elimination half-life was 139 hours
in CKD patients on dialysis.
Following intravenous administration to CKD patients on dialysis, the total systemic clearance was
0.494 ml/h per kg. The elimination half-life after intravenous administration of methoxy polyethylene
glycol-epoetin beta is 134 hours.
A comparison of serum concentrations of methoxy polyethylene glycol-epoetin beta measured before
and after haemodialysis in 41 CKD patients showed that haemodialysis has no effect on the
pharmacokinetics of this medicinal product.
An analysis in 126 CKD patients showed no pharmacokinetic difference between patients on dialysis
and patients not on dialysis.
In a single dose study, after intravenous administration, the pharmacokinetics of methoxy polyethylene
glycol-epoetin beta are similar in patients with severe hepatic impairment as compared to healthy
subjects (see section 4.2).
5.3 Preclinical safety data
Non-clinical data show no special hazard for humans based on conventional studies of cardiovascular
safety pharmacology, repeat dose toxicity and reproductive toxicity.
The carcinogenic potential of methoxy polyethylene glycol-epoetin beta has not been evaluated in
long-term animal studies. It did not induce a proliferative response in non-haematological tumor cell
lines
in vitro
. In a six-month rat toxicity study no tumorigenic or unexpected mitogenic responses were
observed in non-haematological tissues. In addition, using a panel of human tissues, the
in vitro
binding of methoxy polyethylene glycol-epoetin beta was only observed in target cells (bone marrow
progenitor 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 foetal
weight and a decrease in postnatal body-weight gain of offspring at the doses causing exaggerated
pharmacodynamic effects in mothers. Physical, cognitive, or sexual developments in the offspring of
mothers receiving methoxy polyethylene glycol-epoetin beta during gestation and lactation were not
affected. When methoxy polyethylene glycol-epoetin beta was administered subcutaneously to male
and female rats prior to and during mating, reproductive performance, fertility, and sperm assessment
parameters were not affected.
17
6.
6.1 List of excipients
Sodium dihydrogen phosphate monohydrate
Sodium sulphate
Mannitol (E421)
Methionine
Poloxamer 188
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
3 years
6.4 Special precautions for storage
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 temperature
not above 30°C for one single period of 1 month. Once removed from the refrigerator the medicinal
product must be used within this period.
6.5 Nature and contents of container
Pre-filled syringe (type I glass) with laminated plunger stopper (bromobutyl rubber material) and tip
cap (bromobutyl rubber material) and a needle 27G1/2. Pack size of 1.
6.6 Special precautions for disposal and other handling
The pre-filled syringe is ready for use. The sterile pre-filled syringe does not contain any preservative
and is to be used for a single injection only. Only one dose should be administered per syringe. 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 local
requirements.
7.
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
8.
18
EU/1/07/400/009
9.
20 July 2007
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
19
1.
MIRCERA 100 micrograms/0.3 ml solution for injection in pre-filled syringe.
2.
One pre-filled syringe contains 100 micrograms of methoxy polyethylene glycol-epoetin beta* at a
concentration of 333 micrograms/ml. The strength indicates the quantity of the protein moiety of the
methoxy polyethylene glycol-epoetin beta molecule without consideration of the glycosylation.
* Protein produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells and
covalently conjugated to a linear methoxy-polyethylene glycol (PEG).
The potency of methoxy polyethene glycol-epoetin beta should not be compared to the potency of
another pegylated or non-pegylated protein of the same therapeutic class. For more information, see
section 5.1.
For a full list of excipients, see section 6.1.
3.
Solution for injection (injection).
The solution is clear and colourless to slightly yellowish.
4.
Treatment of
symptomatic
anaemia associated with chronic kidney disease (CKD).
The safety and efficacy of MIRCERA therapy in other indications has not been established.
Treatment of symptomatic anaemia in adult chronic kidney disease patients
Treatment with MIRCERA has to be initiated under the supervision of a physician experienced in the
management of patients with renal impairment.
Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a
physician’s evaluation of the individual patient’s clinical course and condition is necessary.
MIRCERA should be administered either subcutaneously or intravenously in order to increase
haemoglobin to not greater than 12 g/dl (7.45 mmol/l). Subcutaneous use is preferable in patients who
are not receiving haemodialysis to avoid puncture of peripheral veins.
MIRCERA can be injected subcutaneously in the abdomen, arm or thigh. All three injection sites are
equally suitable.
Due to intra-patient variability, occasional individual haemoglobin values for a patient above and
below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed
through 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 haemoglobin values
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) over a four-week period should be avoided.
If it occurs, appropriate dose adjustment should be made as provided.
20
Patients should be monitored closely to ensure that the lowest approved dose of MIRCERA is used to
provide adequate control of the symptoms of anaemia.
It is recommended that haemoglobin is monitored every two weeks until stabilized and periodically
thereafter.
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 recommended
starting dose in patients not on dialysis is 1.2 microgram/kg body weight, administered once every
month as a single subcutaneous injection.
Alternatively, a starting dose of 0.6 microgram/kg bodyweight may be administered once every two
weeks 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 in
haemoglobin is less than 1.0 g/dl (0.621 mmol/l) over a month. Further increases of approximately
25% 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 the
haemoglobin level is increasing and approaching 12 g/dl (7.45 mmol/l), the dose is to be reduced by
approximately 25%. If the haemoglobin level continues to increase, therapy should be interrupted until
the haemoglobin level begins to decrease, at which point therapy should be restarted at a dose
approximately 25% below 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.
Patients treated once every two weeks whose haemoglobin concentration above is 10 g/dl
(6.21 mmol/l) may receive MIRCERA administered once-monthly using the dose equal to twice the
previous once-every–two-weeks dose.
Patients currently treated with an ESA:
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 methoxy polyethylene glycol-
epoetin beta is based on the calculated previous weekly dose of darbepoetin alfa or epoetin at the time
of substitution as described in Table 1. The first injection should start at the next scheduled dose of the
previously administered darbepoetin alfa or epoetin.
Table 1: MIRCERA starting doses
Previous weekly
darbepoetin alfa
intravenous or
subcutaneous dose
(microgram/week)
Previous weekly
epoetin
intravenous or
subcutaneous
dose (IU/week)
Monthly MIRCERA
intravenous or
subcutaneous dose
(microgram/once
monthly)
<40
<8000
120
40-80
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 the
haemoglobin level is increasing and approaching 12 g/dl (7.45 mmol/l), the dose is to be reduced by
approximately 25%. If the haemoglobin level continues to increase, therapy should be interrupted until
the haemoglobin level begins to decrease, at which point therapy should be restarted at a dose
approximately 25% below the previously administered dose. After dose interruption a haemoglobin
21
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.
Since the treatment experience is limited in patients on peritoneal dialysis, regular haemoglobin
monitoring and strict adherence to dose adjustment guidance is recommended in these patients.
Treatment interruption
Treatment with MIRCERA is normally long-term. However, it can be interrupted at any time, if
necessary.
Missed dose
If one dose of MIRCERA is missed, the missed dose is to be administered as soon as possible and
administration of MIRCERA is to be restarted at the prescribed dosing frequency.
Paediatric use
MIRCERA is not recommended for use in children and adolescents below 18 years due to a lack of
safety and efficacy data.
Elderly patients
In clinical studies 24% of patients treated with MIRCERA were aged 65 to 74 years, while 20% were
aged 75 years and over. No dose adjustment is required in patients aged 65 years or older.
Patients with hepatic impairment
No adjustments of the starting dose nor of the dose modification rules are required in patients with
hepatic impairment (see section 5.2).
Hypersensitivity to the active substance or to any of the excipients.
Uncontrolled hypertension.
Supplementary iron therapy
is recommended for all patients with serum ferritin values below
100 microgram/l or with transferrin saturation below 20%. To ensure effective erythropoiesis, iron
status has to be evaluated for all patients prior to and during treatment.
Failure to respond to MIRCERA therapy 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, severe
aluminium toxicity, underlying haematologic diseases, 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 haemoglobin associated
with reticulocytopenia and anti-erythropoietin antibodies, examination of the bone marrow for the
diagnosis of Pure Red Cell Aplasia (PRCA) should be considered. In case PRCA is diagnosed, therapy
with MIRCERA must be discontinued and patients should not be switched to another ESA.
Pure Red Cell Aplasia
caused by anti-erythropoietin antibodies has been reported in association with
ESAs. These antibodies have been shown to cross-react with all ESAs, and patients suspected or
confirmed to have antibodies to erythropoietin should not be switched to MIRCERA.
PRCA in patients with Hepatitis C:
A paradoxical decrease in haemoglobin and development of severe
anaemia associated with low reticulocyte counts should prompt to discontinue treatment with epoetin
and perform anti-erythropoietin antibody testing. Cases have been reported in patients with hepatitis C
treated with interferon and ribavirin, when epoetins are used concomitantly. Epoetins are not approved
in the management of anaemia associated with hepatitis C.
22
Haemoglobin concentration:
In patients with chronic kidney disease, maintenance haemoglobin
concentration should not exceed the upper limit of the target haemoglobin concentration recommended
in section 4.2. In clinical trials, an increased risk of death and serious cardiovascular events was
observed when erythropoiesis stimulating agents (ESAs) were administered to target a haemoglobin of
greater than 12g/dl (7.5 mmol/l).
Controlled clinical trials have not shown significant benefits attributable to the administration of
epoetins when haemoglobin concentration is increased beyond the level necessary to control
symptoms of anaemia and to avoid blood transfusion.
Blood pressure monitoring:
As with other ESAs, blood pressure may rise during treatment with
MIRCERA. Blood pressure should be adequately controlled in all patients before, at initiation of, and
during treatment with MIRCERA. If high blood pressure is difficult to control by medical treatment or
dietary measures, the dose must be reduced or administration discontinued (see section 4.2).
Effect on tumour growth:
MIRCERA, like other ESAs, is a growth factor that primarily stimulates red
blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour
cells. As with all growth factors, there is a concern that ESAs could stimulate the growth of any type
of malignancy. Two controlled clinical studies in which epoetins were administered to patients with
various cancers including head and neck cancers, and breast cancer, have shown an unexplained
excess mortality.
MIRCERA is not approved for the treatment of anaemia in patients with cancer.
The safety and efficacy of MIRCERA therapy has not been established in patients with
haemoglobinopathies, seizures, bleeding or a recent history of bleeding requiring transfusions or with
platelet levels greater than 500 x 10
9
/l. Therefore, caution should be used in these patients.
Misuse
of MIRCERA by healthy people may lead to an excessive increase in haemoglobin. This may
be associated with life-threatening cardiovascular complications.
Traceability
of MIRCERA: In order to improve the traceability of erythropoiesis-stimulating agents
(ESAs), the trade name of the administered ESA should be clearly recorded (or stated) in the patient
file.
No interaction studies have been performed. There is no evidence that MIRCERA alters the
metabolism of other medicinal products.
Pregnancy:
There are no data from the use of MIRCERA in pregnant women.
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryofoetal
development, parturition or postnatal development but indicate a class-related reversible reduction in
foetal weight (see section 5.3). Caution should be exercised when prescribing to pregnant women.
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.
A decision on whether to continue or discontinue breast-feeding or to continue or discontinue therapy
with MIRCERA should be made taking into account the benefit of breast-feeding to the child and the
benefit of MIRCERA therapy to the woman.
MIRCERA has no or negligible influence on the ability to drive and use machines.
23
The safety data base from clinical trials comprised 3’042 CKD patients, including 1’939 patients
treated with MIRCERA and 1’103 with another ESA. Approximately 6% of patients treated with
MIRCERA are expected to experience adverse reactions. The most frequent reported adverse reaction
was hypertension (common).
The frequencies are defined as follows:
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 2: Adverse reactions attributed to the treatment with MIRCERA in controlled clinical
trials in CKD patients
System organ class
Frequency
Adverse reaction
Nervous system disorders
Uncommon
Headache
Nervous system disorders
Rare
Hypertensive encephalopathy
Skin and subcutaneous tissue
disorders
Rare
Rash, maculo-papular
Injury, poisoning and
procedural complications
Uncommon
Vascular access thrombosis
Vascular disorders
Common
Hypertension
Vascular disorders
Rare
Hot flush
Immune system disorders
Rare
Hypersensitivity
All other events attributed to MIRCERA were reported with rare frequency and the majority were
mild to moderate in severity. These events were consistent with comorbidities known in the population.
Hypersensitivity reactions, including cases of anaphylactic reaction, have been spontaneously reported,
frequency unknown.
During treatment with MIRCERA, a slight decrease in platelet counts remaining within the normal
range was observed in clinical studies.
Platelet counts below 100 x 10
9
/l were observed in 7% of patients treated with MIRCERA and 4% of
patients treated with other ESAs.
The therapeutic range of MIRCERA is wide. Individual responsiveness must be considered when
effect, e.g. excessive erythropoiesis. In case of excessive haemoglobin levels, treatment with
MIRCERA should be temporarily discontinued (see section 4.2). If clinically indicated, phlebotomy
may be performed.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other antianemic preparations, ATC code: B03XA03
24
Methoxy polyethylene glycol-epoetin beta, the active substance of MIRCERA, is a continuous
erythropoietin receptor activator that shows a different activity at the receptor level characterized by a
slower association to and faster dissociation from the receptor, a reduced specific activity
in vitro
with
an increased activity
in vivo
, as well as an increased half-life, in contrast to erythropoietin. The
average molecular mass is approximately 60 kDa of which the protein moiety plus the carbohydrate
part constitutes approximately 30 kDa.
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 in the kidney and released into the bloodstream in response to hypoxia. In
responding to hypoxia, the natural hormone erythropoietin interacts with erythroid progenitor cells to
increase red cell production.
Data from correction studies with patients treated once every two weeks and once every four weeks
show that the haemoglobin response rates in the MIRCERA group at the end of the correction period
were high and comparable to comparators. The median time to response was 43 days in the MIRCERA
arm and 29 days in the comparator arm, with increases of haemoglobin within the first 6 weeks of
0.2 g/dl/week and 0.3 g/dl/week, respectively.
Four randomized controlled studies were performed in dialysis patients treated with darbepoetin alfa
or epoetin at the time of enrollment. Patients were randomized to stay on their treatment at the time of
enrollment or to be switched to MIRCERA in order to maintain stable haemoglobin levels. At the
evaluation period (week 29-36), the mean and median level of haemoglobin in patients treated with
MIRCERA was virtually identical to their baseline haemoglobin level.
Erythropoietin is a growth factor that primarily stimulates red cell production. Erythropoietin receptors
may 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 total
of 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. The
target 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 treated
with recombinant human erythropoietin and controls. In the four placebo-controlled studies the hazard
ratios for overall survival ranged between 1.25 and 2.47 in favour of controls. These studies have
shown a consistent unexplained statistically significant excess mortality in patients who have anaemia
associated with various common cancers who received recombinant human erythropoietin compared
to controls. Overall survival outcome in the trials could not be satisfactorily explained by differences
in the incidence of thrombosis and related complications between those given recombinant human
erythropoietin 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 several
epoetins. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.06 in
favour of controls (95% CI: 1.00, 1.12; 53 trials and 13933 patients) and for the cancer patients
receiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38 trials and
10,441 patients). Meta-analyses also indicate consistently a significantly increased relative risk of
thromboembolic events in cancer patients receiving recombinant human erythropoietin (see section
4.4). Mircera is not approved for treatment of patients with chemotherapy induced anaemia (see
section 4.1), no patients treated with MIRCERA were part of this data analysis.
5.2 Pharmacokinetic properties
The pharmacokinetics of methoxy polyethylene glycol-epoetin beta were studied in healthy volunteers
and in anaemic patients with CKD including patients on dialysis and not on dialysis.
25
Following subcutaneous administration to CKD patients not on dialysis, the maximum serum
concentrations of methoxy polyethylene glycol-epoetin beta were observed 95 hours (median value)
after administration. The absolute bioavailability of methoxy polyethylene glycol-epoetin beta after
subcutaneous 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 serum
concentrations of methoxy polyethylene glycol-epoetin beta were observed 72 hours (median value)
after administration. The absolute bioavailability of methoxy polyethylene glycol-epoetin beta after
subcutaneous administration was 62% and the observed terminal elimination half-life was 139 hours
in CKD patients on dialysis.
Following intravenous administration to CKD patients on dialysis, the total systemic clearance was
0.494 ml/h per kg. The elimination half-life after intravenous administration of methoxy polyethylene
glycol-epoetin beta is 134 hours.
A comparison of serum concentrations of methoxy polyethylene glycol-epoetin beta measured before
and after haemodialysis in 41 CKD patients showed that haemodialysis has no effect on the
pharmacokinetics of this medicinal product.
An analysis in 126 CKD patients showed no pharmacokinetic difference between patients on dialysis
and patients not on dialysis.
In a single dose study, after intravenous administration, the pharmacokinetics of methoxy polyethylene
glycol-epoetin beta are similar in patients with severe hepatic impairment as compared to healthy
subjects (see section 4.2).
5.3 Preclinical safety data
Non-clinical data show no special hazard for humans based on conventional studies of cardiovascular
safety pharmacology, repeat dose toxicity and reproductive toxicity.
The carcinogenic potential of methoxy polyethylene glycol-epoetin beta has not been evaluated in
long-term animal studies. It did not induce a proliferative response in non-haematological tumor cell
lines
in vitro
. In a six-month rat toxicity study no tumorigenic or unexpected mitogenic responses were
observed in non-haematological tissues. In addition, using a panel of human tissues, the
in vitro
binding of methoxy polyethylene glycol-epoetin beta was only observed in target cells (bone marrow
progenitor 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 foetal
weight and a decrease in postnatal body-weight gain of offspring at the doses causing exaggerated
pharmacodynamic effects in mothers. Physical, cognitive, or sexual developments in the offspring of
mothers receiving methoxy polyethylene glycol-epoetin beta during gestation and lactation were not
affected. When methoxy polyethylene glycol-epoetin beta was administered subcutaneously to male
and female rats prior to and during mating, reproductive performance, fertility, and sperm assessment
parameters were not affected.
6.
26
6.1 List of excipients
Sodium dihydrogen phosphate monohydrate
Sodium sulphate
Mannitol (E421)
Methionine
Poloxamer 188
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
3 years
6.4 Special precautions for storage
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 temperature
not above 30°C for one single period of 1 month. Once removed from the refrigerator the medicinal
product must be used within this period.
6.5 Nature and contents of container
Pre-filled syringe (type I glass) with laminated plunger stopper (bromobutyl rubber material) and tip
cap (bromobutyl rubber material) and a needle 27G1/2. Pack size of 1.
6.6 Special precautions for disposal and other handling
The pre-filled syringe is ready for use. The sterile pre-filled syringe does not contain any preservative
and is to be used for a single injection only. Only one dose should be administered per syringe. 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 local
requirements.
7.
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
27
8.
EU/1/07/400/010
9.
20 July 2007
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
28
1.
FURTHER INFORMATION
What MIRCERA contains
-
The active substance is methoxy polyethylene glycol-epoetin beta. One pre-filled syringe with
0.3 ml or 0.6 ml contains 30, 40, 50, 60, 75, 100, 120, 150, 200, 250 micrograms or
360 micrograms.
-
The other ingredients are sodium dihydrogen phosphate monohydrate, sodium sulphate,
mannitol (E421), methionine, poloxamer 188 and water for injections.
What MIRCERA looks like and contents of the pack
MIRCERA 0.3 ml or 0.6 ml is a solution for injection in pre-filled syringe.
The solution is clear, colourless to slightly yellowish and free of visible particles.
MIRCERA comes in pre-filled syringes with laminated plunger stopper and tip cap with one needle
27G1/2. Each pre-filled syringe contains 0.3 ml or 0.6 ml. MIRCERA is available, for all strengths, in
pack sizes of 1 and also multipacks of 3 x 1pre-filled syringes for the strengths 30, 50,
75 micrograms/0.3ml. Not all pack sizes may be marketed.
Marketing Authorisation Holder
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
186
Manufacturer
Roche Pharma AG
Emil-Barell-Strasse 1
D-79639 Grenzach-Wyhlen
Germany
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
N.V. Roche S.A.
Tél/Tel: +32 (0) 2 525 82 11
Luxembourg/Luxemburg
(Voir/siehe Belgique/Belgien)
България
Рош България ЕООД
Тел: +359 2 818 44 44
Magyarország
Roche (Magyarország) Kft.
Tel: +36 - 23 446 800
Česká republika
Roche s. r. o.
Tel: +420 - 2 20382111
Malta
(See United Kingdom)
Danmark
Roche a/s
Tlf: +45 - 36 39 99 99
Nederland
Roche Nederland B.V.
Tel: +31 (0) 348 438050
Deutschland
Roche Pharma AG
Tel: +49 (0) 7624 140
Norge
Roche Norge AS
Tlf: +47 - 22 78 90 00
Eesti
Roche Eesti OÜ
Tel: + 372 - 6 177 380
Österreich
Roche Austria GmbH
Tel: +43 (0) 1 27739
Ελλάδα
Roche (Hellas) A.E.
Τηλ: +30 210 61 66 100
Polska
Roche Polska Sp.z o.o.
Tel: +48 - 22 345 18 88
España
Roche Farma S.A.
Tel: +34 - 91 324 81 00
Portugal
Roche Farmacêutica Química, Lda
Tel: +351 - 21 425 70 00
France
Roche
Tél: +33 (0) 1 46 40 50 00
România
Roche România S.R.L.
Tel: +40 21 206 47 01
Ireland
Roche Products (Ireland) Ltd.
Tel: +353 (0) 1 469 0700
Slovenija
Roche farmacevtska družba d.o.o.
Tel: +386 - 1 360 26 00
Ísland
Roche a/s
c/o Icepharma hf
Sími: +354 540 8000
Slovenská republika
Roche Slovensko, s.r.o.
Tel: +421 - 2 52638201
187
Italia
Roche S.p.A.
Tel: +39 - 039 2471
Suomi/Finland
Roche Oy
Puh/Tel: +358 (0) 10 554 500
Kύπρος
Γ.Α.Σταμάτης & Σια Λτδ.
Τηλ: +357 - 22 76 62 76
Sverige
Roche AB
Tel: +46 (0) 8 726 1200
Latvija
Roche Latvija SIA
Tel: +371 – 6 7039831
United Kingdom
Roche Products Ltd.
Tel: +44 (0) 1707 366000
Lietuva
UAB “Roche Lietuva”
Tel: +370 5 2546799
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/.
---------------------------------------------------------------------------------------------------------------------------
HOW TO SELF INJECT MIRCERA
Always use MIRCERA exactly as your doctor has told you. Check with your doctor or nurse if you
are unsure.
The MIRCERA pre-filled syringe is ready for use and can be self-injected by yourself either under the
skin or if you are on haemodialysis, through the haemodialysis line according to your doctor’s advice.
The pre-filled syringe does not contain any preservative and is to be used for one single injection only.
More than one dose must not be administered per pre-filled syringe.
Do not mix the solution with other injectable medicines. Store the pre-filled syringe in the outer carton
box.
Safety tips
●
Make sure that the pre-filled syringe has not been removed from the fridge for more than a
single period not extending 1 month.
Do not use a pre-filled syringe that has been frozen and do not expose it to temperatures above
30°C.
●
Do not use a pre-filled syringe after the expiry date stated on the label.
●
Only use the pre-filled syringe if the solution is clear, colourless (slightly yellow in colour is
acceptable) and is free of visible particles.
●
Do not shake the pre-filled syringe, if the solution has been shaken and appears foamy, do not
use it (shaking MIRCERA or exposing it to light may damage the medicine).
●
●
When handling the syringe, do not touch the needle.
Do not use a syringe more than once
●
Setting up for an injection
Assemble all of the supplies you will need for an injection on a clean surface:
Included in the pack:
●
A pre-filled syringe of MIRCERA and a separate injection needle
Not included in the pack:
●
Cleansing alcohol swabs
●
Sterile gauze
A container for the waste material
●
188
The following instructions explain how to use MIRCERA pre-filled syringes to inject yourself. Please
read the instructions carefully and follow them step by step.
Remove the box containing MIRCERA from the refrigerator. Keep the medicine in the box to protect
it from light and allow it to reach room temperature for at least 30 minutes
Remove the plastic tray of MIRCERA from the box without peeling back the protective film.
Wash your hands well with soap and warm water.
●
Peel back plastic foil from plastic tray and remove syringe and needle
Preparing the MIRCERA pre-filled syringe and the needle for injection
Picture 1. Grasp the needle firmly in both
hands. Break seal of the needle, using a
twisting motion and remove the cap. Do not
remove the needle shield.
Picture 2. Remove the rubber tip cap from the
syringe (bend and pull)
Picture 3.
Attach the needle to the syringe by
pushing firmly together.
Picture 4. Choose one of the recommended
injection sites, arm abdomen or thigh (exept the
navel or waistline). Do not inject MIRCERA
into an area that is tender or healing
Picture 5. Clean the site with a new alcohol
swab and wait for the area to dry.
Grab syringe and needle shield and pull firmly
to remove shield. To remove air bubbles from
the syringe, hold the syringe with the needle
pointing up. Tap the syringe gently to bring any
bubbles to the top. Push the plunger up slowly
to the correct dose, as shown to you by a health
care professional.
189
Injecting the solution
If your doctor has advised you to inject MIRCERA through the haemodialysis line or into a vein,
please administer your dose as shown by your health care professional.
If you are advised to inject MIRCERA under your skin please administer your dose as described
below.
Picture 6. Pinch a fold of skin at the site and
insert the needle. Insert the needle in a quick,
“dart-like” motion.
Picture 7. Slowly push the plunger all the way
down until all the medicine is injected. Do not
release plunger.
Removing the needle
Picture 8 Take the needle out of the skin without
releasing the plunger.
Picture 9. Release the plunger allowing the
needle guard to protect the needle.
Place a cotton ball over the injection site.
Do not massage the injection site.
Any bleeding may be covered with an adhesive bandage.
Disposal
The syringe is intended for single use and must be thrown away after the injection. Dispose of the
syringe in a puncture-proof disposal container..
Medicines should not be disposed of via wastewater or household waste.
Ask your pharmacist how to dispose of medicines that are no longer required. These measures will
help to protect the environment.
190
Source: European Medicines Agency
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