Mircera

Methoxy polyethylene glycol-epoetin beta.

Single dose pre-filled syringes: containing 50μg, 75μg, 100μg, 150μg or 200μg methoxy polyethylene glycol-epoetin beta in 0.3 ml.
The active substance, methoxy polyethylene glycol-epoetin beta, is a covalent conjugate of a protein produced by recombinant DNA technology in Chinese Hamster Ovarian cells and a linear methoxy-polyethylene glycol (PEG). This results in an approximate molecular weight of 60 kDa. The dosage strength in μg indicates the quantity of the protein moiety of the methoxy polyethylene glycol-epoetin beta molecule without consideration of the glycosylation.
Therapeutic / Pharmacologic Class of Drug: MIRCERA is the first molecule of a new class of Continuous Erythropoietin Receptor Activators called methoxy polyethylene glycol-epoetin beta.
Excipients/Inactive Ingredients: Sodium dihydrogen phosphate monohydrate, Sodium sulphate, Mannitol, Methionine, Poloxamer 188, Hydrochloric acid, Sodium hydroxide, Water for injections.

Pharmacotherapeutic group: Other antianemic preparations. ATC code: B03XA03.
Pharmacology: Pharmacodynamics: Mechanism of action: MIRCERA stimulates erythropoiesis by interaction with the erythropoietin receptor on progenitor cells in the bone marrow. 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.
Pharmacodynamic effects: 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.
Clinical efficacy and safety: 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 currently 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.
In a randomised, double-blind, placebo-controlled study of 4,038 CRF patients not on dialysis with type 2 diabetes and haemoglobin levels ≤ 11 g/dL, patients received either treatment with darbepoetin alfa to target haemoglobin levels of 13 g/dL or placebo (see Precautions). The study did not meet either primary objective of demonstrating a reduction in risk for all-cause mortality, cardiovascular morbidity, or end stage renal disease (ESRD). Analysis of the individual components of the composite endpoints showed the following HR (95% CI): death 1.05 (0.92, 1.21), stroke 1.92 (1.38, 2.68), congestive heart failure (CHF) 0.89 (0.74, 1.08), myocardial infarction (MI) 0.96 (0.75, 1.23), hospitalisation for myocardial ischaemia 0.84 (0.55, 1.27), ESRD 1.02 (0.87, 1.18).
Pooled post-hoc analyses of clinical studies of ESAs have been performed in chronic renal failure patients (on dialysis, not on dialysis, in diabetic and non-diabetic patients). A tendency towards increased risk estimates for all-cause mortality, cardiovascular and cerebrovascular events associated with higher cumulative ESA doses independent of the diabetes or dialysis status was observed (see Dosage & Administration and Precautions).
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 13,933 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 Precautions). No patients treated with MIRCERA were included in this data analysis.
MIRCERA is not approved for treatment of patients with chemotherapy induced anaemia (see Indications/Uses and Precautions).
Pharmacokinetics: 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.
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 Dosage & Administration).
Toxicology: 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 MIRCERA was administered subcutaneously to male and female rats prior to and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected.

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 with MIRCERA has to be initiated under the supervision of a physician experienced in the management of patients with renal impairment.
Posology: Treatment of symptomatic anaemia in adult chronic kidney disease patients: 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.
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 as follows.
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.
Patients should be monitored closely to ensure that the lowest approved effective dose of MIRCERA is used to provide adequate control of the symptoms of anaemia whilst maintaining a haemoglobin concentration below or at 12 g/dl (7.45 mmol/l).
Caution should be exercised with escalation of MIRCERA doses in patients with chronic renal failure. In patients with a poor haemoglobin response to MIRCERA, alternative explanations for the poor response should be considered (see Precautions and Pharmacodynamics).
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 is above 10 g/dl (6.21 mmol/l) may receive MIRCERA administered once-monthly using the dose equal to twice the previous once-every-two-week 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 MIRCERA 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. (See Table 1.)

Click on icon to see table/diagram/image

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 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 are 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.
Patients with hepatic impairment: No adjustments of the starting dose nor of the dose modification rules are required in patients with hepatic impairment (see Pharmacokinetics).
Elderly population: 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.
Paediatric population: MIRCERA is not recommended for use in children and adolescents below 18 years due to a lack of safety and efficacy data.
Method of administration: MIRCERA should be administered either subcutaneously or intravenously. It can be injected subcutaneously in the abdomen, arm or thigh. All three injection sites are equally suitable. For instructions on the administration of the medicinal product, see Special Instructions for Use, Handling and Disposal under Cautions for Usage.
Route of Administration: Subcutaneous or intravenous.

The therapeutic range of MIRCERA is wide. Individual responsiveness must be considered when treatment is initiated. Overdose can result in manifestations of an exaggerated pharmacodynamic effect, e.g. excessive erythropoiesis. In case of excessive haemoglobin levels, treatment with MIRCERA should be temporarily discontinued (see Dosage & Administration). If clinically indicated, phlebotomy may be performed.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Uncontrolled hypertension.

The safety and efficacy of MIRCERA therapy in other indications, including anaemia in patients with cancer, has not been established.
Caution should be exercised with escalation of MIRCERA doses in patients with chronic renal failure since high cumulative epoetin doses may be associated with an increased risk of mortality, serious cardiovascular and cerebrovascular events. In patients with a poor haemoglobin response to epoetins, alternative explanations for the poor response should be considered (see Dosage & Administration and Pharmacodynamics).
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 all ESAs, including MIRCERA. 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 (see Adverse Reactions).
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.
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 Dosage & Administration).
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 treatment (see Adverse Reactions). 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. If signs and symptoms suggestive of these reactions appear, Mircera should be withdrawn immediately and an alternative treatement considered. If the patient has developed a severe cutaneous skin reaction such as SJS or TEN due to the use of Mircera, treatment with ESA must not be restarted in this patient at any time.
Haemoglobin concentration: In patients with chronic kidney disease, maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration recommended in Dosage & Administration. In clinical trials, an increased risk of death, serious cardiovascular events including thrombosis or cerebrovascular events including stroke was observed when ESAs were administered to target a haemoglobin of greater than 12 g/dl (7.5 mmol/l) (see Adverse Reactions).
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.
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 10⁹/l. Therefore, caution should be used in these patients.
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.
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 ESAs, the trade name of the administered ESA should be clearly recorded (or stated) in the patient file.
This medicinal product contains less than 1 mmol sodium (23 mg) per ml, i.e. essentially sodium free.
Effects on ability to drive and use machines: MIRCERA has no or negligible influence on the ability to drive and use machines.

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 Preclinical safety data). Caution should be exercised when prescribing to pregnant women.
Breast-feeding: It is unknown whether MIRCERA 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.
Fertility: Studies in animals have shown no evidence of impaired fertility (see Preclinical safety data). The potential risk for humans is unknown.

Summary of the safety profile: 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).
Tabulated list of adverse reactions: Adverse reactions in Table 2 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

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Description of selected adverse reactions: Cases of thrombocytopenia have been spontaneously reported, frequency unknown. A slight decrease in platelet counts remaining within the normal range was observed in clinical studies.
Platelet counts below 100 x 10⁹/l were observed in 7% of patients treated with MIRCERA and 4% of patients treated with other ESAs.
Data from a controlled clinical trial with epoetin alfa or darbepoetin alfa reported an incidence of stroke as common.
As with other ESAs, cases of thrombosis, including pulmonary embolism, have been reported in the post-marketing setting, frequency unknown (see Precautions).
Neutralising anti-erythropoietin antibody-mediated pure red cell aplasia (PRCA) has been reported, frequency unknown. In case PRCA is diagnosed, therapy with MIRCERA must be discontinued, and patients should not be switched to another recombinant erythropoietic protein (see Precautions).
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

No interaction studies have been performed. There is no evidence that MIRCERA alters the metabolism of other medicinal products.

Special Instructions for Use, Handling and Disposal: MIRCERA should not be mixed with other products.
MIRCERA is a sterile but unpreserved product. Do not administer more than one dose per pre-filled syringe.
Any unused product remaining in the pre-filled syringe or vial should be discarded.
Only solutions which are clear, colourless to slightly yellowish and free of visible particles must be injected.
Do not shake.
Allow the product to reach room temperature before injecting.
Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided.

Store in the refrigerator at 2°C to 8°C.
Keep the pre-filled syringe in the outer carton in order to protect from light.
Do not freeze.
Patient Use Conditions (Pre-filled syringe): The patient may remove the product from refrigeration for storage at room temperature (not above 30°C) for one single period of 1 month. Once removed from the refrigerator the product must be used within this period.

Haematopoietic Agents

B03XA03 - methoxy polyethylene glycol-epoetin beta ; Belongs to the class of other antianemic preparations. Used in the treatment of anemia.

P₁S₁S₃

Pre-filled syringe (clear and colourless to slightly yellowish solution) 50 mcg/0.3 mL x 1's. 75 mcg/0.3 mL x 1's. 100 mcg/0.3 mL x 1's. 150 mcg/0.3 mL x 1's. 200 mcg/0.3 mL x 1's.