MIRCERA Solution for injection Ref.[9292] Active ingredients: Epoetin beta

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 section 4.2 and 5.1).

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.

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

Pure Red Cell Aplasia caused by anti-erythropoietin antibodies has been reported in association 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 section 4.8).

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 section 4.2).

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 section 4.8). 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 treatment 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 section 4.2. 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 section 4.8).

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 × 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.

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.

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 section 5.3). The potential risk for humans is unknown.

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

(a) 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).

(b) 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).

Table 2. Adverse reactions attributed to the treatment with MIRCERA in CKD patients. Adverse reactions observed only during post-marketing are marked (*):

Blood and lymphatic system disorders

Uncommon: Thrombocytopenia*

Not known: Pure red cell aplasia*

Immune system disorders

Rare: Hypersensitivity

Not known: Anaphylactic reaction*

Nervous system disorders

Uncommon: Headache

Rare: Hypertensive encephalopathy

Vascular disorders

Common: Hypertension

Rare: Hot flush

Uncommon: Thrombosis*

Rare: Pulmonary embolism*

Skin and subcutaneous disorders

Rare: Rash, maculopapular

Not known: Stevens-Johnson syndrome/toxic epidermal necrolysis*

Injury, poisoning and procedural complications

Uncommon: Vascular access thrombosis

© Description of selected adverse reactions

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

Platelet counts below 100 × 10⁹/l were observed in 7% of patients treated with MIRCERA and 4% of patients treated with other ESAs during clinical development. In a post-authorisation safety study with long treatment exposure of up to 8.4 years, baseline platelet counts below 100 × 10⁹/l was present in 2.1% of patients in the MIRCERA group and 2.4% of patients in other ESAs group. During the study, platelet counts below 100 × 10⁹/l were observed yearly in 1.5% to 3.0% of patients treated with MIRCERA and 1.6% to 2.5% 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. A post-authorisation safety study showed similar incidence of stroke between MIRCERA (6.3%) and reference ESAs groups (epoetin alfa, darbepoetin alfa and epoetin beta) (7%).

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

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

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 via the national reporting system listed in Appendix V.

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