Mircera Injection

Mircera is indicated for the treatment of anaemia associated with chronic kidney disease (CKD) in adult patients. (see section 5.1).

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 or vial. 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.

Standard dosage

Treatment with Mircera has to be initiated under the supervision of a medical doctor.

Treatment of anaemic patients with chronic kidney disease

The solution can be administered subcutaneously (SC) or intravenously (IV), according to clinical preference. Mircera can be injected subcutaneously in the abdomen, arm or thigh. All three injection sites are equally suitable for subcutaneous injection with Mircera.

It is recommended that haemoglobin is monitored every two weeks until stabilised, and periodically thereafter. As recommended in current guidelines, the rate of increase in Hb and the target Hb should be determined for each patient individually. In CKD patients, the aim of treatment is to reach a target Hb level of 10 - 12 g/dL. Patients should be monitored closely to ensure that the lowest effective dose of Mircera is used to provide adequate control of the symptoms of anaemia.

Patients currently not treated with an Erythropoiesis Stimulating Agent (ESA): Patients not on dialysis - In order to increase the haemoglobin to greater than, 10 g/du2113 (6,21 mmol/L) the recommended starting dose is 1,2 u03bcg/kg body weight administered once every month as a single subcutaneous injection. Alternatively, a starting dose of 0,6 u03bcg/kg body weight may be administered once every two weeks as a single IV or SC injection.

Patients on dialysis u2013 The recommended starting dose of 0,6 u03bcg/kg body weight, may be administered once every two weeks as a single IV or SC injection in order to increase the haemoglobin to greater than 11 g/du2113 (6,83 mmol/L). The dose of Mircera may be increased by approximately 25 % to 50 % of the previous dose if the rate of rise in haemoglobin is less than 1,0 g/du2113 (0,621 mmol/L) over a month. Further increases of approximately 25 % to 50 % 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/du2113 (1,24 mmol/L) in one month or if the haemoglobin levels exceed 12 g/du2113, reduce the dose of Mircera by 25 % to 50 %. If the haemoglobin level exceeds 13 g/du2113 (8,07 mmol/L), therapy is to be interrupted until the haemoglobin level falls below 13 g/du2113, and then restarted with approximately 50 % of the previously administered dose. After dose interruption, a haemoglobin decrease of approximately 0,35 g/du2113 per week is expected.

Patients treated once every two weeks whose haemoglobin concentration is in the target range may receive Mircera administered once monthly using the dose equal to twice the previous once every two weeks dose. Dose adjustments should not be made more often than once a month.

Patients currently treated with an epoetin. Patients currently treated can be converted to Mircera administered once a month or, if desired, once every 2 weeks as a single IV or SC injection. The starting dose of Mircera is based on the calculated previously given weekly dose of darbepoetin alfa or epoetin at the time of substitution as described in the table below.

Previous Weekly Epoetin Dose (Units/week) Previous Weekly Darpoetin Alfa Dose (u03bcg/week) Mircera Dose Once Monthly (u03bcg/month) Once Every Two Weeks (u03bcg/q2w)

< 8 000 < 40 120 60

8 000 -16 000 40 u2013 80 200 100

> 16 000 > 80 360 180

If a dose adjustment is required to maintain the target haemoglobin concentration above 10 g/du2113, the monthly dose may be adjusted by approximately 25 %. If the rate of rise in haemoglobin is greater than 2 g/du2113 (1,24 mmol/L) over a month or if the haemoglobin levels exceed 12 g/du2113 (7,45 mmol/L), the dose is to be reduced by approximately 25 to 50 %. If the haemoglobin level exceeds 13 g/du2113 (8,07 mmol/L), therapy is to be interrupted until the haemoglobin level falls below 13 g/du2113 and then restarted with approximately 50 % of the previously administered dose. After dose interruption a haemoglobin decrease of approximately 0,35 g/du2113 (0,22 mmol/L) per week is expected. Dose adjustments should not be made more often than once a month. Since the treatment experience is limited in patients on peritoneal dialysis, regular Hb monitoring and strict adherence to dose adjustment guidance are recommended in these patients.

Treatment interruption: Treatment with Mircera is usually long-term. However, it can be interrupted at any time, if necessary.

Missed dose: If one dose of Mircera is missed, the missed dose should be administered as soon as possible and administration of Mircera is to be restarted at the prescribed dosing frequency.

Special dosage instructions

Paediatric use: No dose recommendations can be made for use in patients aged less than 18 years due to the limited data on safety and efficacy.

Geriatric use: Of the 1 789 Mircera -treated CKD patients in Phase II and Phase III clinical studies of Mircera, 24 % were 65 to 74 years, while 20 % were 75 years and over. Based on population analyses, no adjustment of the starting dose is required in patients aged 65 years or older.

Hepatic impairment: No adjustments of the starting dose nor dose modification rules are required in patients with any degree of hepatic impairment.

Mircera is contraindicated in patients with:

• Uncontrolled hypertension.
• Known hypersensitivity to the active substance or any of the excipients listed in section 6.1.
• Pregnancy and lactation (see section 4.6).

WARNINGS AND SPECIAL PRECAUTIONS

The safety and efficacy of Mircera therapy in other indications than in anaemia associated with CKD, including anaemia in patients with cancer, has not been established.

Supplementary iron therapy: In order to ensure effective erythropoiesis, iron status should be evaluated for all patients prior to and during treatment and supplementary iron therapy may be necessary and conducted in accordance with treatment guidelines.

Pure Red Cell Aplasia (PRCA): caused by anti-erythropoietin antibodies has been reported in association with 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.

PRCA in patients with Hepatitis C: A paradoxical decrease in haemoglobin and development of severe anaemia associated with low reticulocyte counts should prompt discontinuation of treatment with Mircera and testing for anti-erythropoietin antibodies. Cases have been reported in patients with hepatitis C treated with interferon and ribavirin, when erythropoietins, such as Mircera were used concomitantly. Mircera is not approved in the management of anaemia associated with hepatitis C.

Blood pressure monitoring: Blood pressure may rise during treatment of anaemia with Mircera. Blood pressure should be adequately controlled 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 of Mircera must be reduced or withheld (see section 4.2).

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. In clinical trials, an increased risk of death, serious cardiovascular events including thrombosis or cerebrovascular events including stroke, was observed when ESAs such as Mircera were administered to target a haemoglobin of greater than 12 g/du2113 (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.

Effect on tumour growth: Mircera, 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. There is a concern that ESAu2019s 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. 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 a platelet level greater than 500 x 109/u2113. Therefore, caution should be used in these patients. Mircera is not recommended for use in patients aged less than 18 years due to lack of data on safety and efficacy. In order to improve traceability of biological medicinal products, the tradename of the administered product should be clearly recorded (or stated) in the patient file. Mircera contains less than 1 mmol sodium (23 mg) per ml, i.e. essentially sodium free.

Sugar alcohol: Mircera contains mannitol and may have a laxative effect.

No interaction studies have been performed. The clinical results do not indicate any interaction of Mircera with other medicinal products. The effect of other medicines on the pharmacokinetics and pharmacodynamics of Mircera was explored using a population analysis approach. There was no indication of an effect of concomitant medications on the pharmacokinetics and pharmacodynamics of Mircera.

Pregnancy

As safety in pregnancy and lactation has not been established, Mircera is contraindicated during pregnancy (see section 4.3). There are no adequate data on the use of Mircera in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Breastfeeding mothers

It is unknown whether Mircera is excreted in human breast milk. In animals Mircera is excreted into maternal milk. Mothers receiving Mircera should not breastfeed their infants.

No studies on the ability to drive and use machines have been performed. However, no effects are expected based on the mechanism of action and the known safety profile of Mircera.

The safety database for Mircera from controlled clinical trials comprised 1 939 chronic kidney disease (CKD) patients treated with Mircera. The most frequent reported adverse reaction was hypertension (common). The frequencies are defined as follows: Very common (u2265 1/10); common (u2265 1/100 to < 1/10), uncommon (u2265 1/1 000 to < 1/100), rare (u2265 1/10 000 to < 1/1 000) and very rare (< 1/10 000).

Adverse reactions attributed to the treatment with Mircera in controlled clinical trials in CKD patients.

System organ class Frequency Adverse reaction

Immune system disorders Rare Hypersensitivity

Nervous system disorders Uncommon Headache

Rare Hypertensive encephalopathy

Vascular disorders Common Hypertension

Rare Hot flushes

Skin and subcutaneous tissue disorders Rare Maculo-papular rash

Injury, poisoning and procedural complications Uncommon Vascular access thrombosis

All other events attributed to Mircera were reported with rare frequency and the majority was mild to moderate in severity. These events were consistent with co-morbidities known in the population. Data from a controlled clinical trial with epoetin alfa reported an incidence of stroke as common.

Laboratory Abnormalities

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 /u2113 were observed in 7 % of patients treated with Mircera and 4 % of patients treated with ESAs.

Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 u03bcg/u2113 or whose transferrin saturation is below 20 %. To ensure effective erythropoiesis, iron status should be evaluated for all patients prior to and during treatment.

Failure to respond to Mircera therapy should prompt 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. If PRCA is diagnosed, therapy with Mircera must be discontinued and patients should not be switched to another ESA.

Post-marketing Neutralising anti-erythropoietin antibody-mediated pure red cell aplasia (AEAB-PRCA) has been reported. When PRCA is diagnosed, therapy with Mircera must be discontinued, and patients should not be switched to another erythropoietic agent (see WARNINGS AND SPECIAL PRECAUTIONS).

Overdose can result in manifestations of an exaggerated pharmacodynamic effect, e.g. excessive erythropoiesis which may lead to arterial and venous thromboembolism, including stroke, myocardial infarction and shunt thrombosis. In case of excessive haemoglobin levels, Mircera should be temporarily withheld (see section 4.2). If clinically indicated, phlebotomy may be performed.