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General Information

Mircera (methoxy polyethylene glycol-epoetin beta) is an erythropoiesis-stimulating agent (ESA). A primary growth factor for erythroid development, erythropoietin is produced in the kidney and released into the bloodstream in response to hypoxia. In responding to hypoxia, erythropoietin interacts with erythroid progenitor cells to increase red cell production. Production of endogenous erythropoietin is impaired in patients with chronic renal failure (CRF) and erythropoietin deficiency is the primary cause of their anemia.

Mircera is specifically indicated for the treatment of anemia associated with chronic renal failure, including patients on dialysis and patients not on dialysis. Mircera is supplied as a solution designed for intravenous or subcutaneous administration.

The recommended initial dose of the drug for subjects not receiving erythropoiesis-stimulating agents (ESAs) is .6 mcg/kg body weight administered as a single IV or SC injection once every two weeks. Once hemoglobin has been maintained between 10 and 12 g/dL, Mircera may be administered once monthly using a dose that is twice that of the every-two-week dose and subsequently titrated as necessary.

The recommended initial dose of the drug for subjects who are receiving erythropoiesis-stimulating agents is once every two weeks or once monthly, given as a single iv or SC injection, with dosage based on the total weekly ESA dose at the time of conversion:

Previous weekly epoetin alfa dose <8000 units/week and darbepoetin alfa dose <40 mcg/week- once monthly Mircera should be 120 mcg and once every two weeks dose should be 60 mcg.

Previous weekly epoetin alfa dose 8000 - 16000 units/week and darbepoetin alfa dose 40 - 80 mcg/week- once monthly Mircera should be 200 mcg and once every two weeks dose should be 100 mcg.

Previous weekly epoetin alfa dose >16000 units/week and darbepoetin alfa dose >80 mcg/week- once monthly Mircera should be 360 mcg and once every two weeks dose should be 180 mcg.

When Mircera therapy is initiated or adjusted, the hemoglobin should be monitored every two weeks until stabilized, and every two to four weeks thereafter.

Clinical Results

FDA Approval
FDA approval of Mircera was based on the results of six open-label clinical trials. Two studies evaluated anemic subjects with chronic renal failure (CRF) who were not treated with an ESA at baseline and four studies evaluated anemic subjects who were receiving an ESA.

Subjects Not Treated With An ESA
In Study 1 subjects who were not receiving dialysis were randomized to Mircera or darbepoetin alfa, administered for 28 weeks. The starting dose of Mircera was 0.6 mcg/kg administered subcutaneously (SC) once every two weeks and the starting dose of darbepoetin alfa was 0.45 mcg/kg administered SC once a week. In Study 2, subjects who were receiving dialysis were randomized to Mircera or another ESA (Epoetin alfa or Epoetin beta), administered for 24 weeks. The starting dose of Mircera was 0.4 mcg/kg administered intravenously (IV) once every two weeks and the starting dose of the comparator was administered iv three times a week. The primary endpoint was hemoglobin increase of at least 1 gldL and to a level of at least 11 g/dL without red blood cell (RBC) transfusion; hemoglobin levels were to be maintained within the range of 11 to 13 gldL.

Study 1 Results
The primary endpoint was reached by 98% of the subjects in the Mircera arm and 96% of the subjects in the Darbepoetin alfa arm. In addition, the subjects in the Mircera arm had a mean hemoglobin change from baseline of 2.1g/dL and a 2.5% red blood cell transfusion rate. The subjects in the Darbepoetin alfa arm had a mean hemoglobin change from baseline of 2.0 g/dL and a 6.8% red blood cell transfusion rate.

Study 2 Results
The primary endpoint was reached by 93% of the subjects in the Mircera arm and 91% of the subjects in the Epoetin alfa/beta arm. In addition, the subjects in the Mircera arm had a mean hemoglobin change from baseline of 2.7g/dL and a 5.2% red blood cell transfusion rate. The subjects in the Epoetin alfa/beta arm had a mean hemoglobin change from baseline of 2.6 g/dL and a 4.3% red blood cell transfusion rate.

Subjects Treated With An ESA
These trials assessed the ability of Mircera to maintain hemoglobin concentrations in subjects who were also treated with other ESA's. The subjects were randomized to receive Mircera administrations either once every two weeks or once every four weeks, or to continue their current ESA dose and schedule. The initial Mircera dose was determined based on the patient's previous weekly ESA dose. The targeted hemoglobin maintainence range was 10 to 13.5 g/dL.

Study 3 Results
Mircera IV every 2 weeks: the mean baseline hemoglobin level was 12.0 g/dL and at the evaluation period the mean hemoglobin level was 11.9 g/dL.
Mircera IV every 4 weeks: the mean basline hemoglobin level was 11.9 g/dL and at the evaluation period the mean hemoglobin level was 11.9 g/dL.
Epoetin alfa/beta IV: the mean baseline hemoglobin level was 12.0 g/dL and at the evaluation period the mean hemoglobin level was 11.9 g/dL.

Study 4 Results
Mircera SC every 2 weeks: the mean baseline hemoglobin level was 11.7 g/dL and was still 11.7 g/dL at the evaluation period.
Mircera SC every 4 weeks: the mean baseline hemoglobin level was 11.6 g/dL and at the evaluation period the mean hemoglobin level was 11.5 g/dL.
Epoetin beta SC: the mean baseline was 11.6 g/dL and at the evaluation period the mean hemoglobn level was 11.5 g/dL.

Study 5 Results
Mircera IV every 2 weeks: the mean baseline hemoglobin level was 12.0 g/dL and at the evaluation period was 12.1 g/dL.
Darbepoetin alfa iv: the mean baseline hemoglobin was 11.9 g/dL and at the evaluation period the mean level was 11.8 g/dL.

Study 6 Results
Mircera IV/SC every 2 weeks: the mean baseline hemoglobin level was 11.8 g/dL and the mean level at the evaluation period was 11.9 g/dL.
Epoetin alfa IV/SC: the mean baseline hemoglobin level was 11.9 g/dL and at the evaluation period the mean level was 11.8 g/dL.

Side Effects

Adverse events associated with the use of Mircera may include, but are not limited to, the following:

Hypertension
Diarrhea
Nasopharyngitis
Upper Respiratory Tract Infection
Headache
Muscle Spasms
Procedural Hypotension
Fluid Overload

Mechanism of Action

Literature References

Klinger M, Arias M, Vargemezis V, Besarab A, Sulowicz W, Gerntholtz T, Ciechanowski K, Dougherty FC, Beyer U Efficacy of intravenous methoxy polyethylene glycol-epoetin beta administered every 2 weeks compared with epoetin administered 3 times weekly in patients treated by hemodialysis or peritoneal dialysis: a randomized trial. American journal of kidney diseases : the official journal of the National Kidney Foundation 2007 Dec;50(6):989-1000

Levin NW, Fishbane S, Cañedo FV, Zeig S, Nassar GM, Moran JE, Villa G, Beyer U, Oguey D; MAXIMA study investigators Intravenous methoxy polyethylene glycol-epoetin beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a randomised non-inferiority trial (MAXIMA). Lancet 2007 Oct 20;370(9596):1415-21

Sulowicz W, Locatelli F, Ryckelynck JP, Balla J, Csiky B, Harris K, Ehrhard P, Beyer U; PROTOS Study Investigators Once-monthly subcutaneous C.E.R.A. maintains stable hemoglobin control in patients with chronic kidney disease on dialysis and converted directly from epoetin one to three times weekly. Clinical journal of the American Society of Nephrology 2007 Jul;2(4):637-46

de Francisco AL, Sulowicz W, Klinger M, Niemczyk S, Vargemezis V, Metivier F, Dougherty FC, Oguey D; BA16260 Study Invesigators Continuous Erythropoietin Receptor Activator (C.E.R.A.) administered at extended administration intervals corrects anaemia in patients with chronic kidney disease on dialysis: a randomised, multicentre, multiple-dose, phase II study. International journal of clinical practice 2006 Dec;60(12):1687-96

Macdougall IC, Robson R, Opatrna S, Liogier X, Pannier A, Jordan P, Dougherty FC, Reigner B Pharmacokinetics and pharmacodynamics of intravenous and subcutaneous continuous erythropoietin receptor activator (C.E.R.A.) in patients with chronic kidney disease. Clinical journal of the American Society of Nephrology 2006 Nov;1(6):1211-5