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Mechanism Of Action
Mircera is an erythropoietin receptor activator with greater activity in vivo as well as increased half-life, in contrast to erythropoietin. 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 CKD and erythropoietin deficiency is the primary cause of their anemia.
Following a single-dose of Mircera in CKD patients, the onset of hemoglobin increase (defined as an increase > 0.4 g/dL from baseline) was observed 7 to 15 days following initial dose administration [see DOSAGE AND ADMINISTRATION].
The pharmacokinetics of Mircera were studied in anemic patients with CKD including patients on dialysis and those not on dialysis. Mircera pharmacokinetics, based on population analyses, were not altered by age, gender, race, or the use of dialysis.
Following an IV administration of Mircera 0.4 mcg/kg body weight to CKD patients receiving peritoneal dialysis, the observed terminal half-life was 134 ± 65 hours (mean ± SD), and the total systemic clearance was 0.49 ± 0.18 mL/hr/kg. Following a SC administration of Mircera 0.8 mcg/kg to CKD patients receiving peritoneal dialysis, the terminal half-life was 139 ± 67 hours. The maximum serum concentrations of Mircera were observed 72 hours (median value) following the SC administration. The absolute bioavailability of Mircera after the SC administration was 62%.
In CKD patients receiving multiple Mircera doses, pharmacokinetics were studied after the first dose and on week 9 and week 19 or 21. Multiple dosing was found to have no effect on clearance, volume of distribution or bioavailability of Mircera. Based on population analyses of the clinical studies, Mircera did not accumulate following administration every four weeks. However, when Mircera was administered every 2 weeks, blood concentrations at steady state increased by 12%.
A comparison of serum concentrations of Mircera measured before and after hemodialysis in 41 patients showed that hemodialysis did not alter serum concentrations.
The single-dose pharmacokinetics of Mircera in patients with severe (Child-Pugh Classification Grade C) hepatic impairment and healthy volunteers were similar.
The site of SC injection (abdomen, arm or thigh) had no clinically important effects on the pharmacokinetics or pharmacodynamics of Mircera in healthy volunteers.
Patients With Chronic Kidney Disease On Dialysis: ESA Effects On Rates Of Transfusion
In early clinical studies conducted in CKD patients on dialysis, ESAs have been shown to reduce the use of RBC transfusions. These studies enrolled patients with mean baseline hemoglobin levels of approximately 7.5 g/dL and ESAs were generally titrated to achieve a hemoglobin level of approximately 12 g/dL. Fewer transfusions were given during the ESA treatment period when compared to a pre-treatment interval.
In NHS, the yearly transfusion rate was 51.5% in the lower hemoglobin group (10 g/dL) and 32.4% in the higher hemoglobin group (14 g/dL).
Patients With Chronic Kidney Disease Not On Dialysis: ESA Effects On Rates Of Transfusion
In TREAT, a randomized, double-blind trial of 4038 patients with CKD and type 2 diabetes not on dialysis, a post-hoc analysis showed that the proportion of patients receiving RBC transfusions was lower in patients administered an ESA to target a hemoglobin of 13 g/dL compared to the control arm in which the ESA was administered intermittently if hemoglobin concentration decreased to less than 9 g/dL (15% versus 25%, respectively). In CHOIR, a randomized open-label study of 1432 patients with CKD not on dialysis, use of an ESA to target a higher (13.5 g/dL) versus lower (11.3 g/dL) hemoglobin goal did not reduce the use of RBC transfusions. In each trial, no benefits occurred for the cardiovascular or end-stage renal disease outcomes. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile [see WARNINGS AND PRECAUTIONS].
ESA Effects On Quality Of Life
Mircera use has not been demonstrated in controlled clinical trials to improve quality of life, fatigue, or patient well-being.
ESA Effects On Rates Of Death And Other Serious Cardiac Adverse Events
Three randomized outcome trials (NHS, CHOIR and TREAT) have been conducted in patients with CKD using Epogen/PROCRIT/Aranesp to target higher vs. lower hemoglobin levels. Though these trials were designed to establish a cardiovascular or renal benefit of targeting higher hemoglobin levels, in all 3 studies, patients randomized to the higher hemoglobin target experienced worse cardiovascular outcomes and showed no reduction in progression to ESRD. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile [see WARNINGS AND PRECAUTIONS].
Other ESA trials
The efficacy and safety of Mircera were assessed in six open-label, multi-center clinical studies that randomized patients to either Mircera or a comparator ESA. Two studies evaluated anemic patients with CKD who were not treated with an ESA at baseline and four studies evaluated patients who were receiving an ESA for treatment of the anemia of CKD. In all studies, patients were assessed as clinically stable at baseline and without evidence of infection or inflammation as determined by history and laboratory data, including C-reactive protein (CRP ≤ 15 mg/L for study 1 and CRP ≤ 30 mg/L for studies 2 to 6). A CRP value above the threshold led to the exclusion of no more than 3% of the screened patients.
In the clinical studies, ESAs were administered to achieve specific hemoglobin levels (see Table 5 and Table 6). Following stabilization of hemoglobin levels (12 g/dL), the median monthly Mircera dose was 150 mcg (range of 97 mcg to 270 mcg).
Patients Not Currently Treated with an ESA
In Study 1 patients 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 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, patients 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 IV once every two weeks and the starting dose of the comparator was administered IV three times a week, consistent with the product's recommended dose. In these studies, the observed median dose of Mircera once every two weeks over the course of the correction/evaluation period was 0.6 mcg/kg. Table 5 provides the results of the two studies.
Table 5 : Clinical Studies in Patients Not Currently
Treated with an ESA
|Group (n)||Percent Achieving Goal* (95% CI)||Mean Hemoglobin Change from Baseline (g/dL)||RBC Transfusion, %|
|Mircera (n=162)||98 (94, 99)||2.1||2.5|
|Darbepoetin alfa (n=162)||96 (92, 99)||2.0||6.8|
|Mircera (n=135)||93 (88, 97)||2.7||5.2|
|Epoetin alfa/beta (n=46)||91 (79, 98)||2.6||4.3|
|*Goal: hemoglobin increase of at least 1 g/dL and to a level of at least 11 g/dL without RBC transfusion; hemoglobin levels were to be maintained within the range of 11 to 13 g/dL.|
Patients Currently Treated with an ESA
Four studies assessed the ability of Mircera to maintain hemoglobin concentrations among patients currently treated with other ESAs. Patients 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. As shown in Table 6, treatment with Mircera once every two weeks and once every four weeks maintained hemoglobin concentrations within the targeted hemoglobin range (10 to 13.5 g/dL).
Table 6 : Clinical Studies
in Patients Currently Treated with an ESA
|Group (n)||Mean Baseline Hemoglobin||Evaluation Period Hemoglobin (Mean)||Between-group Difference *, g/dL (95% or 97.5% CI)|
|Mircera IV every 2 weeks (n=223)||12.0||11.9||0.0 (-0.2, 0.2)|
|Mircera IV every 4 weeks (n=224)||11.9||11.9||0.1 (-0.2, 0.3)|
|Epoetin alfa/beta IV (n=226)||12.0||11.9||n/a|
|Mircera SC every 2 weeks (n=190)||11.7||11.7||0.1 (-0.1, 0.4)|
|Mircera SC every 4 weeks (n=191)||11.6||11.5||-0.0 (-0.3, 0.2)|
|Epoetin beta SC (n=191)||11.6||11.5||n/a|
|Mircera IV every 2 weeks (n=157)||12.0||12.1||0.2 (-0.0, 0.4)|
|Darbepoetin alfa IV||11.9||11.8||n/a|
|Mircera IV/SC every 2 weeks (n= 68)||11.8||11.9||0.1 (-0.1, 0.4)|
|Epoetin alfa IV/SC (n=168)||11.9||11.8||0.1 (-0.1, 0.4)|
|*Mircera versus comparator mean hemoglobin difference in the evaluation period; 97.5% CI are shown for studies that compared two Mircera groups to another ESA (Studies 3 and 4) and 95% CI are shown for the other studies. n/a = not applicable|
Last reviewed on RxList: 5/9/2016
This monograph has been modified to include the generic and brand name in many instances.
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