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MIRCERA® Clinical Data

Clinical Studies in Adult Patients*1

The efficacy and safety of MIRCERA® in adult patients were assessed in 6 open-label, multicenter 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) (CRP ≤ 15 mg/L for the ARCTOS study and CRP ≤ 30 mg/L for the remaining studies). A CRP value above the threshold led to the exclusion of no more than 3% of the screened patients.

*Note: At the time of the studies, higher hemoglobin targets were recommended compared to current clinical guidelines and MIRCERA® Prescribing Information.

Patients Not Currently Treated with an ESA

In the

ARCTOSx

ARCTOS Study Design

ARCTOS

QW = once weekly, Q2W = once every 2 weeks, Q4W = once every 4 weeks, SC = subcutaneous, R = randomization

Macdougall IC, Walker R, Provenzano R, et al. C.E.R.A. corrects anemia in patients with Chronic Kidney Disease not on dialysis: results of a randomized clinical trial. Clin J Am Soc Nephrol. 2008;3(2):337-347

(Administration of C.E.R.A. in CKD patients to treat anemia with a Twice-mOnthly Schedule) study, patients not on dialysis were randomized to MIRCERA® or darbepoetin alfa for 28 weeks. The starting dose of MIRCERA® was 0.6 mcg/kg administered subcutaneously once every 2 weeks and the starting dose of darbepoetin alfa was 0.45 mcg/kg administered subcutaneously once a week.2

.

In the

AMICUSx

AMICUS Study Design

AMICUS

Q2W = once every 2 weeks, TIW = 3 times weekly, IV = intravenous, R = randomization

Klinger M, Arias M, Vargemezis V, et al. 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. Am J Kidney Dis. 2007;50(6):989-1000.

(C.E.R.A. adMinistered Intravenously for anemia Correction and sUStained maintenance in dialysis) study, patients on hemodialysis or peritoneal dialysis were randomized to MIRCERA® or another ESA (epoetin alfa or epoetin beta) for 24 weeks. The starting dose of MIRCERA® was 0.4 mcg/kg administered intravenously once every 2 weeks and the starting dose of the comparator was administered intravenously 3 times a week, consistent with the product’s recommended dose.3

In these studies, the observed median dose of MIRCERA® once every 2 weeks over the course of the correction/evaluation period was 0.6 mcg/kg.

The primary endpoints of these studies were:

  • ARCTOS: Hemoglobin level response rate during correction and evaluation period and difference in mean change in hemoglobin concentration between baseline and evaluation period.
  • AMICUS: Hemoglobin level response rate during correction period.

In both studies, response rate was defined as an increase in hemoglobin level of at least 1 g/dL versus baseline and to a hemoglobin level of at least 11 g/dL without blood transfusion during the correction and evaluation period in the intent-to-treat (ITT) population. Hemoglobin levels were to be maintained within the range of 11 to 13 g/dL.

Phase III Clinical Studies in Patients Not Currently Treated with an ESA1,2,3

PIII

*Primary endpoint: Hemoglobin level response rate (hemoglobin increase of at least 1 g/dL and to a level of at least 11 g/dL without RBC transfusion) in ITT population. Hemoglobin levels were to be maintained within the range of 11 to 13 g/dL.

ND-CKD = non-dialysis chronic kidney disease, RBC = red blood cell, CI = confidence interval

ARCTOS: MIRCERA® administered subcutaneously once every two weeks has been proven to correct anemia in ESA-naive patients who are not on dialysis.2

Mean Monthly Hemoglobin Concentrations
(in the ITT population)

ARCTOS

Secondary endpoint: Mean hemoglobin concentration during the correction and evaluation period in ITT population.

QW = once every week, Q2W = once every 2 weeks, SD = standard deviation, Hb = hemoglobin, BL = baseline, ITT population = intent-to-treat population

AMICUS: MIRCERA® administered intravenously once every two weeks was shown to be safe and effective as three-times-weekly epoetin for correcting anemia in ESA-naive dialysis patients.3

Mean Monthly Hemoglobin Concentrations
(in the ITT population)

AMICUS

Secondary endpoint: Mean hemoglobin concentration during the correction period in ITT population.

Q2W = once every 2 weeks, TIW = 3 times weekly, SD = standard deviation, Hb = hemoglobin, BL = baseline, ITT population = intent-to-treat population

Patients Currently Treated with an ESA

Four studies assessed the ability of MIRCERA® to maintain hemoglobin levels among patients currently treated with other ESAs. Patients were randomized to receive MIRCERA® either once every 2 weeks or once every 4 weeks, or to continue their current ESA dose and schedule.

At the time of the studies, higher hemoglobin targets were recommended compared to current clinical guidelines and the MIRCERA® Prescribing Information.

The initial MIRCERA® dose was determined based on the patient’s previous weekly ESA dose. Treatment with MIRCERA® once every 2 weeks and once every 4 weeks maintained hemoglobin levels within the targeted hemoglobin range (10-13.5 g/dL).1

.

In the

MAXIMAx

MAXIMA Study Design

MAXIMA

QW = once weekly, Q2W = once every 2 weeks, Q4W = once every 4 weeks, TIW = 3 times weekly, IV = intravenous, R = randomization

Levin NW, Fishbane S, Cañedo FV, et al. 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;370(9596):1415-1421.

(Maintenance of hAemoglobin eXcels with IV adMinistration of C.E.R.A.) study, the observed median doses of MIRCERA® were 57 mcg once every 2 weeks and 175 mcg once every 4 weeks during the assessment period and the rest of the study.4

.

In the

PROTOSx

PROTOS Study Design

PROTOS

QW = once weekly, Q2W = once every 2 weeks, Q4W = once every 4 weeks, TIW = 3 times weekly, SC = subcutaneous, R = randomization

Sulowicz W, Locatelli F, Ryckelynck JP, et al. 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. Clin J Am Soc Nephrol. 2007;2(4):637-646.

(Patients Receiving C.E.R.A. Once a month for the mainTenance Of Stable haemoglobin) study, the MIRCERA® median doses over the evaluation period and the rest of the study were 56 mcg once every 2 weeks and 150 mcg once every 4 weeks. In this study, MIRCERA® was administered subcutaneously.5

The primary endpoint in these trials was a mean change in hemoglobin level between baseline and evaluation period.

Phase III Clinical Studies in Patients Currently Treated with an ESA1,4,5

PIII

Primary endpoint: Mean change in hemoglobin level between baseline and evaluation period.

This analysis is from the per-protocol (primary analysis) population; numbers indicate total patients randomized.

*MIRCERA® versus comparator mean hemoglobin difference in the evaluation period.

CI = confidence interval, n/a = not applicable

MAXIMA: MIRCERA® was found to be as safe as conventional epoetin treatment given three times a week, while maintaining hemoglobin levels in dialysis patients when given intravenously once per month.4

Mean Monthly Hemoglobin Concentrations
(in the ITT population)

MAXIMA

QW = once every week, Q2W = once every 2 weeks, Q4W = once every 4 weeks, TIW = 3 times weekly, SD = standard deviation, Hb = hemoglobin, BL = baseline, ITT population = intent-to-treat population

PROTOS: MIRCERA® administered subcutaneously every two weeks or once monthly successfully maintained stable Hb levels in dialysis patients converted from epoetin administered once to three times a week.5

Mean Monthly Hemoglobin Concentrations
(in the ITT population)

PROTOS

QW = once every week, Q2W = once every 2 weeks, Q4W = once every 4 weeks, TIW = 3 times weekly, SD = standard deviation, Hb = hemoglobin, BL=baseline, ITT population=intent-to-treat population

.

In the

STRIATAx

STRIATA Study Design

STRIATA

DA = darbepoetin alfa, QW = once weekly, Q2W = once every 2 weeks, IV = intravenous, R = randomization

Canaud B, Mingardi G, Braun J, et al. Intravenous C.E.R.A. maintains stable haemoglobin levels in patients on dialysis previously treated with darbepoetin alfa: results from STRIATA,a randomized phase III study. Nephrol Dial Transplant. 2008;23(11):3654-3661.

(Stabilizing haemoglobin TaRgets in dialysis following IV C.E.R.A. Treatment of Anaemia) study, the median dose of MIRCERA® was 0.35 mcg/kg/week during the evaluation period and the rest of the study.6

.

In the

RUBRAx

RUBRA Study Design

RUBRA

QW = once weekly, Q2W = once every 2 weeks, TIW = 3 times weekly, IV = intravenous, SC = subcutaneous, R = randomization

Spinowitz B, Coyne DW, Lok CE, et al. C.E.R.A. maintains stable control of hemoglobin in patients with chronic kidney disease on dialysis when administered once every two weeks. Am J Nephrol. 2008;28(2):280-289.

(TaRgeting sUstained haemogloBin in dialysis with IV and SC C.E.R.A. Administration) study, the MIRCERA® median dose was 60 mcg once every 2 weeks during the evaluation period.7

The primary endpoint in these trials was a mean change in hemoglobin level between baseline and evaluation period.

Phase III Clinical Studies in Patients Currently Treated with an ESA1,6,7

PIII

Primary endpoint: Mean change in hemoglobin between baseline and the evaluation period.

This analysis is from the per-protocol (primary analysis) population; numbers indicate total patients randomized.

*MIRCERA® versus comparator mean hemoglobin difference in the evaluation period.

CI = confidence interval, n/a = not applicable

STRIATA: MIRCERA® administered intravenously every two weeks successfully maintained hemoglobin levels in patients on dialysis directly converted from darbepoetin alfa administered once weekly or every two weeks.6

Mean Monthly Hemoglobin Concentrations
(in the ITT population)

STRIATA

QW = once every week, Q2W = once every 2 weeks, SD = standard deviation, Hb = hemoglobin, BL = baseline, ITT population = intent-to-treat population

RUBRA: MIRCERA® administered every two weeks effectively maintained stable control of hemoglobin in dialysis patients who were converted from epoetin given once to three times a week.7

Mean Monthly Hemoglobin Concentrations
(in the ITT population)

RUBRA

QW = once every week, Q2W = once every 2 weeks, TIW = three times weekly, SD = standard deviation, Hb = hemoglobin, BL = baseline, ITT population = intent-to-treat population

Clinical Studies in Pediatric Patients1,8

  • An open-label, multiple dose, multicenter, dose-finding pediatric study was conducted to determine the dose of intravenous MIRCERA® when converting from treatment with another ESA (epoetin alfa/beta or darbepoetin alfa).
  • The study was conducted in 64 pediatric patients (ages 5 to 17 years) with CKD who were on hemodialysis and who had stable hemoglobin (Hb) levels while previously receiving another ESA.
  • MIRCERA® was administered intravenously once every 4 weeks for 20 weeks. After the first administration of MIRCERA®, dosage adjustments were permitted to maintain target hemoglobin levels.

Efficacy was established based on the change in hemoglobin concentration (g/dL) between the baseline and evaluation period. Of the two conversion factors studied, the recommended conversion factor for MIRCERA® was confirmed based on patients maintaining hemoglobin within target levels.

.

  • Among the 48 patients who received MIRCERA® dosed using the recommended conversion factor, 9 patients withdrew due to renal transplant, 2 patients withdrew due to administrative reasons, 1 died, and 1 patient refused treatment. One of the 13 patients who withdrew from the study entered the evaluation period (weeks 17-21).
  • For the 36 patients who entered the evaluation period and received the dose of MIRCERA® calculated using the recommended conversion factor, the mean change in hemoglobin concentration from baseline between the baseline and the evaluation period was -0.15 g/dL with 95% CI (-0.49 to 0.2).
  • Supportive efficacy results in the group treated with MIRCERA® using the recommended conversion factor demonstrated that 75% of patients maintained hemoglobin values within ±1 g/dL of baseline and 81% maintained hemoglobin values within 10 to 12 g/dL during the evaluation period. Dose decreases and increases were reported in 38% of patients.

.

The efficacy and safety of MIRCERA® have not been established in pediatric patients of any age in the following conditions:

  • For subcutaneous administration
  • For treatment of anemia in patients with CKD on peritoneal dialysis
  • For treatment of anemia in patients with CKD not yet on dialysis
  • For patients whose hemoglobin level has not been previously stabilized by treatment with an ESA

For more information, please see the full Prescribing Information, including Boxed WARNING, and Medication Guide (English, Español) for MIRCERA®.

References >

x

References

1MIRCERA® [prescribing information]. St. Gallen, Switzerland: Vifor (International) Inc.; June 2018.

2Macdougall IC, Walker R, Provenzano R, et al. C.E.R.A. corrects anemia in patients with Chronic Kidney Disease not on dialysis: results of a randomized clinical trial. Clin J Am Soc Nephrol. 2008;3(2):337-347.

3Klinger M, Arias M, Vargemezis V, et al. 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. Am J Kidney Dis. 2007;50(6):989-1000.

4Levin NW, Fishbane S, Cañedo FV, et al. 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;370(9596):1415-1421.

5Sulowicz W, Locatelli F, Ryckelynck JP, et al. 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. Clin J Am Soc Nephrol. 2007;2(4):637-646.

6Canaud B, Mingardi G, Braun J, et al. Intravenous C.E.R.A. maintains stable haemoglobin levels in patients on dialysis previously treated with darbepoetin alfa: results from STRIATA, a randomized phase III study. Nephrol Dial Transplant. 2008;23(11):3654-3661.

7Spinowitz B, Coyne DW, Lok CE, et al. C.E.R.A. maintains stable control of hemoglobin in patients with chronic kidney disease on dialysis when administered once every two weeks. Am J Nephrol. 2008;28(2):280-289.

8Fischbach M, Wuhl E, Reigner SCM, Morgan Z, Schaefer F. Efficacy and long-term safety of C.E.R.A. maintenance in pediatric hemodialysis patients with anemia of CKD. Clin J Am Soc Nephrol. 2018;13(1):81-90.

IMPORTANT SAFETY INFORMATION

+

WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS and TUMOR PROGRESSION OR RECURRENCE CHRONIC KIDNEY DISEASE:

CHRONIC KIDNEY DISEASE:

  • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL.
  • No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks.
  • Use the lowest Mircera dose sufficient to reduce the need for red blood cell (RBC) transfusions.

CANCER:

  • MIRCERA® is not indicated and is not recommended for the treatment of anemia due to cancer chemotherapy. A dose-ranging study of MIRCERA® was terminated early because of more deaths among patients receiving MIRCERA® than another ESA.
  • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers.

CONTRAINDICATIONS

MIRCERA® is contraindicated in patients with:

  • Uncontrolled hypertension
  • Pure red cell aplasia (PRCA) that begins after treatment with Mircera or other erythropoietin protein drugs
  • History of serious or severe allergic reactions to Mircera (e.g., anaphylactic reactions, angioedema, bronchospasm, pruritus, skin rash, and urticaria).

INCREASED MORTALITY, MYOCARDIAL INFARCTION, STROKE, AND THROMBOEMBOLISM

  • In controlled clinical trials of patients with CKD comparing higher hemoglobin targets (13 to 14 g/dL) to lower targets (9 to 11.3 g/dL), ESAs increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups.
  • Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Use caution in patients with coexistent cardiovascular disease and stroke. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks.
  • In controlled clinical trials of patients with cancer, ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke.
  • In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures.

INCREASED MORTALITY AND/OR INCREASED RISK OF TUMOR PROGRESSION OR RECURRENCE IN PATIENTS WITH CANCER

  • MIRCERA® is not indicated and is not recommended for use in the treatment of anemia due to cancer chemotherapy. A dose-ranging trial of MIRCERA® in 153 patients who were undergoing chemotherapy for non-small cell lung cancer was terminated prematurely because more deaths occurred among patients receiving
  • MIRCERA® than another ESA. ESAs resulted in decreased locoregional control/progression-free survival and/or overall survival. These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy, in patients receiving chemotherapy for metastatic breast cancer or lymphoid malignancy, and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy.

HYPERTENSION

  • MIRCERA® is contraindicated in patients with uncontrolled hypertension.
  • In MIRCERA® clinical studies, approximately 27% of patients with CKD, including patients on dialysis and patients not on dialysis, required intensification of antihypertensive therapy. Hypertensive encephalopathy and/or seizures have been observed in patients with CKD treated with MIRCERA®.
  • Appropriately control hypertension prior to initiation of and during treatment with MIRCERA®. Reduce or withhold MIRCERA® if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions.

SEIZURES

  • Seizures have occurred in patients participating in MIRCERA® clinical studies. During the first several months following initiation of MIRCERA®, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency.

LACK OR LOSS OF HEMOGLOBIN RESPONSE TO MIRCERA®

  • For lack or loss of hemoglobin response to MIRCERA®, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding).
  • If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA. In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient response to MIRCERA® therapy.

PURE RED CELL APLASIA (PRCA)

  • Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in the postmarketing setting in patients treated with MIRCERA®. This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. PRCA was not observed in clinical studies of MIRCERA®.
  • PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which MIRCERA® is not approved).
  • If severe anemia and low reticulocyte count develop during treatment with MIRCERA®, withhold MIRCERA® and evaluate patients for neutralizing antibodies to erythropoietin. Serum samples should be obtained at least a month after the last MIRCERA® administration to prevent interference of MIRCERA® with the assay. Contact Vifor at 1-800-576-8295 to perform assays for binding and neutralizing antibodies. Permanently discontinue MIRCERA® in patients who develop PRCA following treatment with MIRCERA® or other erythropoietin protein drugs. Do not switch patients to other ESAs as antibodies may cross-react.

SERIOUS ALLERGIC REACTIONS

  • Blistering and skin exfoliation reactions including Erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including MIRCERA®) in the postmarketing setting. Discontinue MIRCERA® therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected.

SEVERE CUTANEOUS REACTIONS

  • Blistering and skin exfoliation reactions including Erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including MIRCERA®) in the postmarketing setting. Discontinue MIRCERA® therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected.

DIALYSIS MANAGEMENT

  • Patients may require adjustments in their dialysis prescription after initiation of MIRCERA®. Patients receiving MIRCERA® may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.

ADVERSE EVENTS IN PATIENTS WITH CHRONIC KIDNEY DISEASE

  • Most frequent adverse reactions (≥5%) in adult patients with CKD treated with MIRCERA® were hypertension, diarrhea, nasopharyngitis, upper respiratory tract infection, headache, muscle spasms, procedural hypotension, fluid overload, vomiting, back pain, cough, hypotension, constipation, urinary tract infection, pain in extremity, arteriovenous fistula thrombosis, arteriovenous fistula site complication.
  • In pediatric patients on hemodialysis, all reported adverse reactions regardless of causality (more than 5% incidence) were headache, nasopharyngitis, hypertension, vomiting, bronchitis, abdominal pain, arteriovenous fistula thrombosis, cough, device related infection, hyperkalemia, pharyngitis, pyrexia, thrombocytopenia, and thrombosis in device.

INDICATIONS AND LIMITATIONS OF USE

  • MIRCERA® is indicated for the treatment of anemia associated with chronic kidney disease (CKD) in adult patients on dialysis and adult patients not on dialysis, and pediatric patients 5 to 17 years of age on hemodialysis who are converting from another ESA after their hemoglobin level was stabilized with an ESA.
  • MIRCERA® is not indicated and is not recommended for use in the treatment of anemia due to cancer chemotherapy, or as a substitute for RBC transfusions in patients who require immediate correction of anemia.
  • MIRCERA® has not been shown to improve quality of life, fatigue, or patient well-being.

Please see full Prescribing Information including Boxed WARNING, and Medication Guide (English, Español) for MIRCERA® (methoxy polyethylene glycol-epoetin beta) Injection, for Intravenous or Subcutaneous Use.

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