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Increased Mortality, Myocardial Infarction, Stroke, And Thromboembolism
- In controlled clinical trials of patients with CKD comparing higher hemoglobin targets (13 -14 g/dL) to lower targets (9 -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 [see Clinical Studies]. Use caution in patients with coexistent cardiovascular disease and stroke [see DOSAGE AND ADMINISTRATION]. 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.
The design and overall results of the 3 large trials comparing higher and lower hemoglobin targets are shown in Table 2 (Normal Hematocrit Study (NHS), Correction of Hemoglobin Outcomes in Renal Insufficiency (CHOIR) and Trial to Reduce Cardiovascular Events with Aranesp® Therapy (TREAT)).
Table 2: Randomized Controlled Trials Showing Adverse
Cardiovascular Outcomes in Patients With CKD
(N = 1265)
(N = 1432)
(N = 4038)
|Time Period of Trial||1993 to 1996||2003 to 2006||2004 to 2009|
|Population||CKD patients on hemodialysis with coexisting CHF or CAD, hematocrit 30 ± 3% on epoetin alfa||CKD patients not on dialysis with hemoglobin < 11 g/dL not previously administered epoetin alfa||CKD patients not on dialysis with type II diabetes, hemoglobin ≤ 11 g/dL|
|Hemoglobin Target; Higher vs. Lower (g/dL)||14.0 vs. 10.0||13.5 vs. 11.3||13.0 vs. ≥ 9.0|
|Median (Q1, Q3) Achieved Hemoglobin level (g/dL)||12.6 (11.6, 13.3) vs. 10.3 (10.0, 10.7)||13.0 (12.2, 13.4) vs. 11.4 (11.1, 11.6)||12.5 (12.0, 12.8) vs. 10.6 (9.9, 11.3)|
|Primary Endpoint||All-cause mortality or nonfatal MI||All-cause mortality, MI, hospitalization for CHF, or stroke||All-cause mortality, MI, myocardial ischemia, heart failure, and stroke|
|Hazard Ratio or Relative Risk (95% CI)||1.28 (1.06 - 1.56)||1.34 (1.03 - 1.74)||1.05 (0.94 - 1.17)|
|Adverse Outcome for Higher Target Group||All-cause mortality||All-cause mortality||Stroke|
|Hazard Ratio or Relative Risk (95% CI)||1.27 (1.04 - 1.54)||1.48 (0.97 -2.27)||1.92 (1.38 -2.68)|
Patients with Chronic Kidney Disease
NHS: A prospective, randomized, open-label study of 1265 patients with chronic kidney disease on dialysis with documented evidence of congestive heart failure or ischemic heart disease was designed to test the hypothesis that a higher target hematocrit (Hct) would result in improved outcomes compared with a lower target Hct. In this study, patients were randomized to epoetin alfa treatment targeted to a maintenance hemoglobin of either 14 ± 1 g/dL or 10 ± 1 g/dL. The trial was terminated early with adverse safety findings of higher mortality in the high hematocrit target group. Higher mortality (35% vs. 29%) was observed for the patients randomized to a target hemoglobin of 14 g/dL than for the patients randomized to a target hemoglobin of 10 g/dL. For all-cause mortality, the HR=1.27; 95% CI (1.04, 1.54); p=0.018. The incidence of nonfatal myocardial infarction, vascular access thrombosis, and other thrombotic events was also higher in the group randomized to a target hemoglobin of 14 g/dL.
CHOIR: In a randomized prospective trial, 1432 patients with anemia due to CKD who were not undergoing dialysis were assigned to epoetin alfa treatment targeting a maintenance hemoglobin concentration of 13.5 g/dL or 11.3 g/dL. The trial was terminated early with adverse safety findings. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher hemoglobin group compared to 97 (14%) among the 717 patients in the lower hemoglobin group (HR 1.3, 95% CI: 1.0, 1.7 p=0.03).
TREAT: A randomized, double-blind, placebo-controlled, prospective trial of 4038 patients with: CKD not on dialysis (eGFR of 20 – 60 mL/min), anemia (hemoglobin levels ≤ 11 g/dL), and type 2 diabetes mellitus, patients were randomized to receive either darbepoetin alfa treatment or a matching placebo. Placebo group patients also received darbepoetin alfa when their hemoglobin levels were below 9 g/dL. The trial objectives were to demonstrate the benefit of darbepoetin alfa treatment of the anemia to a target hemoglobin level of 13 g/dL, when compared to a “placebo” group, by reducing the occurrence of either of two primary endpoints: (1) a composite cardiovascular endpoint of all-cause mortality or a specified cardiovascular event (myocardial ischemia, CHF, MI, and CVA) or (2) a composite renal endpoint of all-cause mortality or progression to end stage renal disease. The overall risks for each of the two primary endpoints (the cardiovascular composite and the renal composite) were not reduced with darbepoetin alfa treatment (see Table 2), but the risk of stroke was increased nearly two-fold in the darbepoetin alfa -treated group versus the placebo group: annualized stroke rate 2.1% vs. 1.1%, respectively, HR 1.92; 95% CI: 1.38, 2.68; p < 0.001. The relative risk of stroke was particularly high in patients with a prior stroke: annualized stroke rate 5.2% in the darbepoetin alfa-treated group and 1.9% in the placebo group, HR 3.07; 95% CI: 1.44, 6.54.Also, among darbepoetin alfa-treated subjects with a past history of cancer, there were more deaths due to all causes and more deaths adjudicated as due to cancer, in comparison with the control group.
Patients with Cancer
An increased incidence of thromboembolic reactions, some serious and life-threatening, occurred in patients with cancer treated with ESAs.
In a randomized, placebo-controlled study (Study 1 in Table 3 [see Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer] of 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). This study was terminated prematurely when interim results demonstrated a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic reactions (1.1% vs. 0.2%) in the first 4 months of the study among patients treated with epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).
Patients Having Surgery
Mircera is not approved for reduction of RBC transfusions in patients scheduled for surgical procedures.
An increased incidence of deep vein thrombosis (DVT) in patients receiving epoetin alfa undergoing surgical orthopedic procedures has been observed. In a randomized controlled study (referred to as the “SPINE” study), 681 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, received epoetin alfa and standard of care (SOC) treatment, or SOC treatment alone. Preliminary analysis showed a higher incidence of DVT, determined by either Color Flow Duplex Imaging or by clinical symptoms, in the epoetin alfa group [16 patients (4.7%)] compared to the SOC group [7 patients (2.1%)]. In addition, 12 patients in the epoetin alfa group and 7 patients in the SOC group had other thrombotic vascular events.
Increased mortality was observed in a randomized placebo-controlled study of epoetin alfa in adult patients who were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to epoetin alfa versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all four deaths were associated with thrombotic events.
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 (see Table 3). These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy (Studies 5 and 6), in patients receiving chemotherapy for metastatic breast cancer (Study 1) or lymphoid malignancy (Study 2), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Studies 7 and 8).
Table 3 Randomized, Controlled Trials with Decreased
Survival and/or Decreased Locoregional Control
|Study/Tumor (n)||Hemoglobin Target||Achieved Hemoglobin (Median Q1,Q3*)||Primary Endpoint||Adverse Outcome for ESA-containing Arm|
|Cancer Study 1 Metastatic breast cancer (n=939)||12-14 g/dL||12.9 g/dL||12-month overall survival||Decreased 12-month survival|
|12.2, 13.3 g/dL|
|Cancer Study 2 Lymphoid malignancy (n=344)||13-15 g/dL (M)||11.0 g/dL||Proportion of patients achieving a hemoglobin response||Decreased overall survival|
|13-14 g/dL (F)||9.8, 12.1 g/dL|
|Cancer Study 3 Early breast cancer (n=733)||12.5-13 g/dL||13.1 g/dL||Relapse-free and overall survival||Decreased 3-year relapse-free and overall survival|
|12.5, 13.7 g/dL|
|Cancer Study 4 Cervical cancer (n=114)||12-14 g/dL||12.7 g/dL||Progression-free and overall survival and locoregional control||Decreased 3-year progression-free and overall survival and locoregional control|
|12.1, 13.3 g/dL|
|Cancer Study 5 Head and neck cancer (n=351)||> 15 g/dL (M)||Not available||Locoregional progression-free survival (LRPFS)||Decreased 5-year locoregional progression-free survival Decreased overall survival|
|> 14 g/dL (F)|
|Cancer Study 6 Head and neck cancer (n=522)||14-15.5 g/dL||Not available||Locoregional disease control (LRC)||Decreased locoregional disease control|
|No Chemotherapy or Radiotherapy|
|Cancer Study 7 Non-small cell lung cancer (n=70)||12-14 g/dL||Not available||Quality of life||Decreased overall survival|
|Cancer Study 8 Non-myeloid malignancy (n=989)||12-13 g/dL||10.6 g/dL||RBC transfusions||Decreased overall survival|
|9.4, 11.8 g/dL|
|*Q1= 25th percentile; Q3= 75th percentile|
Decreased Overall Survival
Cancer Study 1 (the “BEST” study) was previously described [see Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism]. Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator assessed time to tumor progression was not different between the two groups. Survival at 12 months was significantly lower in the epoetin alfa arm (70% vs. 76%, HR 1.37, 95% CI: 1.07, 1.75; p=0.012).
Cancer Study 2 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo) study conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).
Cancer Study 7 was a Phase 3, multicenter, randomized (epoetin alfa vs. placebo), double-blind study, in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 of 300 patients planned, a significant difference in survival in favor of the patients on the placebo arm of the trial was observed (median survival 63 vs. 129 days; HR 1.84; p=0.04).
Cancer Study 8 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo), 16-week study in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group (8 months) compared with the placebo group (10.8 months); HR 1.30, 95% CI: 1.07, 1.57.
Decreased Progression-Free Survival And Overall Survival
Cancer Study 3 (the “PREPARE” study) was a randomized controlled study in which darbepoetin alfa was administered to prevent anemia conducted in 733 women receiving neo-adjuvant breast cancer treatment. A final analysis was performed after a median follow-up of approximately 3 years at which time the survival rate was lower (86% vs. 90%, HR 1.42, 95% CI: 0.93, 2.18) and relapse-free survival rate was lower (72% vs. 78%, HR 1.33, 95% CI: 0.99, 1.79) in the darbepoetin alfa-treated arm compared to the control arm.
Cancer Study 4 (protocol GOG 191) was a randomized controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic events in epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the epoetin alfa-treated group compared to control (59% vs. 62%, HR 1.06, 95% CI: 0.58, 1.91). Overall survival at 3 years was lower in the epoetin alfa-treated group compared to control (61% vs. 71%, HR 1.28, 95% CI: 0.68, 2.42).
Cancer Study 5 (the “ENHANCE” study) was a randomized controlled study in 351 head and neck cancer patients where epoetin beta or placebo was administered to achieve target hemoglobins of 14 and 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving epoetin beta (HR 1.62, 95% CI: 1.22, 2.14, p=0.0008) with a median of 406 days epoetin beta vs. 745 days placebo. Overall survival was significantly shorter in patients receiving epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p=0.02).
Decreased Locoregional Control
Cancer Study 6 (DAHANCA 10) was conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy randomized to darbepoetin alfa with radiotherapy or radiotherapy alone. An interim analysis on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p=0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p=0.08).
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 [see Seizures].
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 [see PATIENT INFORMATION].
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 [see Pure Red Cell Aplasia]. In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient response to Mircera therapy [see DOSAGE AND ADMINISTRATION].
Pure Red Cell Aplasia
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 SC 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 [see Lack or Loss of Hemoglobin Response to Mircera]. Serum samples should be obtained at least a month after the last Mircera administration to prevent interference of Mircera with the assay. Contact Roche at 1-888-835-2555 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 [see ADVERSE REACTIONS].
Serious Allergic Reactions
Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, tachycardia, pruritus skin rash, urticaria, and Stevens-Johnson syndrome/toxic epidermal necrolysis have been reported in patients treated with Mircera. If a serious allergic or anaphylactic reaction occurs due to Mircera, immediately and permanently discontinue Mircera and administer appropriate therapy.
Therapy with Mircera results in an increase in red blood cells and a decrease in plasma volume, which could reduce dialysis efficiency; 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.
Evaluate transferrin saturation and serum ferritin prior to and during Mircera treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20% [see DOSAGE AND ADMINISTRATION].
The majority of patients with CKD will require supplemental iron during the course of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin is stable and sufficient to minimize the need for RBC transfusion. Thereafter, hemoglobin should be monitored at least monthly provided hemoglobin levels remain stable [see DOSAGE AND ADMINISTRATION].
Patient Counseling Information
Prior to treatment, inform patients of the risks and benefits of Mircera.
- To read the Medication Guide and to review and discuss any questions or concerns with their healthcare provider before starting Mircera and at regular intervals while receiving Mircera
- Of the increased risks of mortality, serious cardiovascular reactions, thromboembolic reactions, stroke, and tumor progression [see WARNINGS AND PRECAUTIONS]
- To undergo regular blood pressure monitoring, adhere to prescribed anti-hypertensive regimen and follow recommended dietary restrictions
- To seek medical care immediately if they experience any symptoms of an allergic reaction with use of Mircera [see WARNINGS AND PRECAUTIONS]
- To contact their healthcare provider for new-onset neurologic symptoms or change in seizure frequency
- Of the need to have regular laboratory tests for hemoglobin
Administer Mircera under the direct supervision of a healthcare provider or, in situations where a patient has been trained to administer Mircera at home, provide instruction on the proper use of Mircera, including instructions to:
- Carefully review the Medication Guide and the Instructions for Use
- Avoid the reuse of needles, syringes, or unused portions of the Mircera single-use prefilled syringes and to properly dispose of these items
Always keep a puncture-proof disposal container available for the disposal of used syringes and needles
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No carcinogenicity or genotoxicity studies have been conducted with Mircera. Methoxy polyethylene glycolepoetin beta did not induce a proliferative response in either the erythropoietin receptor positive cell lines HepG2 and K562 or the erythropoietin receptor negative cell line RT112 in vitro. In addition, using a panel of human tissues, the in vitro binding of methoxy polyethylene glycol-epoetin beta was observed only in bone marrow progenitor cells.
When methoxy polyethylene glycol-epoetin beta was administered subcutaneously to male and female rats prior to and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected.
Use In Specific Populations
Pregnancy: Category C
There are no adequate and well-controlled studies in pregnant women. Mircera should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
When methoxy polyethylene glycol-epoetin beta was administered subcutaneously to rats and rabbits during gestation, bone malformation was observed in both species at 50 mcg/kg once every three days. This effect was observed as missing caudal vertebrae resulting in a thread-like tail in one rat fetus, absent first digit metacarpal and phalanx on each forelimb resulting in absent polex in one rabbit fetus, and fused fourth and fifth cervical vertebrae centra in another rabbit fetus. Dose-related reduction in fetal weights was observed in both rats and rabbits. At doses 5 mcg/kg once every three days and higher, methoxy polyethylene glycol-epoetin beta caused exaggerated pharmacodynamic effects in dams. Once-weekly doses of methoxy polyethylene glycol-epoetin beta up to 50 mcg/kg/dose given to pregnant rats did not adversely affect pregnancy parameters, natural delivery or litter observations. Increased deaths and significant reduction in the growth rate of the F1 generation were observed during lactation and early post weaning period. However, no remarkable effect on reflex, physical and cognitive development or reproductive performance was observed in F1 generation of any dose groups.
It is not known whether Mircera is excreted into human breast milk. In one study in rats, methoxy polyethylene glycol-epoetin beta was excreted into maternal milk. Because many drugs are excreted in human milk, caution should be exercised when Mircera is administered to a nursing woman.
The safety and efficacy of Mircera in pediatric patients have not been established.
Clinical studies of Mircera did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
In a study comparing 12 patients with severe (Child-Pugh Classification Grade C) hepatic impairment to 12 healthy volunteers, the single-dose pharmacokinetic disposition of Mircera was not altered in patients with hepatic impairment. No adjustment of the starting dose is necessary in patients with hepatic impairment.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 9/3/2015
Additional Mircera Information
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