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Mircera (methoxy polyethylene glycol-epoetin beta)
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Mircera safely and effectively. See full prescribing information for Mircera.
Mircera ® (methoxy polyethylene glycol-epoetin beta)
Solution for Injection: Intravenous [IV] or Subcutaneous [SC] use
Initial U.S. Approval: 2007
WARNINGS: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE
See full prescribing information for complete boxed warning
Chronic Kidney Disease:
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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 (5.1).
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No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks (5.1).
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Use the lowest Mircera dose sufficient to reduce the need for red blood cell (RBC) transfusions (5.1).
Cancer:
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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 (5.2).
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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 (5.2).
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
Mircera is an erythropoiesis-stimulating agent (ESA) indicated for the treatment of anemia associated with chronic kidney disease (CKD in adult patients on dialysis and patients not on dialysis (1.1).
Limitations of Use
Mircera is not indicated and is not recommended for use:
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In the treatment of anemia due to cancer chemotherapy (1.2).
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As a substitute for RBC transfusions in patients who require immediate correction of anemia (1.2)
Mircera has not been shown to improve quality of life, fatigue, or patient well-being.
DOSAGE AND ADMINISTRATION
Mircera is administered by subcutaneous (SC) or intravenous (IV) injection (2.2).
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Initial Treatment: 0.6 mcg/kg body weight administered once every two weeks (2.2).
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Conversion from Another ESA: dosed once monthly or once every two weeks based on total weekly epoetin alfa or darbepoetin alfa dose at time of conversion (2.2).
DOSAGE FORMS AND STRENGTHS
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Injection: 50, 75, 100, 150, 200, or 250 mcg in 0.3 mL solution of Mircera in single-use prefilled syringes (3).
CONTRAINDICATIONS
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Uncontrolled hypertension (4).
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Pure red cell aplasia (PRCA) that begins after treatment with Mircera or other erythropoietin protein drugs (4)
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History of serious allergic reactions to Mircera, including anaphylaxis (4).
WARNINGS AND PRECAUTIONS
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Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism: 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 benefits (5.1 and 14). Use caution in patients with coexistent cardiovascular disease and stroke (5.1).
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Hypertension: Control hypertension prior to initiating and during treatment with Mircera (5.3).
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Seizures: Seizures have occurred in CKD patients participating in Mircera clinical studies. Increase monitoring of these patients for changes in seizure frequency or premonitory symptoms (5.4).
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PRCA: If severe anemia and low reticulocyte count develop during Mircera treatment, withhold Mircera and eva luate for PRCA (5.6).
The most common adverse reactions (≥ 10%) are hypertension, diarrhea, nasopharyngitis. (6).
To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 8/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNINGS: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS, AND TUMOR PROGRESSION OR RECURRENCE
1 INDICATIONS AND USAGE
1.1 Anemia Due to Chronic Kidney Disease
Mircera is indicated for the treatment of anemia associated with chronic kidney disease (CKD) in adult patients on dialysis and patients not on dialysis.
1.2 Limitations of Use
Mircera is not indicated and is not recommended:
Mircera has not been shown to improve symptoms, physical functioning or health-related quality of life.
2 DOSAGE AND ADMINISTRATION
2.1 eva luation of Iron Stores and Nutritional Factors
eva luate the iron status in all patients before and during treatment and maintain iron repletion. Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating Mircera [see Warnings and Precautions (5.9)].
2.2 Patients with Chronic Kidney Disease
Individualize dosing and use the lowest dose of Mircera sufficient to reduce the need for RBC transfusions [see Warnings and Precautions (5.1)]. 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. Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events [see Boxed Warning and Clinical Studies (14)].
For all patients with CKD:
When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.
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Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments.
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If the hemoglobin rises rapidly (e.g., more than 1 g/dL in any 2-week period), reduce the dose of Mircera by 25% or more as needed to reduce rapid responses.
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For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%.
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For patients who do not respond adequately over a 12-week escalation period, increasing the Mircera dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions. eva luate other causes of anemia. Discontinue Mircera if responsiveness does not improve.
Mircera is administered either intravenously (IV) or subcutaneously (SC). When administered SC, Mircera should be injected in the abdomen, arm or thigh.
For Patients with CKD on dialysis:
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Initiate Mircera treatment when the hemoglobin level is less than 10 g/dL.
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If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Mircera.
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The recommended starting dose of Mircera for the treatment of anemia in adult CKD patients who are not currently treated with an ESA is 0.6 mcg/kg body weight administered as a single IV or SC injection once every two weeks. The IV route is recommended for patients receiving hemodialysis because the IV route may be less immunogenic [see Adverse Reactions (6.2)].
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Once the hemoglobin has been stabilized, Mircera may be administered once monthly using a dose that is twice that of the every-two-week dose and subsequently titrated as necessary.
For Patients with CKD not on dialysis:
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Consider initiating Mircera treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply:
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The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and,
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Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal
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If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of Mircera, and use the lowest dose of Mircera sufficient to reduce the need for RBC transfusions.
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The recommended starting dose of Mircera for the treatment of anemia in adult CKD patients who are not currently treated with an ESA is 0.6 mcg/kg body weight administered as a single IV or SC injection once every two weeks.
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Once the hemoglobin has been stabilized, Mircera may be administered once monthly using a dose that is twice that of the every-two-week dose and subsequently titrated as necessary.
Refer patients who self-administer Mircera to the Instructions for Use [see Patient Counseling Information (17)].
Conversion from Epoetin alfa or Darbepoetin alfa to Mircera in Patients with CKD
Mircera can be administered once every two weeks or once monthly to patients whose hemoglobin has been stabilized by treatment with an ESA (see Table 1). The dose of Mircera, given as a single IV or SC injection, should be based on the total weekly ESA dose at the time of conversion.
2.3 Preparation and Administration of Mircera
Mircera is packaged as single-use prefilled syringes. Mircera contains no preservatives. Discard any unused portion. Do not pool unused portions from the prefilled syringes. Do not use the prefilled syringe more than one time.
Always store Mircera prefilled syringes in their original cartons. Vigorous shaking or prolonged exposure to light should be avoided.
Do not mix Mircera with any parenteral solution.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any prefilled syringes exhibiting particulate matter or a coloration other than colorless to slightly yellowish.
For administration using the prefilled syringe, the plunger must be fully depressed during injection in order for the needle guard to activate. Following administration, remove the needle from the injection site and then release the plunger to allow the needle guard to move up until the entire needle is covered.
See "Instructions for Use" for complete instructions on the preparation and administration of Mircera. Examine each prefilled syringe for the expiration date. Do not use Mircera after the expiration date.
3 DOSAGE FORMS AND STRENGTHS
Injection: 50, 75, 100, 150, 200, or 250 mcg of Mircera in 0.3 mL solution in single-use prefilled syringes
4 CONTRAINDICATIONS
Mircera is contraindicated in patients with:
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Uncontrolled hypertension [see Warnings and Precautions (5.3)]
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Pure red cell aplasia (PRCA) that begins after treatment with Mircera or other erythropoietin protein drugs [see Warnings and Precautions (5.6)]
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History of serious or severe allergic reactions to Mircera (e.g. anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria).
5 WARNINGS AND PRECAUTIONS
5.1 Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism
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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.
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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 (14)]. Use caution in patients with coexistent cardiovascular disease and stroke [see Dosage and Administration (2.2)]. 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.
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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.
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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)).
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.
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