Methoxy polyethylene glycol-epoetin beta

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# Black Box Warning

# Overview
Methoxy polyethylene glycol-epoetin beta is an erythropoiesis-stimulating agent that is FDA approved for the treatment of anemia associated with chronic kidney disease (CKD in adult patients on dialysis and patients not on dialysis). There is a Black Box Warning for this drug as shown here.  Common adverse reactions include hypertension, diarrhea, nasopharyngitis.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- 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.
- Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments.
- 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.
- 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%.
- 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. Evaluate 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:
- Initiate Mircera treatment when the hemoglobin level is less than 10 g/dL.
- If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Mircera.
- 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.
- 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:
- Consider initiating Mircera treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply:
- The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and,
- Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal
- 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.
- 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.
- 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.
- 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.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Methoxy polyethylene glycol-epoetin beta in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Methoxy polyethylene glycol-epoetin beta in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Methoxy polyethylene glycol-epoetin beta in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Methoxy polyethylene glycol-epoetin beta in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Methoxy polyethylene glycol-epoetin beta in pediatric patients.

# 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, skin rash, and urticaria).

# Warnings

### Precautions
- 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. 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.
- 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.
- 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) 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  compared to the SOC group . 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).
- Decreased overall survival:
- Cancer Study 1 (the "BEST" study) was previously described. 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).
- 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
- 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. 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.
- Serious Allergic Reactions
- Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, tachycardia, pruritus, skin rash, and urticaria 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.
- Dialysis Management
- 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.
- Laboratory Monitoring
- 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%.
- 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.

# Adverse Reactions

## Clinical Trials Experience
- The data described below reflect exposure to Mircera in 2737 patients, including 1451 exposed for 6 months and 1144 exposed for greater than one year. Mircera was studied primarily in active-controlled studies (n=1789 received Mircera, and n=948 received another ESA) and in long-term follow up studies. The population was 18 to 92 years of age, 58% male, and the percentage of Caucasian, Black (including African Americans), Asian and Hispanic patients were 73%, 20%, 5%, and 9%, respectively. Approximately 85% of the patients were receiving dialysis. Most patients received Mircera using dosing regimens of once every two or four weeks, administered SC or IV.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of Mircera cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.
- Some of the adverse reactions reported are typically associated with CKD, or recognized complications of dialysis, and may not necessarily be attributable to Mircera therapy. Adverse reaction rates did not importantly differ between patients receiving Mircera or another ESA.
- Table 4 summarizes the most frequent adverse reactions ( 5%) in patients treated with Mircera.
- In the controlled trials, the rates of serious adverse reactions did not importantly differ between patients receiving Mircera and another ESA (38% vs. 42%) except for the occurrence of serious gastrointestinal hemorrhage (1.2% vs. 0.2%). Serious hemorrhagic adverse reactions of all types occurred among 5% and 4% of patients receiving Mircera or another ESA, respectively.

## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Methoxy polyethylene glycol-epoetin beta in the drug label.

# Drug Interactions
- No formal drug/drug interaction studies have been performed.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Risk Summary
- 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.
- Animal Data
- 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.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Methoxy polyethylene glycol-epoetin beta in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Methoxy polyethylene glycol-epoetin beta during labor and delivery.

### Nursing Mothers
- 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.

### Pediatric Use
- The safety and efficacy of Mircera in pediatric patients have not been established.

### Geriatic Use
- 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.

### Gender
There is no FDA guidance on the use of Methoxy polyethylene glycol-epoetin beta with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Methoxy polyethylene glycol-epoetin beta with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Methoxy polyethylene glycol-epoetin beta in patients with renal impairment.

### Hepatic Impairment
- 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.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Methoxy polyethylene glycol-epoetin beta in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Methoxy polyethylene glycol-epoetin beta in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Intravenous

### Monitoring
There is limited information regarding Monitoring of Methoxy polyethylene glycol-epoetin beta in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Methoxy polyethylene glycol-epoetin beta in the drug label.

# Overdosage

## Acute Overdose
- Mircera overdosage can elevate hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of Mircera dosage and/or with phlebotomy, as clinically indicated. Cases of severe hypertension have been observed following overdose with ESAs.

## Chronic Overdose
There is limited information regarding Chronic Overdose of Methoxy polyethylene glycol-epoetin beta in the drug label.

# Pharmacology

## 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.

## Structure
- Mircera, methoxy polyethylene glycol-epoetin beta, is an ESA which differs from erythropoietin through formation of a chemical bond between either the N-terminal amino group or the -amino group of any lysine present in erythropoietin, predominantly Lys52 and Lys45, and methoxy polyethylene glycol (PEG) butanoic acid (approximately 30,000 daltons). This results in a total molecular weight of approximately 60,000 daltons. Mircera is formulated as a sterile, preservative-free protein solution for intravenous or subcutaneous administration.
- Injectable solutions of Mircera in prefilled syringes are formulated in an aqueous solution containing sodium phosphate, sodium sulphate, mannitol, methionine and poloxamer 188. The solution is clear, colorless to slightly yellowish and the pH is 6.2  0.2.

## Pharmacodynamics
- 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.

## Pharmacokinetics
- 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.

## Nonclinical Toxicology
- No carcinogenicity or genotoxicity studies have been conducted with Mircera. Methoxy polyethylene glycol-epoetin 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.

# Clinical Studies
- 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.
- 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.
- 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.
- 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).

# How Supplied
- Mircera is available in single-use prefilled syringes. The syringe plungers are designated with unique colors for each dosage strength. The prefilled syringes are supplied with a 27 gauge, 12 inch needle. To reduce the risk of accidental needlesticks after application, each prefilled syringe is equipped with a needle guard that covers the needle during disposal.
- Mircera is available in the following pack sizes:
- Single Use Prefilled Syringe (PFS) with a Needle Guard. A 27 Gauge, 12 Inch Needle is also provided:
- 1 PFS/Pack
- 50 mcg/0.3 mL
- (NDC 0004-0401-09)
- 75 mcg/0.3 mL
- (NDC 0004-0402-09)
- 100 mcg/0.3 mL
- (NDC 0004-0403-09)
- 150 mcg/0.3 mL
- (NDC 0004-0404-09)
- 200 mcg/0.3 mL
- (NDC 0004-0405-09)
- 250 mcg/0.3 mL
- (NDC 0004-0406-09)
- Stability and Storage
- The recommended storage temperature is at 2C to 8C (36F to 46F). Do not freeze or shake. Protect from light. Keep Mircera in the original package until use.
- Storage of prefilled syringes over the recommended temperature (2C to 8C), when necessary, is permissible only for temperatures up to 25C (77F) and for no more than 30 days.

## Storage
There is limited information regarding Methoxy polyethylene glycol-epoetin beta Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Prior to treatment, inform patients of the risks and benefits of Mircera.
- Inform patients:
- 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
- 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
- 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.

# Precautions with Alcohol
- Alcohol-Methoxy polyethylene glycol-epoetin beta interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- MIRCERA

# Look-Alike Drug Names
There is limited information regarding Methoxy polyethylene glycol-epoetin beta Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price