Methoxy Polyethylene Glycol-epoetin Beta (Monograph)

Brand name: Mircera
Drug class: Hematopoietic Agents
Chemical name: Methoxy Polyethylene Glycol-epoetin Beta
CAS number: 677324-53-7

Medically reviewed by Drugs.com on Jun 29, 2022. Written by ASHP.

Introduction

Methoxy polyethylene glycol-epoetin beta is a hematopoietic agent.

Uses for Methoxy Polyethylene Glycol-epoetin Beta

Methoxy polyethylene glycol-epoetin beta has the following uses:

Methoxy polyethylene glycol-epoetin beta is an erythropoiesis-stimulating agent (ESA) indicated for the treatment of anemia associated with chronic kidney disease (CKD) in adult patients on dialysis and adult patients not on dialysis.

Methoxy polyethylene glycol-epoetin beta also is indicated for the treatment of anemia associated with CKD in 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.

Methoxy polyethylene glycol-epoetin beta has the following limitations of use:

Methoxy polyethylene glycol-epoetin beta 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.

Methoxy polyethylene glycol-epoetin beta has not been shown to improve quality of life, fatigue, or patient well-being.

Methoxy Polyethylene Glycol-epoetin Beta Dosage and Administration

General

Methoxy polyethylene glycol-epoetin beta is available in the following dosage form(s) and strength(s):

• Injection: 30 mcg, 50 mcg, 75 mcg, 100 mcg, 120 mcg, 150 mcg, 200 mcg, or 250 mcg in 0.3 mL solution (in single-dose prefilled syringes).

• Injection: 360 mcg in 0.6 mL solution (in single-dose prefilled syringes).

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Important Dosing Information

Evaluation of Iron Stores and Nutritional Factors

Evaluate the iron status in all patients before and during 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.

Monitoring of Response to Therapy

Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating methoxy polyethylene glycol-epoetin beta. Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin level is stable and sufficient to minimize the need for RBC transfusion.

Patients with Chronic Kidney Disease

Individualize dosing and use the lowest dose of methoxy polyethylene glycol-epoetin beta sufficient to reduce the need for RBC transfusions. In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered 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.

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 methoxy polyethylene glycol-epoetin beta 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 methoxy polyethylene glycol-epoetin beta 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 methoxy polyethylene glycol-epoetin beta if responsiveness does not improve.

Administer methoxy polyethylene glycol-epoetin beta either intravenously or subcutaneously in adult patients and only intravenously in pediatric patients. When administered subcutaneously, methoxy polyethylene glycol-epoetin beta should be injected in the abdomen, arm or thigh.

For Adult Patients with CKD on Dialysis

• Initiate methoxy polyethylene glycol-epoetin beta 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 methoxy polyethylene glycol-epoetin beta.

• The recommended starting dose of methoxy polyethylene glycol-epoetin beta 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 intravenous or subcutaneous injection once every two weeks. The intravenous route is recommended for patients receiving hemodialysis because the intravenous route may be less immunogenic.

• Once the hemoglobin has been stabilized, methoxy polyethylene glycol-epoetin beta may be administered once monthly using a dose that is twice that of the every-two-week dose and subsequently titrated as necessary.

For Adult Patients with CKD Not on Dialysis

• Consider initiating methoxy polyethylene glycol-epoetin beta treatment only when the hemoglobin level is less than 10 g/dL, 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 methoxy polyethylene glycol-epoetin beta, and use the lowest dose of methoxy polyethylene glycol-epoetin beta sufficient to reduce the need for RBC transfusions.

• The recommended starting dose of methoxy polyethylene glycol-epoetin beta 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 intravenous or subcutaneous injection once every two weeks.

• Once the hemoglobin has been stabilized, methoxy polyethylene glycol-epoetin beta 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 methoxy polyethylene glycol-epoetin beta to the “Instructions for Use” in the manufacturer’s labeling.

Conversion from Epoetin Alfa or Darbepoetin Alfa to Methoxy Polyethylene Glycol-epoetin Beta in Adult Patients with CKD: Methoxy polyethylene glycol-epoetin beta 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 methoxy polyethylene glycol-epoetin beta, given as a single intravenous or subcutaneous injection, should be based on the total weekly ESA dose at the time of conversion.

For Pediatric Patients with CKD on Hemodialysis

Conversion from Epoetin Alfa or Darbepoetin Alfa to Methoxy Polyethylene Glycol-epoetin Beta in Pediatric Patients with CKD Treated with Hemodialysis: Administer methoxy polyethylene glycol-epoetin beta intravenously once every 4 weeks to pediatric patients (ages 5 to 17 years) whose hemoglobin level has been stabilized by treatment with an ESA. Administer methoxy polyethylene glycol-epoetin beta as an intravenous injection at the dose (in micrograms) based on the total weekly ESA dose at the time of conversion. (See Table 2.)

Preparation and Administration of Methoxy Polyethylene Glycol-epoetin Beta

Methoxy polyethylene glycol-epoetin beta is packaged as single-dose prefilled syringes. Methoxy polyethylene glycol-epoetin beta contains no preservatives. Discard any unused portion. Do not pool unused portions from the prefilled syringes. Do not use the prefilled syringe more than once.

Always store methoxy polyethylene glycol-epoetin beta prefilled syringes in their original cartons. Vigorous shaking or prolonged exposure to light should be avoided.

Do not mix methoxy polyethylene glycol-epoetin beta 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” in the manufacturer's labeling for complete instructions on the preparation and administration of methoxy polyethylene glycol-epoetin beta. Examine each prefilled syringe for the expiration date. Do not use methoxy polyethylene glycol-epoetin beta after the expiration date.

Cautions for Methoxy Polyethylene Glycol-epoetin Beta

Contraindications

• Uncontrolled hypertension.

• Pure red cell aplasia (PRCA) that begins after treatment with methoxy polyethylene glycol-epoetin beta or other erythropoietin protein drugs.

• History of serious allergic reactions to methoxy polyethylene glycol-epoetin beta, including anaphylaxis.

Warnings/Precautions

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.

The design and overall results of the 3 large trials comparing higher and lower hemoglobin targets are shown in Table 3 (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 would result in improved outcomes compared with a lower target hematocrit. 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: In a randomized, double-blind, placebo-controlled, prospective trial, 4038 patients with CKD not on dialysis (eGFR of 20–60 mL/min), anemia (hemoglobin levels ≤ 11 g/dL), and type 2 diabetes mellitus 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 3), but the risk of stroke was increased nearly twofold 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 less than 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 4) 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

Methoxy polyethylene glycol-epoetin beta 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 (SPINE), 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

Methoxy polyethylene glycol-epoetin beta is not indicated and is not recommended for use in the treatment of anemia due to cancer chemotherapy. A dose-ranging trial of methoxy polyethylene glycol-epoetin beta in 153 patients who were undergoing chemotherapy for non-small cell lung cancer was terminated prematurely because more deaths occurred among patients receiving methoxy polyethylene glycol-epoetin beta than another ESA.

ESAs resulted in decreased locoregional control/progression-free survival and/or overall survival (see Table 4). 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).

Q1= 25th percentile; Q3= 75th percentile

Decreased Overall Survival

Cancer Study 1 (the “BEST” study) was previously described (see Patients with Cancer under Warnings/Precautions). 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

Methoxy polyethylene glycol-epoetin beta is contraindicated in patients with uncontrolled hypertension.

In methoxy polyethylene glycol-epoetin beta 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 methoxy polyethylene glycol-epoetin beta.

Appropriately control hypertension prior to initiation of and during treatment with methoxy polyethylene glycol-epoetin beta. Reduce or withhold methoxy polyethylene glycol-epoetin beta 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 methoxy polyethylene glycol-epoetin beta clinical studies. During the first several months following initiation of methoxy polyethylene glycol-epoetin beta, 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 Methoxy Polyethylene Glycol-epoetin Beta

For lack or loss of hemoglobin response to methoxy polyethylene glycol-epoetin beta, 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 methoxy polyethylene glycol-epoetin beta 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 methoxy polyethylene glycol-epoetin beta. This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. PRCA was not observed in clinical studies of methoxy polyethylene glycol-epoetin beta.

PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which methoxy polyethylene glycol-epoetin beta is not approved).

If severe anemia and low reticulocyte count develop during treatment with methoxy polyethylene glycol-epoetin beta, withhold methoxy polyethylene glycol-epoetin beta and evaluate patients for neutralizing antibodies to erythropoietin. Serum samples should be obtained at least a month after the last methoxy polyethylene glycol-epoetin beta administration to prevent interference of methoxy polyethylene glycol-epoetin beta with the assay. Contact the manufacturer (Vifor) at 1-800-576-8295 to perform assays for binding and neutralizing antibodies. Permanently discontinue methoxy polyethylene glycol-epoetin beta in patients who develop PRCA following treatment with methoxy polyethylene glycol-epoetin beta 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 methoxy polyethylene glycol-epoetin beta. If a serious allergic or anaphylactic reaction occurs due to methoxy polyethylene glycol-epoetin beta, immediately and permanently discontinue methoxy polyethylene glycol-epoetin beta and administer appropriate therapy.

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 methoxy polyethylene glycol-epoetin beta) in the postmarketing setting. Discontinue methoxy polyethylene glycol-epoetin beta 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 methoxy polyethylene glycol-epoetin beta. Patients receiving methoxy polyethylene glycol-epoetin beta may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.

Specific Populations

Pregnancy

Risk Summary: Available data from a small number of published case reports and postmarketing experience with methoxy polyethylene glycol-epoetin beta use in pregnancy are insufficient to identify a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Chronic kidney disease is associated with maternal and embryo-fetal risks. In animal reproduction studies, administration of methoxy polyethylene glycol-epoetin beta to rats and rabbits during pregnancy and lactation adversely affected offspring at doses 17-fold and greater than the recommended human dose.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Disease Associated Maternal and/or Embryo-Fetal Risk: Pregnancy in women with chronic kidney disease has been associated with adverse outcomes including hypertension, pre-eclampsia, miscarriage, premature birth, low-birth-weight, polyhydramnios, and intrauterine growth restriction.

Data: When methoxy polyethylene glycol-epoetin beta was administered subcutaneously to rats and rabbits during gestation (including the period of organogenesis), bone malformation was observed in both species at 50 mcg/kg once every three days (corresponding to 500 mcg/kg/month or 417-fold the recommended human dose) in studies of embryo-fetal development. 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 pollex 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, corresponding to 50 mcg/kg/month or 42-fold the recommended human dose, 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 (corresponding to 200 mcg/kg/month or 167-fold the recommended human dose) given to pregnant and lactating rats did not adversely affect pregnancy parameters, natural delivery or litter observations in a study of pre-and postnatal development. Increased deaths and significant reduction in the growth rate of the F1 generation were observed during lactation and early post weaning period at 20 and 50 mcg/kg/dose, corresponding to 80 and 200 mcg/kg/month or 67- and 167-fold the recommended human dose. A significant reduction in the growth rate of the F1 generation was evident already at 5 mcg/kg/dose, corresponding to 20 mcg/kg/month or 17-fold the recommended human dose. However, no remarkable effect on reflex, physical and cognitive development or reproductive performance was observed in F1 generation of any dose groups.

The dose level not causing any adverse effect on dams or offspring was not determined.

Lactation

Risk Summary: There are no data on the presence of methoxy polyethylene glycol-epoetin beta in human milk, the effects on the breastfed child, or the effects on milk production. However, endogenous erythropoietin is present in human milk. In rats, methoxy polyethylene glycol-epoetin beta was present in maternal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The lack of clinical data during lactation precludes a clear determination of the risk of methoxy polyethylene glycol-epoetin beta to a child during lactation. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methoxy polyethylene glycol-epoetin beta and any potential adverse effects on the breastfed child from methoxy polyethylene glycol-epoetin beta or from the underlying maternal condition.

Data: A dose of methoxy polyethylene glycol-epoetin beta approximately 3-fold greater than the recommended human dose was administered to lactating rats. Methoxy polyethylene glycol-epoetin beta was detected in maternal milk 4 hours postdose and reached maximum concentration 48 hours postdose. The maximum amount of methoxy polyethylene glycol-epoetin beta in milk was about 10-fold lower than in serum. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.

Pediatric Use

The safety and effectiveness of methoxy polyethylene glycol-epoetin beta for the treatment of anemia due to CKD have been established in 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. The use of methoxy polyethylene glycol-epoetin beta in this pediatric age group is supported by evidence from adequate and well-controlled studies of methoxy polyethylene glycol-epoetin beta in adults and a dose-finding study in 64 pediatric patients 5 to 17 years of age with CKD on hemodialysis. The adverse reaction profile observed in pediatric patients was consistent with the safety profile found in adults. The safety and effectiveness of methoxy polyethylene glycol-epoetin beta have not been established in patients less than 5 years of age.

The safety and effectiveness of methoxy polyethylene glycol-epoetin beta have not been established in pediatric patients of any age for subcutaneous administration; for treatment of anemia in patients with CKD on peritoneal dialysis; for treatment of anemia in patients with CKD who are not yet on dialysis; and for patients whose hemoglobin level has not been previously stabilized by treatment with an ESA.

Geriatric Use

Clinical studies of methoxy polyethylene glycol-epoetin beta 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.

Common Adverse Effects

The most common adverse reactions (≥ 10%) are hypertension, diarrhea, and nasopharyngitis.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism Of Action

Methoxy polyethylene glycol-epoetin beta 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.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

• Advise patients of the increased risks of mortality, serious cardiovascular reactions, thromboembolic reactions, stroke, and tumor progression.

• Advise patients to undergo regular blood pressure monitoring, adhere to prescribed anti-hypertensive regimen and follow recommended dietary restrictions.

• Advise patients to seek medical care immediately if they experience any symptoms of an allergic reaction with use of methoxy polyethylene glycol-epoetin beta.

• Advise patients to contact their healthcare provider for new-onset neurologic symptoms or change in seizure frequency.

• Advise patients of the need to have regular laboratory tests for hemoglobin.

• Administer methoxy polyethylene glycol-epoetin beta under the direct supervision of a healthcare provider or, in situations where a patient has been trained to administer methoxy polyethylene glycol-epoetin beta at home, provide instruction on the proper use of methoxy polyethylene glycol-epoetin beta. Instruct patients administering methoxy polyethylene glycol-epoetin beta at home to carefully review the Medication Guide and the Instructions for Use sections of the manufacturer's labeling. Instruct patients to not reuse needles, syringes, or unused portions of the methoxy polyethylene glycol-epoetin beta single-dose 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.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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