Methoxy Polyethylene Glycol-Epoetin Beta

• If you have an allergy to methoxy polyethylene glycol-epoetin beta or any part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have high blood pressure.
• If you have a kind of anemia called Pure Red Cell Aplasia (PRCA).
• If you have anemia caused by chemo or if you need a blood transfusion to treat anemia.

This is not a list of all drugs or health problems that interact with methoxy polyethylene glycol-epoetin beta.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Very bad dizziness or passing out.
• Chest pain or pressure.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Swelling, warmth, numbness, change of color, or pain in a leg or arm.
• Cool or pale arm or leg.
• Very bad headache.
• Coughing up blood.
• A fast heartbeat.
• Feeling very tired or weak.
• Seizures.
• Trouble walking.
• Change in balance.
• Wheezing.
• A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection [preservative free]:

Mircera: 50 mcg/0.3 mL (0.3 mL); 75 mcg/0.3 mL (0.3 mL); 100 mcg/0.3 mL (0.3 mL); 200 mcg/0.3 mL (0.3 mL)

Solution Prefilled Syringe, Injection:

Mircera: 30 mcg/0.3 mL (0.3 mL); 50 mcg/0.3 mL (0.3 mL); 75 mcg/0.3 mL (0.3 mL); 100 mcg/0.3 mL (0.3 mL); 200 mcg/0.3 mL (0.3 mL)

Solution Prefilled Syringe, Injection [preservative free]:

Mircera: 150 mcg/0.3 mL (0.3 mL)

• Mircera

• Colony Stimulating Factor
• Erythropoiesis-Stimulating Agent (ESA)
• Hematopoietic Agent

Anemia: Treatment of anemia associated with chronic kidney disease (CKD) in adult patients on dialysis and patients not on dialysis.

Limitations of use: Not indicated and is not recommended in the treatment of anemia due to cancer chemotherapy or as a substitute for red blood cell (RBC) transfusions in patients who require immediate correction of anemia; has not been shown to improve symptoms, physical functioning or health-related quality of life.

Note: Evaluate iron status before and during treatment and maintain iron repletion.

Anemia associated with chronic kidney disease (CKD): Individualize dosing and use the lowest dose necessary to reduce the need for RBC transfusions:

Patients not currently taking an ESA:

Chronic kidney disease patients on dialysis (IV route is preferred for hemodialysis patients; initiate treatment when hemoglobin <10 g/dL): Initial: IV, SubQ: 0.6 mcg/kg once every 2 weeks. Reduce dose or interrupt treatment if hemoglobin approaches or exceeds 11 g/dL. After hemoglobin stabilizes, may administer once monthly with a dose that is double the dose administered every 2 weeks; titrate as necessary.

Chronic kidney disease patients NOT on dialysis (consider initiating treatment when hemoglobin <10 g/dL and the rate of hemoglobin decline would likely result in RBC transfusion and goal is to reduce risk of alloimmunization or other RBC transfusion-related risks): Initial: IV, SubQ: 0.6 mcg/kg once every 2 weeks. Reduce dose or interrupt treatment if hemoglobin exceeds 10 g/dL. After hemoglobin stabilizes, may administer once monthly with a dose that is double the dose administered every 2 weeks; titrate as necessary.

Patients converting from epoetin alfa or darbepoetin alfa: IV, SubQ: Based on total weekly ESA dose at the time of conversion (if hemoglobin is stabilized):

For epoetin alfa dose <8,000 units/week or darbepoetin alfa dose <40 mcg/week: Administer methoxy polyethylene glycol-epoetin beta 120 mcg once monthly or 60 mcg every 2 weeks.

For epoetin alfa dose 8,000 to 16,000 units/week or darbepoetin alfa dose 40 to 80 mcg/week: Administer methoxy polyethylene glycol-epoetin beta 200 mcg once monthly or 100 mcg every 2 weeks.

For epoetin alfa dose >16,000 units/week or darbepoetin alfa dose >80 mcg/week: Administer methoxy polyethylene glycol-epoetin beta 360 mcg once monthly or 180 mcg every 2 weeks.

Dosage adjustments for all CKD patients: Do not increase dose more frequently than every 4 weeks (dose decreases may occur more often); avoid frequent dosage adjustments.

If hemoglobin increases >1 g/dL in any 2-week period: Decrease dose by ≥25% as needed to reduce rapid responses.

If hemoglobin does not increase by >1 g/dL after 4 weeks of therapy: Increase dose by 25%.

Inadequate or lack of response over 12 weeks of therapy: If adequate response is not achieved after 12 weeks of therapy, further increases are unlikely to be of benefit and may increase the risk for adverse events; use the minimum effective dose that will maintain a hemoglobin level sufficient to avoid red blood cell transfusions and evaluate patient for other causes of anemia. Discontinue treatment if responsiveness does not improve.

Store at 2°C to 8°C (36°F to 46°F); may store at temperatures up to 25°C (77°F) for no more than 30 days. Do not freeze. Protect from light. Keep in the original package until use. Do not shake.

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

Methoxy polyethylene glycol-epoetin beta is not indicated and is not recommended for the treatment of anemia due to cancer chemotherapy. A dose-ranging study was terminated early because of more deaths among patients receiving methoxy polyethylene glycol-epoetin beta than another ESA. ESAs have shown 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.

Adverse events were observed in some animal reproduction studies.

Methoxy polyethylene glycol-epoetin beta is a hematopoietic agent.1

Contraindications

• Uncontrolled hypertension.1

• Pure red cell aplasia (PRCA) that begins after treatment with methoxy polyethylene glycol-epoetin beta or other erythropoietin protein drugs.1

• History of serious allergic reactions to methoxy polyethylene glycol-epoetin beta, including anaphylaxis.1

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.1

• 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.1

• 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.1

• 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.1

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]).1

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.1

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).1

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.1

An increased incidence of thromboembolic reactions, some serious and life-threatening, occurred in patients with cancer treated with ESAs.1

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).1

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.1

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.1

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.1

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).1

Q1= 25th percentile; Q3= 75th percentile

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).1

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).1

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).1

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, 1.57.1

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.1

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).1

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).1

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).1

Hypertension

Methoxy polyethylene glycol-epoetin beta is contraindicated in patients with uncontrolled hypertension.1

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.1

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.1

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.1

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).1

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.1

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.1

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).1

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.1

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.1

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. 1

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.1

Specific Populations

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. 1

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. 1

1

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.1

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.1

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.1

The dose level not causing any adverse effect on dams or offspring was not determined.1

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.1

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.1

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. 1

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.1

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.1

Common Adverse Effects

The most common adverse reactions (≥ 10%) are hypertension, diarrhea, and nasopharyngitis.1