Methoxy polyethylene glycol-epoetin beta (MPG-epoetin beta), also called continuous erythropoietin receptor activator, is a long-acting synthetic erythropoietin protein approved for the treatment of anemia associated with chronic kidney disease (CKD) in adult patients on or off dialysis and pediatric patients 5 years and older on hemodialysis who are converting from another erythropoiesis-stimulating agent (ESA) after their hemoglobin concentration was stabilized with an ESA. Studies in adult patients with CKD who were either dialysis-dependent or dialysis-independent have shown similar efficacy in achieving target hemoglobin (Hgb) concentrations and reducing red blood cell transfusion dependence as comparator ESAs. In an open-label, multiple dose, dose finding pediatric study (n = 36, ages 5 to 17 years), the mean change in Hgb concentration from baseline was -0.15 g/dL (95% CI:-0.49 to 0.2) for patients receiving MPG-epoetin beta using the recommended dose conversion factor. Supportive efficacy results showed that 75% of pediatric patients maintained Hgb values within +/- 1 g/dL of baseline and 81% maintained Hgb values within 10 to 12 g/dL when using the conversion factor to calculate the MPG-epoetin beta dose. The primary advantage of MPG-epoetin beta vs. other ESAs is that it can be dosed less frequently (up to every 4 weeks) due to its extremely long half-life. MPG-epoetin beta should only be used in patients with CKD and should not be used to treat cancer-related anemia. In adult patients, ESAs have been shown to increase the risk of death, myocardial infarction, stroke, venous thromboembolism, thrombosis of vascular access, and tumor progression or recurrence.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration. Do not use the prefilled syringe if:-The prefilled syringe has been dropped or shaken.
-Any part of the prefilled syringe appears cracked or damaged.
-The liquid is foamy, cloudy, hazy, contains particles, or is a color other than colorless to slightly yellow.
-The expiration date has passed.
-Avoid vigorous shaking of the drug.
-Do not mix methoxy polyethylene glycol-epoetin beta with any parenteral solution.
-Remove the prefilled syringe pack from the refrigerator. Keep the prefilled syringe in the pack to protect it from light and allow it to reach room temperature for about 30 minutes. If the prefilled syringe does not reach room temperature, this could cause discomfort with the injection, and it may be difficult to depress the plunger. Do not warm up the prefilled syringe in any other way.
-Open the prefilled syringe pack and remove the plastic tray containing the prefilled syringe without peeling back the protective film.
-Open the plastic tray by peeling back the protective film. Remove the prefilled syringe by holding only the device body; touching the activation guards could cause the needle safety device to be released too early.
-Remove the needle from the plastic tray.
-Grasp the prefilled syringe in the middle of the syringe body with a hand. With the other hand, hold the rubber tip cap firmly, and remove the rubber tip cap from the prefilled syringe. Do not touch the activation guard or push/pull on the plunger.
-Place the prefilled syringe on the work surface. Ensure that the tip of the prefilled syringe does not touch anything. If the tip of the prefilled syringe touches anything, dispose of the prefilled syringe and use a new prefilled syringe and needle for the injection.
-Use a twisting motion to remove the plastic needle cap. Do not remove the needle shield that protects the needle.
-Attach the needle to the prefilled syringe by pushing it firmly straight onto the prefilled syringe and slightly twisting or turning.
-Place the prefilled needle on its side with the needle shield on to prevent the needle from touching anything before use.
-Hold the prefilled syringe firmly with a hand and remove the needle shield with the other hand.
-Do not touch the needle or allow it to touch any surface; do not reattach the needle shield after removal. A small drop of liquid may be visible at the end of the needle.
-Check the prefilled syringe for air bubbles. To remove air bubbles from the prefilled syringe, hold the prefilled syringe by the device body with the needle pointing up. Tap the prefilled syringe body gently to bring the air bubbles to the top.
-Push the plunger up gently and slowly until a drop of liquid appears.
-The tear-off label can be removed to keep a record of the dose administered, if necessary.
-Storage: Store in prefilled syringe pack until time of use. Protect from light. The product is for single-use only and does not contain preservatives. Discard any unused portion; do not pool unused portions from prefilled syringes. Do not reuse the prefilled syringe or needle.
Intravenous Administration
-Clean the venous port of the hemodialysis tubing with an alcohol swab.
-Insert the needle on the prefilled syringe into the cleaned venous port of the hemodialysis tubing. Do not move the needle while it is inserted in the port.
-Push the plunger all the way down until hearing a click indicating the activation of the needle guard. Do not release the plunger before the end of injection or before the plunger is completely pushed down. The plastic needle guard will not move forward to cover the needle unless the full dose is administered.
-Pull back on the prefilled syringe and remove the needle from the venous port without releasing the plunger.
-Release the plunger after removing the needle from the port. This will allow the prefilled syringe to move back until the entire needle is covered with the needle guard.
Subcutaneous Administration
-Choose a subcutaneous injection site on the outer aspect of the upper arms, abdomen (except for 2 inches around the navel), or front aspect of the middle thighs. Do not inject into moles or into an area of the body that is tender, red, bruised, or hard, that has scars or stretch marks, or is not intact. Also do not inject into areas that could be irritated by a belt or waistband.
-Rotate injection sites with each injection (at least 1-inch from the area used for the previous injection) to prevent soreness.
-Clean the injection site with an alcohol swab and allow the skin to dry for about 10 seconds.
-Pinch a fold of loose skin at the injection site and insert the needle into the skin at a 90-degree angle. Do not move the needle while it is inserted in the skin.
-Push the plunger rod all the way down slowly until hearing a click indicating the activation of the needle guard. Do not release the plunger before the end of injection or before the plunger is completely pushed down. The plastic needle guard will not move forward to cover the needle unless the full dose is administered.
-Release the plunger after removing the needle from the skin. This will allow the prefilled syringe to move back until the entire needle is covered with the needle guard.
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), erythropoiesis-stimulating agents (ESAs) increased the risk of death, myocardial infarction, stroke, congestive heart failure, thromboembolism, and thrombosis of vascular access in the higher target groups. Using MPG-epoetin beta to target a hemoglobin concentration more than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Vascular access thrombosis (5%, adults; 6%, pediatrics) and arteriovenous fistula site complication (5%, adults) were reported with MPG-epoetin beta during clinical trials.
As with all therapeutic proteins, there is a potential for immunogenicity with MPG-epoetin beta. The presence of neutralizing antibodies (i.e., anti-erythropoietin antibodies) has been associated with the development of pure red cell aplasia (PRCA) or severe anemia (with or without other cytopenias) in patients receiving recombinant erythropoietin products. PRCA cases have been reported predominantly in patients with chronic kidney disease (CKD) receiving erythropoiesis-stimulating agents (ESAs) by subcutaneous administration. If severe anemia and low reticulocyte count develop during treatment, withhold MPG-epoetin beta and evaluate patients for neutralizing antibodies to erythropoietin. Further, evaluate any patient experiencing a lack or a loss of response to MPG-epoetin beta to determine the etiology of the lack or loss of effect. If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA. Permanently discontinue MPG-epoetin beta in patients who develop PRCA after treatment with any erythropoietin protein drug. Do not switch patients to other ESAs. Contact the manufacturer (1-800-576-8295) to perform assays for binding and neutralizing antibodies. Neutralizing antibodies to erythropoietin were not detected in patients receiving MPG-epoetin beta in clinical trials. However, the incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay and comparisons should not be drawn between the incidence of neutralizing antibodies observed with MPG-epoetin beta and other ESAs.
Hypertension was reported in 13% of adult patients and 19% of pediatric patients in clinical trials. In studies of adult patients with renal failure, intensification of antihypertensive therapy was required in approximately 27% of patients. Cases of hypertensive encephalopathy have also been reported. Reduce or withhold MPG-epoetin beta alfa if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions. In adult patients, hypotension (5%), procedural hypotension (8%), and fluid overload or edema (7%) have also been reported during therapy with MPG-epoetin beta.
Thrombocytopenia was reported in 6% of pediatric patients receiving MPG-epoetin beta in an open-label trial (n = 64).
Serious allergic reactions, including anaphylactoid reactions, angioedema, bronchospasm, sinus tachycardia, skin rash, pruritus, and urticaria, have been reported with the use of MPG-epoetin beta. Erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported during postmarketing use of MPG-epoetin beta therapy. If a serious allergic or skin reaction occurs, immediately and permanently discontinue MPG-epoetin beta and administer appropriate therapy.
Diarrhea (11%), vomiting (6%), and constipation (5%) were reported with MPG-epoetin beta during adult clinical trials. Vomiting (11%) and abdominal pain (8%) were reported in pediatric patients receiving MPG-epoetin beta in an open-label trial (n = 64).
MPG-epoetin beta increases the risk of seizures in patients with chronic kidney disease, and seizures have been observed during therapy. During the first several months after MPG-epoetin beta initiation, closely monitor patients for premonitory neurologic symptoms. Advise patients to contact their health care practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency.
Headache (9%), muscle spasms or muscle cramps (8%), back pain (6%), and musculoskeletal pain (extremity pain, 5%) were reported with MPG-epoetin beta during adult clinical trials. Headache was reported in 22% of pediatric patients receiving MPG-epoetin beta in an open-label trial (n = 64).
Naso-pharyngitis (11%), upper respiratory tract infection (9%), urinary tract infection (5%), and cough (6%) were reported with MPG-epoetin beta during adult clinical trials. Naso-pharyngitis (22%), bronchitis (9%), cough (6%), device-related infection (6%), pharyngitis (6%), and fever (6%) were reported in pediatric patients receiving MPG-epoetin beta in an open-label trial (n = 64).
Hyperkalemia was reported in 6% of pediatric patients receiving MPG-epoetin beta in an open-label trial (n = 64).
MPG-epoetin beta is contraindicated in patients with pure red cell aplasia (PRCA) that begins after treatment with an erythropoietin protein drug. Cases of pure red cell aplasia (PRCA) and severe anemia, with or without other cytopenias associated with neutralizing antibodies to erythropoietin, have been reported in patients treated with MPG-epoetin beta. This has been reported predominantly in patients with chronic kidney failure receiving an erythropoiesis-stimulating agent (ESA) by subcutaneous administration. Intravenous administration of MPG-epoetin beta may decrease the chance of anti-erythropoietin antibody formation. If severe anemia and low reticulocyte count develop during treatment with MPG-epoetin beta, withhold MPG-epoetin beta and evaluate patients for neutralizing antibodies to erythropoietin. Obtain serum samples at least 1 month after the last MPG-epoetin beta dose to prevent interference of MPG-epoetin beta with the assay. Contact the manufacturer (1-800-576-8295) to perform assays for binding and neutralizing antibodies. Permanently discontinue MPG-epoetin beta in patients who develop PRCA following treatment with MPG-epoetin beta or other erythropoietin protein drugs. Do not switch patients to other ESAs as antibodies may cross-react.
In controlled clinical trials of adult patients with chronic kidney disease (CKD) comparing higher hemoglobin targets (13 to 14 g/dL) to lower targets (9 to 11.3 g/dL), erythropoiesis-stimulating agents (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 concentration greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. No trial has identified a hemoglobin target concentration, ESA dose, or dosing strategy that does not increase these risks. Use the lowest dose of MPG-epoetin beta sufficient to reduce the need for red blood cell transfusions. For adult patients with chronic kidney disease either on or off dialysis, a hemoglobin less than 10 g/dL is advised before MPG-epoetin beta initiation. Use caution in patients with coexistent cardiac disease, stroke, and cardiovascular disease. 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. Additionally, a rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may also contribute to these risks; decrease the dose of MPG-epoetin beta to reduce rapid responses.
In controlled clinical trials in adult patients, erythropoiesis-stimulating agents (ESAs) increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of thromboembolism (deep venous thrombosis [DVT]) in patients undergoing orthopedic procedures. MPG-epoetin is not approved for reduction of red blood cell (RBC) transfusions in patients scheduled for surgery or surgical procedures.
During hemodialysis, patients treated with MPG-epoetin beta may require increased anticoagulant therapy with heparin to prevent clotting of the dialysis machine. Administration of MPG-epoetin beta by the IV route is recommended for patients receiving hemodialysis, as the IV route may be less immunogenic than the subcutaneous route.
MPG-epoetin beta should not be used to treat patients with neoplastic disease or chemotherapy-induced anemia. A dose-ranging study of MPG-epoetin beta in patients undergoing chemotherapy for non-small cell lung cancer was terminated early due to significantly more deaths in the patients receiving MPG-epoetin beta compared to another ESA. Further information on the nature of these deaths is currently unavailable. In clinical trials with similar ESAs, but not specifically MPG-epoetin beta, patients with certain types of neoplastic disease (i.e., breast, head and neck, non-small cell lung, cervical, and lymphoid malignancies) experienced an increased incidence of thrombotic events, tumor progression, and/or death when receiving ESAs. These events occurred predominantly in patients treated to a target hemoglobin concentration more than 12 g/dL. However, the potential risk for tumor progression and increased mortality in patients treated to target hemoglobin concentrations less than 12 g/dL cannot be excluded.
MPG-epoetin beta is contraindicated for use in patients with uncontrolled hypertension; control hypertension before and during MPG-epoetin beta therapy in all patients. Reduce or withhold MPG-epoetin beta if blood pressure becomes difficult to control. Advise patients about the importance of compliance with antihypertensive therapy and dietary restrictions. During clinical studies of MPG-epoetin beta therapy in patients with chronic kidney disease on and off dialysis, approximately 27% of patients required initiation of or intensification of antihypertensive therapy.
Virtually all patients receiving MPG-epoetin beta therapy will require iron supplementation to achieve and maintain optimal erythropoietic response. Patients with iron-deficiency anemia should be treated with appropriate iron supplementation to correct the deficiency prior to initiation of MPG-epoetin beta. Concurrent iron-deficiency may develop in patients receiving treatment with MPG-epoetin beta, as iron stores are utilized in the production of red blood cells. Supplemental iron therapy should be given to patients with serum ferritin less than 100 mcg/L or serum transferrin saturation less than 20%. MPG-epoetin beta is not indicated in patients with iron-deficiency anemia or anemias due to acute or chronic blood loss. It is also not indicated for the immediate correction of severe anemia; MPG-epoetin beta therapy should not replace the need for an RBC transfusion in patients with emergent needs.
Conditions that may interfere with response to MPG-epoetin beta include infection, inflammation, malignancy, malnutrition, hypothyroidism, bleeding, hyperparathyroidism, vitamin B12 deficiency, folate deficiency, hematological disease (e.g., hemolytic anemia, sickle cell disease, thalassemia, refractory anemia), and bone marrow disorders, such as myelodysplastic syndrome (MDS). Evaluate for the cause of a lack of a hemoglobin response or failure to maintain a hemoglobin response with MPG-epoetin beta. If possible, correct the etiology such as vitamin B12 or folate deficiency. In the absence of another etiology, evaluate the patient for evidence of pure red cell aplasia (PRCA), including tests for the presence of antibodies to erythropoietin. In patients in whom all correctable causes have been maximally treated but who remain hyporesponsive, ESA therapy may be continued cautiously at doses up to 4 times the initial dose to prevent a further decline in hemoglobin concentration. Red blood cell transfusions can be used to prevent or treat anemia-related symptoms and signs.
In patients with chronic kidney disease, MPG-epoetin beta increases the risk of seizures. During the first several months after MPG-epoetin beta initiation, closely monitor patients for premonitory neurologic symptoms. Advise patients to contact their health care provider for new-onset seizures or premonitory symptoms, or in patients with history of seizure disorder, a change in seizure frequency.
MPG-epoetin beta should be used during pregnancy only when the benefits of treatment outweighs any risk to the fetus. Available data from a small number of published case reports and postmarketing experience is 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. Animal studies have shown bone malformation and reduced fetal weights at doses 17-fold or more of the recommended human dose.
There are no data on the presence of MPG-epoetin beta in human milk, the effects on the breastfed child, or the effects on milk production. Endogenous erythropoietin is present in human milk. Although MPG-epoetin beta is similar to an endogenous hormone already present in breast milk, the unknown risk of administering MPG-epoetin beta to a breast-feeding woman should be weighed against the known benefit of continued breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities (LTCFs). According to the OBRA guidelines, assessment of causes and categories of anemia should precede or accompany use of an erythropoiesis stimulant such as methoxy polyethylene glycol-epoetin beta. Use must be monitored according to individual manufacturer instructions, including blood pressure, baseline serum iron or ferritin levels, and frequent complete blood count (CBC) to permit tapering or discontinuation when hemoglobin/hematocrit reaches or exceeds target ranges. Erythropoiesis stimulants may cause or worsen hypertension, and excess doses or duration can lead to polycythemia or serious thrombotic events (e.g., myocardial infarction, stroke).
General Dosing Information
-Evaluate the iron status before and during treatment. Administer supplemental iron when the serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%.
-Correct or exclude other causes of anemia such as vitamin deficiency, metabolic or chronic inflammatory conditions, and bleeding before initiating methoxy polyethylene glycol-epoetin beta (MPG-epoetin beta).
-Monitor hemoglobin (Hgb) weekly until stable and sufficient to minimize the need for red blood cell (RBC) transfusions.
-MPG-epoetin beta has not been shown to improve symptoms, physical functioning, or health-related quality of life.
-MPG-epoetin beta is not indicated and is not recommended:-In the treatment of anemia due to cancer chemotherapy
-As a substitute for RBC transfusions in patients who require immediate correction of anemia
-In adults with chronic kidney disease on dialysis, initiate when the Hgb concentration is less than 10 g/dL.
-In adults with chronic kidney disease not on dialysis, initiate when the Hgb is less than 10 g/dL, the rate of Hgb decline indicates the likelihood of requiring an RBC transfusion, and reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal.
-For children with chronic kidney disease, base the Hgb concentration at which to initiate therapy on individual consideration of potential benefits (e.g., improvement in quality of life, school attendance/performance, and avoidance of transfusion) and potential harms.
-In pediatric populations, a target Hgb concentration of 11 to 12 g/dL is recommended.
For the treatment of anemia associated with chronic kidney disease:
-for dialysis-independent adults not receiving another erythropoietin-stimulating agent:
Subcutaneous dosage:
Adults: 1.2 mcg/kg/dose subcutaneously every 4 weeks or 0.6 mcg/kg/dose subcutaneously every 2 weeks. Monitor hemoglobin weekly until stable and then at least monthly (after initiation of therapy and each dose adjustment) and adjust dose based on hemoglobin. Do not increase the dose more frequently than every 4 weeks; decreases in dose can occur more frequently. Decrease or interrupt the dose if hemoglobin exceeds 10 g/dL. Use the lowest dose possible that will maintain a hemoglobin concentration sufficient to reduce the need for red blood cell transfusion. If response is not seen over a 12-week escalation period, increasing the dose further is unlikely to improve response and may increase risks; evaluate other causes of anemia and discontinue if responsiveness does not improve.
Intravenous dosage:
Adults: 0.6 mcg/kg/dose IV every 2 weeks. Monitor hemoglobin weekly until stable and then at least monthly (after initiation of therapy and each dose adjustment) and adjust dose based on hemoglobin. Do not increase the dose more frequently than every 4 weeks; decreases in dose can occur more frequently. Decrease or interrupt the dose if hemoglobin exceeds 10 g/dL. Use the lowest dose possible that will maintain a hemoglobin concentration sufficient to reduce the need for red blood cell transfusion. If response is not seen over a 12-week escalation period, increasing the dose further is unlikely to improve response and may increase risks; evaluate other causes of anemia and discontinue if responsiveness does not improve.
-for dialysis-dependent adults not receiving another erythropoietin-stimulating agent:
Intravenous or Subcutaneous dosage:
Adults: 0.6 mcg/kg/dose IV or subcutaneously every 2 weeks. Monitor hemoglobin weekly until stable and then at least monthly (after initiation of therapy and each dose adjustment) and adjust dose based on hemoglobin. Do not increase the dose more frequently than every 4 weeks; decreases in dose can occur more frequently. Decrease or interrupt the dose if hemoglobin approaches or exceeds 11 g/dL. Use the lowest dose possible that will maintain a hemoglobin concentration sufficient to reduce the need for red blood cell transfusion. If response is not seen over a 12-week escalation period, increasing the dose further is unlikely to improve response and may increase risks; evaluate other causes of anemia and discontinue if responsiveness does not improve.
-for adults currently receiving less than 40 mcg/week of darbepoetin alfa or less than 8,000 units/week of epoetin alfa:
Intravenous or Subcutaneous dosage:
Adults: 60 mcg IV or subcutaneously every 2 weeks or 120 mcg IV or subcutaneously every 4 weeks. Monitor hemoglobin weekly until stable and then at least monthly (after initiation of therapy and each dose adjustment) and adjust dose based on hemoglobin. Do not increase the dose more frequently than every 4 weeks; decreases in dose can occur more frequently. Decrease or interrupt the dose if hemoglobin exceed 10 g/dL for dialysis-independent adults or approaches or exceeds 11 g/dL for dialysis-dependent adults. Use the lowest dose possible that will maintain a hemoglobin concentration sufficient to reduce the need for red blood cell transfusion. If response is not seen over a 12-week escalation period, increasing the dose further is unlikely to improve response and may increase risks; evaluate other causes of anemia and discontinue if responsiveness does not improve.
-for adults currently receiving 40 to 80 mcg/week darbepoetin alfa or 8,000 to 16,000 units/week epoetin alfa:
Intravenous or Subcutaneous dosage:
Adults: 100 mcg IV or subcutaneously every 2 weeks or 200 mcg IV or subcutaneously every 4 weeks. Monitor hemoglobin weekly until stable and then at least monthly (after initiation of therapy and each dose adjustment) and adjust dose based on hemoglobin. Do not increase the dose more frequently than every 4 weeks; decreases in dose can occur more frequently. Decrease or interrupt the dose if hemoglobin exceed 10 g/dL for dialysis-independent adults or approaches or exceeds 11 g/dL for dialysis-dependent adults. Use the lowest dose possible that will maintain a hemoglobin concentration sufficient to reduce the need for red blood cell transfusion. If response is not seen over a 12-week escalation period, increasing the dose further is unlikely to improve response and may increase risks; evaluate other causes of anemia and discontinue if responsiveness does not improve.
-for adults currently receiving more than 80 mcg/week darbepoetin alfa or more than 16,000 units/week epoetin alfa:
Intravenous or Subcutaneous dosage:
Adults: 180 mcg IV or subcutaneously every 2 weeks or 360 mcg IV or subcutaneously every 4 weeks. Monitor hemoglobin weekly until stable and then at least monthly (after initiation of therapy and each dose adjustment) and adjust dose based on hemoglobin. Do not increase the dose more frequently than every 4 weeks; decreases in dose can occur more frequently. Decrease or interrupt the dose if hemoglobin exceed 10 g/dL for dialysis-independent adults or approaches or exceeds 11 g/dL for dialysis-dependent adults. Use the lowest dose possible that will maintain a hemoglobin concentration sufficient to reduce the need for red blood cell transfusion. If response is not seen over a 12-week escalation period, increasing the dose further is unlikely to improve response and may increase risks; evaluate other causes of anemia and discontinue if responsiveness does not improve.
-for dialysis-dependent pediatric patients whose hemoglobin is currently stabilized with epoetin alfa:
Intravenous dosage:
Children and Adolescents 5 to 17 years: 4 times the previous weekly epoetin alfa dose (units) divided by 125 administered IV every 4 weeks. Monitor hemoglobin weekly until stable and then at least monthly (after initiation of therapy and each dose adjustment) and adjust dose based on hemoglobin. Do not increase the dose more frequently than every 4 weeks; decreases in dose can occur more frequently. Use the lowest dose possible that will maintain a hemoglobin concentration sufficient to reduce the need for red blood cell transfusion. If response is not seen over a 12-week escalation period, increasing the dose further is unlikely to improve response and may increase risks; evaluate other causes of anemia and discontinue if responsiveness does not improve.
-for dialysis-dependent pediatric patients whose hemoglobin is currently stabilized with darbepoetin alfa:
Intravenous dosage:
Children and Adolescents 5 to 17 years: 4 times the previous weekly darbepoetin alfa dose (mcg) divided by 0.55 administered IV every 4 weeks. Monitor hemoglobin weekly until stable and then at least monthly (after initiation of therapy and each dose adjustment) and adjust dose based on hemoglobin. Do not increase the dose more frequently than every 4 weeks; decreases in dose can occur more frequently. Use the lowest dose possible that will maintain a hemoglobin concentration sufficient to reduce the need for red blood cell transfusion. If response is not seen over a 12-week escalation period, increasing the dose further is unlikely to improve response and may increase risks; evaluate other causes of anemia and discontinue if responsiveness does not improve.
Therapeutic Drug Monitoring:
Dosage Adjustment Based on Hemoglobin
-Monitor hemoglobin (Hgb) at least weekly until stable and then at least monthly (after initiation of therapy and each dose adjustment) and adjust dose based on Hgb (rate of Hgb rise and decline as well as erythropoietin-stimulating agent responsiveness and Hgb variability).
-Do not increase the dose more frequently than once every 4 weeks; decreases in dose can occur more frequently. Avoid frequent dose adjustments. A single Hgb excursion may not require a dosing change.
-Decrease or interrupt the dose if Hgb exceeds 10 g/dL for dialysis-independent adults, approaches or exceeds 11 g/dL for dialysis-dependent adults, or exceeds 12 g/dL for pediatric populations.
-If the Hgb rises rapidly (e.g., more than 1 g/dL in a 2-week period), decrease the dose by 25% or more.
-If the Hgb has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%.
-Once the Hgb is stabilized, methoxy polyethylene glycol-epoetin beta may be given once monthly using a dose that is twice that of the every-2-week dose and subsequently titrated as necessary.
-Use the lowest dose possible that will maintain a Hgb concentration sufficient to reduce the need for red blood cell transfusion.
-If response is not seen over a 12-week escalation period, increasing the dose further is unlikely to improve response and may increase risks; evaluate other causes of anemia and discontinue if responsiveness does not improve.
Maximum Dosage Limits:
-Adults
Varies depending on individual response and frequency of administration.
-Geriatric
Varies depending on individual response and frequency of administration.
-Adolescents
Varies depending on individual response.
-Children
5 to 12 years: Varies depending on individual response.
1 to 4 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
No dosage adjustments are needed.
*non-FDA-approved indication
Lenalidomide: (Moderate) Monitor for signs and symptoms of thromboembolic events if concomitant use of lenalidomide and an erythropoiesis-stimulating agent (ESA) is required. Both medications have been associated with venous thromboembolism and concomitant use may increase the risk of thrombosis.
Thalidomide: (Moderate) Monitor for signs and symptoms of thromboembolic events if concomitant use of thalidomide and an erythropoiesis-stimulating agent (ESA) is required. Both medications have been associated with venous thromboembolism and concomitant use may increase the risk of thrombosis.
Methoxy polyethylene glycol-epoetin beta (MPG-epoetin beta) is a synthetic, continuous erythropoietin-receptor activator. Endogenous erythropoietin is a primary growth factor in the generation of red blood cells. Erythropoietin is produced primarily in the kidneys and responds to hypoxic conditions to stimulate erythroid progenitor cells to increase red blood cell production. Synthesis of endogenous erythropoietin is frequently impaired in patients with renal failure. MPG-epoetin beta contains a methoxy polyethylene-glycol polymer attached to recombinant human erythropoietin at either the N-terminal amino or the epsilon-amino group of any lysine. As a result of this structural modification, MPG-epoetin beta remains in the circulation much longer than endogenous erythropoietin (approximately 134 hours vs. 7 to 8 hours). It also binds the erythropoietin-receptor much slower and dissociates at a much faster rate, which helps prevent internalization and degradation of the molecule, thus keeping it biologically active. Prolonged biologic activity allows for dosing intervals of every 2 to 4 weeks.
Methoxy polyethylene glycol-epoetin beta (MPG-epoetin beta) can be administered either intravenously or subcutaneously. Vd at steady state is 61 mL/kg. Clinically significant differences have not been observed between different routes of administration nor sites of administration (i.e., thigh, arm, or abdomen for subcutaneous administration). Metabolism and elimination of both endogenous and exogenous erythropoietin proteins are poorly understood. Steady-state concentrations increased by 12% after repeat dosing every 2 weeks as compared to repeat dosing every 4 weeks, where no accumulation is observed. Multiple dosing has no effect on Vd, clearance, or bioavailability of MPG-epoetin beta.
Onset of hemoglobin increase, defined as an increase of more than 0.4 g/dL, was noted 7 to 15 days after initial dose administration.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Intravenous Route
Observed terminal half-life after IV administration is 119 hours and total systemic clearance is 0.47 mL/kg/hour.
Subcutaneous Route
Maximum serum concentrations of MPG-epoetin beta occur at a median time of 72 hours (range: 24 to 192 hours). Absolute bioavailability is 62% and terminal half-life is 124 hours.
-Special Populations
Hepatic Impairment
The pharmacokinetics of MPG-epoetin beta were not affected by severe hepatic impairment (Child-Pugh Class C).
Renal Impairment
The pharmacokinetics of MPG-epoetin beta were not affected by the use of dialysis.
Pediatrics
The pharmacokinetics of MPG-epoetin beta were not affected by age. During pediatric clinical trials (n = 64; 5 to 17 years), steady state Cmax was 66 ng/mL and AUC was 7,170 ng x hour/mL in patients receiving the recommended conversion factor of MPG-epoetin beta. Serum concentrations declined with an apparent half-life of 121 hours and a total systemic clearance of 0.51 mL/kg/hour.
Geriatric
The pharmacokinetics of MPG-epoetin beta were not affected by age (up to 89 years).
Gender Differences
The pharmacokinetics of MPG-epoetin beta were not affected by gender.
Ethnic Differences
The pharmacokinetics of MPG-epoetin beta were not affected by race.