SIZE XSSIZE SMSIZE MDSIZE LG

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.

June 7, 2018

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125164s078lbl.pdf

On June 7, 2018, the Food and Drug Administration approved methoxy polyethylene glycol-epoetin beta (Mircera®, Vifor Pharma Inc.) for the treatment of 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.

Approval was based on data from an open-label, multiple dose, multicenter, dose-finding trial (NCT00717366) in 64 pediatric patients (ages 5 to 17 years) with CKD on hemodialysis and had stable hemoglobin (Hb) levels while previously receiving another ESA (epoetin alfa/beta or darbepoetin alfa). Patients were administered Mircera intravenously once every 4 weeks for 20 weeks. After the first administration of Mircera, dosage adjustments were permitted to maintain target Hb levels.

Efficacy was based on maintaining Hb levels within target levels in the above clinical trial, and also from extrapolation from trials of Mircera in adult patients with CKD. The safety findings observed in pediatric patients were consistent with those previously reported in adults.

For conversion from another ESA, Mircera is dosed intravenously once every 4 weeks based on total weekly epoetin alfa or darbepoetin alfa dose at time of conversion. Full prescribing information is available at Mircer PI.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Application to Practice

Methoxy Polyethylene Glycol-Epoetin Beta for Treatment of Anemia Associated with Chronic Kidney Disease in Pediatric Patients on Dialysis

Author: Ellen Burke, PharmD BCOP
Pediatric Clinical Pharmacist—Oncology and Stem Cell Transplant
Children’s Hospital Colorado
Aurora, CO

What is the potential role of methoxy polyethylene glycol-epoetin beta in the treatment of anemia associated with chronic kidney disease?1-5

  • Methoxy polyethylene glycol-epoetin beta is an erythropoiesis-stimulating agent (ESA) originally approved by the U.S. Food and Drug Administration (FDA) for the treatment of anemia associated with chronic kidney disease (CDK) in adults either on or not on dialysis. The FDA recently expanded approval for treatment of pediatric patients 5–17 years old who are currently on hemodialysis and are stable on another ESA.
  • Methoxy polyethylene glycol-epoetin beta is different from natural erythropoietin because of the formation of a chemical bond between either the N-terminal amino group or the ϵ-amino group of any lysine and the addition of polyethylene glycol (PEG) butanoic acid. Methoxy polyethylene glycol-epoetin displays greater activity in the body and also has a longer half-life than erythropoietin. The total molecular weight is approximately 60,000 daltons. For comparison, the molecular weight of darbepoetin is ~37,000 daltons.
  • The current treatment of anemia of CKD in pediatric patients on hemodialysis is with either epoetin alfa or darbepoetin. Recommended starting doses of epoetin alfa are 50 units/kg three times/week and darbepoetin 0.45 mcg/kg weekly.
  • Methoxy polyethylene glycol-epoetin was studied in an open-label multicenter trial among 64 pediatric patients (ages 6–17 years) on hemodialysis for CKD. Patients received methoxy polyethylene glycol-epoetin beta every 4 weeks, with the dose based on recommended conversion factors from the previous ESA (epoetin alfa or darbepoetin).
  • This trial demonstrated safety, long-term efficacy, and a suitable conversion factor for initiation of methoxy polyethylene glycol-epoetin beta in pediatric hemodialysis patients already on a stable alternative ESA product. Sixty-four patients were evaluated over a 16-week dose-titration period followed by a 4-week dose-stabilization period. If patients had stable hemoglobin at the end of the 20-week period, they could continue into a 1-year optional safety extension study. Eighty-one percent of patients maintained their hemoglobin between 10 and 12 g/dL, and 75% of patients maintained hemoglobin values within ±1 g/dL of baseline after 20 weeks. The mean change in hemoglobin using the recommended conversion factor was -0.09 g/dL (95% confidence interval, -0.45 to 0.26). Thirty-seven patients continued into the 1-year safety extension. Safety was similar between adult and pediatric patients on methoxy polyethylene glycol-epoetin beta, and 70% of patients maintained their hemoglobin between 10–12 g/dL at the last observation. Pharmacokinetics were similar in pediatric patients compared to adults, with a mean half-life of 121 hours in pediatric patients.

What role can pharmacists play in the management of patients on methoxy polyethylene glycol-epoetin beta?1

  • Methoxy polyethylene glycol-epoetin is not approved for anemia treatment in patients undergoing chemotherapy for cancer or as a substitute for red blood cell transfusions in patients who need fast correction of anemia.
  • Contraindications for use include uncontrolled hypertension, pure red cell aplasia (PRCA), and serious allergic reactions to methoxy polyethylene glycol-epoetin beta.
  • Most common adverse effects in clinical trials (occurring in 10% of patients or more) were hypertension, diarrhea, and nasopharyngitis.
  • Methoxy polyethylene glycol-epoetin beta should be administered intravenously every 4 weeks based on the conversion from the pediatric patient’s previous stable ESA dose. The final dose will be in mcg of methoxy polyethylene glycol-epoetin.
    • Epoetin alfa: 4 × previous weekly epoetin alfa unit dose/125
      • Example: 4 × 1,500 units/125 = 48 mcg methoxy polyethylene glycol-epoetin every 4 weeks.
    • Darbepoetin: 4 × previous weekly darbepoetin mcg dose/0.55
      • Example: 4 × 20 mcg/0.55 = 145.5 mcg methoxy polyethylene glycol-epoetin every 4 weeks
  • Methoxy polyethylene glycol-epoetin beta should be administered via the intravenous route for patients on hemodialysis because of the lower risk of immunogenicity with that route.
  • Monitor patients on methoxy polyethylene glycol-epoetin beta for hypertension, new-onset seizures, and severe anemia or low reticulocyte counts during treatment. Patients should be reminded to stay compliant with antihypertensives if they are already taking them and should have their blood pressure checked frequently. Twenty-seven percent of adult patients who received methoxy polyethylene glycol-epoetin needed intensification of their antihypertensives while on therapy. Patients should report any new-onset seizures, premonitory symptoms, or change in seizure activity. Patients who develop severe anemia and low reticulocyte counts during treatment should have methoxy polyethylene glycol-epoetin discontinued, and the patient should be evaluated for PRCA.
  • Serum samples used to evaluate for PRCA must be obtained at least 1 month after the last methoxy polyethylene glycol-epoetin dose to prevent interference with the assay. Samples can be sent to Roche for evaluation of neutralizing antibodies. Patients diagnosed with PRCA from methoxy polyethylene glycol-epoetin should not be started on another ESA because of possible cross-reactions.
  • Iron status should be evaluated prior to initiation of and during treatment with methoxy polyethylene glycol-epoetin beta. If serum ferritin is less than 100 mcg/L or serum transferrin is less than 20%, iron supplementation should be initiated. Most patients did require iron supplementation.
  • No significant drug interactions with methoxy polyethylene glycol-epoetin beta were identified, and pharmacokinetics were not significantly altered by hemodialysis.

Clinical Pearls1

  • Methoxy polyethylene glycol-epoetin beta is supplied as a prefilled single-use syringe. Each syringe is 0.3 mL, and syringes are identified by different-colored packages to indicate dose strengths of 30 mcg, 50 mcg, 75 mcg, 100 mcg, 120 mcg, 150 mcg, 200 mcg, and 250 mcg. A 360-mcg syringe is also available in 0.6 mL.
  • Syringes should be stored refrigerated (2°C–8°C) and should not be used past the indicated expiration date. The syringe may be stored up to 30 days at room temperature (25°C). After 30 days at room temperature the syringe should be discarded if it has not been used.
  • Each syringe is for a single use and should be discarded after the dose has been given. Partial syringes should not be reused.
  • All patients should have their hemoglobin (Hgb) monitored weekly until it is stable. Once it is stable, Hgb can be monitored monthly.
  • Dose adjustments are as follows:
    • If Hgb increases by more than 1g/dL in 2 weeks, decrease the dose by a minimum of 25%.
    • If Hgb does not increase by more than 1g/dL after 4 weeks of treatment, increase the dose by 25%.
    • If no response is seen after at least 12 weeks of treatment, evaluate for continued cause of anemia and consider discontinuation of treatment if it is deemed ineffective.
    • Dose increases should not be made more frequently than once per month.
    • Dose decreases can be made more frequently than once per month.
  • If hypertension is difficult to control, the dose should be withheld or reduced until hypertension is controlled.
  • If the pediatric dose does not match a prefilled syringe size, it is suggested that the exact mL amount needed be calculated and transferred to a new syringe for intravenous administration.

References

  1. Mircera (methoxy polyethylene glycol-epoetin beta) [prescribing information]. South San Francisco, CA: Hoffmann-La Roche Inc.; June 2018.
  2. FDA approves treatment of Mircera for use in pediatric patients. FDAnews Daily Drug Bulletin. Available at https://www.fdanews.com/articles/187200-fda-approves-mircera-for-use-in-pediatric-patients. Accessed September 28, 2018.
  3. Epogen (epoetin alfa) [prescribing information]. Thousand oaks, CA: Amgen Inc.; July 2018.
  4. Aranesp (darbepoetin alfa) [prescribing information]. Thousand Oaks, CA: Amgen Inc.; January 2018.
  5. Fischbach M, Wühl E, Reigner SCM, et al. Efficacy and long-term safety of C.E.R.A maintenance in pediatric hemodialysis patients with anemia of CKD. Clin J Am Soc Nephrol. 2018;13:81-90.
xs
sm
md
lg