Mircera (Methoxy polyethylene glycol-epoetin beta) is a third-generation pegylated epoetin. It is categorized under a novel category called "CERA" (continuous erythropoietin receptor activator) and is used in patients with anemia associated with chronic kidney disease.

Mircera (Methoxy polyethylene glycol-epoetin beta) Uses:

• Anemia:

  • Used in the treatment of anemia associated with chronic kidney disease (CKD) in adult patients on dialysis, adult patients not on dialysis, and in pediatric patients 5 to 17 years of age on hemodialysis who are converting from another erythropoiesis-stimulating agent (ESA) after their hemoglobin level was stabilized with an ESA.
  • Limitations of use: Not indicated and is not necessary for the treatment of anemia due to cancer chemotherapy or as a substitute for 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.

Methoxy polyethylene glycol-epoetin beta Dose in Adults:

Note:

• Evaluate iron status before and during treatment; consider supplemental iron therapy if serum ferritin is less than 100 ng per mL or when transferrin saturation (TSAT) is less than 20 percent  (most patients will require iron supplementation during the course of erythropoiesis-stimulating agent [ESA] therapy).

Mircera (Methoxy polyethylene glycol-epoetin beta) Dose in the treatment of Anemia associated with chronic kidney disease (CKD):

Individualize dosing and use the lowest dose required 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 per kg once every 2 weeks.
    • Reduce dose or interrupt treatment if hemoglobin approaches or exceeds 11 g per dL.
    • After hemoglobin stabilizes, may administer once monthly with a dose that is double the dose administered every 2 weeks; titrate as required.
  • 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 per kg once every 2 weeks.
    • Reduce dose or interrupt treatment if hemoglobin exceeds 10 g per dL.
    • After hemoglobin stabilizes, may consider once monthly with a dose that is double the dose consider every 2 weeks; titrate as required.

• 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 less than 8,000 units per week or darbepoetin alfa dose less than 40 mcg per week:
      • consider 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 per week or darbepoetin alfa dose 40 to 80 mcg per week:
      • Consider methoxy polyethylene glycol-epoetin beta 200 mcg once monthly or 100 mcg every 2 weeks.
    • For epoetin alfa dose more than 16,000 units per week or darbepoetin alfa dose more than 80 mcg per week:
      • Administer methoxy polyethylene glycol epoetin beta 360 mcg once monthly or 180 mcg every 2 weeks.

• Mircera (Methoxy polyethylene glycol-epoetin beta) Dosage adjustments for all CKD patients:

  • Do not increase the dose more frequently than every 4 weeks (dose decreases may occur more often); Restrict frequent dosage adjustments.
  • If hemoglobin increases more than 1 g per dL in any 2-week period: Decrease dose by ≥25 percent as required to reduce rapid responses.
  • If hemoglobin does not increase by more than 1 g per dL after 4 weeks of therapy: Increase dose by 25 percent.
  • 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 the patient for other causes of anemia.
    • Discontinue treatment if responsiveness does not improve.

Methoxy polyethylene glycol-epoetin beta Dose in Childrens:

Note:

• Evaluate iron status before and during treatment;
• administer supplemental iron therapy if serum ferritin is <100 ng/mL or when transferrin saturation (TSAT) is <20% (most patients will require iron supplementation during the course of erythropoiesis-stimulating agent [ESA] therapy).
• Individualize dosing and use the lowest dose necessary to reduce the need for red blood cell transfusions.

Mircera (Methoxy polyethylene glycol-epoetin beta) Dose in Anemia associated with chronic kidney disease (CKD) on hemodialysis;

conversion from either epoetin alfa or darbepoetin alfa:

Note: Patients should already have hemoglobin stabilized on either current epoetin or darbepoetin therapy.

• Children ≥5 years and Adolescents ≤17 years:

  • IV: Methoxy polyethylene glycol-epoetin beta dose should be calculated on the following product-specific equations and administered IV every 4 weeks;
  • begin therapy when the next scheduled ESA dose would be due; discontinue other ESA agents.
  • Conversion from epoetin alfa:
    • Dose (mcg) = [4 x weekly epoetin alfa dose (units)]/125
    • For example, in a patient receiving epoetin alfa 1,500 units weekly: Methoxy PEGepoetin beta dose (mcg) = [4 x 1,500 units epoetin alfa]/125 = 48 mcg every 4 weeks
  • Conversion from darbepoetin alfa:
    • Dose (mcg) = [4 x weekly darbepoetin alfa dose (mcg)]/0.55
    • For example, in a patient receiving darbepoetin 20 mcg weekly: Methoxy PEGepoetin beta dose (mcg) = [4 x 20 mcg darbepoetin alfa]/0.55 = 145.5 mcg every 4 weeks

Mircera (Methoxy polyethylene glycol-epoetin beta) Dosage adjustments:

• Children ≥5 years and Adolescents ≤17 years: IV:

  • Do not increase the 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 the patient for other causes of anemia.
    • Discontinue treatment if responsiveness does not improve.

Mircera (Methoxy polyethylene glycol-epoetin beta) Dosing adjustment for toxicity:

• Children ≥5 years and Adolescents ≤17 years:

  • Serious allergic/anaphylactic reactions:
    • Discontinue immediately (and permanently).
  • Hypertension (difficult to control):
    • Lower the dose or retain treatment (Its use is contraindicated in uncontrolled hypertension).
  • Pure red cell aplasia (PRCA):
    • Permanently discontinue treatment.

Mircera (Methoxy polyethylene glycol-epoetin beta) Pregnancy Category: C

• In some studies on animal reproduction, adverse events were observed.
• Limited information is available on the pregnancy use of methoxypolethylene glycol epoetin Beta

Use of methoxy polyethylene glycol -epoetin Beta during breastfeeding

• It is unknown if methoxypolethylene glycol-epoetin Beta is found in breastmilk.
• However, it is known that endogenous Erythropoietin can be found in breastmilk.
• According to the manufacturer the decision to stop or start breastfeeding while on therapy should consider the potential hazard to infants and the benefits to mothers.

Dose in Kidney Disease:

The manufacturer's labeling doesn't provide any dosage adjustments; however, methoxy polyethylene glycol-epoetin beta is indicated for use in patients with chronic kidney disease.

Dose in Liver disease:

The manufacturer's labeling doesn't provide any dosage adjustments; however, the severe hepatic impairment does not appear to alter the pharmacokinetics.

Common Side Effects of Mircera (Methoxy polyethylene glycol-epoetin beta):

• Cardiovascular:

  • Exacerbation of hypertension
  • Hypertension

• Central nervous system:

  • Headache

• Gastrointestinal:

  • Diarrhea
  • Vomiting

• Respiratory:

  • Nasopharyngitis

Less Common Side Effects of Mircera (Methoxy polyethylene glycol-epoetin beta):

• Cardiovascular:

  • Procedural Hypotension
  • Thrombosis Of Arteriovenous Shunt Used For Hemodialysis
  • Arteriovenous Fistula Site Complication
  • Hypotension
  • Thrombosis

• Endocrine & Metabolic:

  • Hypervolemia
  • Hyperkalemia

• Gastrointestinal:

  • Abdominal Pain
  • Constipation
  • Gastrointestinal Hemorrhage

• Genitourinary:

  • Urinary Tract Infection

• Hematologic & Oncologic:

  • Thrombocytopenia
  • Hemorrhage

• Infection:

  • Infection

• Neuromuscular & Skeletal:

  • Muscle Spasm
  • Back Pain
  • Limb Pain

• Respiratory:

  • Bronchitis
  • Upper Respiratory Tract Infection
  • Cough
  • Pharyngitis

• Miscellaneous:

  • Fever

Contraindications to Mircera (Methoxy polyethylene glycol-epoetin beta):

• Severe or severe hypersensitivity to methoxypolethylene glycol-epoetin Beta (e.g. angioedema and bronchospasms, skin rash, anaphylactic reaction, and urticaria).
• Pure red cell aplasia is a condition that develops after treatment with methoxypolethylene glycol-epoetin Beta or other erythropoietin proteins drugs.
• Hypertension uncontrolled

Warnings and precautions

• Cardiovascular events: [US Boxed Warn]

  • Erythropoiesis-stimulating agents (ESAs) increase the risk of death, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access.
  • Studies of chronic kidney disease patients (CKD) comparing high hemoglobin targets (13-14 g/dL to lower targets (9-11.3 g/dL), showed that ESAs increased the risk for death, MI, stroke and heart failure in those with higher hemoglobin targets.
  • ESAs that target hemoglobin greater than 11 g/dL do not provide any additional benefits and could increase these risks.
  • Patients who have had strokes or are currently suffering from cardiovascular disease should be cautious.
  • Cardiovascular hazards can also be caused by hemoglobin levels that rise more than 1 g per day over 2 weeks.
  • ESAs were found to increase the risk of death in patients with cancer (including stroke) in controlled trials.
  • Patients who have had cancer treatment with ESAs may experience an increase in the incidence of thromboembolic episodes. These events can be life-threatening or serious.
  • ESAs were found to increase the risk of death for patients who had CABG surgery, and to increase the risk of DVT among patients who underwent orthopedic procedures.

• Dermatologic toxicities:

  • Patients treated with ESAs (epoetin beta, methoxy polyethylene glycol-epoetin benzo) have reported severe cutaneous blistering and skin exfoliation reactions.
  • If you suspect a severe cutaneous reaction, such as SJS and TEN, stop treatment immediately.

• Hypersensitivity

  • There have been reports of severe allergic reactions, including anaphylactic reactions angioedema and bronchospasm as well as pruritus, rash and tachycardia.
  • Retains or discontinue early (and permanently) in patients who experience serious allergic/anaphylactic reactions.

• Hypertension:

  • Studies of methoxy polyethylenegl epoetin Beta in patients with CKD showed that over one-fourth needed intensification of antihypertensive treatment.
  • Reports of hypertensive encephalopathy (HE) and/or seizures were made.
  • Before and during treatment, it is important to control blood pressure.
  • If blood pressure is difficult to manage, reduce or withhold treatment.
  • Uncontrolled hypertension is a reason to avoid its use.
  • Patients must adhere to antihypertensive therapy.

• Pure red cell aplasia

  • Postmarketing cases of severe anemia, and PRCA (with or with out other cytopenias), have been reported even though they were not seen in clinical trials.
  • These cases have occurred following the creation of neutralizing antibodies against erythropoietin.
  • PRCA reports related to ESAs were mainly in patients with CKD who received subQ administration.
  • Patients with hepatitis C and receiving ESAs for their anemia have also reported cases.
  • Keep the dose unchanged and test for antibodies to erythropoietin neutralizing agents in patients with severe anemia or low reticulocyte counts during treatment.
  • Patients who develop PRCA (to any ESA) should be discontinued from treatment immediately.
  • Antibodies may cross-react and it is important to not switch to another ESA.

• Seizures:

  • Studies with methoxypolethylene glycol beta have shown seizures.
  • Premonitory symptoms of neurologic disorders should be monitored closely during the first few months following treatment.
  • If seizures occur (new onset or change in frequency), or if there are premonitory symptoms, patients should contact their health care provider immediately.

• Cancer: [US Boxed Warning]

  • Treatment of anemia caused by cancer chemotherapy is not recommended and does not require methoxy polyethylene glycol epoetin Beta.
  • Due to an increase in deaths among patients who received methoxy polyethylenegl-epoetin Beta, a dose-ranging study was stopped early.
  • ESAs were evaluated in the treatment of patients with cervical, breast, non-small-cell lung, head and neck, lymphoid and other cancers.
  • The use of Methoxy polyethylenegl epoetin Beta in the treatment for anemia caused by cancer chemotherapy is not recommended.
  • ESA use can lead to decreased locoregional control and progression-free survival.

• Chronic kidney disease: [US-Boxed Warning]

  • In controlled trials, Sufferer administered greater hazards for death, serious adverse cardiovascular reactions, and stroke when considered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of more than 11 g per dL.
  • There is no trial that has found a hemoglobin target, ESA dose or dosing strategy that doesn't increase these risks.
  • You should only use the lowest dose necessary to decrease the need for red blood cell transfusions (RBC).
  • Consider the benefits of reducing transfusions in comparison to the risk of serious cardiovascular events or death.
  • This may reduce dialysis efficiency (due to an increased number of red blood cells and a decreased plasma volume); adjustments to dialysis parameters might be necessary.
  • To prevent extracorporeal circuit clotting, patients may need to increase their heparinization.

• Patients undergoing peri-surgical procedures:

  • For patients undergoing surgery, Methoxy polyethylenegl epoetin Beta is not recommended to reduce allogeneic red cell transfusions.
  • Patients who have had surgery with orthotic devices such as epoetinalfa have been found to be more likely to develop DVT.
  • Patients who had coronary bypass surgery were more likely to die.

Methoxy polyethylene glycol-epoetin beta: Drug Interaction

Monitoring parameters:

• Hemoglobin levels (at least weekly following therapy initiation and dosage adjustments until stable, then at least monthly);
• iron stores (transferrin saturation and serum ferritin) at baseline and during therapy;
• monitor blood pressure;
• monitor for signs/symptoms of premonitory neurologic symptoms of seizures,
• hypersensitivity

How to administer Mircera (Methoxy polyethylene glycol-epoetin beta)?

Administer IV or SubQ.

• For administration using the prefilled syringe, the plunger must be fully depressed during injection to activate the needle guard.
• Following administration, remove the needle from the injection site and release the plunger to allow the needle guard to move up until the entire needle is covered.

SubQ:

• Inject in the abdomen, arm, or thigh.

Mechanism of action of Mircera (Methoxy polyethylene glycol-epoetin beta):

• Methoxy polyethyleneglycol-epoetin Beta is an activator of the erythropoietin erythropoietin receptor; erythropoietin, a primary growth factor in erythroid development, is produced in the kidneys and released into bloodstream when hypoxia occurs.
• Hypoxia is caused by erythropoietin interfacing with erythroid progenitor cell cells to increase red blood cells production.

Note: Age has not been shown to affect pharmacokinetics (range: 6 to 89 years).

Onset of action:

• Hemoglobin increase (following a single initial dose): 7 to 15 days

Bioavailability:

• SubQ: 62 percent

Half-life elimination:

• IV: 119 hours;
• SubQ: 124 hours

Time to peak:

• SubQ: 72 hours

International Brand Names of Methoxy polyethylene glycol-epoetin beta:

• Mircera

Methoxy polyethylene glycol-epoetin beta Brand Names in Pakistan:

There is no brand available in Pakistan.