Mircera (methoxy polyethylene glycol-epoetin beta)

Individualize dosing and use the lowest dosage of methoxy polyethylene glycol-epoetin beta sufficient to reduce the need for RBC transfusions. In clinical trials, administration of ESAs, to targethemoglobin levels >11 g/dLincreased the risk of death, serious adverse cardiovascular reactions, and stroke. No target hemoglobin level, erythropoiesis-stimulating agent (ESA) dose, or dosing strategy has been identified that decreases these risks. Weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events.

When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly. When adjusting therapy, consider the rate of increase or decrease in hemoglobin concentration, responsiveness to the ESA, and hemoglobin concentration variability. A single hemoglobin excursion may not require a dosage change.

Avoid frequent dosage adjustments of methoxy polyethylene glycol-epoetin beta. Do not increase dosage more frequently than once every 4 weeks; decreases in dosage can occur more frequently. If the hemoglobin concentration rises rapidly (e.g., >1 g/dL in any 2-week period), reduce the dosage by >=25% as needed to reduce rapid responses. If the hemoglobin concentration has not increased by >1 g/dL after 4 weeks of therapy, increase the dosage by 25%.

If an adequate response is not obtained over a 12-week period of escalating dosages, evaluate the patient for other causes of anemia; further dosage increases are unlikely to improve patient response and may increase risks of therapy. Use the lowest dosage that will maintain a hemoglobin concentration sufficient to reduce the need for RBC transfusions. If responsiveness does not improve, discontinue the drug.

Methoxy polyethylene glycol-epoetin beta is administered by IV or subcutaneous injection. Administer by IV or subcutaneous injection in adult patients, and only by IV injection in pediatric patients. For subcutaneous administration, inject methoxy polyethylene glycol-epoetin beta in the abdomen, arm, or thigh.

Methoxy polyethylene glycol-epoetin beta injection is available as single-dose prefilled syringes in various strengths for IV or subcutaneous administration.

Methoxy polyethylene glycol-epoetin beta is preservative-free; discard any unused portions. Do not mix the drug with any parenteral solution.

Inspect the prefilled syringes visually for particulate matter and/or discoloration prior to administration; do not use if either is observed. Avoid vigorous shaking of the syringes or prolonged exposure to light.

Do not pool unused portions from the prefilled syringes. Do not use the prefilled syringe more than once.

Store methoxy polyethylene glycol-epoetin beta syringes in the refrigerator at 2-8degreesC in the original carton to protect from light. Do not freeze or shake. The patient may store methoxy polyethylene glycol-epoetin beta at room temperature up to 25degreesC in the original carton for up to 30 days.

No dosing information is available for this tab.

No formal drug interaction studies have been performed with methoxy polyethylene glycol-epoetin beta.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Erythropoietic Agents/Lovotibeglogene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Erythropoietic agents may interfere with hematopoietic stem cell (HSC) mobilization of CD34+ cells.(1)

CLINICAL EFFECTS: Use of erythropoietic agents before mobilization may result in unsuccessful stem cell mobilization.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue erythropoietic agents at least 2 months prior to mobilization.(1)

DISCUSSION: Erythropoietic agents may interfere with the manufacturing of lovotibeglogene autotemcel therapy. There are no data regarding use of erythropoietin between apheresis and conditioning or after lovotibeglogene autotemcel therapy.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Erythropoietic Agents/Lenalidomide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The mechanism of this interaction is unknown.

CLINICAL EFFECTS: Concurrent use of erythropoietic agents, such as darbepoetin or epoetin, with lenalidomide may increase the risk of thrombosis.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of lenalidomide states the risk of venous thromboembolism (VTE) may be increased when patients are taking concomitant therapy with erythropoietin stimulating agents. Use caution with concomitant use after a patient specific risk-benefit assessment has been completed. Observe patients for signs and symptoms of VTE and instruct patients to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling.(1) The National Comprehensive Cancer Network (NCCN) Guidelines include use of erythropoietic stimulating agents as a high risk factor for venous thromboembolism (VTE). Other risk factors include: active cancer, advanced stage cancer, certain cancer types, regional bulky lymphadenopathy, familial and/or acquired hypercoagulability, medical comorbidities, poor performance status, older age, major surgery, central venous catheter, chemotherapy including lenalidomide plus high-dose dexamethasone, hormone replacement therapy, contraceptives, tamoxifen/raloxifene, diethylstilbestrol, smoking, obesity, or activity level/exercise.(3) The NCCN Guidelines utilize a Risk Assessment Model to determine chemoprophylaxis. In patients with 0-1 risk factors, consider VTE chemoprophylaxis with aspirin 81-325 mg once daily. In patients with >/= 2 risk factors, consider VTE chemoprophylaxis with low-molecular weight heparin (LMWH) with a dose equivalent to enoxaparin 40 mg once daily or full-dose warfarin with a dose to maintain a target international normalized ratio (INR) 2-3.(3)

DISCUSSION: The National Comprehensive Cancer Network (NCCN) Guidelines include use of erythropoietin as an individual risk factor for venous thromboembolism (VTE). Patients should be assessed for total risk based on NCCN guidelines and recommended for the appropriate VTE chemoprophylaxis agent based on risk category.(3) A pooled analysis of two placebo-controlled trials in multiple myeloma noted an incidence rate for VTE of 23% in patients receiving lenalidomide, dexamethasone and erythropoietic therapy versus 5% in patients without erythropoietic therapy. A multivariate analysis indicated an independent correlation between thrombosis and patients with concomitant erythropoietin therapy.(4) A pooled analysis of 125 patients from 3 trials with multiple myeloma on lenalidomide therapy noted a 17% incidence of VTE in patients on lenalidomide with concurrent erythropoietin therapy.(5) Several studies have evaluated the optimal VTE prophylaxis agent with lenalidomide-treated patients. Patients receiving lenalidomide/dexamethasone and no chemoprophylaxis had a VTE incidence of 11-75%, 26% with the use of aspirin, 17% with the use of aspirin/LMWH/warfarin combination therapy, and 2-15% with the use of LMWH. (6)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Erythropoietin Stimulating Agents/Vadadustat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Vadadustat and erythropoietin stimulating agents (ESAs) both stimulate endogenous erythropoietin production, resulting in increased red blood cell production.(1-2)

CLINICAL EFFECTS: Concurrent use of vadadustat and erythropoietin stimulating agents may increase the risk of thrombosis.

PREDISPOSING FACTORS: Predisposing factors include a history of thromboembolic disorder, thrombophilia, malignancy, hyperlipidemia, hypertension, heart failure, diabetes mellitus, chronic kidney disease, COPD, obesity, tobacco smoking, major surgery with prolonged post-operative immobilization, and being bed-ridden.

PATIENT MANAGEMENT: ESAs should be stopped before initiating vadadustat.(1) For patients receiving temporary ESA rescue treatment, vadadustat should be held until hemoglobin levels are greater than or equal to 10 g/dL. The pause in vadadustat treatment should be extended to: - 2 days after last dose of epoetin - 7 days after last dose of darbepoetin alfa - 14 days after last dose of methoxy polyethylene glycol-epoetin beta Vadadustat should be resumed at the prior dose or one dose higher, with subsequent titration according to the dose titration guidelines in the vadadustat package insert.(1-2) Monitor hemoglobin levels every two weeks until stable, then monitor at least monthly.(1-2) Observe patients for signs and symptoms of venous thromboembolism and instruct patients to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling.

DISCUSSION: Vadadustat increases endogenous erythropoietin by decreasing degradation of hypoxia-inducible factor (HIF), which increases transcription of the HIF-responsive genes including EPO. Thromboembolic events were reported as very common (13.7%) in two active-controlled clinical trials in chronic kidney disease.(1-2) Controlled clinical trials of patients showed that ESAs increased the risk of death, myocardial infarction, stroke, congestive heart failure, and other thromboembolic events with a higher target hemoglobin.(3)

*Uncontrolled hypertension.

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

*History of serious or severe allergic reactions (including anaphylaxis) to methoxy polyethylene glycol-epoetin beta.

• Pure red cell aplasia
• Severe uncontrolled hypertension

• Acute decompensated heart failure
• Acute myocardial infarction
• Cerebrovascular accident
• Coronary artery disease
• Deep venous thrombosis
• Hypertension
• Pulmonary thromboembolism
• Thromboembolic disorder
• Vascular access thrombosis

• Folate deficiency
• Iron deficiency anemia
• Lower seizure threshold
• Porphyria
• Seizure disorder
• Vitamin b12 deficiency

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

More Frequent

• Edema
• Hypertension
• Tachycardia
• Vascular access thrombosis

Less Frequent

• Acute myocardial infarction
• Cerebrovascular accident
• Headache disorder
• Hypokalemia
• Pulmonary thromboembolism
• Seizure disorder
• Thrombotic disorder
• Transient cerebral ischemia

Rare or Very Rare

• Anaphylaxis
• Angioedema
• Chest pain
• Chronic heart failure
• Deep venous thrombosis
• Erythema multiforme
• Porphyria
• Pure red cell aplasia
• Shortened time to tumor progression
• Stevens-johnson syndrome
• Thromboembolic disorder
• Toxic epidermal necrolysis
• Urticaria

More Frequent

• Anorexia
• Arthralgia
• Cough
• Diarrhea
• Fatigue
• Fever
• General weakness
• Injection site sequelae
• Insomnia
• Leukopenia
• Muscle spasm
• Nausea
• Vomiting

Less Frequent

• Bone pain
• Depression
• Dizziness
• Dysphagia
• Hyperglycemia
• Myalgia
• Stomatitis
• Upper respiratory infection

Rare or Very Rare

• Chills
• Flu-like symptoms
• Hyperhidrosis
• Skin rash

No enhanced messaging available.

The efficacy and safety of methoxy polyethylene glycol-epoetin beta for the treatment of anemia due to CKD have been established in pediatric patients 5-17 years of age on hemodialysis who are converting from another ESA after their hemoglobin level was stabilized with an ESA. Use of methoxy polyethylene glycol-epoetin beta in this age group is supported by evidence from adequate and well-controlled studies in adults and a dose-finding study in 64 pediatric patients 5-17 years of age with CKD on hemodialysis. The observed safety profile in pediatric patients was similar to that found in adults.

The efficacy and safety of methoxy polyethylene glycol-epoetin beta have not been established in pediatric patients <5 years of age. The efficacy and safety of subcutaneously-administered methoxy polyethylene glycol-epoetin beta have not been established in pediatric patients of any age. Efficacy and safety of methoxy polyethylene glycol-epoetin beta have not been established for the treatment of anemia in pediatric patients with CKD on peritoneal dialysis; the treatment of anemia in pediatric patients with CKD who are not yet on dialysis; and for pediatric patients whose hemoglobin level has not been previously stabilized by treatment with an ESA.

Available data from a small number of published case reports and postmarketing experience with methoxy polyethylene glycol-epoetin beta 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 (e.g., hypertension, pre-eclampsia, miscarriage, premature birth, low-birth-weight, polyhydramnios, intrauterine growth restriction).

In animal reproduction studies, subcutaneous administration of methoxy polyethylene glycol-epoetin beta to rats and rabbits during pregnancy adversely affected offspring at doses 17-fold greater than the recommended human dose.

It is not known whether methoxy polyethylene glycol-epoetin beta is distributed into human milk; however, endogenous erythropoietin is present in human milk. When methoxy polyethylene glycol-epoetin beta was administered to lactating rats, the drug was detected in maternal milk. The effects of methoxy polyethylene glycol-epoetin beta on breast-fed infants or on milk production are unknown.

A clear determination of the risks of methoxy polyethylene glycol-epoetin beta to breast-fed infants cannot be made due to lack of clinical data during lactation. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for methoxy polyethylene glycol-epoetin beta and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

The manufacturer makes no specific dosage recommendations for geriatric patients, but recommends cautious dosage selection, usually starting at the low end of the dosing range, due to the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.

Clinical studies of methoxy polyethylene glycol-epoetin beta did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, select dosage with caution in geriatric patients, usually starting at the low end of the dosing range; geriatric patients have a greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.