Aranesp (In Polysorbate) (darbepoetin alfa in polysorbate 80)

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Darbepoetin alfa is administered by IV or subcutaneous injection. The subcutaneous route of administration was most frequently associated with cases of pure red cell aplasia (PRCA) in patients with CKD receiving ESAs. The manufacturer recommends the IV route of administration in patients on hemodialysis.

Because of its longer plasma half-life, darbepoetin alfa should be administered less frequently than epoetin alfa. Patients being switched from epoetin alfa to darbepoetin alfa should receive darbepoetin alfa by the same route of administration (IV or subcutaneous) that they were receiving epoetin alfa. Patients receiving epoetin alfa 2 or 3 times weekly should be switched to darbepoetin alfa once weekly, and those receiving epoetin alfa once weekly should be switched to darbepoetin alfa once every 2 weeks. The first dose of darbepoetin alfa should be administered in place of epoetin alfa at the time of the next scheduled dose.

Darbepoetin alfa should not be diluted or administered in conjunction with other drug solutions. Commercially available prefilled syringes and single-use vials of darbepoetin alfa should be stored in the carton until use between 2-8degreesC, and not be exposed to light, frozen, or shaken prior to use. If shaken or frozen, the product should not be used. Unused portions of the single-use vials or prefilled syringes of darbepoetin alfa should be discarded and vials should not be reentered. Contents of vials and prefilled syringes of darbepoetin alfa should be inspected visually for discoloration and/or particulate matter prior to administration; if either is present, the solution should be discarded.

The needle cover of the prefilled syringe contains natural latex proteins in the form of dry natural rubber (latex). Individuals sensitive to latex should not handle the needle cover due to the potential for allergic reactions.

No dosing information is available for this tab.

No dosing information is available for this tab.

No formal drug interaction studies have been performed.

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 darbepoetin alfa or other erythropoietin proteins.

*Serious allergic reactions to darbepoetin alfa.

• Pure red cell aplasia
• Severe uncontrolled hypertension

• Acute decompensated heart failure
• Acute myocardial infarction
• Cerebrovascular accident
• Deep venous thrombosis
• Hypertension
• Pulmonary thromboembolism
• Thromboembolic disorder
• Thrombotic disorder
• Vascular access thrombosis
• Vitamin b12 deficiency

• Edema
• Folate deficiency
• Iron deficiency anemia
• Lower seizure threshold
• Porphyria
• Seizure disorder

Adverse effects occurring in at least 10% of patients with CKD receiving darbepoetin alfa in clinical studies include hypertension, dyspnea, peripheral edema, cough, and procedural hypotension.

Adverse effects occurring in at least 1% of adults with cancer receiving chemotherapy and darbepoetin alfa in clinical studies include abdominal pain, edema, and thrombovascular events (myocardial infarction, pulmonary embolism, cerebrovascular accidents, CNS hemorrhage).

More Frequent

• Chronic heart failure
• Dyspnea
• Hypertension
• Thrombotic disorder

Less Frequent

• Acute myocardial infarction
• Angina
• Cerebrovascular accident
• Hypotension
• Pulmonary thromboembolism
• Seizure disorder
• Thromboembolic disorder
• Transient cerebral ischemia
• Vascular access thrombosis

Rare or Very Rare

• Anaphylaxis
• Angioedema
• Bronchospastic pulmonary disease
• Deep venous thrombosis
• Erythema multiforme
• Exfoliative dermatitis
• Hypertensive crisis
• Pure red cell aplasia
• Shortened time to tumor progression
• Stevens-johnson syndrome
• Toxic epidermal necrolysis
• Urticaria

More Frequent

• Cough
• Edema
• Injection site sequelae
• Pain in extremities
• Peripheral edema

Less Frequent

• Acute abdominal pain
• Erythema
• Hypervolemia
• Skin rash

No enhanced messaging available.

Safety and efficacy of darbepoetin alfa in the treatment of pediatric patients ages 1 month to 16 years old with CKD on dialysis and not on dialysis have been established. No data are available in patients less than 1 month old. The use in this patient population is supported by evidence from the use in adults in controlled trials, a study evaluating weekly and every 2 week dosing in 114 pediatric patients ages 1 to 16 years of age, and an observational registry study in 319 pediatric patients ages less than 1 to 16 years of age. Safety and efficacy were similar between adult and pediatric patients with CKD on dialysis and not on dialysis when darbepoetin alfa was used for the initial treatment of anemia, or when transitioning from epoetin to darbepoetin.

Safety and efficacy in pediatric cancer patients not established.

There is insufficient evidence to determine if darbepoetin use in pregnant women causes birth defects or miscarriage. In animal studies, darbepoetin increased early post-implantation loss at equivalent clinical recommended starting doses, and when administered IV during organogenesis, there was no evidence of embryofetal toxicity or adverse outcomes in doses up to 20 mcg/kg/day. Consider the benefits and risks of darbepoetin for the mother and possible risks to the fetus when prescribing darbepoetin.

Not known whether darbepoetin alfa is distributed into milk. Caution is advised if the drug is administered in nursing women.

No clinically significant differences have been observed in the pharmacokinetics, safety, or efficacy of darbepoetin alfa in patients 65 years of age and older; however, increased sensitivity cannot be completely ruled out.

No substantial differences in safety and efficacy of darbepoetin alfa relative to younger adults were observed, but increased sensitivity cannot be ruled out.