Jesduvroq (daprodustat)

When clopidogrel or a moderate CYP2C8 inhibitor is used concomitantly with daprodustat, reduce the initial dosage of daprodustat by 50% (see Tables 1 and 2), except in patients whose initial recommended dosage is 1 mg.

Monitor hemoglobin and adjust the daprodustat dosage when initiating or discontinuing concomitant therapy with clopidogrel or a moderate CYP2C8 inhibitor.

Administer daprodustat tablets orally once daily, with or without food. Tablets may be administered without regard to iron or phosphate binders.

Swallow tablets whole; do not cut, crush, or chew.

Daprodustat tablets may be administered without regard to the type or timing of dialysis treatment.

If a dose of daprudostat is missed, take the missed dose as soon as possible, unless it is on the same day as the next dose. If on the same day as the next dose, skip the missed dose and resume dosing at the normal time. Do notadminister double doses to make up for a missed dose.

Store tablets at 20--25degreesC; excursions permitted to 15--30degreesC.

No dosing information is available for this tab.

Daprodustat is metabolized principally by cytochrome P450 (CYP) 2C8 and, to a minor extent, by CYP3A4. In vitro, daprodustat does not induce CYP1A2, 2B6, or 3A4.

Daprodustat and its major metabolites do not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, or 3A4. Daprodustat does not inhibit P-glycoprotein (P-gp), or breast cancer resistance protein (BCRP). Daprodustat and its major metabolites do not inhibit organic anion transporter polypeptide (OATP) 1B1, OATP1B3, OATP2B1, organic cation transporter (OCT) 1, organic anion transporter (OAT) 1, OAT3, OCT2, multidrug and toxin extrusion transporter (MATE) 1, or MATE2-K.

Daprodustat is a substrate of BCRP. In vitro, daprodustat is not a substrate of CYP1A2, 2B6, 2C9, 2C19, 2D6, or P-gp. The major metabolites of daprodustat are not substrates of OATP1B1, OATP1B3, OATP2B1, OCT1, OCT2, MATE1, or MATE2-K. Some oxidative metabolites are substrates of OAT1 and OAT3 in vitro, although the clinical significance of this is not known.

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

Daprodustat/Strong Cyp2c8 Inhibitors

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: Strong inhibitors of CYP2C8 may impair the CYP2C8-mediated metabolism of daprodustat.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP2C8 may result in elevated levels of and clinical effects of daprodustat, including the risk for thromboembolic events and hypertension.

PREDISPOSING FACTORS: Patients with a history of myocardial infarction, cerebrovascular event, or acute coronary syndrome within the past 3 months may be at increased risk of thromboembolic events. Other risk factors for thromboembolic events include 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: The manufacturer of daprodustat states that concomitant administration of strong CYP2C8 inhibitors is contraindicated.(1)

DISCUSSION: In an interaction study, gemfibrozil 600 mg twice daily for 5 days increased the area-under-curve (AUC) and maximum concentration (Cmax) of daprodustat (single 100 mg dose) by 18.6-fold and 3.9-fold respectively.(1) Strong inhibitors of CYP2C8 include gemfibrozil.(2,3)

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

Daprodustat; Roxadustat; Vadadustat/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 daprodustat, roxadustat, or vadadustat with lenalidomide may increase the risk of thrombosis.(1-5)

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: 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.(6) 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.(6)

DISCUSSION: Daprodustat, roxadustat, and vadadustat increase endogenous erythropoietin by increasing transcription of the HIF-responsive genes.(2-5) 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.(6) 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.(7) 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.(8) 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.(9)

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

Daprodustat/Moderate Cyp2c8 Inhibitors

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

MECHANISM OF ACTION: Moderate inhibitors of CYP2C8 may impair the CYP2C8-mediated metabolism of daprodustat.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP2C8 may result in elevated levels of and clinical effects of daprodustat, including the risk for thromboembolic events and hypertension.

PREDISPOSING FACTORS: Patients with a history of myocardial infarction, cerebrovascular event, or acute coronary syndrome within the past 3 months may be at increased risk of thromboembolic events. Other risk factors for thromboembolic events include 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: The manufacturer of daprodustat states that the starting dose of daprodustat should be reduced by half when initiating treatment in patients on clopidogrel or moderate CYP2C8 inhibitors except in patients who starting dose is already 1 mg.(1) Monitor hemoglobin and adjust the dose of daprodustat when initiating or stopping therapy with clopidogrel or moderate CYP2C8 inhibitors.(1)

DISCUSSION: In an interaction study, gemfibrozil 600 mg twice daily for 5 days increased the area-under-curve (AUC) and maximum concentration (Cmax) of daprodustat (single 100 mg dose) by 18.6-fold and 3.9-fold respectively.(1) Concomitant administration of daprodustat with clopidogrel 75 mg once daily is expected to increase daprodustat AUC and Cmax by at least 4-fold and 3-fold, respectively.(1) Moderate inhibitors of CYP2C8 include deferasirox, leflunomide, letermovir, mifepristone (chronic therapy), pirtobrutinib, selpercatinib, and teriflunomide.(2,3)

*Concomitant use of potent cytochrome P-450 (CYP) isoenzyme 2C8 inhibitors such as gemfibrozil.

*Uncontrolled hypertension.

• Acute myocardial infarction
• Lactation

• Alcohol use disorder
• Cerebrovascular disorder
• Child-pugh class B hepatic impairment
• Chronic heart failure
• Gastrointestinal ulcer
• Hypertension
• Myocardial ischemia
• Tobacco smoker

There are no moderate contraindications for this drug.

Adverse effects reported in at least 10% of patients receiving daprodustat in clinical trials include hypertension, thrombotic vascular events, and abdominal pain.

Less Frequent

• Acute abdominal pain
• Acute myocardial infarction
• Cerebrovascular accident
• Deep venous thrombosis
• Dizziness
• Erosive esophagitis
• Gastrointestinal hemorrhage
• Gastrointestinal ulcer
• Heart failure
• Hypersensitivity drug reaction
• Hypertension
• Pulmonary thromboembolism
• Thrombotic disorder
• Vascular access thrombosis

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

Safety and efficacy of daprodustat have not been established in pediatric patients.

Available data on daprodustat use in pregnancy are not adequate to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Chronic kidney disease during pregnancy is also associated with maternal and fetal risks (e.g., maternal hypertension, preeclampsia, miscarriage, stillbirth, preterm delivery, low birth weight, and polyhydramnios). Oral administration of daprodustat to pregnant rats and rabbits during organogenesis at doses that caused maternal toxicity and polycythemia was associated with the development of adverse fetal outcomes, which included embryonic and fetal loss and reduced fetal weight. Inform pregnant women of the potential fetal risk when daprodustat is used during pregnancy.

It is not known if daprodustat is present in human milk; however, daprodustat is present in the milk of lactating rats. When a drug is present in animal milk, it is likely to be present in human milk. The effects on the breast-fed infant and the effects on milk production are also not known. Given the risk of serious adverse events seen in adult patients treated with daprodustat (i.e., thrombotic vascular events), advise patients to avoid breast-feeding while receiving daprodustat and for 1 week following the last dose.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In the ASCEND-D study, 32% of patients who received daprodustat were >=65 years of age and 11% of patients were >=75 years of age. No overall differences in safety or efficacy were observed between geriatric patients and younger adult patients. Other reported clinical experience has not identified any difference in response between geriatric and younger adult patients.