Daprodustat (Monograph)

Brand name: Jesduvroq
Drug class: Hematopoietic Agents

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

Hematopoietic agent; a hypoxia-inducible factor prolyl hydroxylase (HIF PH) inhibitor.

Uses for Daprodustat

Anemia of Chronic Kidney Disease

Treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for ≥4 months.

Has been shown to be noninferior to recombinant human erythropoietin (rhEPO) for change in hemoglobin and incidence of cardiovascular events.

Kidney Disease Improving Global Outcomes (KDIGO) guideline recommends erythropoiesis-stimulating agents (ESAs) for anemia of CKD; daprodustat was approved after publication of these guidelines and is therefore not addressed.

Not shown to improve quality of life, fatigue, or patient well-being; not recommended for treatment of anemia of CKD in patients who are not on dialysis and not recommended as a substitute for RBC transfusion in patients requiring immediate correction of anemia.

Daprodustat Dosage and Administration

General

Pretreatment Screening

• Assess iron status (i.e., transferrin saturation, serum ferritin concentration) prior to therapy initiation, and administer supplemental iron when serum ferritin is <100 ng/mL or when serum transferrin saturation is <20%.

• Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding) prior to initiation of daprodustat.

• Prior to treatment initiation, assess liver function (AST, ALT, alkaline phosphatase, and total bilirubin).

Patient Monitoring

• If signs or symptoms of liver disease develop during therapy, repeat liver function testing (AST, ALT, alkaline phosphatase, and total bilirubin).

• Monitor iron status (i.e., transferrin saturation, serum ferritin concentration) during treatment, and administer supplemental iron when serum ferritin is <100 ng/mL or when serum transferrin saturation is <20%.

• Monitor hemoglobin every 2 weeks for the first month after starting daprodustat or changing the dose, and every 4 weeks during treatment.

• Periodically monitor BP and adjust or initiate antihypertensive therapy as needed.

Administration

Oral Administration

Administer tablets orally once daily, with or without food. May administer tablets without regard to iron or phosphate binders.

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

May administer tablets without regard to the type or timing of dialysis treatment.

If a dose is missed, take the next dose as soon as possible. If on the same day as the next dose, skip the missed dose and resume dosing at the normal time. Do not administer double doses to make up for a missed dose.

Dosage

Adults

Anemia of CKD

The starting dosage of daprodustat is based on hemoglobin levels, liver function, and concomitant medications.

Individualize dosing and use the lowest dose sufficient to reduce the need for RBC transfusions. Do not target hemoglobin levels >11 g/dL.

ESA-Naïve Patients

Oral

Adults receiving dialysis for ≥4 months who are ESA-naïve: Initial dosage based on the hemoglobin level (see Table 1).

See dosage modifications in patients with moderate hepatic impairment(Child-Pugh class B) and in patients concomitantly taking a moderate CYP2C8 inhibitor.

Patients Switching from an ESA to Daprodustat

Oral

Adults receiving dialysis for ≥4 months switching from ESAs: dosage based on prior ESA regimen at the time of substitution (see Table 2),

PEG, polyethylene glycol.

For patients receiving sub-Q epoetin alfa, multiply the sub-Q dose received per week by 1.42 to obtain the weekly IV dose.

See dosage modifications in patients with moderate hepatic impairment (Child-Pugh class B) and in patients concomitantly taking a moderate CYP2C8 inhibitor.

Monitoring Response to Therapy and Dosage Adjustment

Monitor hemoglobin every 2 weeks for the first month after starting daprodustat or changing the dose, and every 4 weeks during treatment. Consider the hemoglobin rate of rise, rate of decline, and hemoglobin variability during adjustment. Do not adjust dosage more often than once every 4 weeks.

When making dosage adjustments, increase or decrease dosage by one level at a time (see Table 3). If hemoglobin increases rapidly (e.g., >1 g/dL over 2 weeks or >2 g/dL over 4 weeks), or is >11 g/dL at any time, decrease the dosage level. If hemoglobin is >12 g/dL, temporarily withhold daprodustat. When hemoglobin falls within the target range, treatment may be restarted at one dosage level lower. Do not continue treatment beyond 24 weeks if a clinically meaningful increase in hemoglobin does not occur. Identify and treat the underlying cause of the inadequate response before re-initiation of daprodustat.

Dosage Modification for Concomitant Use with Moderate CYP2C8 Inhibitors

If daprodustat is used concomitantly with clopidogrel or a moderate CYP2C8 inhibitor, reduce initial daprodustat dosage by 50% (see Tables 1 and 2), except when the initial dosage is 1 mg.

Monitor hemoglobin and adjust daprodustat dosage during initiation or discontinuation of concomitant therapy with clopidogrel or a moderate CYP2C8 inhibitor.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): No dosage adjustment required.

Moderate hepatic impairment (Child-Pugh class B): Reduce initial dosage by 50% (see Tables 1 and 2), except when the initial dosage is 1 mg.

Severe hepatic impairment (Child-Pugh class C): Not studied. Use not recommended.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Related/similar drugs

ferrous sulfate, FeroSul, Aranesp, Retacrit

Cautions for Daprodustat

Contraindications

• Concomitant use of potent CYP2C8 inhibitors such as gemfibrozil.

• Uncontrolled hypertension.

Warnings/Precautions

Warnings

Increased Risk of Death, MI, Stroke, Venous Thromboembolism, and Thrombosis of Vascular Access

Increased risk of arterial and venous thrombotic events (some fatal), including MI, stroke, venous thromboembolism, and vascular access thrombosis (see Boxed Warning). Underlying cardiovascular or cerebrovascular disease increases risk. Avoid initiation of therapy in patients with a history of MI, cerebrovascular event, or acute coronary syndrome within the previous 3 months.

An increased rate of hemoglobin rise (>1 g/dL increase over 2 weeks) may further contribute to risk. Hemoglobin target levels >11 g/dL expected to further increase risk of mortality and thrombotic events.

Use lowest dose of daprodustat sufficient to reduce RBC transfusion requirements. To avoid excessive erythropoiesis, adhere to recommendations for dosing and monitoring of hemoglobin.

Advise patients to seek out immediate medical attention if signs and symptoms of MI, stroke, venous thromboembolism, or vascular access thrombosis occur.

Other Warnings and Precautions

Risk of Hospitalization for Heart Failure

Hospitalization for heart failure reported; higher rates reported in patients with a history of heart failure.

Consider patient's history of heart failure when deciding whether to initiate daprodustat. Inform patients of the signs and symptoms of heart failure and to promptly report them to their healthcare provider should they occur.

Hypertension

Worsening of hypertension reported; some cases were serious. Use of daprodustat contraindicated in uncontrolled hypertension. Monitor BP periodically and adjust or initiate anti-hypertensives if needed.

GI Erosion

Gastric or esophageal erosions, including serious erosions involving GI bleeding, reported. Risk factors include history of GI erosion, peptic ulcer disease, concurrent use of medications that increase GI erosion risk, and current tobacco or alcohol use.

Advise patients of the signs and symptoms of gastric and esophageal erosions and GI bleeding and to seek immediate medical care if they develop.

Serious Adverse Events in Patients with Anemia Due to CKD and Not on Dialysis

Safety not established in adults with CKD not receiving dialysis; use in such patients not recommended.

Increased risk of cardiovascular mortality, stroke, thromboembolism, serious acute kidney injury, hospitalization for heart failure, and serious GI erosions reported in these patients.

Malignancy

Not studied in patients with active malignancies; not recommended for use in patients with active malignancy.

Specific Populations

Pregnancy

Data not adequate to establish a drug-associated risk. Animal data indicate fetal risk.

Chronic kidney disease during pregnancy also associated with maternal and fetal risk.

Inform pregnant women of the potential fetal risk with daprodustat.

Lactation

Not known if present in human milk; present in the milk of lactating rats. If present in animal milk, likely to be present in human milk. Effects on the breast-fed infant and on milk production not known.

Advise patients to avoid breastfeeding while receiving daprodustat, and for 1 week following the last dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

In the ASCEND-D study, 32% of patients who received daprodustat were ≥65 years of age, and 11% were ≥75 years of age. No overall differences in safety or efficacy observed between geriatric patients and younger adults.

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Daprodustat AUC increased 1.5-fold; no effect on peak plasma concentration. Peak plasma concentration and AUC of unbound daprodustat increased 1.6 and 2.2-fold, respectively.

Moderate hepatic impairment (Child-Pugh class B): Peak plasma concentration and AUC of daprodustat increased by 2-fold; peak plasma concentration and AUC of unbound drug increased by 2.3-fold. Reduced dosage recommended in this population.

Severe hepatic impairment (Child-Pugh class C): Effects on pharmacokinetics not known; not recommended in this population.

Renal Impairment

Steady-state exposure of daprodustat similar in normal renal function compared to varying degrees of renal impairment. Hemodialysis and peritoneal dialysis do not have a significant impact on exposure. Metabolite exposure increased in patients with stage 3—5 CKD and on non-dialysis days compared to dialysis days.

Common Adverse Effects

Adverse effects reported in ≥10% of patients: hypertension, thrombotic vascular events, abdominal pain.

Drug Interactions

Metabolized principally by CYP2C8 and, to a lesser extent, by CYP3A4. In vitro, 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-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.

Substrate of BCRP. In vitro, not a substrate of CYP1A2, 2B6, 2C9, 2C19, 2D6, or P-gp. 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 is not known.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP2C8 inhibitors: Significantly increased exposure to daprodustat with concomitant use. Concomitant use with potent CYP2C8 inhibitors contraindicated.

Moderate CYP2C8 inhibitors: Expected increase in daprodustat AUC and peak plasma concentration. If used concomitantly, reduce initial dosage of daprodustat by 50% (see Tables 1 and 2), unless recommended dosage is 1 mg. Hemoglobin monitoring and adjustment of daprodustat dosage recommended when initiating or discontinuing concomitant therapy with a moderate CYP2C8 inhibitor.

CYP2C8 inducers: Possible decrease in daprodustat exposure and loss of therapeutic efficacy. If used concomitantly, monitor hemoglobin and adjust daprodustat dosage during initiation or discontinuation of CYP2C8 inducers.

Drugs Affecting Transport Systems

BCRP inhibitors: Low risk of significant drug interactions between BCRP inhibitors and daprodustat.

Specific Drugs

Daprodustat Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability of 65%.

Steady-state concentrations achieved within 24 hours of initial dosing.

Onset

Peak plasma concentrations attained in a median of 1—4 hours following oral administration.

Food

Administration with a high-fat, high-calorie meal did not significantly affect daprodustat exposure.

Distribution

Extent

Not known if distributed into human milk. Distributes into animal milk.

Plasma Protein Binding

>99%.

Elimination

Metabolism

Metabolized principally (95%) by CYP2C8, and to a minor extent (5%) by CYP3A4.

Elimination Route

Eliminated in feces (74%), and urine (21%).

Half-life

1—4 hours.

Stability

Storage

Oral

Tablets

Store at 20—25°C; excursions permitted to 15—30°C.

Actions

• Reversibly inhibits hypoxia-inducible factor prolyl hydroxylase (HIF-PH)1, PH2, and PH3, which causes stabilization and nuclear accumulation of HIF-1α and HIF-2α transcription factors, leading to increased transcription of genes responsive to HIF, including erythropoietin.

• Dose-dependent increases in endogenous erythropoeitin observed within 6—8 hours following administration.

• Peak reticulocyte counts attained after 7—15 days; subsequent increases in RBC production.

• Steady-state levels of new hemoglobin achieved after approximately 4 weeks in ESA users, and 16—20 weeks in ESA non-users.

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide).

• Inform patients that daprodustat use is associated with an increased risk of death, MI, stroke, thromboembolism, and vascular access thrombosis.

• Inform patients of the associated risk of hospitalization due to heart failure with daprodustat. Advise patients of the signs and symptoms of heart failure and to promptly report these symptoms to their healthcare provider.

• Inform patients of the associated risk of hypertension with daprodustat. Advise patients that in order to mitigate this risk, they must undergo regular BP monitoring and adhere to any prescribed anti-hypertensive medications.

• Inform patients of the associated risk of gastric erosions and GI bleeding with daprodustat. Advise patients of the signs and symptoms of gastric erosions and GI bleeding and to promptly report these symptoms to their healthcare provider.

• Inform patients that they will need regular hemoglobin monitoring during treatment.

• Advise patients to inform their healthcare provider if they are taking concomitant potent or moderate CYP2C8 inhibitors.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Use of daprudostat during pregnancy may result in fetal harm. Advise women of reproductive potential to inform their healthcare provider of a known or suspected pregnancy. Advise women to avoid breastfeeding while receiving daprodustat and for 1 week following the last dose.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Daprodustat is obtained through designated specialty pharmacies. Contact manufacturer or consult the Jesduvroq website ([Web]) for specific availability information.

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Frequently asked questions

• Jesduvroq vs. Aranesp: How do they compare?

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