Version May 2024
Daprodustat increases the risk of thrombotic vascular events, including major adverse cardiovascular events. Targeting a Hb level >11 g/dL is expected to further increase the risk of death and arterial venous thrombotic events, as occurs with erythropoietin-stimulating agents, which also increase erythropoietin levels. No trial has identified a Hb target level, dose of daprodustat, or dosing strategy that does not increase these risks. Use the lowest dose of daprodustat sufficient to reduce the need for RBC transfusions.
Note: Correct and exclude other causes of anemia (eg, vitamin deficiencies, metabolic or chronic inflammatory conditions, bleeding) prior to therapy. Iron supplementation: Ensure adequate iron stores before initiating and throughout therapy. The manufacturer recommends supplemental iron be administered if serum ferritin is <100 ng/mL or serum transferrin saturation is <20%; however, the threshold for iron replacement should be individualized based on clinical considerations (eg, trends in Hb level, goals of therapy) (Ref). Most patients with chronic kidney disease will require iron supplementation during the course of therapy.
Anemia due to chronic kidney disease (dialysis-dependent): Oral:
Initial dose:
|
Pretreatment hemoglobin level |
Initial dose |
|---|---|
|
<9 g/dL |
4 mg once daily |
|
≥9 to ≤10 g/dL |
2 mg once daily |
|
>10 g/dL |
1 mg once daily |
|
Current dose of erythropoietin-stimulating agent |
Initial daprodustat dose | ||
|---|---|---|---|
|
Epoetin alfa (IV)a |
Darbepoetin alfa (IV or SUBQ) |
Methoxy PEG-epoetin beta (IV or SUBQ) | |
|
a For patients receiving SUBQ epoetin alfa, multiply the SUBQ dose received per week by 1.42 to obtain the weekly IV dose. | |||
|
≤2,000 units per week |
20 to 30 mcg per 4 weeks |
30 to 40 mcg per month |
4 mg once daily |
|
>2,000 to <10,000 units per week |
>30 to 150 mcg per 4 weeks |
>40 to 180 mcg per month |
6 mg once daily |
|
≥10,000 to <20,000 units per week |
>150 to 300 mcg per 4 weeks |
>180 to 360 mcg per month |
8 mg once daily |
|
≥20,000 units per week |
>300 units per 4 weeks |
>360 mcg per month |
12 mg once daily |
Dosage adjustment: Do not increase the dose more frequently than once every 4 weeks. When adjusting doses, consider Hb rate of rise, rate of decline, and variability.
When making dose adjustments: Increase or decrease by 1 dose level at a time (see table below). Maximum dose according to the manufacturer’s labeling is 24 mg once daily. However, some experts avoid doses >12 mg/day due to lack of safety data (Ref).
If Hb increases rapidly (eg, >1 g/dL over 2 weeks or >2 g/dL over 4 weeks): Decrease dose or hold therapy depending on Hb level and rate of increase (Ref).
If Hb >11 g/dL: Decrease dose.
If Hb >12 g/dL: Interrupt treatment. When the Hb falls within treatment range, treatment may be restarted at 1 dose level lower (see table below).
Lack of Hb response: Discontinue treatment after 24 weeks (or sooner) if no meaningful Hb increase is achieved; avoid repeated dose escalations without Hb improvement. Identify and treat underlying causes of inadequate response before restarting therapy (Ref).
|
a Some experts avoid doses >12 mg once daily due to lack of safety data (Berns 2023). | |||||||
|
1 mg once daily |
2 mg once daily |
4 mg once daily |
6 mg once daily |
8 mg once daily |
12 mg once daily |
16 mg once dailya |
24 mg once daily (maximum dose)a |
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Altered kidney function: Not indicated for use in patients with chronic kidney disease not receiving dialysis.
Hemodialysis, intermittent (thrice weekly): Not significantly dialyzable: No dosage adjustment necessary (indicated for use in this population). May be administered without regard to dialysis timing.
Peritoneal dialysis: Not significantly dialyzable: No dosage adjustment necessary (indicated for use in this population).
Mild impairment (Child-Pugh class A): No dosage adjustment necessary.
Moderate impairment (Child-Pugh class B): Administer 50% of usual recommended dose, except in patients in whom the usual recommended dose is 1 mg daily.
Severe impairment (Child-Pugh class C): Use is not recommended.
Refer to adult dosing.
Gastrointestinal events, including gastrointestinal erosions (including esophageal erosions) and gastrointestinal bleeding have been reported with daprodustat. In a clinical trial comparing daprodustat to an erythropoiesis-stimulating agent for the treatment of anemia in patients on dialysis, the incidence of esophageal or gastric erosions was similar between groups (Ref).
Risk factors:
• History of gastrointestinal erosion and/or peptic ulcer disease
• Use of concomitant medications that increase the risk of gastrointestinal erosion
• Current tobacco and/or alcohol use
Malignant neoplasm has rarely been reported with daprodustat. In clinical studies, the incidence of malignancy was similar between patients treated with daprodustat and patients treated with erythropoiesis-stimulating agents. Current data is insufficient to determine if an increased risk of malignancy can be linked with daprodustat treatment (Ref).
Mechanism: Related to the pharmacologic action; daprodustat increases the transcription of hypoxia-inducible factor (HIF)-responsive genes, including vascular endothelial growth factor (VEGF). Upregulation of VEGF results in increased tumor angiogenesis (Ref).
Daprodustat may increase the risk of thrombotic vascular events, including major cardiovascular events (MACE). Arterial and venous thrombotic events (eg, acute myocardial infarction, cerebrovascular accident, venous thromboembolism, vascular access thrombosis) may be fatal. In clinical studies, the incidence of thromboembolic events was similar between patients treated with daprodustat and patients treated with erythropoiesis-stimulating agents (Nangaku 2022). An increased risk of hospitalization for heart failure, exacerbation of hypertension, and hypertensive crisis have also been reported. In clinical trials comparing daprodustat to erythropoiesis-stimulating agents for the treatment of anemia in patients on dialysis, the incidence of MACE was similar between groups (Ref).
Mechanism: Related to the pharmacologic action; daprodustat increases the transcription of hypoxia-inducible factor (HIF)-responsive genes, resulting in increased endogenous erythropoietin. Potential mechanisms for erythropoietin-induced thrombosis include increased blood viscosity, increased subendothelium platelet adhesion, enhanced thrombin generation, and/or depressed levels of proteins C and S. Erythropoietin-induced hypertension may be due to increased blood viscosity, increased vascular reactivity, or catecholamine release and renin-angiotensin system activation (Ref).
Risk factors:
• Preexisting cardiovascular disease, especially acute coronary syndrome (including myocardial infarction within the past 3 months)
• Preexisting cerebrovascular disease (especially cerebrovascular event within the past 3 months)
• Rapid rise in hemoglobin (>1 g/dL over 2 weeks)
• Target hemoglobin >11 g/dL
• Iron deficiency (Ref)
• Preexisting heart failure
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Cardiovascular: Exacerbation of hypertension (24%; serious: 3%) (table 1)
|
Drug (Daprodustat) |
Comparator (Recombinant Human Erythropoietin) |
Number of Patients (Daprodustat) |
Number of Patients (Recombinant Human Erythropoietin) |
|---|---|---|---|
|
24% |
24% |
1,482 |
1,474 |
|
Severe: 3% |
3% |
1,482 |
1,474 |
Gastrointestinal: Abdominal pain (11%) (table 2)
|
Drug (Daprodustat) |
Comparator (Recombinant Human Erythropoietin) |
Number of Patients (Daprodustat) |
Number of Patients (Recombinant Human Erythropoietin) |
Comments |
|---|---|---|---|---|
|
6% |
7% |
1,482 |
1,474 |
Gastric or esophageal erosion |
1% to 10%:
Gastrointestinal: Gastrointestinal erosion (≤6%; including esophageal erosions)
Hematologic & oncologic: Malignant neoplasm (4%) (table 3)
|
Drug (Daprodustat) |
Comparator (Recombinant Human Erythropoietin) |
Number of Patients (Daprodustat) |
Number of Patients (Recombinant Human Erythropoietin) |
|---|---|---|---|
|
4% |
5% |
1,482 |
1,474 |
Hypersensitivity: Hypersensitivity reaction (7%)
Nervous system: Dizziness (7%)
Frequency not defined:
Cardiovascular: Acute myocardial infarction, deep vein thrombosis, heart failure, hypertensive crisis, pulmonary embolism, thrombosis (vascular access), venous thromboembolism
Nervous system: Cerebrovascular accident
Concomitant use with strong CYP2C8 inhibitors (eg, gemfibrozil); uncontrolled hypertension.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Disease-related concerns:
• Chronic kidney disease (patients not on dialysis): Patients with nondialysis-dependent chronic kidney disease (CKD) experienced an increased risk of CV mortality, stroke, thromboembolism, hospitalization for heart failure, serious GI erosions, and acute kidney injury compared to patients who received recombinant human erythropoietin products in a large trial. Use in not recommended in these patients.
• Hepatic impairment: Initial dose reductions are recommended in patients with moderate impairment (Child-Pugh class B). Use is not recommended in patients with severe impairment (Child-Pugh class C).
Other warnings/precautions:
• Abuse: Intentional nontherapeutic use of daprodustat may be seen in athletes due to its effects on erythropoiesis. Misuse by healthy persons may lead to polycythemia, which can lead to life-threatening CV events (eg, stroke, MI, thromboembolism).
• Factors impairing erythropoiesis: Prior to treatment, correct or exclude deficiencies of vitamin B12, and/or folate, as well as other factors that may impair erythropoiesis (metabolic or chronic inflammatory conditions, infections, bleeding). Ensure adequate iron stores before initiating and throughout therapy. The manufacturer recommends supplemental iron be administered if serum ferritin is <100 ng/mL or serum transferrin saturation is <20%; however, the threshold for iron replacement should be individualized based on clinical considerations (eg, trends in Hb level, goals of therapy) (KDIGO 2012). Most patients with CKD will require iron supplementation during the course of therapy.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Jesduvroq: 1 mg, 2 mg, 4 mg, 6 mg, 8 mg
No
Tablets (Jesduvroq Oral)
1 mg (per each): $4.69
2 mg (per each): $9.38
4 mg (per each): $18.77
6 mg (per each): $28.15
8 mg (per each): $37.54
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Oral: Administer without regard to meals. Swallow whole; do not cut, chew, or crush tablets.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216951s000lbl.pdf#page=23, must be dispensed with this medication.
Anemia due to chronic kidney disease (dialysis-dependent): Treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least 4 months.
Limitations of use: Has not been shown to improve quality of life, fatigue, or patient well-being; not indicated as a substitute for RBC transfusions in patients who require immediate correction of anemia or treatment of anemia of CKD in patients who are not on dialysis.
Substrate of BCRP/ABCG2, CYP2C8 (major), CYP3A4 (minor), OAT1/3; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy
CYP2C8 Inducers (Moderate): May decrease the serum concentration of Daprodustat. Risk C: Monitor therapy
CYP2C8 Inhibitors (Moderate): May increase the serum concentration of Daprodustat. Management: Reduce the daprodustat starting dose by half if combined with moderate CYP2C8 inhibitors, unless the dose is 1 mg, then no dose adjustment is required. Monitor hemoglobin and adjust daprodustat dose when starting or stopping moderate CYP2C8 inhibitors. Risk D: Consider therapy modification
CYP2C8 Inhibitors (Strong): May increase the serum concentration of Daprodustat. Risk X: Avoid combination
CYP2C8 Inhibitors (Weak): May increase the serum concentration of Daprodustat. Risk C: Monitor therapy
Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
Adverse events were observed in animal reproduction studies at doses also causing maternal toxicity.
It is not known if daprodustat is present in breast milk.
Due to the potential for serious adverse reactions, breastfeeding is not recommended by the manufacturer during treatment and for 1 week after the last daprodustat dose.
Assess liver function (ALT, AST, alkaline phosphatase, and total bilirubin) prior to initiation and repeat if the patient develops signs or symptoms consistent with liver disease; transferrin saturation and serum ferritin (prior to and during treatment) to ensure adequate stores before initiating and throughout therapy; Hb (every 2 weeks for the first month after initiation and following dose adjustments and then monthly thereafter); BP; signs and symptoms of myocardial infarction, stroke, venous thromboembolism, or thrombosis of vascular access; signs and symptoms of heart failure; signs and symptoms of gastric and esophageal erosions and GI bleeding.
Daprodustat increases the transcription of HIF (hypoxia-inducible factor)-responsive genes (including erythropoietin) through the reversible inhibition of HIF-PH1, PH2 and PH3 (IC50 in the low nM range), resulting in stabilization and nuclear accumulation of HIF-1α and HIF-2α transcription factors.
Onset:
Increases in endogenous erythropoietin: 6 to 8 hours.
Peak increases in reticulocyte counts: 7 to 15 days.
Hb steady state levels: ~4 weeks in patients previously receiving erythropoietin-stimulating agents (ESAs), ~16 to 20 weeks in patients who had not been receiving an ESA.
Distribution: Vdss: 14.3 L.
Protein binding: >99%.
Metabolism: In vitro: Primarily by CYP2C8 (95% contribution), with a minor contribution by CYP3A4 (5%).
Bioavailability: 65%.
Half-life elimination: ~1 to 4 hours.
Time to peak: 1 to 4 hours.
Excretion: Feces: 74% (primarily metabolites); Urine: 21% (primarily metabolites).
Clearance: 18.9 L/hour.
Hepatic function: Following a single 6 mg dose, Cmax was similar, and AUC increased by 1.5-fold in patients with mild impairment (Child-Pugh class A) compared to healthy volunteers. Cmax and AUC were increased 2-fold, respectively in patients with moderate impairment (Child-Pugh class B) compared to healthy volunteers.
Unbound concentrations: Cmax and AUC increased by 1.6 and 2.2-fold, respectively in patients with mild impairment (Child-Pugh class A) compared to healthy volunteers. AUC increased by 2.3-fold in patients with moderate impairment (Child-Pugh class B) compared to healthy volunteers.
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