Daprodustat
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Boxed warning
WARNING: INCREASED RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, and THROMBOSIS OF VASCULAR ACCESS JESDUVROQ increases the risk of thrombotic vascular events, including major adverse cardiovascular events (MACE) [see Warnings and Precautions ( 5.1 )] . Targeting a hemoglobin level greater than 11 g/dL is expected to further increase the risk of death and arterial venous thrombotic events, as occurs with erythropoietin stimulating agents (ESAs), which also increase erythropoietin levels [see Warnings and Precautions ( 5.1 )] .
No trial has identified a hemoglobin target level, dose of JESDUVROQ, or dosing strategy that does not increase these risks [see Dosage and Administration ( 2.4 )]. Use the lowest dose of JESDUVROQ sufficient to reduce the need for red blood cell transfusions [see Dosage and Administration ( 2.4 )] . WARNING: INCREASED RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, and THROMBOSIS OF VASCULAR ACCESS See full prescribing information for complete boxed warning. • JESDUVROQ increases the risk of thrombotic vascular events, including major adverse cardiovascular events (MACE).
( 5.1 ) • Targeting a hemoglobin level greater than 11 g/dL is expected to further increase the risk of death and arterial venous thrombotic events, as occurs with erythropoietin stimulating agents (ESAs), which also increase erythropoietin levels. ( 5.1 ) • No trial has identified a hemoglobin target level, dose of JESDUVROQ, or dosing strategy that does not increase these risks. ( 2.4 ) • Use the lowest dose of JESDUVROQ sufficient to reduce the need for red blood cell transfusions. ( 2.4 )
Hypoxia-inducible Factor Prolyl Hydroxylase Inhibitor
Dosing in kidney impairment
Recommended Starting Dose of JESDUVROQ Adults with Anemia Due to Chronic Kidney Disease Receiving Dialysis for at Least 4 Months Adults Not Being Treated with an ESA: For adults not being treated with an ESA, the starting dose of JESDUVROQ is based on the hemoglobin level (see Table 1 ). Dose modifications are needed for patients receiving concomitant treatment with a moderate CYP2C8 inhibitor or moderate hepatic impairment [see Dosage and Administration ( 2.5 , 2.6 ), Drug Interactions, Use in Specific Populations, Clinical Pharmacology] . [See table below.] a See dosing modifications in Section 2.5 if the patient has moderate hepatic impairment and Section 2.6 if the patient is on a moderate CYP2C8 inhibitor.
Adults Being Switched from an ESA: For adults being switched from an ESA to JESDUVROQ, the starting dose of JESDUVROQ is based on the dose regimen of the ESA at the time of substitution (see Table 2 ). Dose modifications are needed for patients receiving concomitant treatment with a moderate CYP2C8 inhibitor or moderate hepatic impairment [see Dosage and Administration ( 2.5 , 2.6 ), Drug Interactions, Use in Specific Populations, Clinical Pharmacology] . [See table below.] ESA = Erythropoiesis stimulating agent. a See dosing modifications in Section 2.5 if the patient has moderate hepatic impairment and Section 2.6 if the patient is on a moderate CYP2C8 inhibitor. b For patients on subcutaneous epoetin alfa, convert the epoetin alfa subcutaneous dose to intravenous dose equivalent by multiplying the subcutaneous dose received per week by 1.42 to obtain the weekly intravenous dose.
| Pre-Treatment Hemoglobin Level (g/dL) | Starting Dose of JESDUVROQ(Once Daily Dosing)a |
| <9 | 4 mg |
| ≥9 to ≤10 | 2 mg |
| >10 | 1 mg |
| Current Dose of ESA | Dose of JESDUVROQa | ||
| Epoetin AlfabIntravenous(units/week) | Darbepoetin AlfaSubcutaneous/Intravenous(mcg/4 weeks) | Methoxy PEG-Epoetin BetaSubcutaneous/Intravenous(mcg/month) | Once DailyDosing |
| Less than or equal to 2,000 | 20 to 30 | 30 to 40 | 4 mg |
| Greater than 2,000 to less than 10,000 | Greater than30 to 150 | Greater than40 to 180 | 6 mg |
| Greater than or equal to 10,000 to less than 20,000 | Greater than150 to 300 | Greater than180 to 360 | 8 mg |
| Greater than or equal to 20,000 | Greater than 300 | Greater than 360 | 12 mg |
Dosing in liver impairment
Pre-Treatment and On-Treatment Evaluations of Anemia, Iron Stores, and Liver Tests Evaluation of Anemia and Iron Stores Correct and exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding) before initiating JESDUVROQ. Evaluate the iron status in all patients before and during treatment with JESDUVROQ.
Administer supplemental iron therapy when serum ferritin is less than 100 ng/ml or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course of therapy. Liver Testing Assess serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin prior to initiation of JESDUVROQ.
Repeat the liver tests if the patient develops signs or symptoms that could be consistent with liver disease during treatment with JESDUVROQ.
Dosage Modification for Hepatic Impairment Reduce the starting dose of JESDUVROQ by half (see Table 1 and Table 2 ) in patients with moderate hepatic impairment (Child-Pugh Class B) except in patients whose starting dose is already 1 mg. Use of JESDUVROQ in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended [see Use in Specific Populations, Clinical Pharmacology] .
Drug interactions
Check daprodustat against a medication listLabel text (4 paragraphs)
7 DRUG INTERACTIONS • Moderate CYP2C8 Inhibitors: Reduce starting dose. ( 7.1 ) • CYP2C8 Inducers: Monitor hemoglobin and adjust the dose of JESDUVROQ as appropriate. ( 7.2 )
7.1 CYP2C8 Inhibitors Concomitant administration of strong CYP2C8 inhibitors (e.g., gemfibrozil) with JESDUVROQ is contraindicated due to a marked increase in daprodustat exposure [see Contraindications ( 4 ), Clinical Pharmacology ( 12.3 )] . Concomitant administration of moderate CYP2C8 inhibitors (e.g., clopidogrel) increases daprodustat exposure [see Clinical Pharmacology ( 12.3 )] . Reduce the starting dose of JESDUVROQ by half when initiating treatment in patients on clopidogrel or a moderate CYP2C8 inhibitor except in patients whose starting dose is already 1 mg.
Monitor hemoglobin and adjust the dose of JESDUVROQ when initiating or stopping therapy with clopidogrel or a moderate CYP2C8 inhibitor during treatment with JESDUVROQ [see Dosage and Administration ( 2.6 )] .
7.2 CYP2C8 Inducers CYP2C8 inducers (e.g., rifampin) may decrease daprodustat exposure, which may result in loss of efficacy. Monitor hemoglobin and adjust the dose of JESDUVROQ when initiating or stopping therapy with CYP2C8 inducers during treatment with JESDUVROQ [see Clinical Pharmacology ( 12.3 )] .
Contraindications
4 CONTRAINDICATIONS JESDUVROQ is contraindicated in patients: • Receiving a strong CYP2C8 inhibitor such as gemfibrozil [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] . • With uncontrolled hypertension [see Warnings and Precautions ( 5.3 )] . • Strong cytochrome P450 2C8 (CYP2C8) inhibitors such as gemfibrozil. ( 4 ) • Uncontrolled hypertension. ( 4 )
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary Available data with JESDUVROQ use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with CKD ( see Clinical Considerations ) . Daprodustat administered orally to pregnant rats and rabbits during the period of organogenesis was associated with adverse fetal outcomes, including embryonic and fetal loss and reduced fetal weight, at doses that caused maternal toxicity and polycythemia ( see Data ). Advise pregnant women of the potential risk to the fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: CKD in pregnancy increases the risk for maternal hypertension, preeclampsia, miscarriage, stillbirth, preterm delivery, low birth weight infants, and polyhydramnios.
Data Animal Data : Daprodustat was orally administered to pregnant rats at 0.5, 7, or 60 mg/kg/day from gestation day 6 to gestation day 17 during the period of organogenesis. No adverse effects were observed at doses less than or equal to 7 mg/kg/day (3 times the maximum recommended human dose [MRHD] based on body surface area). Daprodustat administration resulted in post-implantation loss, increased embryofetal death, and reduction in skeletal ossification in rats at a dose of 60 mg/kg/day (24 times the MRHD based on body surface area), which was associated with maternal toxicity (reduced body weight gain or weight loss). Maternal toxicity occurred at doses associated with polycythemia.
Daprodustat was orally administered to pregnant rabbits at doses of 4, 30, or 60 mg/kg/day from gestation day 7 until gestation day 19 during the period of organogenesis. No adverse effects were observed at doses less than or equal to 30 mg/kg/day (24 times the MRHD based on body surface area). Daprodustat administration was associated with a low incidence of abortions and fetal skeletal malformations (irregularly shaped anterior fontanelle, manubrium, fused sternal centra, and microphthalmia) at a dose of 60 mg/kg/day (49 times the MRHD based on body surface area) in the presence of maternal toxicity (reduced body weight gain or weight loss)…
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
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