Dosing & Uses
Dosage Forms & Strengths
tablet
- 1mg
- 2mg
- 4mg
- 6mg
- 8mg
Anemia of Chronic Kidney Disease
Indicated for treatment of anemia due to chronic kidney disease (CKD) in adults on dialysis for ≥4 months
Individualize dosing and use lowest dose sufficient to reduce need for red blood cell (RBC) transfusions
Do not target a hemoglobin >11 g/dL
Dosing in patients not treated with an erythropoietin-stimulating agent (ESA)
- Starting dose is based on pretreatment hemoglobin (Hgb) level
- Hgb <9 g/dL: Start at 4 mg PO qDay
- 9-10 g/dL: Start at 2 mg PO qDay
- >10 g/dL: Start at 1 mg PO qDay
Switching from an ESA
- Starting dose of daprodustat is based on dosing regimen of ESA at time of substitution
-
Epoetin alfa IV
- Note: For patients on SC epoetin alfa, convert epoetin alfa SC dose to IV dose equivalent by multiplying SC dose received per week by 1.42 to obtain weekly IV dose
- ≤2,000 units/week: Start daprodustat at 4 mg PO qDay
- >2,000 to <10,000 units/week: Start daprodustat at 6 mg PO qDay
- ≥10,000 to <20,000 units/week: Start daprodustat at 8 mg PO qDay
- ≥20,000 units/week: Start daprodustat at 12 mg PO qDay
-
Darbepoetin alfa IV/SC
- 20-30 mcg/4 weeks: Start daprodustat at 4 mg PO qDay
- >30 to 150 mcg/4 weeks: Start daprodustat at 6 mg PO qDay
- >150 to 300 mcg/4 weeks: Start daprodustat at 8 mg PO qDay
- >300 mcg/4 weeks: Start daprodustat at 12 mg PO qDay
-
Methoxy polyethylene glycol (PEG)-epoetin beta SC/IV
- 30-40 mcg/month: Start daprodustat at 4 mg PO qDay
- >40 to 180 mcg/month: Start daprodustat at 6 mg PO qDay
- >180 to 360 mcg/month: Start daprodustat at 8 mg PO qDay
- >360 mcg/month: Start daprodustat at 12 mg PO qDay
Dosage Modifications
Recommended dose levels
- 1 mg/day
- 2 mg/day
- 4 mg/day
- 6 mg/day
- 8 mg/day
- 12 mg/day
- 16 mg/day
- 24 mg/day (maximum recommended dose)
Dosage adjustments
- When adjusting doses, consider Hgb rate of rise, rate of decline, and variability
- Do not increase dose more frequently than once q4Weeks
- If dose needs to be adjusted, increase or decrease by 1 dose level at a time
-
Decrease dose
- Hgb increases rapidly (eg, >1 g/dL over 2 weeks or >2 g/dL over 4 weeks), OR
- Hgb >11 g/dL
-
Interrupt treatment
- Hgb >12 g/dL
- Restart at 1 dose level lower once Hgb is within target range
- Do not continue therapy beyond 24 weeks if no clinically meaningful increase in Hgb is achieved
- Seek alternative explanations for an inadequate response and treat before restarting
Coadministration with moderate CYP2C8 inhibitors
- Coadministration with clopidogrel or moderate CYP2C8 inhibitor: Reduce starting dose by half except in patients whose starting dose is 1 mg
- Monitor Hgb and adjust dose when initiating or stopping therapy with clopidogrel or moderate CYP2C8 inhibitor during treatment
Renal impairment
- Steady-state exposure of daprodustat is similar in patients with normal renal function and those with varying degrees of renal impairment
-
Hemodialysis or peritoneal dialysis
- Daprodustat exposure not significantly impacted
- Systemic exposure of daprodustat metabolites was higher in patients with Stage 3-5 CKD than in those with normal renal function
- Exposures of metabolites were higher on non-dialysis days than on dialysis days
Hepatic impairment
- Mild (Child-Pugh Class A): No dosage adjustment necessary
- Moderate (Child-Pugh Class B): Reduce starting dose by half except in patients whose starting dose is 1 mg
- Severe (Child-Pugh C): Not studied; not recommended
Dosing Considerations
Monitoring response to therapy
- Following initiation and after each dose adjustment, monitor Hgb q2Weeks for first month and then q4Weeks thereafter
Anemia or iron status
- Correct and exclude other causes of anemia (eg, vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding) before initiating
- Evaluate iron status before and during treatment
- Serum ferritin <100 mcg/mL or serum transferrin saturation <20%: Administer supplemental iron therapy
- Majority of patients with CKD will require supplemental iron during course of therapy
Liver testing
- Assess serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin before initiating
- Repeat liver tests if signs or symptoms consistent with liver disease develop during treatment
Limitations of use
- Not shown to improve quality of life, fatigue, or patient well-being
-
Not indicated
- As a substitute for RBC transfusion in patients requiring immediate correction of anemia
- For patients not on dialysis
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (0)
Monitor Closely (0)
Minor (0)
Adverse Effects
>10%
Hypertension (24%)
Abdominal pain (11%)
1-10%
Dizziness (7%)
Hypersensitivity (7%)
Vascular access thrombosis (5%)
Myocardial infarction (3.4%)
Stroke (1.2%)
<1%
Deep vein thrombosis (0.7%)
Pulmonary embolism (0.3%)
Warnings
Black Box Warnings
Increased risk of death, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access
- Increased risk of thrombotic vascular events, including major adverse cardiovascular events (MACE)
- Hemoglobin rise >1 g/dL over 2 weeks may contribute to these risks
- Target hemoglobin level >11 g/dL is expected to further increase risk of death and arterial venous thrombotic events, as occurs with erythropoietin-stimulating agents (ESAs), which also increase erythropoietin levels
- No trial has identified a hemoglobin target level, daprodustat dose, or dosing strategy that avoids these risks
- Use lowest dose to reduce need for red blood cell transfusion
- Avoid use in patients with a history of myocardial infarction, cerebrovascular event, or acute coronary syndrome within 3 months before starting
Contraindications
Strong CYP2C8 inhibitors (eg, gemfibrozil)
Uncontrolled hypertension
Cautions
Increased risk of cardiovascular mortality, stroke, thromboembolism, serious acute kidney injury, hospitalization for heart failure, and serious gastrointestinal erosions observed
Advise patients to seek immediate medical attention if signs or symptoms of MI, stroke, VTE, or thrombosis of vascular access develop; evaluate and manage promptly if these occur (see Black Box Warning)
Hospitalization for heart failure reported; consider patient’s history of heart failure before prescribing; advise patients on signs and symptoms of heart failure and to immediately their healthcare provider if these symptoms worsen
Contraindicated in uncontrolled hypertension; periodically monitor blood pressure and adjust or initiate antihypertensive therapy as needed
Safety not established for treatment of anemia due to CKD in adults not on dialysis; use not recommended in this setting
Not studied and not recommended in patients with active malignancies; malignancies reported
Gastrointestinal erosion
- Gastric or esophageal erosions occurred
- Consider this risk particularly in patients with risk factors for gastrointestinal (GI) erosions, such as history of GI erosion, peptic ulcer disease, concomitant use of medications that increase the risk of GI erosion, current tobacco smoking, and alcohol use
- Advise patients of symptoms and signs of gastric and esophageal erosions and of GI bleeding and to seek prompt medical care if these occur
Drug interaction overview
- CYP2C8 substrate
-
Strong CYP2C8 inhibitors (eg, gemfibrozil)
- Contraindicated
- Strong CYP2C8 inhibitors are contraindicated due to marked increase in daprodustat exposure
-
Moderate CYP2C8 inhibitors (eg, clopidogrel)
- Reduce daprodustat dose by half when initiating moderate CYP2C8 inhibitors, except with a starting dose of 1 mg/day
- Monitor Hgb and adjust daprodustat dose when initiating or stopping moderate CYP2C8 inhibitor
- Moderate CYP2C8 inhibitors increase daprodustat exposure
-
CYP2C8 inducers (eg, rifampin)
- Monitor Hgb and adjust dose when initiating or stopping therapy with CYP2C8 inducers during treatment
- CYP2C8 inducers may decrease exposure and efficacy of daprodustat
Pregnancy & Lactation
Pregnancy
Available data are insufficient in pregnant females to establish a drug-associated risk of major birth defects, miscarriages, or adverse maternal or fetal outcomes
Animal data
- Oral administration to pregnant rats and rabbits during organogenesis was associated with adverse fetal outcomes (eg, embryonic and fetal loss, reduced fetal weight) at doses that caused maternal toxicity and polycythemia
- Advise pregnant females regarding potential risk to fetus
Clinical consideration
- CKD during pregnancy increases risk for maternal hypertension, preeclampsia, miscarriage, stillbirth, preterm delivery, low birth weight infants, and polyhydramnios
Lactation
There are no data on drug presence in human milk, effects on breastfed infants, or effects on milk production
Daprodustat is present in the milk of lactating rats
When a drug is present in animal milk, it is likely that drug will be present in human milk
Advise patients not to breastfeed during treatment and for 1 week after final dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Reversible inhibitor of hypoxia inducible factor (HIF)-PH1, PH2, and PH3
Inhibition of oxygen-sensing prolyl hydroxylase enzymes stabilizes hypoxia-inducible factors, which can lead to transcription of erythropoietin and other genes involved in the correction of anemia
Daprodustat increases endogenous erythropoietin in a dose-dependent manner
Also increases serum transferrin and total iron binding capacity (TIBC) and decreased serum ferritin, transferrin saturation, and hepcidin when administered for 52 weeks in adults on dialysis with anemia due to CKD
Absorption
Peak plasma time: 1-4 hr
Bioavailability: 65%
Steady-state achieved within 24 hr of dosing
Effects of food
- High-fat/high-calorie: No significant changes in daprodustat exposure compared with fasted state
Distribution
Vd (steady-state): 14.3 L (healthy subjects)
Protein bound: > 99%
Metabolism
Primarily metabolized by CYP2C8 (95%); minor contribution by CYP3A4 (5%)
Elimination
Half-life: 1-4 hr
Clearance: 18.9 L/hr (plasma)
Excretion: Feces (74%); urine (21%); ~99.5% of dose excreted as oxidative metabolites and remainder as daprodustat
Administration
Oral Administration
May take with or without food
May take without regard to concomitant administration of iron or phosphate binders
Swallow tablet whole; do NOT cut, crush, or chew
Administer without regard to timing or type of dialysis
Missed dose
- Take as soon as possible, unless it is the same day as next scheduled dose
- In this case, skip missed dose, and take next dose at scheduled time; do NOT double dose
Storage
Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
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