Daprodustat

Concomitant administration of moderate CYP2C8 inhibitors (e.g., clopidogrel) increases daprodustat exposure. Reduce the starting dose of daprodustat 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 daprodustat when initiating or stopping therapy with clopidogrel or a moderate CYP2C8 inhibitor during treatment with daprodustat.

CYP2C8 inducers (e.g., rifampin) may decrease daprodustat exposure, which may result in loss of efficacy. Monitor hemoglobin and adjust the dose of daprodustat when initiating or stopping therapy with CYP2C8 inducers during treatment with daprodustat.

Reduce the starting dose of daprodustat by half in patients with moderate hepatic impairment (Child-Pugh Class B) except in patients whose starting dose is already 1 mg.

Consider the patient’s history of heart failure when deciding whether to prescribe daprodustat. Advise patients of the symptoms and signs of heart failure and to immediately report any worsening to their healthcare provider.

In clinical trials, patients with a pre-existing history of heart failure were at increased risk of hospitalization for heart failure with daprodustat (14.5%; 6.8 per 100 PY) compared to recombinant human erythropoietin (11.3%; 5.1 per 100 PY).

In clinical trials, gastric or esophageal erosions occurred in patients receiving daprodustat.

Consider this risk particularly in patients at increased risk for gastrointestinal erosions, such as those with a history of gastrointestinal erosion, peptic ulcer disease, use of concomitant medications that increase the risk of gastrointestinal erosion, and current tobacco smokers and alcohol drinkers.

Advise patients of the symptoms and signs of gastric and esophageal erosions and of gastrointestinal bleeding and to seek prompt medical care if these occur.

Because increased hypoxia inducible factor (HIF)-1 levels may be associated with unfavorable effects on cancer growth, daprodustat has not been studied and is not recommended in patients with active malignancies. Malignancies were observed in 4.4% (1.9 per 100 PY) of patients treated with daprodustat and 5.2% (2.3 per 100 PY) of patients treated with recombinant human erythropoietin (rhEPO). No evidence of increased carcinogenicity was observed in animal studies.

Daprodustat increases the risk of arterial and venous thrombotic events, that may be fatal, including myocardial infarction, stroke, venous thromboembolism and vascular access thrombosis. Patients with cardiovascular or cerebrovascular disease are at increased risk of these events. Avoid use in patients with a history of myocardial infarction, cerebrovascular event, or acute coronary syndrome within the 3 months prior to starting daprodustat.

A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks. Targeting a hemoglobin level of greater than 11 g/dL is expected to further increase the risk of death and arterial and venous thrombotic events, as occurs with ESAs, which also increase erythropoietin levels.

No trial has identified a hemoglobin 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 red blood transfusions. Adherence to dosing and hemoglobin monitoring recommendations is important to avoid excessive erythropoiesis.

Advise patients to seek immediate medical attention if they develop signs or symptoms of myocardial infarction, stroke, venous thromboembolism, or thrombosis of vascular access. Evaluate and manage promptly if these occur.

Risk Summary

Available data with daprodustat 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. 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. 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) and polycythemia.

In a pre- and postnatal development study, pregnant rats were dosed orally with daprodustat from implantation until weaning (gestation day 6 to lactation day 21) at 0.8, 7, or 40 mg/kg/day concomitantly with 3 major human metabolites of daprodustat. No adverse effects were observed at doses less than or equal to 7 mg/kg/day (3 times the MRHD based on body surface area). Maternal toxicity (in the presence of polycythemia) was noted at 40 mg/kg/day (16 times the MRHD based on body surface area), which was associated with increased pup deaths and decreased pup weights.

Risk Summary

There are no data on the presence of daprodustat in human milk, the effects on the breastfed child, or the effects on milk production. Daprodustat is present in the milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Given the serious adverse reactions seen in adults treated with daprodustat, such as thrombotic vascular events, advise patients not to breastfeed during treatment with daprodustat, and for one week after the final dose.

Data

In a pre- and postnatal development study in rats, when daprodustat was orally administered to maternal rats during the lactation period, the drug was detected in plasma of suckling pups on postnatal day 10. The plasma concentration of daprodustat in pups was 2.3% to 3.7% of daprodustat detected in the plasma of dams when dosed at 40 mg/kg/day.

Daprodustat was not carcinogenic in two-year carcinogenicity studies when administered orally at doses of 0.02, 0.1, 0.8, or 4 mg/kg/day (males) / 7 mg/kg/day (females) in rats (up to 3 times the MRHD based on body surface area) and 0.2, 0.8, or 3 mg/kg/day (including subcutaneous injection of major human metabolites of daprodustat) in mice (approximating the MRHD based on body surface area).

Daprodustat was negative for mutagenic or clastogenic potential in the in vitro bacterial reverse mutation assay, the in vitro human lymphocyte chromosomal aberration assay, and the in vivo rat bone marrow micronucleus assay.

In a fertility and early embryonic development study in rats, daprodustat was administered orally at doses of 2, 7, or 100 mg/kg/day in females, resulting in maternal toxicity of reduced body weight gain and decreased mean uterine weight (in the presence of polycythemia), associated with decreased number of corpora lutea, implantations, and live fetuses, and increased post-implantation loss at the dose of 100 mg/kg/day (41 times the MRHD based on body surface area).

• Increased Risk of Death, Myocardial Infarction, Stroke, Venous Thromboembolism, and Thrombosis of Vascular Access
• Risk of Hospitalization for Heart Failure
• Hypertension
• Gastrointestinal Erosion

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of daprodustat was evaluated in adults with dialysis-dependent chronic kidney disease with anemia in the ASCEND-D trial based on an on-study analysis (on and off treatment). Patients were randomized to daprodustat or rhEPO (epoetin alfa for patients on hemodialysis; darbepoetin alfa for patients on peritoneal dialysis). Of the 2,964 patients randomized in the trial, 1,487 were randomized to daprodustat, 1,316 (88.5%) of whom were on hemodialysis and 171 (11.5%) of whom were on peritoneal dialysis.

The median extent of exposure to daprodustat and rhEPO was similar. In the daprodustat treatment arm, 65% of the participants were exposed to at least 18 months of daprodustat and 29% of participants received daprodustat for at least 2.5 years.

Daprodustat was non-inferior to rhEPO on the time to first occurrence of major adverse cardiovascular events (MACE) in adults with anemia due to CKD who were on dialysis.

Permanent treatment discontinuation due to an adverse reaction was reported in 19% of patients treated with daprodustat and 18% of patients treated with rhEPO. No specific adverse reaction resulted in permanent treatment discontinuation in >1% of patients treated with daprodustat.

The most common adverse reactions (≥10% of daprodustat-treated patients) were hypertension, thrombotic vascular events, and abdominal pain.

Table 1 lists the most common adverse reactions (reported in ≥5% of patients treated with daprodustat).

Table 1. Adverse Reactions Reported in ≥5% of Patients Treated with daprodustat in the ASCEND-D Trial:

rhEPO = Recombinant human erythropoietin.
^a Includes unspecified abdominal pain, upper abdominal pain, abdominal discomfort.
^b Includes rash, urticaria and dermatitis.

Thrombotic Vascular Events

Adjudicated thrombotic vascular events (fatal and non-fatal) were observed in 9.8 per 100 PY of patients receiving daprodustat and in 11.7 per 100 PY of patients receiving rhEPO (see Table 2).

Table 2. Adjudicated Thrombotic Vascular Events (Fatal and Non-Fatal) in the ASCEND‑D Trial^a:

PY = Person Years; rhEPO = Recombinant human erythropoietin.
^a These data are not an adequate basis for comparison of rates between the study drug and the active control.