Jesduvroq

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.

Important Dosing Information

Individualize dosing and use the lowest dose of JESDUVROQ sufficient to reduce the need for red blood cell transfusions. Do not target a hemoglobin higher than 11 g/dL.

JESDUVROQ can be taken with or without food, and without regard to concomitant administration of iron or phosphate binders [see Clinical Pharmacology ].

JESDUVROQ should be swallowed whole. Tablets should not be cut, crushed, or chewed.

JESDUVROQ can be administered without regard to the timing or type of dialysis [see Clinical Pharmacology ].

If a dose of JESDUVROQ is missed, it should be taken as soon as possible, unless it is the same day as the next dose. In this case, the missed dose should be skipped, and the next dose taken at the usual time. Double-doses should not be taken to make-up for a missed dose.

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 , Drug Interactions , Use in Specific Populations , Clinical Pharmacology ].

 

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 , Drug Interactions , Use in Specific Populations , Clinical Pharmacology ].

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.

Monitoring Response to Therapy and Dose Adjustment

Following initiation of therapy and after each dose adjustment, monitor hemoglobin every 2 weeks for the first month and then every 4 weeks thereafter.

When adjusting doses of JESDUVROQ, consider hemoglobin rate of rise, rate of decline and hemoglobin variability. Do not increase the dose of JESDUVROQ more frequently than once every 4 weeks.

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If the dose of JESDUVROQ needs to be adjusted, increase or decrease by one dose level at a time (see Table 3).

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Decrease the dose of JESDUVROQ if hemoglobin increases rapidly (e.g., greater than 1 g/dL over 2 weeks or greater than 2 g/dL over 4 weeks) or if the hemoglobin exceeds 11 g/dL.

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If hemoglobin exceeds 12 g/dL, interrupt treatment with JESDUVROQ. When the hemoglobin is within the target range, treatment may be restarted at one dose level lower (see Table 3).

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Treatment with JESDUVROQ should not be continued beyond 24 weeks of therapy if a clinically meaningful increase in hemoglobin level is not achieved. Alternative explanations for an inadequate response should be sought and treated before re-starting therapy.

a 24 mg is the maximum recommended once daily dose.

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 ].

Dosage Modification for Concomitant Treatment with Moderate CYP2C8 Inhibitors

Reduce the starting dose of JESDUVROQ by half (see Table 1 and Table 2) in patients who are on clopidogrel or a moderate CYP2C8 inhibitor except in patients whose starting dose is already 1 mg [see Drug Interactions , Clinical Pharmacology ].

Monitor hemoglobin and adjust the dose of JESDUVROQ when initiating or stopping therapy with clopidogrel or a moderate CYP2C8 inhibitor during treatment with JESDUVROQ.

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) 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.

Lactation

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 JESDUVROQ, such as thrombotic vascular events, advise patients not to breastfeed during treatment with JESDUVROQ, 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.

Pediatric Use

Safety and effectiveness of JESDUVROQ in pediatric patients have not been established.

Geriatric Use

Of the total number of subjects treated with JESDUVROQ in the ASCEND-D study (n = 2,964), 480 (32%) subjects were aged 65 years and older, and 159 (11%) were aged 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. No other reported clinical experience has identified differences in responses between the elderly and younger patients.

Hepatic Impairment

No adjustment of the starting dose is required in patients with mild hepatic impairment (Child-Pugh Class A).

Reduce the starting dose of JESDUVROQ by half in patients with moderate hepatic impairment (Child-Pugh Class B) except in patients whose starting dose is already 1 mg [see Clinical Pharmacology ].

JESDUVROQ has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, JESDUVROQ is not recommended in patients with severe hepatic impairment.