Daprodustat

JESDUVROQ is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least four months. Limitations of Use JESDUVROQ has not been shown to improve quality of life, fatigue, or patient well-being. JESDUVROQ is not indicated for use:

• As a substitute for red blood cell transfusions in patients who require immediate correction of anemia.
• For treatment of anemia of chronic kidney disease in patients who are not on dialysis. JESDUVROQ is a hypoxia-inducible factor prolyl hydroxylase (HIF PH) inhibitor indicated for the treatment of anemia due to chronic kidney disease in adults who have been receiving dialysis for at least four months. ( 1 ) Limitations of Use Not shown to improve quality of life, fatigue, or patient well-being. Not indicated for use:
• As a substitute for transfusion in patients requiring immediate correction of anemia.
• In patients not on dialysis.

Tablets:

• 1 mg, gray, biconvex, round film-coated tablets debossed with “GS KF” on one face.
• 2 mg, yellow, biconvex, round film-coated tablets debossed with “GS V7” on one face.
• 4 mg, white, biconvex, round film-coated tablets debossed with “GS 13” on one face.
• 6 mg, pink, biconvex, round film-coated tablets debossed with “GS IM” on one face.
• 8 mg, orange, biconvex, round film-coated tablets debossed with “GS 5E” on one face. Tablets: 1 mg, 2 mg, 4 mg, 6 mg, and 8 mg. ( 3 )

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 )

• Risk of Hospitalization for Heart Failure: Increased in patients with a history of heart failure. ( 5.2 )
• Hypertension: Worsening hypertension, including hypertensive crisis may occur. Monitor blood pressure. Adjust anti-hypertensive therapy as needed. ( 5.3 )
• Gastrointestinal Erosion: Gastric or esophageal erosions and gastrointestinal bleeding have been reported. ( 5.4 )
• Not indicated for treatment of anemia of CKD in patients who are not dialysis-dependent ( 5.5 )
• Malignancy: May have unfavorable effects on cancer growth. Not recommended if active malignancy. ( 5.6 )

5.1 Increased Risk of Death, Myocardial Infarction, Stroke, Venous Thromboembolism, and Thrombosis of Vascular Access JESDUVROQ increases the risk of arterial and venous thrombotic events, that may be fatal, including myocardial infarction, stroke, venous thromboembolism and vascular access thrombosis [see Boxed Warning, Adverse Reactions ( 6.1 )] . 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 JESDUVROQ. 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 JESDUVROQ, or dosing strategy that does not increase these risks. Use the lowest dose of JESDUVROQ sufficient to reduce the need for red blood transfusions. Adherence to dosing and hemoglobin monitoring recommendations is important to avoid excessive erythropoiesis [see Dosage and Administration ( 2.4 )] . 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.

5.2 Risk of Hospitalization for Heart Failure In the ASCEND-D trial, hospitalization for heart failure was observed in 7.5% (3.3 per 100 Person Years [PY]) of patients on dialysis receiving JESDUVROQ and 6.8% (3.0 per 100 PY) of patients receiving recombinant human erythropoietin (rhEPO). Patients with a pre-existing history of heart failure were at increased risk of hospitalization for heart failure with JESDUVROQ (14.5%; 6.8 per 100 PY) compared to rhEPO (11.3%; 5.1 per 100 PY). Consider the patient’s history of heart failure when deciding whether to prescribe JESDUVROQ. Advise patients of the symptoms and signs of heart failure and to immediately report any worsening to their healthcare provider.

5.3 Hypertension JESDUVROQ is contraindicated in patients with uncontrolled hypertension. In the ASCEND-D trial, worsening of hypertension occurred in 24% (12 per 100 PY) of patients receiving JESDUVROQ and 24% (12 per 100 PY) of patients receiving rhEPO [see Adverse Reactions ( 6.1 )] . Serious worsening of hypertension occurred in 3.1% of patients receiving JESDUVROQ and 3.1% of patients receiving rhEPO. Cases of hypertensive crisis including hypertensive encephalopathy and seizures have also been reported in patients receiving JESDUVROQ. Periodically monitor blood pressure and adjust or initiate anti-hypertensive therapy as needed.

5.4 Gastrointestinal Erosion In the ASCEND-D trial, gastric or esophageal erosions occurred in 5.7% (2.5 per 100 PY) of patients receiving JESDUVROQ and 6.6% (2.9 per 100 PY) of rhEPO-treated patients. Serious erosions, including gastrointestinal bleeding and the need for red blood cell transfusions, were reported in 3.6% and 3.1% of those receiving JESDUVROQ and rhEPO, respectively. 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.

5.5 Serious Adverse Events in Patients with Anemia Due to Chronic Kidney Disease and Not on Dialysis The safety of JESDUVROQ has not been established for the treatment of anemia due to CKD in adults not on dialysis and its use is not recommended in this setting [see Indications and Usage ( 1 )] . In a large cardiovascular outcomes trial in adults with anemia of CKD who were not on dialysis (ASCEND-ND), an increased risk of cardiovascular mortality, stroke, thromboembolism, serious acute kidney injury, hospitalization for heart failure, and serious gastrointestinal erosions was observed in patients treated with JESDUVROQ compared to rhEPO.

5.6 Malignancy Because increased hypoxia inducible factor (HIF)-1 levels may be associated with unfavorable effects on cancer growth, JESDUVROQ 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 JESDUVROQ and 5.2% (2.3 per 100 PY) of patients treated with rhEPO. No evidence of increased carcinogenicity was observed in animal studies [see Nonclinical Toxicology ( 13.1 )] .

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Increased Risk of Death, Myocardial Infarction, Stroke, Venous Thromboembolism, and Thrombosis of Vascular Access [see Boxed Warning, Warnings and Precautions ( 5.1 )] .
• Risk of Hospitalization for Heart Failure [see Warnings and Precautions ( 5.2 )] .
• Hypertension [see Warnings and Precautions ( 5.3 )] .
• Gastrointestinal Erosion [see Warnings and Precautions ( 5.4 )] . Most common adverse reactions (incidence ≥10%) are hypertension, thrombotic vascular events, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 JESDUVROQ 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) [see Clinical Studies ( 14.1 )] . Patients were randomized to JESDUVROQ 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 JESDUVROQ, 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 JESDUVROQ and rhEPO was similar. In the JESDUVROQ treatment arm, 65% of the participants were exposed to at least 18 months of JESDUVROQ and 29% of participants received JESDUVROQ for at least 2.5 years. JESDUVROQ 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 [see Clinical Studies ( 14.1 )] . Permanent treatment discontinuation due to an adverse reaction was reported in 19% of patients treated with JESDUVROQ and 18% of patients treated with rhEPO. No specific adverse reaction resulted in permanent treatment discontinuation in >1% of patients treated with JESDUVROQ. The most common adverse reactions (≥10% of JESDUVROQ-treated patients) were hypertension, thrombotic vascular events, and abdominal pain. Table 4 lists the most common adverse reactions (reported in ≥5% of patients treated with JESDUVROQ). Table 4: Adverse Reactions Reported in ≥5% of Patients Treated with JESDUVROQ in the ASCEND-D Trial Adverse Reaction JESDUVROQ (n = 1,482) % rhEPO (n = 1,474) % Hypertension 24 24 Abdominal pain a 11 8 Dizziness 7 6 Hypersensitivity b 7 7 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 JESDUVROQ and in 11.7 per 100 PY of patients receiving rhEPO (see Table 5 ). Table 5: Adjudicated Thrombotic Vascular Events (Fatal and Non-Fatal) in the ASCENDD Trial a Event JESDUVROQ (n = 1,482) rhEPO (n = 1,474) Rate per 100 PY Rate per 100 PY Vascular access thrombosis 5.0

6.3 Myocardial infarction 3.4

4.1 Stroke 1.2

1.5 Deep vein thrombosis 0.7

0.6 Pulmonary embolism 0.3 0.4 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.

• 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 )] .

• Pregnancy: May cause fetal harm. ( 8.1 )
• Lactation: Breastfeeding not recommended until one week after the final dose. ( 8.2 )
• Hepatic Impairment: Reduce the starting dose in patients with moderate hepatic impairment (Child-Pugh Class B). JESDUVROQ not recommended in severe hepatic impairment (Child-Pugh Class C). ( 8.6 )

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) 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.

8.2 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.

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

8.5 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.

8.6 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 ( 12.3 )] . 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.

Daprodustat is a reversible inhibitor of HIF-PH1, PH2 and PH3 (IC 50 in the low nM range). This activity results in the stabilization and nuclear accumulation of HIF-1α and HIF-2α transcription factors, leading to increased transcription of the HIF-responsive genes, including erythropoietin.