Daprodustat
FDA Drug Information • Also known as: Jesduvroq
- Brand Names
- Jesduvroq
- Dosage Form
- TABLET, FILM COATED
- Product Type
- DRUG FOR FURTHER PROCESSING
⚠ Boxed Warning (Black Box)
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 )Description
11 DESCRIPTION JESDUVROQ contains daprodustat, an inhibitor of hypoxia inducible factor (HIF), prolyl 4-hydroxylases (PH)1, PH2 and PH3. The chemical name of daprodustat is N‑[(1,3‑dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl) carbonyl]glycine. The molecular formula of daprodustat is C 19 H 27 N 3 O 6 , and its molecular mass is 393.43. The structural formula is shown below. Daprodustat is a white to off-white powder that is poorly soluble in water. Each JESDUVROQ oral tablet contains 1 mg, 2 mg, 4 mg, 6 mg, or 8 mg of daprodustat. Inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, mannitol and microcrystalline cellulose. The tablet film-coating inactive ingredients include hypromellose, iron oxide black (1 mg, 2 mg, and 6 mg tablets), iron oxide red and iron oxide yellow (1 mg, 2 mg, 6 mg, and 8 mg tablets), polyethylene glycol, and titanium dioxide. N [(1,3 dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl) carbonyl]glycine chemical structure
What Is Daprodustat Used For?
1 INDICATIONS AND USAGE 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.Dosage and Administration
2 DOSAGE AND ADMINISTRATION
Administer orally once daily, with or without food. ( 2.2 , 2.3 ) See Full Prescribing Information for starting dosage based on hemoglobin level, liver function and concomitant medications, and for dose titration and monitoring recommendations. ( 2.3 , 2.4 , 2.5 , 2.6 ) 2.1 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. 2.2 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 ( 12.3 )] . 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 ( 12.3 )] . 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. 2.3 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 ( 7.1 ), Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] . Table 1: Starting Dose of JESDUVROQ for Adults on Dialysis not Receiving an Erythropoiesis-Stimulating Agent 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 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...Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS 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.Drug Interactions
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 Breastfeeding
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...
Overdosage
10 OVERDOSAGE Headache and gastrointestinal adverse reactions (e.g., nausea) may be seen with acute overdose with JESDUVROQ. There is no specific antidote. Hemodialysis will not substantially remove daprodustat because it is highly protein bound.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied JESDUVROQ tablets contain 1 mg, 2 mg, 4 mg, 6 mg or 8 mg of daprodustat. Tablet Strength Package Configuration and NDC Number Tablet Description and Markings 1 mg 30 count bottle (NDC 0173-0897-13) Round, gray, biconvex, film-coated tablets debossed with “GS KF” on one side 100 count blister pack (NDC 0173-0897-56) 2 mg 30 count bottle (NDC 0173-0903-13) Round, yellow, biconvex, film-coated tablets debossed with “GS V7” on one side 100 count blister pack (NDC 0173-0903-56) 4 mg 30 count bottle (NDC 0173-0906-13) Round, white, biconvex, film-coated tablets debossed with “GS 13” on one side 100 count blister pack (NDC 0173-0906-56) 6 mg 30 count bottle (NDC 0173-0911-13) Round, pink, biconvex, film-coated tablets debossed with “GS IM” on one side 100 count blister pack (NDC 0173-0911-56) 8 mg 30 count bottle (NDC 0173-0914-13) Round, orange, biconvex, film-coated tablets debossed with “GS 5E” on one side 100 count blister pack (NDC 0173-0914-56) Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F). [See USP Controlled Room Temperature].
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.