DRUG INTERACTIONS-(summary)

 • Moderate CYP2C8 Inhibitors: Reduce starting dose.

 • CYP2C8 Inducers: Monitor hemoglobin and adjust the dose of JESDUVROQ as appropriate.

DRUG INTERACTIONS-( details)

1. CYP2C8 Inhibitors- Concomitant administration of strong CYP2C8 inhibitors (e.g., gemfibrozil) with JESDUVROQ is contraindicated due to a marked increase in daprodustat exposure.

 Concomitant administration of moderate CYP2C8 inhibitors (e.g., clopidogrel) increases daprodustat exposure.

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.

.2. CYP2C8 Inducers CYP2C8 inducers (e.g., rifampin) may decrease daprodustat exposure, which may result in loss of efficacy. M

onitor hemoglobin and adjust the dose of JESDUVROQ when initiating or stopping therapy with CYP2C8 inducers during treatment with JESDUVROQ.

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BRIEF SUMMARY-

DAPRODUSTAT-(Feb 2023)-

Indn- To  treat anemia caused by chronic kidney   disease for adults on dialysis for at least four  months  

Comp- Tablets: 1 mg, 2 mg, 4 mg, 6 mg, and 8 mg.  Administer orally once daily, with or without food. 

ADR- Most common adverse reactions are hypertension, thrombotic vascular events, and abdominal pain.

CI-  Strong cytochrome P450 2C8 (CYP2C8) inhibitors such as gemfibrozil.  Uncontrolled hypertension

WARNINGS-  Risk of Hospitalization for Heart Failure: Increased in patients with a history of heart failure.                                                                             Hypertension: Worsening hypertension, including hypertensive crisis may occur. Monitor blood pressure. Adjust anti-hypertensive therapy as needed.

Pat inform- Inform patients:                                                                                              the increased risks of death, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access.                                                                                   

 the risk of hospitalization due to heart failure, the symptoms and signs of heart failure and to promptly report these symptoms to their healthcare provider.                                 

  the risk of hypertension, to undergo regular blood pressure monitoring and to adhere to the prescribed anti-hypertensive regimen .

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 5

Name-        JESDUVROQ

Acive  Ingredient -  Daprodustat

 Pharmacological clssificiation-        To  treat anemia caused by chronic kidney                                                                    disease for adults on dialysis for at least four                                                                 months                                                                                                                                                                                                           Date of Approval-         2/1/2023                                                                                                                                                                                         

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                       JESDUVROQ safely and effectively.                                                                             See full prescribing information for JESDUVROQ. JESDUVROQ (daprodustat) tablets, for oral use

Initial U.S. Approval: 2023

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.

INDICATIONS AND USAGE-

 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.

 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-

 • Administer orally once daily, with or without food.

 • See Full Prescribing Information for starting dosage based on hemoglobin level, liver function and concomitant medications, and for dose titration and monitoring recommendations.

 DOSAGE FORMS AND STRENGTHS-

 Tablets: 1 mg, 2 mg, 4 mg, 6 mg, and 8 mg. (3) 

 ADVERSE REACTIONS -

 Most common adverse reactions (incidence =10%) are hypertension, thrombotic vascular events, and abdominal pain.

 CONTRAINDICATIONS-

 • Strong cytochrome P450 2C8 (CYP2C8) inhibitors such as gemfibrozil.

 • Uncontrolled hypertension.

 WARNINGS AND PRECAUTIONS-

 • Risk of Hospitalization for Heart Failure: Increased in patients with a history of heart failure.

 • Hypertension: Worsening hypertension, including hypertensive crisis may occur. Monitor blood pressure. Adjust anti-hypertensive therapy as needed.

 • Gastrointestinal Erosion: Gastric or esophageal erosions and gastrointestinal bleeding have been reported.

 • Not indicated for treatment of anemia of CKD in patients who are not dialysis-dependent

 • Malignancy: May have unfavorable effects on cancer growth. Not recommended if active malignancy.

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DOSAGE AND ADMINISTRATION-

 • Administer orally once daily, with or without food.

 • See Full Prescribing Information for starting dosage based on hemoglobin level, liver function and concomitant medications, and for dose titration and monitoring recommendations.

 DOSAGE FORMS AND STRENGTHS-

 Tablets: 1 mg, 2 mg, 4 mg, 6 mg, and 8 mg. 

PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients:                                                                                                                   • Of the increased risks of death, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access.

 • Of the risk of hospitalization due to heart failure, the symptoms and signs of heart failure and to promptly report these symptoms to their healthcare provider.

 • Of the risk of hypertension, to undergo regular blood pressure monitoring and to adhere to the prescribed anti-hypertensive regimen .

 • Of the risk of gastric erosions and gastrointestinal bleeding, the associated symptoms and signs and to report these symptoms to their healthcare provider.

. • Of the need to have regular laboratory tests for hemoglobin .

 • Of the need to inform their healthcare provider if they are taking strong CYP2C8 inhibitors, including gemfibrozil or moderate CYP2C8 inhibitors.

  • Pregnancy JESDUVROQ may cause fetal harm. Advise females to inform their healthcare provider of a known or suspected pregnancy .

 • Lactation Advise females not to breastfeed during treatment with JESDUVROQ and for one week after the final dose .

  JESDUVROQ-. Trademarks are owned by or licensed to the GSK group of companies. Manufactured by GlaxoSmithKline Durham, NC 27701 ©2023 GSK group of companies or its licensor. JDV:1P

CLINICAL PHARMACOLOGY

1. Mechanism of Action-

Daprodustat is a reversible inhibitor of HIF-PH1, PH2 and PH3 (IC50 in the low nM range). This activity results in the stabilization and nuclear accumulation of HIF-1a and HIF-2a transcription factors, leading to increased transcription of the HIF-responsive genes, including erythropoietin.

2. Pharmacodynamics-                                                                                               Effects on Erythropoiesis Daprodustat increases endogenous erythropoietin in a dose-dependent manner within 6 to 8 hours after administration.

With repeat doses, peak increases in reticulocyte counts occur between 7 and 15 days, with subsequent increases in red blood cell production.

New hemoglobin steady-state levels are reached several weeks (approximately 4 weeks in ESA-users and approximately 16-20 weeks in ESA-non-users) after initial administration. 

. Effects on Iron Metabolism and Utilization-                                                   Daprodustat increased 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.

Cardiac Electrophysiology At a dose 10 times the maximum recommended dose, daprodustat does not prolong the QTc interval to any clinically relevant extent.

3. Pharmacokinetics-                                                                                             Daprodustat exposure generally increases in a dose-proportional manner over the range of approved doses. Steady-state concentrations are achieved within 24-hours of dosing.

Absorption-                                                                                                             Following oral administration, daprodustat is readily absorbed with median time to peak concentration (Tmax) in healthy subjects ranging from 1 hour to 4 hours. The absolute bioavailability of daprodustat is 65%.

Administration of JESDUVROQ with a high fat/high calorie meal did not significantly alter daprodustat exposure compared to administration in the fasted state.

Distribution -                                                                                                            Daprodustat has an approximately equal distribution between plasma and blood cells (blood:plasma ratio of 1.23). Following intravenous dosing, the volume of distribution at steadystate in healthy subjects is 14.3 L. In vitro, plasma protein binding of daprodustat is >99%.

Elimination -The terminal elimination half-life of daprodustat is approximately 1 hour to 4 hours.

Metabolism: In vitro, daprodustat is primarily metabolized by CYP2C8 (95% contribution), with a minor contribution by CYP3A4 (5%).

Following oral or intravenous administration of radiolabeled daprodustat to healthy adults, approximately 40% of the total circulating radioactivity in plasma was daprodustat, and the remaining 60% was metabolites. In patients treated with JESDUVROQ, the parent drug is the principal circulating component in plasma.

 Excretion: Mean clearance from plasma was 18.9 L/h, which correlates to blood clearance of 15 L/h and equates to a hepatic extraction of approximately 18%.       Within seven days of an oral dose of radiolabeled daprodustat, 74% of the radioactivity was recovered in the feces, and 21% in the urine. Approximately 99.5% of the dose was excreted as oxidative metabolites, with the rest accounted for by daprodustat.

Specific Populations -                                                                                              Elderly: Population pharmacokinetic analyses in adults with CKD (22 years to 93 years) showed that age did not influence the pharmacokinetics of daprodustat.

Renal Impairment: The steady-state exposure of daprodustat is similar in patients with normal renal function and those with varying degrees of renal impairment; daprodustat exposure is not significantly impacted by hemodialysis or peritoneal dialysis.

The systemic exposure of daprodustat metabolites was higher in patients with Stage 3 to 5 CKD compared to those with normal renal function. Exposures of metabolites were higher on non-dialysis days compared to dialysis days.

Hepatic Impairment: Following administration of a single JESDUVROQ 6 mg dose, mean daprodustat Cmax and AUC increased by 2-fold and unbound exposure increased by 2.3-fold in subjects with moderate hepatic impairment (Child-Pugh Class B) compared to subjects with normal hepatic and renal function.

For those with mild hepatic impairment (Child-Pugh Class A), mean daprodustat Cmax was similar while AUC increased by 1.5-fold and unbound Cmax and AUC increased by 1.6 and 2.2-fold, respectively, compared to subjects with normal hepatic and renal function.

The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of daprodustat is unknown as there have been no studies of JESDUVROQ in patients with severe hepatic impairment.

Drug Interaction Studies Clinical Studies:                                                                Effect of CYP2C8 Inhibitors on the Pharmacokinetics of Daprodustat: The concomitant administration of gemfibrozil 600 mg twice a day for 5 days (strong CYP2C8 inhibitor) with a single 100 mg dose of JESDUVROQ on Day 4 of gemfibrozil administration resulted in an 18.6-fold increase in AUC(0-?) and a 3.9-fold increase in Cmax of daprodustat.

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USE IN SPECIFIC POPULATIONS (summary)-

 • Pregnancy: May cause fetal harm.

 • Lactation: Breastfeeding not recommended until one week after the final dose.

 • 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). 

USE IN SPECIFIC POPULATIONS(details)

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.

 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.

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 

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

4. 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.

5 Hepatic Impairment-                                                                                                   No adjustment of the starting dose is required in patients with mild hepatic impairment (ChildPugh 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 

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.

DRUG ABUSE AND DEPENDENCE-

1. Controlled Substance JESDUVROQ contains daprodustat, which is not a controlled substance.

2. Abuse Drug abuse  1is intentional non-therapeutic use of a drug, even once, for its rewarding psychological or physiological effects. Abuse of JESDUVROQ may be seen in athletes for the effects on erythropoiesis.

Abuse-Related Adverse Reactions There are no data on the abuse of JESDUVROQ in humans. Daprodustat and its metabolites neither selectively penetrate the central nervous system, nor produce behavioral effects in animals that are consistent with central nervous system activity.

Misuse of drugs that increase erythropoiesis, such as JESDUVROQ, by healthy persons may lead to polycythemia, which may be associated with life-threatening cardiovascular complications (e.g., stroke, myocardial infarction, and thromboembolism).

 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.