Vadadustat (Monograph)

Brand name: Vafseo
Drug class: Hematopoietic Agents

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

Warning

Increased risk of thrombotic vascular events, including major adverse cardiovascular events (MACE).
Targeting a hemoglobin level >11 g/dL is expected to further increase risks of mortality and arterial/venous thrombotic events.
Studies have not identified a target hemoglobin level, dose, or dosing strategy that does not increase these risks.
Use lowest dose sufficient to reduce RBC transfusion requirements.

Introduction

Hematopoietic agent; a hypoxia-inducible factor prolyl hydroxylase (HIF PH) inhibitor.

Uses for Vadadustat

Anemia of Chronic Kidney Disease

Treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for ≥3 months.

Not shown to improve quality of life, fatigue, or patient well-being; not indicated for use as a substitute for RBC transfusions in patients requiring immediate correction of anemia or for the treatment of anemia of CKD in patients who are not on dialysis.

Safety and efficacy of vadadustat for this use were established in 2 randomized, open-label trials (INNO₂VATE-1 and INNO₂VATE-2), with vadadustat found noninferior to darbepoetin alfa for change in hemoglobin from baseline and occurrence of cardiovascular events.

Approved after publication of current guidelines; place in therapy not yet addressed.

Vadadustat Dosage and Administration

General

Pretreatment Screening

Assess iron status prior to therapy initiation, and administer supplemental iron when serum ferritin is <100 ng/mL or when serum transferrin saturation is <20%.
Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding) prior to initiation of vadadustat.
Measure baseline hemoglobin.
Assess liver function (AST, ALT, and bilirubin).

Patient Monitoring

Monitor iron status during treatment, and administer supplemental iron when serum ferritin is <100 ng/mL or when serum transferrin saturation is <20%.
Monitor hemoglobin levels every 2 weeks until stable after initiating vadadustat or after each dosage adjustment, then monitor levels at least monthly.
Assess liver function (AST, ALT, and bilirubin) monthly after starting vadadustat for the first 6 months of treatment and then monitor as clinically indicated.
Periodically monitor blood pressure and adjust or initiate antihypertensive therapy as needed.
Monitor patients for new-onset seizures, premonitory neurologic symptoms, or change in seizure frequency.

Administration

Oral Administration

Available as tablets containing 150 mg, 300 mg, or 450 mg.

Administer orally once daily, with or without food. Swallow tablets whole; do not cut, crush, or chew.

Administer ≥1 hour before oral iron supplements, products containing iron, or iron-containing phosphate binders. Administer ≥1 hour before or 2 hours after non-iron-containing phosphate binders.

May be administered without regard to type or timing of dialysis treatment.

If a dose is missed, take missed dose as soon as possible, unless it is on the same day as the next dose. If on same day as next dose, skip missed dose and resume dosing at normal time. Do not double doses to make up for a missed dose.

Dosage

Individualize dosing and use the lowest dosage sufficient to reduce need for RBC transfusions. Do not target a hemoglobin level >11 g/dL.

Adults

Anemia of CKD

ESA-Naïve Patients

Oral

Recommended starting dosage: 300 mg once daily. Titrate dosage as recommended. Dosage may range from 150 mg to maximum of 600 mg.

Patients Switching from an ESA to Vadadustat

Oral

Recommended starting dosage: 300 mg once daily. Titrate dosage as recommended. Dosage may range from 150 mg to maximum of 600 mg.

RBC transfusions or ESA treatment may be considered during transition phase if hemoglobin values fall to <9 g/dL or if hemoglobin response is unacceptable. In patients receiving RBC transfusions, continue vadadustat during transfusion period. In patients receiving temporary ESA rescue treatment, hold vadadustat until hemoglobin level ≥10 g/dL. Depending on ESA used for rescue, hold vadadustat until 2 days after last dose of epoetin, 7 days after last dose of darbepoetin alfa, or 14 days after last dose of methoxy polyethylene glycol-epoetin beta. Following ESA rescue, resume vadadustat at previous dosage or increase previous dosage by 150 mg; then, titrate dosage according to dosage titration guidelines.

Monitoring Response to Therapy and Dosage Adjustment

When adjusting therapy, adjust dosage in increments of 150 mg to achieve or maintain hemoglobin levels within 10–11 g/dL. Do not increase dosage more often than once every 4 weeks; decreases in dosage can occur more frequently. When adjusting therapy, consider rate of increase or decrease in hemoglobin concentration, hemoglobin concentration variability, and responsiveness to vadadustat. A single hemoglobin excursion may not require a dosage change.

If hemoglobin rises rapidly (e.g., >1 g/dL in any 2-week period or >2 g/dL in 4 weeks), interrupt or reduce dosage. If hemoglobin level exceeds 11 g/dL, interrupt dosage until hemoglobin ≤11 g/dL, then resume with a dose that is 150 mg less than the dose prior to interruption.

Do not continue therapy beyond 24 weeks if clinically meaningful increase in hemoglobin not achieved. Investigate alternative explanations for inadequate response and treat before re-starting vadadustat.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Not recommended in patients with cirrhosis or active, acute liver disease.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Vadadustat

Contraindications

Known hypersensitivity to vadadustat or any component of the drug.
Uncontrolled hypertension.

Warnings/Precautions

Warnings

Increased Risk of Mortality, MI, Stroke, Venous Thromboembolism, and Thrombosis of Vascular Access

Increased risk of arterial and venous thrombotic events (sometimes fatal), including MI, stroke, venous thromboembolism, and vascular access thrombosis. (See Boxed Warning).

Patients with underlying cardiovascular or cerebrovascular disease at greater risk. Increases in hemoglobin >1 g/dL during any 2-week period may further contribute to these risks. Targeting hemoglobin levels >11 g/dL expected to further increase risks of mortality and arterial/venous thrombotic events.

Use lowest vadadustat dose sufficient to reduce RBC transfusion requirements. Adhere to recommendations for dosing and monitoring of hemoglobin to avoid excessive erythropoiesis.

Avoid vadadustat in patients with a history of MI, cerebrovascular event, or acute coronary syndrome within the 3 months prior to initiation. Advise patients to seek immediate medical attention for evaluation and management if signs and symptoms of MI, stroke, venous thromboembolism, or vascular access thrombosis occur.

<C> Other Warnings and Precautions

Hepatotoxicity

Hepatotoxicity, including elevated ALT, AST, and bilirubin, reported.

Assess liver function (ALT, AST, and bilirubin) prior to initiating vadadustat, monthly after initiation for the first 6 months of treatment, and then as clinically indicated.

Discontinue vadadustat if there are persistent ALT or AST elevations >3 times ULN, or if ALT or AST elevations >3 times ULN are accompanied by bilirubin increase >2 times ULN.

Use not recommended in patients with cirrhosis or active, acute hepatic disease.

Hypertension

Contraindicated in patients with uncontrolled hypertension.

Hypertensive worsening (including serious worsening) and cases of hypertensive crisis reported.

Monitor blood pressure periodically during treatment; adjust or initiate antihypertensive treatment as needed.

Seizures

Seizures reported.

Monitor closely for premonitory neurologic symptoms following therapy initiation. Advise patients to contact clinician if new-onset seizures, premonitory symptoms, or change in seizure frequency occurs.

GI Erosion

Gastric or esophageal erosions, including serious erosions, reported.

Consider risk of GI erosions, particularly in patients with risk factors (e.g., history of GI erosion, peptic ulcer disease, concurrent use of drugs that increase GI erosion risk, current tobacco or alcohol use).

Advise patients of the signs and symptoms of gastric and esophageal erosions and of GI bleeding, and to seek immediate medical care if they develop.

Serious Adverse Events in Patients with Anemia Due to CKD and Not on Dialysis

Safety not established for treatment of anemia due to CKD in adults not on dialysis; use not recommended in this setting.

Malignancy

Not been studied in patients with active malignancies; use not recommended in these patients.

Increased levels of hypoxia inducible factor (HIF)-1 potentially associated with unfavorable effects on cancer growth.

Specific Populations

Pregnancy

Available data insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Chronic kidney disease during pregnancy associated with maternal and fetal risks (e.g., maternal hypertension, preeclampsia, miscarriage, stillbirth, preterm delivery, low birth weight, and polyhydramnios).

In animal studies, reduced fetal weight observed at doses that caused maternal toxicity; no teratogenicity observed.

Use during pregnancy only if the benefits justify the potential risks to the fetus.

Lactation

Unknown if present in human milk; detected in milk of lactating rats. Effects on breast-fed infants or on milk production unknown.

Advise patients to avoid breast-feeding during treatment and for 2 days following the last dose.

Pediatric Use

Safety and effectiveness not established.

Geriatric Use

No overall differences in safety or effectiveness observed between patients ≥65 years of age and younger adults.

Hepatic Impairment

No clinically important differences in pharmacokinetics observed based on moderate hepatic impairment (Child-Pugh class B). Effect of severe hepatic impairment (Child-Pugh Class C) on vadadustat pharmacokinetics unknown.

Not recommended in patients with cirrhosis or active, acute liver disease.

Renal Impairment

Vadadustat clearance decreased with decreasing renal function; drug exposures approximately 2-fold higher in patients with dialysis-dependent-CKD compared to healthy adults.

In patients with Stage 5 dialysis-dependent-CKD, no important differences in vadadustat pharmacokinetics observed when vadadustat administered 4 hours before dialysis or 2 hours after dialysis.

Common Adverse Effects

Most common adverse effects (≥10%): hypertension, diarrhea.

Drug Interactions

Primarily metabolized via glucuronidation by UGT enzymes.

Does not inhibit major CYP isoenzymes and UGT isoforms; does not induce CYP isoenzymes 1A2, 2B6, or 3A4.

Inhibits P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, organic anion transporter (OAT) 1, and OAT3.

Drugs Affecting or Affected by Transport Systems

OAT1 or OAT3 Inhibitors

Concomitant use with OAT1 inhibitors (e.g., probenecid, rifampicin) or OAT3 inhibitors (e.g., gemfibrozil, probenecid, teriflunomide) may increase vadadustat AUC and consequently increase risk of adverse reactions related to vadadustat.

Closely monitor for too large/rapid an increase in hemoglobin response and for adverse reactions.

Substrates of BCRP

Concomitant use with BCRP substrates (e.g., sulfasalazine) may increase exposure of BCRP substrate and consequently increase risk of adverse reactions related to substrate.

Monitor for signs of adverse effects of BCRP substrate; reduce dosage of substrate in accordance with approved product labeling, if needed.

Substrates of OAT3

Concomitant use with OAT3 substrates (e.g., cefaclor, ceftizoxime, famotidine, furosemide, oseltamivir carboxylate, penicillin G, sitagliptin) may increase exposure of OAT3 substrate and consequently increase risk of adverse reactions related to substrate.

Monitor for signs of adverse effects of OAT3 substrate; reduce dosage of substrate in accordance with approved product labeling, if needed.

Specific Drugs

Drug	Interaction	Comments
Adefovir (OAT1 substrate)	No changes in adefovir pharmacokinetics
Celecoxib (CYP2C9 substrate)	Peak plasma concentration of celecoxib increased 60%; corresponding AUC values increased <25%	No dosage adjustments recommended
Cyclosporine (OATP1B1 and BCRP inhibitor)	No clinically important changes in vadadustat peak plasma concentration and AUC
Digoxin (P-gp substrate)	Total exposure to digoxin unchanged
HMG Co-A reductase inhibitors	Increased peak plasma concentration and AUC of certain statins (i.e., simvastatin, rosuvastatin) No changes in pravastatin pharmacokinetics observed with concurrent use	Monitor for possible adverse reactions related to the statin Simvastatin: When used concomitantly with vadadustat, starting dose of simvastatin should be 5 mg daily, and maximum daily dose of simvastatin should not exceed 20 mg Rosuvastatin: When used concomitantly with vadadustat, maximum daily dose of rosuvastatin should not exceed 5 mg
Iron supplements (oral) (e.g., ferric citrate, ferrous sulfate, sodium ferrous citrate); other products containing iron	Decreased vadadustat exposure; may reduce vadadustat effectiveness	Stagger administration; administer vadadustat ≥1 hour before dosing oral iron supplements or products containing iron
Phosphate binders: iron-containing (e.g., sucroferric oxyhydroxide), or non-iron-containing (e.g., calcium acetate, sevelamer carbonate)	Decreased vadadustat exposure; may reduce vadadustat effectiveness	Stagger administration Iron-containing phosphate binders: administer vadadustat ≥1 hour before dosing iron-containing phosphate binders Non-iron-containing phosphate binders: administer vadadustat ≥1 hour before or 2 hours after dosing non-iron-containing phosphate binders
Rabeprazole	No clinically important changes in vadadustat peak plasma concentration and AUC

Vadadustat Pharmacokinetics

Absorption

Bioavailability

Dose-dependent increases in endogenous erythropoietin observed after single dose of 80–1200 mg (0.27–4 times the approved recommended starting dosage) in healthy male adults.

Plasma concentration and AUC increased proportionally after single doses from 80–1200 mg.

Expected to reach steady state by day 3 following once daily dosing; no significant drug accumulation.

Time to peak plasma concentration: approximately 2–3 hours.

Food

No clinically important effect on vadadustat pharmacokinetics following administration with high-fat meal.

Distribution

Extent

Not known whether distributed into human milk; present in the milk of lactating rats.

Does not distribute into RBCs.

Plasma Protein Binding

≥99.5%.

Elimination

Metabolism

Principally metabolized via glucuronidation by UGT enzymes.

Elimination Route

After administration of single radiolabeled oral dose in healthy adults, 85.9% of total dose recovered; 58.9% recovered in urine (<1% unchanged) and 26.9% recovered in feces (9% unchanged).

Half-life

Mean half-life in patients undergoing chronic hemodialysis: 9.2 hours.

Special Populations

Age, sex, and race/ethnicity do not significantly influence vadadustat pharmacokinetics.

Stability

Storage

Oral

Tablets, Film-Coated

20—25°C; excursions permitted to 15—30°C.

Actions

Reversibly inhibits hypoxia-inducible factor prolyl hydroxylase (HIF-PH)1, PH2, and PH3.
Causes stabilization and nuclear accumulation of HIF-1α and HIF-2α transcription factors and increased erythropoietin production.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Medication Guide).
Advise patients of the increased risk of death, myocardial infarction, stroke, and thromboembolism including vascular access thrombosis with vadadustat therapy.
Inform patients that hemoglobin levels will be monitored when initiating or adjusting vadadustat therapy, every 2 weeks until stable, then at least monthly.
Advise patients of the risk of hepatotoxicity and that liver tests will be measured prior to the initiation of vadadustat, monthly after initiation for the first 6 months, and then as clinically indicated.
Advise patients of the risk of hypertension and of the importance of complying with antihypertensive therapy and monitoring of blood pressure.
Advise patients of the risk of seizures and to contact their clinician for new-onset neurologic symptoms or change in seizure frequency.
Advise patients of the risk of GI erosions and advise patients to contact their clinician for signs and symptoms of gastric and esophageal erosions and of GI bleeding.
Advise women to inform their clinician if they are or plan to become pregnant.
Advise patients to avoid breast-feeding while receiving vadadustat and for 2 days following the last dose.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Vadadustat is obtained through designated specialty distributors. Contact the manufacturer or consult the Vafseo website ([Web]) for specific availability information.