Vadadustat (Monograph)

Brand name: Vafseo
Drug class: Hematopoietic Agents

Introduction

Vadadustat is a hypoxia-inducible factor prolyl hydroxylase (HIF PH) inhibitor.

Uses for Vadadustat

Vadadustat has the following uses:

Vadadustat is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least 3 months.

Vadadustat has not been shown to improve quality of life, fatigue, or patient well-being.

Vadadustat is not indicated for use as a substitute for transfusion in patients requiring immediate correction of anemia.

Vadadustat is not indicated for use in patients with anemia due to CKD not on dialysis.

Vadadustat Dosage and Administration

General

Vadadustat is available in the following dosage form(s) and strength(s):

• Tablets: 150 mg, 300 mg, and 450 mg

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Recommended starting dose is 300 mg orally once daily, with or without food.

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

• Following initiation of therapy and after each dose adjustment, monitor hemoglobin levels every 2 weeks until stable, then monitor at least monthly.

• Increase the dose no more frequently than once every 4 weeks. Decreases in dose can occur more frequently.

• Adjust dose in increments of 150 mg to achieve or maintain hemoglobin levels within 10 g/dL to 11 g/dL. Doses may range from 150 mg to a maximum of 600 mg.

• Treatment with vadadustat 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 restarting therapy.

• See Full Prescribing Information for additional information on pretreatment evaluations, monitoring, and dosage adjustment recommendations.

Related/similar drugs

ferrous sulfate, FeroSul, Infed, Aranesp

Cautions for Vadadustat

Contraindications

• Known hypersensitivity to vadadustat or any of its components.

• Uncontrolled hypertension.

Warnings/Precautions

Increased Risk of Death, Myocardial Infarction (MI), Stroke, Venous Thromboembolism, and Thrombosis of Vascular Access

Vadadustat increases the risk of arterial and venous thrombotic events, that may be fatal, including MI, stroke, venous thromboembolism and vascular access thrombosis. Patients with cardiovascular or cerebrovascular disease are at increased risk of these events. Avoid use in patients with a history of MI, cerebrovascular event, or acute coronary syndrome within the 3 months prior to starting vadadustat.

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 vadadustat, or dosing strategy that does not increase these risks. Use the lowest dose of vadadustat sufficient to reduce the need for red blood cell transfusions. Adherence to dosing and hemoglobin monitoring recommendations is important to avoid excessive erythropoiesis.

Advise patients to seek immediate medical attention if they develop signs or symptoms of MI, stroke, venous thromboembolism, or thrombosis of vascular access. Evaluate and manage promptly if these occur.

Hepatotoxicity

Vadadustat may cause hepatotoxicity. In clinical trials, hepatocellular injury attributed to vadadustat was reported in less than 1% of patients, including one case of severe hepatocellular injury with jaundice. All events were asymptomatic and resolved after discontinuation of vadadustat. The time to onset was generally within the first 3 months of treatment.

Elevated serum ALT, AST, and bilirubin were seen in 1.8%, 1.8% and 0.3% of CKD patients treated with vadadustat, respectively.

Measure ALT, AST and bilirubin prior to the initiation of vadadustat and monthly after initiation for the first 6 months and then monitor as clinically indicated.

Discontinue vadadustat if there is persistent ALT or AST greater than 3 times ULN or if ALT or AST elevations greater than 3 times upper limit of normal (ULN) are accompanied by a bilirubin increase greater than 2 times ULN.

Vadadustat is not recommended in patients with cirrhosis or active, acute liver disease.

Hypertension

Vadadustat is contraindicated in patients with uncontrolled hypertension. In the INNO₂VATE-1 and INNO₂VATE-2 clinical trials, worsening of hypertension was reported in 14% (9.4 per 100 person-years [PY]) of patients receiving vadadustat and 17% (11.8 per 100 PY) of patients receiving darbepoetin alfa. Serious worsening of hypertension was reported in 2.7% (1.7 per 100 PY) of patients receiving vadadustat and 3% (1.8 per 100 PY) of patients receiving darbepoetin alfa. Cases of hypertensive crisis including hypertensive encephalopathy and seizures have also been reported in patients receiving vadadustat. Periodically monitor blood pressure and adjust or initiate anti-hypertensive therapy as needed.

Seizures

Seizures have occurred in patients treated with vadadustat. In the INNO₂VATE-1 and INNO₂VATE-2 clinical trials, seizures occurred in 1.6% (1.0 per 100 PY) of patients who received vadadustat and 1.6% (1.0 per 100 PY) of patients who received darbepoetin alfa. Following initiation of vadadustat, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency.

GI Erosion

In the INNO₂VATE-1 and INNO₂VATE-2 clinical trials, gastric or esophageal erosions occurred in 6.4% (4.0 per 100 PY) of patients receiving vadadustat and 5.3% (3.3 per 100 PY) of darbepoetin alfa-treated patients. Serious GI erosions, including GI bleeding and the need for red blood cell transfusions were reported in 3.4% (2.1 per 100 PY) and 3.3% (2.0 per 100 PY) of those receiving vadadustat and darbepoetin alfa, respectively. Consider this risk particularly in patients with risk factors, such as those with a history of GI erosion, peptic ulcer disease, use of concomitant medications that increase the risk of GI erosion, and current tobacco smokers and alcohol drinkers.

Advise patients of the symptoms and signs of gastric and esophageal erosions and of GI bleeding and to seek prompt medical care if these occur.

Serious Adverse Reactions in Patients with Anemia Due to Chronic Kidney Disease and Not on Dialysis

The safety of vadadustat 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.

In large clinical trials in adults with anemia of CKD who were not on dialysis (PRO₂TECT-1 and PRO₂TECT-2), an increased risk of mortality, stroke, MI, serious acute kidney injury, serious hepatic injury, and serious GI erosions was observed in patients treated with vadadustat compared to darbepoetin alfa.

Malignancy

Because increased hypoxia inducible factor (HIF)-1 levels may be associated with unfavorable effects on cancer growth, vadadustat has not been studied and is not recommended in patients with active malignancies. In the INNO₂VATE-1 and INNO₂VATE-2 clinical trials, malignancies were observed in 2.2% (1.3 per 100 PY) of patients treated with vadadustat and 3.0% (1.8 per 100 PY) of patients treated with darbepoetin alfa. No evidence of increased carcinogenicity was observed in animal studies.

Specific Populations

Pregnancy

Available data with vadadustat 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 fetus associated with CKD. Vadadustat administration orally to pregnant rats and rabbits during the period of organogenesis was associated with reduced fetal weight at doses that caused maternal toxicity. In rat and rabbit studies, vadadustat was not teratogenic.

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 risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Vadadustat should only be used during pregnancy if the benefit justifies the potential risk to the fetus.

CKD in pregnancy increases the risk for maternal hypertension, preeclampsia, miscarriage, stillbirth, preterm delivery, low birth weight infants, and polyhydramnios.

Lactation

There are no data on the presence of vadadustat in human milk, the effects of vadadustat on the breastfed child, or the effects on milk production. Vadadustat is present in the milk of lactating rats. 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 vadadustat, such as thrombotic vascular events, advise patients not to breastfeed during treatment with vadadustat, and for 2 days after the final dose.

Pediatric Use

The safety and effectiveness of vadadustat in pediatric patients have not been established.

Geriatric Use

There were 1330 patients 65 years of age and older in the pooled INNO₂VATE-1 and INNO₂VATE-2 clinical trials. Of the total number of vadadustat-treated patients in these studies, 449 (23%) were 65 to 74 years of age, 194 (10%) were 75 to 84 years of age, and 24 (1%) were 85 years of age and older. No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients.

Hepatic Impairment

Vadadustat is not recommended in patients with cirrhosis or active, acute liver disease.

Common Adverse Effects

The most common adverse reactions (occurring at ≥ 10%) were hypertension and diarrhea.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Iron supplements and iron-containing phosphate binders: Administer vadadustat at least 1 hour before products containing iron.

• Non-iron-containing phosphate binders: Administer vadadustat at least 1 hour before or 2 hours after non-iron-containing phosphate binders.

• Breast cancer resistance protein (BCRP) substrates: Monitor for signs of substrate adverse reactions and consider substrate dose reduction.

• Statins: Monitor for statin-related adverse reactions.

Actions

Mechanism of Action

Vadadustat is a reversible inhibitor of hypoxia inducible factor (HIF)-prolyl-4-hydroxylases (PH)1, PH2, and PH3 (IC₅₀ in the nM range). This activity results in the stabilization and nuclear accumulation of HIF-1α and HIF-2α transcription factors, and increased production of erythropoietin (EPO).

Advice to Patients

• Advise patients to read the FDA-approved patient labeling.

• Inform patients of the increased risk of death, MI, stroke, and thromboembolism including vascular access thrombosis.

• Inform patients that hemoglobin levels will be monitored when initiating or adjusting therapy, every 2 weeks until stable, then at least monthly.

• Inform 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, then as clinically indicated.

• Inform patients of the risk of hypertension and advise patients of the importance to comply with antihypertensive therapy and monitoring of blood pressure.

• Inform patients of the risk of seizures and advise patients to contact their healthcare provider for new-onset neurologic symptoms or change in seizure frequency.

• Inform patients of the risk of GI erosions and advise patients to contact their healthcare provider for signs and symptoms of gastric and esophageal erosions and of GI bleeding.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

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