Dahlia Medical Communications

Vadadustat Essentials for Healthcare Professionals

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by

Rachael Hills
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What is vadadustat?1

The FDA approved vadadustat (Vafseo®) in March 2024 for the treatment of anemia due to chronic kidney disease (CKD). Vadadustat is only approved for dialysis dependent CKD patients. It is not indicated to replace blood transfusions.

What is vadadustat’s mechanism of action?

Vadadustat is a hypoxia-inducible factor prolyl hydroxylase (HIF PF) inhibitor. The inhibition leads to increased erythropoietin (EPO) production.1 EPO and iron are instrumental in red blood cell (RBC) formation.2 In advanced CKD, the kidney does not make enough EPO, which leads to anemia.3

Why is vadadustat only approved for dialysis dependent patients?

The clinical trials PRO2TECT-1 and PRO2TECT-2 compared vadadustat to darbepoetin in non-dialysis CKD patients with anemia.1 Vadadustat had noninferior efficacy compared to darbepoetin but had inferior safety.4 The vadadustat group experienced more adverse events compared to darbepoetin. These events included stroke, myocardial infarction (MI), acute kidney injury, hepatic injury, and gastrointestinal (GI) erosions.4 Thus, vadadustat was not approved for non-dialysis CKD patients.

How does vadadustat compare to erythropoietin stimulating agents (ESAs)?5

The INNO2VATE-1 and INNO2VATE-2 trials used darbepoetin, an ESA, as the control intervention. The randomized, open label, noninferiority phase 3 trials compared vadadustat and darbepoetin. Participants were dialysis dependent CKD patients.

The primary endpoint was mean change in hemoglobin (Hb) from baseline to weeks 24 to 36. The primary safety endpoint was time to death from any cause, a nonfatal MI, or nonfatal stroke. The vadadustat group received vadadustat 300 mg once daily. Researchers could adjust doses to 150 mg, 450 mg, or 600 mg once daily. Darbepoetin patients received their current therapeutic doses by either subcutaneous or intravenous routes. Darbepoetin-naïve participants received initial doses based on the product’s label.

The results showed vadadustat was noninferior to darbepoetin. Both the efficacy and safety endpoints demonstrated noninferiority.

How is vadadustat dosed?1

Initial Dosing

  • Patients not receiving an ESA: start vadadustat at 300 mg orally once a day.
  • Patients switching from an ESA to vadadustat: start vadadustat at 300 mg orally once a day.
    • If Hb decreases below 9 g/dL during the transition period
      • Continue vadadustat if patient receives an RBC transfusion.
      • Pause vadadustat if patient receives ESA rescue treatment until Hb is ≥ 10 g/dL. The ESA used will determine when to restart vadadustat, for example:
        • 2 days after last dose of epoetin
        • 7 days after last dose of darbepoetin
        • 14 days after last dose of methoxy polyethylene glycol-epoetin beta
      • Restart vadadustat at the prior dose or with a 150 mg increase.

Maintenance Dosing

  • Do NOT increase dose more often than every 4 weeks.
  • Adjust doses to maintain a Hb of 10-11 g/dL.
  • The maximum dose is 600 mg once daily.
  • If Hb increases by > 1 g/dL in 2 weeks or > 2 g/dL in 4 weeks, then pause vadadustat or decrease dose.
  • If Hb is > 11 g/dL, then pause vadadustat until Hb is ≤ 11 g/dL. Restart at 150 mg less than prior dose.
  • If no improvement occurs after 24 weeks, then discontinue vadadustat.

Hepatic Dose Adjustments

Vadadustat can elevate liver enzymes. If the elevations are consistent and greater than 3 times the upper limit of normal (ULN), then discontinue vadadustat. If the elevations appear with a bilirubin increase of 2 times the ULN, then discontinue vadadustat.

How is vadadustat administered?1

Vadadustat is taken by mouth with or without food. Do not cut, crush, or chew tablets. Vadadustat dosing time does not need to coordinate with dialysis times.

If a patient misses a dose on the same day it is due, then administer the missing dose. If a patient discovers the missed dose the following day, then skip the missed dose. Do NOT double doses on the same day.

Administer vadadustat 1 hour prior to taking iron supplements or iron-containing products. Iron-containing phosphate binders include sucroferric oxyhydroxide (Velphoro®) and ferric citrate (Auryxia®).6 Administer non-iron phosphate binders 1 hour before or 2 hours after vadadustat.

How are vadadustat patients monitored?1

Baseline Labs

  • Iron studies
    • If serum ferritin is < 100 mcg/L or if serum transferrin saturation is < 20%, then prescribe supplemental iron.
  • Hb
  • Liver Function Tests

Maintenance Labs

  • After initiating vadadustat, check Hb every 2 weeks until Hb is stable. Afterwards, check Hb at least once a month.
  • Check Liver Function Tests monthly for 6 months and then as needed.

What are vadadustat’s contraindications?1

Vadadustat’s contraindications are uncontrolled hypertension and hypersensitivities to vadadustat or its inactive ingredients.

Which patients should avoid vadadustat or use it with caution?1

Vadadustat increases the risk of cardiovascular events, such as stroke, MI, or clotting. The package insert recommends avoiding vadadustat in patients with a history of MI, stroke, or acute coronary syndrome in the last 3 months.

In clinical trials, blood pressure worsened in patients with controlled hypertension at baseline. Discuss risks of high blood pressure with patients before prescribing vadadustat.

Seizures occurred in clinical trials. The vadadustat and darbepoetin groups had similar seizure rates. Use vadadustat with caution in patients with epilepsy or history of seizures.

GI erosion occurred in 6.4% of vadadustat patients in clinical trials. Use with caution in patients receiving NSAIDs, oral steroids, or other GI-irritating drugs. Avoid vadadustat in patients with a history of GI erosion or peptic ulcer disease. Use with caution in smokers and alcohol consumers.

Vadadustat increases HIF-1 levels. HIF-1 can enhance cancer growth. No evidence exists showing that vadadustat worsens cancer, but it is theoretically possible. Avoid vadadustat in patients with active cancer.

What are vadadustat’s side effects?1

Vadadustat’s most common side effects are hypertension, nausea/vomiting, diarrhea, headache, abdominal pain, and fatigue.

Less common, but serious side effects include GI erosion, elevated liver enzymes, seizures, and cardiovascular events.

References

  1. Vafseo. Prescribing Information. Akebia Therapeutics Inc. Accessed April 15, 2024. https://www.vafseo.com/pdf/prescribing-information.pdf
  2. Veterans Affairs. Iron and EPO for anemia. Veterans Affairs eKidney Clinic. Updated February 2, 2021. Accessed April 15, 2024. https://www.va.gov/EKIDNEYCLINIC/rooms/pharmacy/topics/iron-and-epo-for-anemia/index.asp
  3. Berns J, Cavanaugh K. Anemia in chronic kidney disease. National Institute of Diabetes and Digestive and Kidney Diseases. Updated September 2020. Accessed April 15, 2024. https://www.niddk.nih.gov/health-information/kidney-disease/anemia#CKD
  4. Chertow G, Pergola P, Farag Y, et al. Vadadustat in patients with anemia and non-dialysis dependent CKD. N Engl J Med. 2021;384(17):1589-1600. doi: 10.1056/NEJMoa2025938.
  5. Eckardt K, Agarwal R, Aswad A, et al. Safety and efficacy of vadadustat for anemia in patients undergoing dialysis. N Engl J Med. 2021;384:1601-12. doi: 10.1056/NEJMoa2025956.
  6. Sekar A, Kaur T, Nally J, Rincon-Choles H, Jolly S, and Nakhoul G. Phosphorus binder: the new and the old, and how to choose. Clev Clin J Med. 2018;85(8):629-638. doi: 10.3949/ccjm.85a.17054.

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