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Vafseo dosing as studied in clinical trials1,2
Percent of subjects by Vafseo dose level: Prevalent Dialysis Trial
(INNO2VATE-2)1,2,*
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Data presented are the most common administered dose received during that study week. Data are observational, and doses may have been increased or decreased per protocol.1,2
- The distribution of doses from 150 mg to 600 mg was similar in the Incident Dialysis Trial (INNO2VATE-1) compared with the Prevalent Dialysis Trial (INNO2VATE-2)1,2
*Percent of patients on 0 mg/L is not shown1,2
The proportion of patients receiving dose adjustments based on Hb assessment during the Incident Dialysis Trial (INNO2VATE-1)1,†,‡,§
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ESA=erythropoiesis-stimulating agent; Hb=hemoglobin.
Additional information on dose modifications1,3
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| Primary Evaluation Period Weeks 24-36 | Secondary Evaluation Period Weeks 40-52 | |||
|---|---|---|---|---|
| Study parameter | Vafseo N=179 n(%) | Darbepoetin alfa N=186 n(%) | Vafseo N=179 n(%) | Darbepoetin alfa N=186 n(%) |
| Number of subjects not discontinuing study treatment permanently | 156 | 169 | 125 | 140 |
| Reason for dose modificationsII | ||||
| Dosing interrupted due to elevated Hb | 29 (18.6) | 52 (30.8) | 23 (18.4) | 28 (20.0) |
| Dose decreased due to AE | 0 | 0 | 0 | 0 |
| Dose interrupted due to AE | 6 (3.8) | 5 (3.0) | 2 (1.6) | 4 (2.9) |
| Dose modifications for ESA rescue¶ | 23 (14.7) | 19 (11.2) | 19 (15.2) | 13 (9.3) |
| Dosing restarted | 34 (21.8) | 48 (28.4) | 37 (29.6) | 34 (24.3) |
Presented data are a descriptive summary using observed data. Data were not corrected for multiplicity. All analyses should be interpreted with caution.1
† The starting dose of Vafseo was 300 mg orally once daily. Darbepoetin alfa dosing was based on prior use or product label. Both drugs were adjusted per protocol-specified dose-adjustment algorithms to achieve target hemoglobin levels (10-11 g/dL in the US; 10-12 g/dL EX-US).2
‡ Vafseo and darbepoetin alfa dose increases, decreases, or interruptions to maintain Hb within geography-specific target range were determined by HemoCue, local laboratory, or central laboratory. From weeks 0-12, Hb was monitored every 2 weeks. From weeks 12 to 52, Hb was monitored every 4 weeks unless more frequent monitoring was clinically indicated or warranted based on dosing changes.1,4
§ Dose adjustments defined as a dose increase or a dose decrease.
|| Each subject may be counted into multiple categories. Percentage of dose modifications for other reasons in the primary evaluation period were 2 (1.3%) for Vafseo and 5 (3.0%) for darbepoetin alfa; and in the secondary evaluation period were 1 (0.8%) for Vafseo and 2 (1.4%) for darbepoetin alfa.1
¶ Starting at week 6, patients in both treatment groups could receive ESAs as “rescue” therapy if they experienced worsening symptoms of anemia of CKD with hemoglobin concentration <9.5 g/dL. In the darbepoetin alfa group, ESA was considered to be a rescue medication if the dose was at least double that of the previous dose. Vadadustat was interrupted for patients who received ESA rescue; darbepoetin alfa was interrupted if another ESA was used for rescue.2
AE=adverse event; CKD=chronic kidney disease; ESA=erythropoiesis-stimulating agent; Hb=hemoglobin.
The proportion of patients receiving dose adjustments based on Hb assessment during the Prevalent Dialysis Trial (INNO2VATE-2)1,2,#,**,††
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ROTATE DEVICE FOR LARGEST VIEW
ESA=erythropoiesis-stimulating agent; Hb=hemoglobin.
Additional information on dose modifications1,3
SWIPE TO SEE ALL COLUMNS IN THIS TABLE
| Primary Evaluation Period Weeks 24-36 | Secondary Evaluation Period Weeks 40-52 | |||
|---|---|---|---|---|
| Study parameter | Vafseo N=1768 n(%) | Darbepoetin alfa N=1769 n(%) | Vafseo N=1768 n(%) | Darbepoetin alfa N=1769 n(%) |
| Number of subjects not discontinuing study treatment permanently | 1473 | 1612 | 1306 | 1486 |
| Reason for dose modifications‡‡ | ||||
| Dosing interrupted due to elevated Hb | 308 (20.9) | 507 (31.5) | 285 (21.8) | 488 (32.8) |
| Dose decreased due to AE | 3 (0.2) | 0 | 2 (0.2) | 0 |
| Dose interrupted due to AE | 59 (4.0) | 44 (2.7) | 48 (3.7) | 41 (2.8) |
| Dose modifications for ESA rescue16,§§ | 253 (17.2) | 301 (18.7) | 273 (20.9) | 260 (17.5) |
| Dosing restarted | 463 (31.4) | 534 (33.7) | 443 (33.9) | 594 (40.0) |
Presented data are a descriptive summary using observed data. Data were not corrected for multiplicity. All analyses should be interpreted with caution.1
# The starting dose of Vafseo was 300 mg orally once daily. Darbepoetin alfa dosing was based on prior use or product label. Both drugs were adjusted per protocol-specified dose-adjustment algorithms to achieve target hemoglobin levels (10-11 g/dL in the US; 10-12 g/dL EX-US).2
** Vafseo and darbepoetin alfa dose increases, decreases, or interruptions to maintain Hb within geography-specific target range were determined by HemoCue, local laboratory, or central laboratory. From weeks 0-12, Hb was monitored every 2 weeks. From weeks 12 to 52, Hb was monitored every 4 weeks unless more frequent monitoring was clinically indicated or warranted based on dosing changes.1,4
†† Dose adjustments defined as a dose increase or a dose decrease.
‡‡ Each subject may be counted into multiple categories. Percentage of dose modifications for other reasons in the primary evaluation period were 37 (2.5%) for Vafseo and 66 (4.1%) for darbepoetin alfa; and in the secondary evaluation period were 36 (2.8%) for Vafseo and 82 (5.5%) for darbepoetin alfa.1
§§ Starting at week 6, patients in both treatment groups could receive ESAs as “rescue” therapy if they experienced worsening symptoms of anemia of CKD with hemoglobin concentration <9.5 g/dL. In the darbepoetin alfa group, ESA was considered to be a rescue medication if the dose was at least double that of the previous dose. Vadadustat was interrupted for patients who received ESA rescue; darbepoetin alfa was interrupted if another ESA was used for rescue.2
AE=adverse event; CKD=chronic kidney disease; ESA=erythropoiesis-stimulating agent; Hb=hemoglobin.
IMPORTANT SAFETY INFORMATION AND INDICATION
WARNING: INCREASED RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS
THROMBOEMBOLISM, and THROMBOSIS OF VASCULAR ACCESS.
VAFSEO increases the risk of thrombotic vascular events, including major adverse cardiovascular events (MACE).
Targeting a hemoglobin level greater than 11 g/dL is expected to further increase the risk of death and arterial and venous thrombotic events, as occurs with erythropoietin stimulating agents (ESAs), which also increase erythropoietin levels.
No trial has identified a hemoglobin target level, dose of VAFSEO, or dosing strategy that does not increase these risks.
Use the lowest dose of VAFSEO sufficient to reduce the need for red blood cell transfusions.
CONTRAINDICATIONS
- Known hypersensitivity to VAFSEO or any of its components
- Uncontrolled hypertension
WARNINGS AND PRECAUTIONS
- Increased Risk of Death, Myocardial Infarction (MI), Stroke, Venous Thromboembolism, and Thrombosis of Vascular AccessA rise in hemoglobin (Hb) levels greater than 1 g/dL over 2 weeks can increase these risks. Avoid in patients with a history of MI, cerebrovascular event, or acute coronary syndrome within the 3 months prior to starting VAFSEO. Targeting a Hb level of greater than 11 g/dL is expected to further increase the risk of death and arterial and venous thrombotic events. Use the lowest effective dose to reduce the need for red blood cell (RBC) transfusions. Adhere to dosing and Hb monitoring recommendations to avoid excessive erythropoiesis.
- HepatotoxicityHepatocellular injury attributed to VAFSEO was reported in less than 1% of patients, including one severe case with jaundice. Elevated serum ALT, AST, and bilirubin levels were observed in 1.8%, 1.8%, and 0.3% of CKD patients treated with VAFSEO, respectively. Measure ALT, AST, and bilirubin before treatment and monthly for the first 6 months, then as clinically indicated. Discontinue VAFSEO if ALT or AST is persistently elevated or accompanied by elevated bilirubin. Not recommended in patients with cirrhosis or active, acute liver disease.
- HypertensionWorsening of hypertension was reported in 14% of VAFSEO and 17% of darbepoetin alfa patients. Serious worsening of hypertension was reported in 2.7% of VAFSEO and 3% of darbepoetin alfa patients. Cases of hypertensive crisis, including hypertensive encephalopathy and seizures, have also been reported in patients receiving VAFSEO. Monitor blood pressure. Adjust anti-hypertensive therapy as needed.
- SeizuresSeizures occurred in 1.6% of VAFSEO and 1.6% of darbepoetin alfa patients. Monitor for new-onset seizures, premonitory symptoms, or change in seizure frequency.
- Gastrointestinal (GI) ErosionGastric or esophageal erosions occurred in 6.4% of VAFSEO and 5.3% of darbepoetin alfa patients. Serious GI erosions, including GI bleeding and the need for RBC transfusions, were reported in 3.4% of VAFSEO and 3.3% of darbepoetin alfa patients. Consider this risk in patients at increased risk of GI erosion. Advise patients about signs of erosions and GI bleeding and urge them to seek prompt medical care if present.
- Serious Adverse Reactions in Patients with Anemia Due to CKD and Not on DialysisThe safety of VAFSEO 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, an increased risk of mortality, stroke, MI, serious acute kidney injury, serious hepatic injury, and serious GI erosions was observed in patients treated with VAFSEO compared to darbepoetin alfa.
- MalignancyVAFSEO has not been studied and is not recommended in patients with active malignancies. Malignancies were observed in 2.2% of VAFSEO and 3.0% of darbepoetin alfa patients. No evidence of increased carcinogenicity was observed in animal studies.
ADVERSE REACTIONS
- The most common adverse reactions (occurring at ≥ 10%) were hypertension and diarrhea.
DRUG INTERACTIONS
- Iron supplements and iron-containing phosphate binders: Administer VAFSEO at least 1 hour before products containing iron.
- Non-iron-containing phosphate binders: Administer VAFSEO at least 1 hour before or 2 hours after non-iron-containing phosphate binders.
- BCRP substrates: Monitor for signs of substrate adverse reactions and consider dose reduction.
- Statins: Monitor for statin-related adverse reactions. Limit the daily dose of simvastatin to 20 mg and rosuvastatin to 5 mg.
USE IN SPECIFIC POPULATIONS
- Pregnancy: May cause fetal harm.
- Lactation: Breastfeeding not recommended until two days after the final dose.
- Hepatic Impairment: Not recommended in patients with cirrhosis or active, acute liver disease
INDICATION
VAFSEO is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months.
Limitations of Use
- VAFSEO has not been shown to improve quality of life, fatigue, or patient well-being.
- VAFSEO is not indicated for use:
- As a substitute for red blood cell transfusions in patients who require immediate correction of anemia.
- In patients with anemia due to CKD not on dialysis.
Please note that this information is not comprehensive. Please click here for the Full Prescribing Information, including BOXED WARNING and Medication Guide.
References: 1. Data on file. Akebia Therapeutics, Inc. 2. Eckardt KU, Agarwal R, Aswad A, et al. Safety and efficacy of vadadustat for anemia in patients undergoing dialysis. N Engl J Med. 2021;384(17):1601-1612. doi:10.1056/NEJMoa2025956 3. Eckardt KU, Agarwal R, Aswad A, et al. Safety and efficacy of vadadustat for anemia in patients undergoing dialysis. N Engl J Med. 2021;384(suppl appendix):1-21. doi:10.1056/NEJMoa2025956 4. Eckardt KU, Agarwal R, Farag YM, et al. Global Phase 3 programme of vadadustat for treatment of anaemia of chronic kidney disease: rationale, study design and baseline characteristics of dialysis-dependent patients in the INNO2VATE trials. Nephrol Dial Transplant. 2021;36(11):2039-2048. doi:10.1093/ndt/gfaa204