Roxadustat (code name FG-4592, also ASP1517; brand name Evrenzo in Europe) is an oral drug that treats anemia caused by chronic kidney disease (CKD). Instead of injecting erythropoietin (EPO), the hormone that tells bone marrow to make red blood cells, it makes the body produce more of its own EPO by switching on the oxygen-sensing pathway that normally responds to low oxygen.
It is approved in the European Union, China, Japan and several other countries, but not in the United States: in August 2021 the FDA issued a complete response letter and asked for additional clinical study before any resubmission. Because it raises red-cell mass, roxadustat is banned in sport at all times under the WADA Prohibited List, and it has appeared in doping cases.
This page summarizes what the European label, the clinical trials and regulators report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Drug class | Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI); oral small molecule |
| Brands / approval | Evrenzo (Astellas) in the EU since August 18, 2021; first approved in China, then Japan |
| Route | Oral tablet, taken three times per week (not on consecutive days) |
| EU strengths | 20, 50, 70, 100 and 150 mg tablets |
| EU starting dose (ESA-naive) | 70 mg three times weekly under 100 kg; 100 mg three times weekly at 100 kg or more |
| Half-life | ≈15 h effective half-life in CKD patients (EU label); ≈12 h in healthy volunteers |
| Key mechanism | Blocks HIF-PH enzymes, raising the body’s own EPO and lowering hepcidin |
| US status | Not FDA-approved; complete response letter issued August 2021 |
| WADA status | Prohibited at all times (S2.1.2, HIF activating agents) |
What it is
Roxadustat is a small, non-peptide molecule: 2-[(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)amino]acetic acid, formula C₁₉H₁₆N₂O₅, molecular weight 352.3 g/mol (PubChem). It was developed by FibroGen with Astellas and AstraZeneca (Dhillon, Drugs 2019).
The drug works on the body’s oxygen sensor. Cells contain a transcription factor called hypoxia-inducible factor (HIF). When oxygen is normal, enzymes called HIF prolyl hydroxylases (HIF-PH) tag HIF for destruction. When oxygen is low, the enzymes slow down, HIF builds up and switches on genes that help the body cope, including the gene for EPO.
Roxadustat reversibly blocks HIF-PH, so HIF accumulates even when oxygen is normal. Per the EU label, this produces a coordinated response (Evrenzo SmPC):
- higher levels of the body’s own (endogenous) EPO;
- changes in iron-transport proteins;
- lower hepcidin, a hormone that blocks iron absorption and is raised by the inflammation common in CKD;
- better iron availability, more hemoglobin and a larger red-cell mass.
This is the key difference from injected EPO drugs (erythropoiesis-stimulating agents, or ESAs): roxadustat is taken by mouth and acts upstream of EPO. In phase 2 studies in CKD it raised endogenous EPO “to within or near the physiologic range” (Chen et al., NEJM 2019). In healthy-volunteer studies reviewed by Czock and Keller, EPO peaked about 8–12 h after a dose, and higher doses of 3–4 mg/kg could produce supraphysiological EPO levels (Czock & Keller, Clin Pharmacokinet 2022).
Pharmacokinetics
From the EU label (Evrenzo SmPC) and a review of published studies (Czock & Keller, Clin Pharmacokinet 2022):
| Parameter | Value |
|---|---|
| Time to peak (fasted) | Usually 2 h |
| Effect of food | Peak level 25% lower; total exposure (AUC) unchanged |
| Protein binding | ≈99%, mostly to albumin |
| Apparent volume of distribution | 24 L at steady state (label) |
| Effective half-life, CKD patients | ≈15 h (label) |
| Half-life, healthy volunteers | Mean 11.8 h (range of study means 9.6–16 h) in White subjects; 12 h in Japanese subjects (review) |
| Metabolism | CYP2C8 and UGT1A9; main metabolites hydroxy-roxadustat and roxadustat-O-glucuronide |
| Excretion (radiolabel, healthy subjects) | 96% recovered: 50% in feces, 46% in urine; under 2% as unchanged drug in urine |
| Removal by hemodialysis | Not significant |
With three-times-weekly dosing, steady state is reached within about one week (3 doses) with minimal accumulation. Age, sex, race, body weight, kidney function and dialysis status had no clinically relevant effect on exposure in CKD patients. In moderate liver impairment (Child-Pugh B), total exposure was 23% higher and unbound exposure 70% higher, which is why the label halves the starting dose in that group.
Although the plasma half-life is short, traces can be detected in urine for months. In a study by anti-doping laboratories, roxadustat was still detectable 8 months after a single dose (at under 10 pg/mL), and 9–18 months after anemic patients stopped three-times-weekly treatment with 70–100 mg (Sobolevsky et al., Drug Test Anal 2025).
Approved medical use
In the EU, Evrenzo is indicated for adults with symptomatic anemia associated with CKD, both on and not on dialysis. Treatment is started by a physician experienced in managing anemia, after other causes of anemia have been checked and iron stores are adequate (Evrenzo SmPC).
| Labeled dosing element (EU) | Detail |
|---|---|
| Schedule | Three times per week, not on consecutive days |
| Target hemoglobin | 10–12 g/dL |
| Starting dose, not previously on an ESA | 70 mg (under 100 kg) or 100 mg (100 kg or more) |
| Starting dose, switching from an ESA | 70–200 mg, based on the average ESA dose over the previous 4 weeks |
| Dose steps | 20–40–50–70–100–150–200–250–300–400 mg (400 mg only on dialysis) |
| Maximum, not on dialysis | 3 mg/kg or 300 mg per dose, whichever is lower |
| Maximum, on dialysis | 3 mg/kg or 400 mg per dose, whichever is lower |
| Hemoglobin checks | Every 2 weeks until stable, then every 4 weeks |
| Rapid rise rule | Reduce by one step immediately if hemoglobin rises more than 2 g/dL in 4 weeks |
| Stopping rule | Do not continue beyond 24 weeks without a meaningful hemoglobin response |
The label says switching dialysis patients who are stable on an ESA should only be considered with a valid clinical reason, because cardiovascular and mortality signals were seen in that setting (see below). Combining roxadustat with an ESA is not recommended, as the combination has not been studied.
Regulatory status
- European Union: authorized August 18, 2021 (Astellas Pharma Europe); latest renewal March 30, 2026 (Evrenzo SmPC).
- China and Japan: China was the first country to approve it, for dialysis-dependent CKD anemia (Dhillon, Drugs 2019). By August 2021 FibroGen reported approvals in China, Japan, Chile and South Korea for both dialysis and non-dialysis patients (FibroGen 8-K, 2021).
- United States: FDA’s Cardiovascular and Renal Drugs Advisory Committee met on July 15, 2021 to discuss the roxadustat application (NDA 213805) (Federal Register, 2021). On August 11, 2021, FibroGen announced a complete response letter: FDA would not approve the application in its present form and requested additional clinical study before resubmission (FibroGen 8-K, 2021).
What the research shows
Anemia in CKD not on dialysis
In a phase 3 trial at 29 sites in China, 154 patients with hemoglobin of 7.0–10.0 g/dL were randomized 2:1 to roxadustat or placebo three times weekly for 8 weeks, followed by 18 weeks of open-label roxadustat (Chen et al., NEJM 2019):
| Outcome (weeks 7–9) | Roxadustat | Placebo |
|---|---|---|
| Change in hemoglobin | +1.9 g/dL | −0.4 g/dL (P under 0.001) |
| Change in hepcidin | −56.1 ng/mL | −15.1 ng/mL |
| Change in total cholesterol | −40.6 mg/dL | −7.7 mg/dL |
Hyperkalemia (high potassium) and metabolic acidosis were more frequent with roxadustat.
The global program pooled three placebo-controlled trials (ALPS, ANDES, OLYMPUS; 2,386 patients on roxadustat, 1,884 on placebo) and one open-label trial against darbepoetin alfa (DOLOMITES) (Evrenzo SmPC):
| Endpoint | Roxadustat | Comparator |
|---|---|---|
| Hemoglobin response in first 24 weeks, vs placebo | 80.2% | 8.7% |
| Hemoglobin change to weeks 28–36, vs placebo | +1.91 g/dL | +0.14 g/dL |
| Rescue therapy (transfusion, IV iron or ESA), vs placebo | 8.9% | 31.1% (HR 0.19, 95% CI 0.16–0.23) |
| Hemoglobin response, vs darbepoetin (DOLOMITES) | 89.5% | 78.0% (non-inferior) |
Anemia in patients on dialysis
In a Chinese phase 3 trial, 305 patients already on dialysis and epoetin alfa were randomized 2:1 to switch to roxadustat or stay on epoetin alfa for 26 weeks (Chen et al., NEJM 2019). Hemoglobin rose 0.7 g/dL on roxadustat vs 0.5 g/dL on epoetin alfa (difference 0.2 g/dL, 95% CI −0.02 to 0.5), meeting the non-inferiority margin. Roxadustat lowered hepcidin and LDL cholesterol (difference −18 mg/dL, 95% CI −23 to −13). Hyperkalemia and upper respiratory infection were more common with roxadustat; hypertension was more common with epoetin alfa.
Four global trials against ESAs (PYRENEES, SIERRAS, HIMALAYAS, ROCKIES; 2,354 on roxadustat, 2,360 on ESA) gave these pooled results (Evrenzo SmPC):
| Setting | Hemoglobin change, roxadustat | Hemoglobin change, ESA | Difference (95% CI) |
|---|---|---|---|
| Newly on dialysis, correcting anemia | +2.17 g/dL | +1.89 g/dL | 0.28 (0.11–0.45) |
| Stable dialysis, switched from ESA | +0.58 g/dL | +0.28 g/dL | 0.30 (0.23–0.37) |
Across both kidney populations, roxadustat lowered LDL and HDL cholesterol, lowered hepcidin and ferritin, and raised serum iron.
Cardiovascular safety and mortality
The central question for any anemia drug in CKD is heart and death risk. The EU label reports a pooled meta-analysis of adjudicated major adverse cardiovascular events (MACE: death, heart attack or stroke) in 8,984 patients (Evrenzo SmPC):
| Dataset (on-treatment analysis) | MACE HR (95% CI) | All-cause death HR (95% CI) |
|---|---|---|
| Not on dialysis, vs placebo | 1.26 (1.02–1.55) | 1.16 (0.90–1.50) |
| Anemia correction, vs ESA | 0.79 (0.61–1.02) | 0.78 (0.57–1.05) |
| Stable dialysis switched from ESA, vs ESA | 1.18 (1.00–1.38) | 1.23 (1.02–1.49) |
The label’s overall conclusion is that the cardiovascular and mortality risk is comparable to ESA therapy, but that the risk versus placebo in non-dialysis patients “could not be estimated with sufficient confidence.” It names non-response to treatment and switching stable ESA-treated dialysis patients as factors that may add risk.
Myelodysplastic syndromes
In the MATTERHORN phase 3 trial, 140 transfusion-dependent patients with lower-risk myelodysplastic syndromes (MDS, a group of bone marrow cancers) were randomized 3:2 to roxadustat or placebo (Mittelman et al., Am J Hematol 2024). The trial was stopped after an interim analysis: transfusion independence for at least 56 days was reached by 47.5% on roxadustat vs 33.3% on placebo (p = 0.217, not significant). A new placebo-controlled phase 3 MDS trial in patients with a high transfusion burden was registered in July 2026 and is not yet recruiting (ClinicalTrials.gov NCT07722988).
Athletic performance
No controlled human trials have tested roxadustat for exercise performance. In mice, 30 mg/kg three times weekly for 5 weeks raised hemoglobin and improved high-intensity treadmill running to exhaustion without changing muscle mass (Takemura et al., Physiol Rep 2025). The benefit disappeared when the mice were hemodiluted back to control hemoglobin levels, showing that the effect came from more red cells rather than any direct muscle action. This is animal data and does not show what happens in people.
Side effects and risks
The EU label draws on 3,542 non-dialysis and 3,353 dialysis patients (Evrenzo SmPC). The most frequent adverse reactions were:
| Adverse reaction | Frequency on roxadustat |
|---|---|
| Hypertension | 13.9% |
| Vascular access thrombosis (dialysis patients) | 12.8% |
| Diarrhea | 11.8% |
| Peripheral edema (swelling) | 11.7% |
| Hyperkalemia | 10.9% |
| Nausea | 10.2% |
The most frequent serious reactions were sepsis (3.4%), hyperkalemia (2.5%), hypertension (1.4%) and deep vein thrombosis (1.2%).
Blood clots and stroke
The label warns about thrombotic vascular events, including deep vein thrombosis (DVT), pulmonary embolism and cerebral infarction (stroke from a blocked artery). Most were serious, and fatal strokes have been reported. A rapid rise in hemoglobin was seen in some cerebrovascular events.
| Event | Roxadustat | Comparator |
|---|---|---|
| DVT, not on dialysis | 1.0% | 0.2% (placebo) |
| DVT, on dialysis | 1.3% | 0.3% (ESA) |
| Pulmonary embolism, not on dialysis | 0.4% | 0.2% (placebo) |
| Vascular access thrombosis, on dialysis | 12.8% | 10.2% (ESA) |
Vascular access clots were most frequent in the first 12 weeks, especially with hemoglobin over 12 g/dL or a rise of more than 2 g/dL in 4 weeks.
Seizures
Seizures occurred in 1.1% of non-dialysis patients on roxadustat vs 0.2% on placebo, and in 2.0% of dialysis patients vs 1.6% on ESA. The label advises caution in people with epilepsy or a history of seizures, and caution when driving.
Infections and sepsis
Sepsis (a body-wide response to infection that can cause organ failure) occurred in 2.1% of non-dialysis patients on roxadustat vs 0.4% on placebo, and in 3.4% in both arms of the dialysis trials. Fatal cases were reported. Pneumonia and urinary tract infections were the most common serious infections.
Thyroid, skin and other effects
- Secondary hypothyroidism: cases of secondary (central) hypothyroidism with decreased TSH have been reported; they reversed when roxadustat was stopped.
- Severe skin reaction: generalized exfoliative dermatitis has been reported after marketing.
- Heart rate: in a thorough QT study in healthy subjects, the QT interval was not prolonged, but heart rate rose by up to 9–10 beats per minute at a 2.75 mg/kg dose and 15–18 beats per minute at 5 mg/kg.
- Excessive red cells: the label states that misuse may lead to an excessive increase in packed cell volume (hematocrit), with possible life-threatening cardiovascular complications.
Pregnancy and breastfeeding
Roxadustat is contraindicated in the third trimester of pregnancy and during breastfeeding, and not recommended earlier in pregnancy. Animal studies showed reproductive toxicity, and women of childbearing potential must use highly effective contraception during treatment and for at least one week after the last dose. In rats, changes in male reproductive organs were seen; the effect on human male fertility is unknown.
Animal toxicology findings
In 26-week rat studies at several times human exposure, the label reports heart valve damage that was not fully reversible and brain necrosis in a few animals. In a 2-year mouse study, lung carcinoma increased at exposures about 1–3 times human exposure. These findings were not observed in the clinical studies.
Interactions
- Phosphate binders and multivalent cations: sevelamer and calcium acetate cut roxadustat exposure (AUC) by 67% and 46%. Roxadustat should be taken at least 1 hour after phosphate binders or products containing calcium, iron, magnesium or aluminum (lanthanum excepted).
- Statins: roxadustat 200 mg raised simvastatin exposure 1.8-fold, rosuvastatin 2.9-fold and atorvastatin 2.0-fold. Statin side effects should be monitored and doses reduced if needed.
- CYP2C8 and UGT1A9 modifiers: gemfibrozil or probenecid raised roxadustat exposure 2.3-fold; hemoglobin should be monitored when these are started or stopped.
Who should not use it
The label lists hypersensitivity to roxadustat, peanut or soy (the tablets contain soy lecithin), the third trimester of pregnancy and breastfeeding as contraindications. It is not recommended in severe liver impairment (Child-Pugh C), and safety in people under 18 has not been established.
Legal status and use in sport
WADA lists roxadustat by name under S2.1.2, “Hypoxia-inducible factor (HIF) activating agents,” alongside daprodustat, molidustat, vadadustat, cobalt and xenon. It is prohibited at all times, in and out of competition, and is a non-specified substance (WADA 2026 Prohibited List).
Detection has two features worth knowing:
- Long detection window. Very low concentrations can remain in urine for many months. One athlete who admitted using roxadustat for almost a year tested positive multiple times over 15 months, the first test being 12 months after stopping (Sobolevsky et al., Drug Test Anal 2025).
- Contamination is possible. In one elite athlete’s case, roxadustat was found at very low, variable concentrations in a collagen powder she used, and a volunteer taking the powder produced positive urine samples. The authors judged the findings consistent with contamination (Alvarez et al., J Pharm Biomed Anal 2024).
Key takeaways
- An oral way to raise the body’s own EPO. Roxadustat blocks HIF prolyl hydroxylase, mimicking the body’s response to low oxygen and raising EPO while improving iron use.
- Approved for CKD anemia outside the US. The EU, China, Japan and other countries approve it; the FDA declined in 2021 and asked for more clinical study.
- Effective on hemoglobin, with a mixed safety picture. It matched injected ESAs on hemoglobin, but MACE was higher than placebo in non-dialysis patients (HR 1.26 on treatment) and all-cause death was higher in stable dialysis patients switched from ESAs (HR 1.23), a result the label says needs cautious interpretation.
- Clots, seizures and sepsis are labeled risks. Rapid hemoglobin rises and values above target are linked to clotting events, so the label requires close hemoglobin monitoring.
- No human performance data. The only exercise evidence is from mice, where the benefit came entirely from higher hemoglobin.
- Banned in sport and detectable for months. WADA prohibits it at all times, and urine traces can persist for over a year after long-term use.
Sources
- Astellas Pharma Europe. Evrenzo (roxadustat) film-coated tablets: summary of product characteristics. European Medicines Agency; first authorized August 18, 2021, renewed March 30, 2026. EMA.
- Dhillon S. Roxadustat: first global approval. Drugs. 2019;79(5):563–572. PubMed.
- Chen N, Hao C, Peng X, et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med. 2019;381(11):1001–1010. PubMed.
- Chen N, Hao C, Liu BC, et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis. N Engl J Med. 2019;381(11):1011–1022. PubMed.
- Czock D, Keller F. Clinical pharmacokinetics and pharmacodynamics of roxadustat. Clin Pharmacokinet. 2022;61(3):347–362. PubMed.
- Mittelman M, Henry DH, Glaspy JA, et al. Roxadustat versus placebo for patients with lower-risk myelodysplastic syndrome: MATTERHORN phase 3, double-blind, randomized controlled trial. Am J Hematol. 2024;99(9):1778–1789. PubMed.
- Kyntra Bio. A study to investigate the efficacy and safety of roxadustat (FG-4592) for treating anemia in participants with myelodysplastic syndromes (MDS). NCT07722988; first posted July 23, 2026. ClinicalTrials.gov.
- Takemura K, Odawara M, Nishi H, et al. Pharmacological prolyl hydroxylase inhibition enhances high-intensity exercise capacity in mice. Physiol Rep. 2025;13(13):e70464. PubMed.
- Sobolevsky T, Fedoruk M, Dellanna F, et al. Long-term excretion of roxadustat in urine. Drug Test Anal. 2025;17(7):1088–1092. PubMed.
- Alvarez JC, Etting I, Gheddar L, et al. Hair and dietary supplements testing to identify contamination with roxadustat in an adverse analytical finding. J Pharm Biomed Anal. 2024;239:115915. PubMed.
- FibroGen, Inc. FibroGen receives complete response letter from the FDA for roxadustat for anemia of chronic kidney disease. Form 8-K, Exhibit 99.1; August 11, 2021. SEC.
- Food and Drug Administration. Cardiovascular and Renal Drugs Advisory Committee; notice of meeting; establishment of a public docket; request for comments. Federal Register. May 21, 2021;86:27626 (FR Doc 2021-10751). Federal Register.
- World Anti-Doping Agency. The 2026 Prohibited List: International Standard. In effect January 1, 2026. WADA 2026 Prohibited List.
- National Center for Biotechnology Information. PubChem compound summary for CID 11256664, roxadustat. PubChem.