What is the indication and dose of Roxadustat (hypoxia-inducible factor prolyl hydroxylase inhibitor) for the treatment of anemia in patients with Chronic Kidney Disease (CKD)?

Roxadustat for Anemia in Chronic Kidney Disease

Roxadustat is indicated for treating anemia in adult CKD patients both on dialysis and not on dialysis, with weight-based starting doses of 70 mg three times weekly (TIW) for patients 45-70 kg or 100 mg TIW for patients ≥70 kg, titrated to maintain hemoglobin between 10-12 g/dL. 1

Indications

Roxadustat is approved for anemia treatment in:

• Non-dialysis-dependent CKD patients (stages 3-5) with hemoglobin <10 g/dL after iron repletion 2, 3
• Dialysis-dependent CKD patients (both hemodialysis and peritoneal dialysis) who are ESA-naïve or converting from ESAs 4, 5

The drug works as an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that stimulates erythropoiesis and improves iron metabolism. 2

Dosing Regimen

Starting Doses

For ESA-naïve patients:

• 45 to <70 kg: 70 mg TIW 1
• ≥70 kg: 100 mg TIW 1

Lower starting doses may be considered for CKD stage 3-4:

• <60 kg: 50 mg TIW 6
• ≥60 kg: 70 mg TIW 6

The lower starting dose showed comparable target achievement with less hemoglobin fluctuation in stage 3-4 CKD, though it was less effective in stage 5 CKD. 6

For ESA-converted patients (peritoneal dialysis):

• 70 mg TIW or 100 mg TIW depending on prior ESA dose 5

Dose Titration

Adjust doses in stepwise fashion based on:

• Current hemoglobin level 1
• Rate of hemoglobin change over 4-week periods 1
• Target hemoglobin range of 10-12 g/dL 1, 4

Temporarily discontinue treatment when:

• Hemoglobin exceeds 12 or 13 g/dL 1

The KDIGO consensus emphasizes that starting doses should be lower for ESA-naïve patients compared to those converting from ESAs. 1

Efficacy Data

In non-dialysis CKD patients:

• Mean hemoglobin increase of 2.00 g/dL (weeks 28-52) versus 0.16 g/dL with placebo 2
• 86.0% achieved hemoglobin response (≥11.0 g/dL and increase ≥1.0 g/dL) at week 24 versus 6.6% with placebo 2
• Only 8.9% required rescue therapy versus 28.9% with placebo 2

In dialysis patients:

• Roxadustat was non-inferior to ESAs in maintaining hemoglobin levels 4
• 84.2% achieved target hemoglobin without rescue therapy (weeks 28-36) 4
• In peritoneal dialysis, maintenance rates were 92.3% (ESA-naïve) and 74.4% (ESA-converted) 5

Critical Safety Considerations and Contraindications

Absolute Contraindications

Do not use roxadustat in:

• Patients with polycystic kidney disease until adequate safety data emerge, as HIF activation may enhance cyst expansion 1
• Pediatric patients (under 18 years), as they were excluded from all phase 3 trials 1
• Patients with active or recent malignancy, as avoidance is recommended pending post-marketing surveillance 1

Important Safety Signals

Cardiovascular concerns:

• The OLYMPUS trial in non-dialysis CKD showed no clear cardiovascular benefit, with the primary MACE outcome not meeting superiority margins 1
• Conference participants noted that cardiovascular safety data are still evolving 1

Infection risk:

• Approximately 2-fold increase in sepsis and septic shock risk reported in pooled non-dialysis studies 1

Metabolic effects:

• Central hypothyroidism reported specifically with roxadustat due to its structural similarity to triiodothyronine (T3) 1
• The Japanese regulatory agency added central hypothyroidism to the package insert 1
• Significant reductions in total cholesterol and LDL cholesterol observed 1, 4

Kidney function:

• One phase 3 trial suggested greater decline in eGFR with roxadustat (-3.70 ml/min/1.73m²) versus placebo (-3.19 ml/min/1.73m²), though clinical relevance is debated 1

Special Populations

Kidney transplant recipients:

• Use with caution due to limited data and potential effects on immune cell function 1

ESA-hyporesponsive patients:

• Data on effectiveness in this population are limited, though HIF-PHIs theoretically may be more effective by lowering hepcidin levels 1
• Do not combine with ESAs, as no data support this strategy 1

Monitoring Requirements

Regular monitoring should include:

• Hemoglobin levels every 4 weeks during titration 1
• Target maintenance range of 10-12 g/dL 1, 4
• Iron parameters (ferritin, transferrin saturation) 3
• Thyroid function given the risk of central hypothyroidism 1

Common Pitfalls

Avoid these errors:

• Starting with standard doses in CKD stage 3-4 when lower doses may provide comparable efficacy with less hemoglobin fluctuation 6
• Targeting hemoglobin >12 g/dL, as treatment should be temporarily discontinued at these levels 1
• Using roxadustat in combination with ESAs without supporting evidence 1
• Failing to monitor for central hypothyroidism, which is specific to roxadustat among HIF-PHIs 1
• Prescribing to patients with polycystic kidney disease or active malignancy 1

Drug Interactions

Be aware of potential drug-drug interactions when roxadustat is used with other oral agents, particularly in patients on multiple medications. 1