Indications

Roxatat (Roxadustat) is indicated for the treatment of symptomatic anemia associated with chronic kidney disease (CKD) in adult patients.

Description

Roxatat is a first-in-class, orally administered HIF-PH (Hypoxia-Inducible Factor Prolyl Hydroxylase) inhibitor that promotes erythropoiesis by increasing endogenous erythropoietin (EPO) production. It also improves iron regulation and counteracts the inflammation-induced suppression of hemoglobin synthesis and red blood cell production by reducing hepcidin levels.

Pharmacology

Roxadustat is an orally bioavailable hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) with anti-anemic activity.

After administration, Roxadustat binds to and inhibits HIF-PH, an enzyme responsible for degradation of HIF transcription factors under normal oxygen conditions. Inhibition of HIF-PH prevents HIF degradation and promotes HIF activity.

Increased HIF activity results in:

Increased endogenous erythropoietin (EPO) production
Enhanced erythropoiesis
Reduced hepcidin expression
Improved iron availability
Increased hemoglobin (Hb) levels

HIF regulates genes involved in adaptation to low oxygen conditions, including genes required for erythropoiesis and iron metabolism.

Clinical studies have demonstrated that Roxadustat:

Stimulates coordinated erythropoiesis
Increases red blood cell count
Maintains plasma EPO levels within or near normal physiological ranges
Remains effective even in CKD patients with inflammation
Reduces the need for supplemental intravenous iron

Roxadustat reversibly and potently inhibits HIF prolyl hydroxylase enzymes, reducing degradation of HIF-α and promoting HIF-mediated gene transcription.

This leads to activation of genes involved in:

EPO production
EPO receptor expression
Iron absorption
Iron transport
Heme synthesis

In patients with CKD-associated anemia, Roxadustat:

Increases hemoglobin levels in a dose-dependent manner
Significantly lowers hepcidin levels
Transiently increases endogenous EPO levels within physiological ranges
Improves iron metabolism
Increases serum transferrin
Enhances intestinal iron absorption
Promotes mobilization of stored iron

Additionally, cholesterol levels are significantly reduced from baseline irrespective of concomitant treatment with statins or other lipid-lowering agents.

Dosage & Administration

Roxadustat should be taken orally three times weekly, ensuring that doses are not taken on consecutive days.

Treatment should be individualized to achieve and maintain target hemoglobin levels of 10–12 g/dL.

Patients Not Receiving Erythropoiesis-Stimulating Agents (ESA)

Adults:

Usual starting dose: 50 mg three times weekly

Recommended starting dose according to body weight:

Body weight <100 kg: 70 mg three times weekly
Body weight ≥100 kg: 100 mg three times weekly

Patients Switching from ESA Therapy

Adults:

Starting dose: 70 mg or 100 mg three times weekly

Subsequent dosage should be adjusted according to the patient's clinical response and condition.

Dose Adjustment

When adjustment is necessary, increase or decrease the dose according to the approved dose-adjustment schedule.

After a dose change:

Maintain the new dose level for 2–4 weeks.
If hemoglobin rises rapidly (>2.0 g/dL within 4 weeks), reduce the dose or temporarily discontinue treatment immediately.

Stepwise Dose Adjustment Sequence

20 mg → 40 mg → 50 mg → 70 mg → 100 mg → 150 mg → 200 mg → 250 mg → 300 mg → 400 mg (for dialysis-dependent CKD patients only)

Missed Dose

If there are ≥24 hours until the next scheduled dose, take the missed dose immediately.
If there are <24 hours until the next scheduled dose, skip the missed dose.
Resume the normal dosing schedule.
Do not take two doses on the same day.

Method of Administration

Roxadustat tablets may be taken:

With food
Without food

Drug Interactions

Roxatat with Phosphate Binders and Other Multivalent Cation Products (Except Lanthanum Carbonate)

Risk:

Decreased Roxatat exposure (AUC) by 67% and 46%
Decreased Cmax by 66% and 52%

Recommendation: Take Roxatat at least 1 hour after phosphate binders or products containing multivalent cations.

Roxatat with Gemfibrozil or Probenecid

Gemfibrozil: CYP2C8 and OATP1B1 inhibitor
Probenecid: UGT and DAT1/DAT3 inhibitor

Risk:

Increased Roxatat AUC by approximately 2.3-fold
Increased Cmax by approximately 1.4-fold

Recommendation: Adjust Roxatat dosage based on hemoglobin monitoring and dose-adjustment guidelines.

Roxatat with OATP1B1 or BCRP Substrates

Examples:

Simvastatin
Rosuvastatin
Atorvastatin

Risk:

Increased AUC and Cmax

Recommendation: Monitor hemoglobin and adjust Roxatat dosage as clinically appropriate.

Side Effects

Common adverse reactions include:

Hypertension
Vascular access thrombosis
Diarrhea
Peripheral edema
Hyperkalemia
Nausea

Pregnancy & Lactation

Roxadustat should not be administered during pregnancy or to women who may become pregnant.
Roxadustat is contraindicated during breastfeeding.