Indications

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

Description

Renesis is a frst-in-class, orally administered HIF-PH inhibitor that promotes erythropoiesis through increasing endogenousproduction of erythropoietin, as well as improving iron regulation and overcoming the EPO-suppressive efects of infammationon hemoglobin syntheses and red blood cell production by downregulating hepcidin.

Pharmacology

Roxadustat is an orally bioavailable, hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), with potential anti-anemicactivity. Upon administration, roxadustat binds to and inhibits HIF-PH, an enzyme responsible for the degradation oftranscription factors in the HIF family under normal oxygen conditions. This prevents HIF breakdown and promotes HIF activity.

Increased HIF activity leads to an increase in endogenous erythropoietin production, thereby enhancing erythropoiesis. It alsoreduces the expression of the peptide hormone hepcidin, improves iron availability, and boosts hemoglobin (Hb) levels. HIFregulates the expression of genes in response to reduced oxygen levels, including genes required for erythropoiesis and ironmetabolism.

Administration of roxadustat has been shown to induce coordinated erythropoiesis, increasing red blood cell count whilemaintaining plasma erythropoietin levels within or near normal physiologic range, in multiple subpopulations of CKD patients,including in the presence of infammation, and without a need for supplemental intravenous iron.

Roxadustat reversibly binds to and potently inhibits hypoxia-inducible factor (HIF) prolyl hydroxylase enzymes, reducing HIF-αbreakdown and promoting HIF transcriptional activity. Activation of the HIF pathway in this manner results in the induction oftarget genes involved in erythropoiesis, such as those for EPO, EPO receptor, proteins promoting iron absorption, iron transportand haem synthesis.

Roxadustat dose-dependently increased haemoglobin (Hb) levels, signifcantly reduced hepcidin levels andtransiently increased endogenous EPO levels within or near physiological range in patients with anemia of CKD who were notdialysis dependent. Roxadustat reduced the dysregulation of iron metabolism associated with CKD by increasing serumtransferrin, intestinal iron absorption and the release of stored iron in a dose-dependent manner in patients with anemiaassociated with dialysis dependent or dialysis-independent CKD.

Cholesterol levels were also signifcantly reduced from baselinewith roxadustat, regardless of the use of statins or other lipid-lowering agents.

Dosage & Administration

The appropriate dose of roxadustat must be taken orally three times per week and not on consecutive days. The dose should be_individualized to achieve and maintain target Hb levels of 10 to 12 g/dL as described below:

Patients not on erythropoiesis-stimulating agent treatment: For adults, the usual starting dose is 50 mg three timesweekly. The recommended starting dose of roxadustat is 70 mg three times per week in patients weighing less than 100 kg and100 mg three times per week in patients weighing 100 kg and over.

Patients switching from erythropoiesis-stimulating agents: For adults, the usual starting dose is 70 or 100mg three timesweekly. The dosage thereafter should be adjusted according to the patient’s condition.

Dose adjustment: When dose adjustments are required, increase or decrease the dose according to the “Doseincrease/decrease table” and “stepwise Dose adjustment sequence” below. Once adjusted, maintain the dose level for ≥4 weeks.

If the hemoglobin concentration increases rapidly (>2.0 g/dL) within 4 weeks of a dose increase, decrease the dose or suspendthe treatment immediately.

The stepwise dose adjustments up or down should follow the sequence of the available doses: 20 mg-40 mg-50 mg-70mg-100 mg-150 mg-200 mg-250 mg-300 mg-400 mg (only for CKD patients on dialysis).

Missed dose: When there is ≥ 24-hour interval until the next scheduled dosing time, take the missed dose immediately andfollow the prescribed schedule for subsequent doses. If there is <24 hours until the next scheduled dosing time, skip the misseddose, and take the next dose as scheduled. Do not take 2 doses on the same day.

Method of administration: Roxadustat tablets are to be taken orally with or without food.

Interaction

Renesis in combination with other medications may have drug-drug interaction.

• Risk: decreased Renesis AUC by 67% and 46% and Cmax by 66% and 52%
• Recommendation: Renesis should be taken at least 1 hour after administration of phosphate binders or other medicinalproducts or supplements containing multivalent cations.

Renesis with gemfbrozil (CYP2C8 and OATP1B1inhibitor) or probenecid (UGT and OAT1/OAT3 inhibitor)

Risk: increased Renesis AUC by 2.3- fold and Cmax by 1.4-fold

Recommendation: Adjust the dose of Renesis following dose adjustment rules based on Hb monitoring.

Renesis with OATP1B1 or BCRP Substrates (simvastatin, rosuvastatin & atorvastatin)

Risk: AUC and Cmax increased

Recommendation: Adjust the dose of Renesis following dose adjustment rules based on Hb monitoring.

Side Effects

The common adverse reactions associated with Renesis are hypertension, vascular access thrombosis, diarrhoea, peripheraloedema, hyperkalaemia and nausea.

Pregnancy & Lactation

Do not administered to women that may be pregnant or pregnant. Roxadustat is contraindicated during breast-feeding.

Precautions & Warnings

Renesis tablets should be used in caution. It may initiate few thrombotic vascular events (TVEs) particularly in patients with pre-existing risk factors for TVE, including obesity and prior history of TVEs. Renesis should be used with caution in patients with ahistory of seizures. Renesis should not be administered if the patient has serious signs and symptoms of an infection. Renesisshould not be administered if the patient has liver disorder. Renesis should not be initiated in pregnant women.

Use in Special Populations

Children: Renesis is not indicated in children.

liver dysfunction patients: Renesis is not recommended for use in patients with severe hepatic impairment.

Overdose Effects

Symptoms: When Renesis was administered 5 mg/kg (510 mg) to a single healthy adult, increased heart rate transient havebeen reported. Hemoglobin concentration by overdosage of Renesis is likely to increase more than necessary.

Treatment: Appropriate measures of dose reduction or interruption, etc. of Renesis. Renesis is not removed by dialysis.

Therapeutic Class

Drugs for Haemolytic Hypoplastic & Renal Anemia

Storage Conditions

Store in a cool (below 30°C), dry place, away from light and moisture. Keep out of the reach of children.