ROXATAT TABLET 50 MG

Indications

• Symptomatic anemia associated with chronic kidney disease in patients not currently treated with an erythropoiesis-stimulating agent.

Dosage

Adults: Initially 70 mg three times a week, adjusted according to response; usual maintenance 20–400 mg three times a week. Doses should not be taken on consecutive days, with adjustments made at intervals of 4 weeks to achieve a hemoglobin concentration of 10 to 12 g/dL.

Mechanism of action

Roxadustat inhibits hypoxia-inducible factor prolyl hydroxylase enzymes (HIF-PHD), leading to the accumulation of functional HIF. This increases plasma EPO production, enhances erythropoiesis, and suppresses hepcidin, which regulates iron metabolism, thereby improving anemia in CKD patients.

Pharmacodynamics

Roxadustat improves iron bioavailability and increases hemoglobin production in a dose-dependent manner. It enhances red blood cell mass and maintains hemoglobin levels in CKD patients for extended periods. The drug exhibits comparable efficacy to erythropoiesis-stimulating agents and also has a cholesterol-lowering effect.

Pharmacokinetics

Roxadustat is absorbed rapidly after oral administration, with peak plasma concentrations occurring within 1 to 2 hours. It has a half-life of approximately 12 hours, allowing for dosing multiple times a week. Roxadustat is metabolized primarily in the liver, with renal excretion playing a minor role in its elimination.

Adverse effects

• Constipation
• Diarrhoea
• Headache
• Hyperkalaemia
• Hypertension
• Insomnia
• Nausea
• Peripheral oedema
• Seizures
• Sepsis
• Vomiting
• Hyperbilirubinaemia
• Increased risk of infection

Interactions

• Fexofenadine - Moderate (increases exposure)
• Bosentan - Moderate (increases exposure)
• Gemfibrozil - Moderate (increases exposure)
• Repaglinide - Moderate (increases exposure)
• Rifampicin - Moderate (decreases exposure)
• Antihistamines, non-sedating - Moderate (increases exposure)
• Endothelin receptor antagonists - Moderate (increases exposure)
• Meglitinides - Moderate (increases exposure)
• Rifamycins - Moderate (decreases exposure)
• Statins - Moderate (increases exposure)

Precautions

• Caution in moderate hepatic impairment; avoid in severe impairment
• Ensure adequate iron levels before starting treatment
• Monitor hemoglobin concentration every 2 weeks until desired level is achieved and stabilized

Pregnancy

Avoid-toxicity observed in animal studies.

Breast-feeding

Avoid-present in milk in animal studies.

Storage

Store at room temperature, protect from light and moisture.

Formulations

• Roxadustat 20 mg, 50 mg, 70 mg, 100 mg, and 150 mg tablets
• Pre-filled syringes for injection

Mechanism of action

Anemia is a common complication of chronic kidney disease that may be caused by reduced production of renal erythropoietin (EPO), functional iron deficiency due to increased levels of hepcidin, blood loss, reduced erythrocyte survival duration, and inflammation. Hypoxia-inducible factor (HIF) is a transcription factor that induces several target oxygen-sensitive genes in response to low oxygen levels in the cellular environment, or hypoxia. Target genes are involved in erythropoiesis, such as those for EPO, EPO receptor, proteins promoting iron absorption, iron transport, and haem synthesis. Activation of the HIF pathway is an important adaptive responsive to hypoxia to increase red blood cell production. HIF is heterodimeric and contains an oxygen-regulated α-subunit. The α-subunit houses an oxygen-dependent degradation (ODD) domain that is regulated and hydroxylated by HIF-prolyl hydroxylase (HIF-PHD) enzymes under normoxic cellular conditions. HIF-PHD enzymes play a crucial role in maintaining a balance between oxygen availability and HIF activity. Roxadustat is a reversible and potent inhibitor of HIF-PHD enzymes: inhibition of HIF-PHD leads to the accumulation of functional HIF, an increase in plasma endogenous EPO production, enhanced erythropoiesis, and indirect suppression of hepcidin, which is an iron regulator protein that is increased during inflammation in chronic kidney disease. Roxadustat can also regulate iron transporter proteins and regulates iron metabolism by increasing serum transferrin, intestinal iron absorption and the release of stored iron in patients with anemia associated with dialysis-dependent or dialysis-independent CKD. Overall, roxadustat improves iron bioavailability, increases Hb production, and increases red cell mass.

Pharmacodynamics

Roxadustat dose-dependently improves iron bioavailability, increases hemoglobin production, and increases red blood cell mass in patients with anemia. In non-dialysis-dependent CKD patients with anemia, roxadustat maintained Hb for up to 2 years. It has a comparable efficacy to erythropoietin-stimulating agents in achieving Hb response. Roxadustat also reduces cholesterol levels from baseline, regardless of the use of statins or other lipid-lowering agents.