Overview
11 DESCRIPTION Belzutifan is an inhibitor of hypoxia-inducible factor-2α (HIF-2α). The chemical name of belzutifan is 3-[[(1S,2S,3R)-2,3-Difluoro-2,3-dihydro-1-hydroxy-7-(methylsulfonyl)-1H-inden-4-yl]oxy]-5-fluorobenzonitrile. The molecular formula is C 17 H 12 F 3 NO 4 S and the molecular weight is 383.34 Daltons.
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Belzutifan is an inhibitor of hypoxia-inducible factor 2 alpha (HIF-2α). HIF-2α is a transcription factor that plays a role in oxygen sensing by regulating genes that promote adaptation to hypoxia. Under normal oxygen levels, HIF-2α is targeted for ubiquitin-proteasomal degradation by VHL protein. Lack of functional VHL protein results in stabilization and accumulation of HIF-2α. Upon stabilization, HIF-2α translocates into the nucleus and interacts with hypoxia-inducible factor 1 beta (HIF-1β) to form a transcriptional complex that induces expression of downstream genes, including genes associated with cellular proliferation, angiogenesis, and tumor growth.
Indications
- 1 INDICATIONS AND USAGE WELIREG is a hypoxia-inducible factor inhibitor indicated: von Hippel-Lindau (VHL) disease for treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. ( 1.1 ) Advanced Renal Cell Carcinoma (RCC) for treatment of adult patients with advanced renal cell carcinoma (RCC) with a clear cell component following a programmed death receptor-1 (PD-1) or programmed death-ligand 1...
Common Doses
- 120 mg
- 80 mg
- 40 mg
- 8 g
Dosage
2 DOSAGE AND ADMINISTRATION The recommended dosage of WELIREG in adult patients is 120 mg administered orally once daily with or without food. ( 2.1 ) The recommended dosage of WELIREG in pediatric patients 12 years and older is based on bodyweight: Patients weighing ≥ 40 kg: 120 mg orally once daily Patients weighing
Black Box Warning
WARNING: EMBRYO-FETAL TOXICITY Exposure to WELIREG during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of WELIREG. Advise patients of these risks and the need for effective non-hormonal contraception. WELIREG can render some hormonal contraceptives ineffective [see Warnings and Precautions (5.3) , Drug Interactions (7.2) , Use in Specific Populations (8.1 , 8.3) ]. WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Exposure to WELIREG during pregnancy can cause embryo-fetal harm.
Contraindications
- 4 CONTRAINDICATIONS None. None. ( 4 )
Side Effects
- 6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Anemia [see Warnings and Precautions (5.1) ] Hypoxia [see Warnings and Precautions (5.2) ] VHL disease : Most common (≥25%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. ( 6.1 ) Advanced RCC : Most common (≥25%) adverse reactions, including laboratory abnormalities were decreased hemoglobin, fatigue, musculoskeletal pain, increased creatinine, decreased...
Interactions
- 7 DRUG INTERACTIONS UGT2B17 or CYP2C19 Inhibitors: Monitor for signs and symptoms of anemia and hypoxia and reduce the dosage of WELIREG as recommended. ( 2.2 , 7.1 ) 7.1 Effects of Other Drugs on WELIREG UGT2B17 or CYP2C19 Inhibitors Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended [see Dosage and Administration (2.2) , Warnings and Precautions (5.1 , 5.2) , Adverse Reactions (6) ] . Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases belzutifan exposure [see Clinical Pharmacology (12.3 , 12.