WELIREG (belzutifan) tablets
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 C17H12F3NO4S and the molecular weight is 383.34 Daltons.
Belzutifan is a white to light brown powder that is soluble in acetonitrile, dimethoxyethane, and acetone, sparingly soluble in ethyl acetate, very slightly soluble in isopropanol and toluene, and insoluble in water.
WELIREG is supplied as blue, film-coated tablets for oral use containing 40 mg of belzutifan together with croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, mannitol, microcrystalline cellulose, and silicon dioxide, as inactive ingredients. In addition, the film-coating contains FD&C Blue #2 aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide.
Indications and usage
WELIREG is a hypoxia-inducible factor inhibitor indicated 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.
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. Belzutifan binds to HIF-2α, and in conditions of hypoxia or impairment of VHL protein function, belzutifan blocks the HIF-2α-HIF-1β interaction, leading to reduced transcription and expression of HIF-2α target genes. In vivo, belzutifan demonstrated anti-tumor activity in mouse xenograft models of renal cell carcinoma.
Dosage and administration
The recommended dosage of WELIREG is 120 mg administered orally once daily with or without food.
Anemia: Monitor for anemia before initiation of and periodically throughout treatment with WELIREG. Withhold WELIREG until hemoglobin ≥9g/dL, then resume at reduced dose or discontinue. For life threatening anemia, or for anemia requiring urgent intervention, withhold WELIREG until hemoglobin ≥9g/dL and resume at a reduced dose or permanently discontinue WELIREG.
Hypoxia: Monitor oxygen saturation before initiation of, and periodically throughout, treatment with WELIREG. For hypoxia at rest, withhold until resolved, resume at reduced dose, or discontinue depending on severity. For life-threatening hypoxia, permanently discontinue WELIREG.
Embryo-Fetal Toxicity: Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of belzutifan to pregnant rats during the period of organogenesis caused embryo-fetal lethality, reduced fetal body weight, and fetal skeletal malformations at maternal exposures ≥0.2 times the human exposures (AUC) at the recommended dose of 120 mg daily.
Adverse drug reactions
Most common (≥ 25%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea.
UGT2B17 or CYP2C19 Inhibitors: Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan, which may increase the incidence and severity of adverse reactions of WELIREG. Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended.
Sensitive CYP3A4 Substrates: Coadministration of WELIREG with CYP3A4 substrates decreases concentrations of CYP3A substrates, which may reduce the efficacy of these substrates. The magnitude of this decrease may be more pronounced in patients who are dual UGT2B17 and CYP2C19 poor metabolizers. Avoid coadministration of WELIREG with sensitive CYP3A4 substrates, for which minimal decrease in concentration may lead to therapeutic failures of the substrate. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information.
Hormonal Contraceptives: Co-administration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding.
Use in specific populations
Pregnancy: Based on findings in animal studies, WELIREG can cause fetal harm when administered to a pregnant woman. There are no available data on the use of WELIREG in pregnant women to inform the drug associated risk. In an animal reproduction study, oral administration of belzutifan to pregnant rats during the period of organogenesis caused embryo-fetal lethality, reduced fetal body weight, and fetal skeletal malformations at maternal exposures ≥0.2 times the human exposure (AUC) at the recommended dose of 120 mg daily. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
Lactation: There are no data on the presence of belzutifan or its metabolites in human milk or their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with WELIREG and for 1 week after the last dose.
Contraception: Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. WELIREG can render some hormonal contraceptives ineffective.
Advise males with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.
Infertility: Based on findings in animals, WELIREG may impair fertility in males and females of reproductive potential. The reversibility of the effect on fertility is unknown.
Pediatric Use: Safety and effectiveness of WELIREG have not been established in pediatric patients.
Geriatric Use: Of the patients who received WELIREG in Study 004, 3.3% were ≥65 years old. Clinical trials of WELIREG did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients
Renal Impairment: No dosage modification of WELIREG is recommended in patients with mild (eGFR 60-89 mL/min/1.73 m2 estimated by MDRD) and moderate (eGFR 30-59 mL/min/1.73 m2) renal impairment. WELIREG has not been studied in patients with severe (eGFR 15-29 mL/min/1.73 m2) renal impairment.
Hepatic Impairment: No dosage modification of WELIREG is recommended in patients with mild [total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin >1 to 1.5 x ULN and any AST] hepatic impairment. WELIREG has not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 x ULN and any AST)
There is no specific treatment for WELIREG overdose. In cases of suspected overdose, withhold WELIREG and institute supportive care. Grade 3 hypoxia occurred at dosages of 120 mg twice a day and Grade 4 thrombocytopenia occurred at dosages of 240 mg once daily (approximately 2 times the recommended dosage).
Storage and Handling
Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].