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. The chemical structure is: 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. image description

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. 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 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). Pheochromocytoma or Paraganglioma (PPGL) for treatment of adult and pediatric patients 12 years and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL)

von Hippel-Lindau (VHL) disease WELIREG is 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

Advanced Renal Cell Carcinoma (RCC) WELIREG is indicated for the 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 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI)

Pheochromocytoma or Paraganglioma (PPGL) WELIREG is indicated for the treatment of adult and pediatric patients 12 years and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL).

Tablets: 40 mg, blue, oval shaped, film-coated, debossed with “177” on one side and plain on the other side. Tablets: 40 mg

The recommended dosage of WELIREG in adult patients is 120 mg administered orally once daily with or without food. 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 < 40 kg: 80 mg orally once daily 2.1 Recommended Dosage The recommended dosage of WELIREG in adult patients is 120 mg administered orally once daily. 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 < 40 kg: 80 mg orally once daily Continue WELIREG until disease progression or unacceptable toxicity. WELIREG should be taken at the same time each day and may be taken with or without food. Advise patients to swallow tablets whole. Do not chew, crush, or split WELIREG prior to swallowing. If a dose of WELIREG is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for WELIREG the next day. Do not take extra tablets to make up for the missed dose. If vomiting occurs any time after taking WELIREG, do not retake the dose. Take the next dose on the next day

Dosage Modifications for Adverse Reactions Dosage modifications for WELIREG for adverse reactions are summarized in Table 1 . The recommended dose reductions are: First dose reduction: WELIREG 80 mg orally once daily Second dose reduction: WELIREG 40 mg orally once daily Third dose reduction: Permanently discontinue Table 1: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity Dosage Modification Anemia Hemoglobin <8 g/dL or transfusion indicated Withhold until hemoglobin ≥8g/dL. Resume at the same or reduced dose; or discontinue depending on the severity of anemia. Life-threatening or urgent intervention indicated Withhold until hemoglobin ≥8g/dL. Resume at a reduced dose or permanently discontinue. Hypoxia Decreased oxygen saturation with exercise (e.g., pulse oximeter <88%) Consider withholding until resolved. Resume at the same dose or at a reduced dose depending on the severity of hypoxia. Decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO 2 ≤55 mm Hg) or urgent intervention indicated Withhold until resolved. Resume at reduced dose or discontinue depending on the severity of hypoxia. Life-threatening or recurrent symptomatic hypoxia Permanently discontinue. Other Adverse Reactions Grade 3 Withhold dosing until resolved to ≤ Grade 2. Consider resuming at a reduced dose (reduce by 40 mg). Permanently discontinue upon recurrence of Grade 3. Grade 4 Permanently discontinue.

Anemia : Monitor for anemia before initiation of and periodically throughout treatment with WELIREG. Withhold WELIREG until hemoglobin ≥8g/dL, then resume at the same or reduced dose or discontinue. For life threatening anemia, or for anemia requiring urgent intervention, withhold WELIREG until hemoglobin ≥8g/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. 5.1 Anemia WELIREG can cause severe anemia that can require blood transfusion. Monitor for anemia before initiation of, and periodically throughout, treatment with WELIREG. Transfuse patients as clinically indicated. For patients with hemoglobin <8g/dL, withhold WELIREG until ≥8g/dL, then resume at the same or reduced dose or permanently discontinue WELIREG, depending on the severity of anemia. For life threatening anemia or when urgent intervention is indicated, withhold WELIREG until hemoglobin ≥8g/dL, then resume at a reduced dose or permanently discontinue WELIREG . von Hippel-Lindau (VHL) disease In LITESPARK-004, decreased hemoglobin occurred in 93% of patients and 7% had Grade 3 events . Median time to onset of anemia was 31 days (range: 1 day to 8.4 months). The safety of erythropoiesis stimulating agents (ESAs) for treatment of anemia in patients with VHL disease treated with WELIREG has not been established. Randomized controlled trials in patients with cancer receiving myelosuppressive chemotherapy with ESAs have shown that ESAs increased the risks of death and serious cardiovascular reactions, and decreased progression-free survival and/or overall survival. See the prescribing information for ESAs for more information. Advanced Renal Cell Carcinoma (RCC) In LITESPARK-005, decreased hemoglobin occurred in 88% of patients and 29% had Grade 3 events . Median time to onset of anemia was 29 days (range: 1 day to 16.6 months). Of the patients with anemia, 22% received transfusions only, 20% of patients received ESAs only and 12% received both transfusion and ESAs. Pheochromocytoma or Paraganglioma (PPGL) In LITESPARK-015, anemia occurred in 96% of patients and 22% had Grade 3 events . Median time to onset of anemia was 29 days (range: 1 day to 22.1 months). Of the patients with anemia, 20% received transfusions only, 26% received ESAs only, and 6% received both transfusion and ESAs

Hypoxia WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization . Monitor oxygen saturation before initiation of, and periodically throughout, treatment with WELIREG. For decreased oxygen saturation with exercise (e.g., pulse oximeter <88% or P a O 2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same dose or at a reduced dose. For decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg) or urgent intervention indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening hypoxia or for recurrent symptomatic hypoxia, permanently discontinue WELIREG . Advise patients to report signs and symptoms of hypoxia immediately to a healthcare provider. von Hippel-Lindau (VHL) disease In LITESPARK- 004, hypoxia occurred in 1.6% of patients . Advanced Renal Cell Carcinoma (RCC) In LITESPARK- 005, hypoxia occurred in 15% of patients and 10% had Grade 3 events . Of the patients with hypoxia, 69% were treated with oxygen therapy. Median time to onset of hypoxia was 30.5 days (range: 1 day to 21.1 months). Pheochromocytoma or Paraganglioma (PPGL) In LITESPARK-015, hypoxia occurred in 13% of patients and 10% had Grade 3 hypoxia . Median time to onset of hypoxia was 35 days (range: 6 days to 23.9 months). Of the patients with hypoxia, 67% were treated with oxygen therapy

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. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose, since WELIREG can render some hormonal contraceptives ineffective . Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose .

UGT2B17 or CYP2C19 Inhibitors: Monitor for signs and symptoms of anemia and hypoxia and reduce the dosage of WELIREG as recommended

Effects of Other Drugs on WELIREG UGT2B17 or CYP2C19 Inhibitors Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended . Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases belzutifan exposure , which may increase the risk of adverse reactions of WELIREG

Effect of WELIREG on Other Drugs CYP3A4 Substrates 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. 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 . Hormonal Contraceptives Coadministration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding .