BELZUTIFAN Drug Interactions: What You Need to Know

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) , Warnings and Precautions (5.1 , 5.2) , Adverse Reactions (6) ]</span> . Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases belzutifan exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3 , 12.5) ]</span> , which may increase the risk of adverse reactions of WELIREG.

7.2 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.

Hormonal Contraceptives

Coadministration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding [see Clinical Pharmacology (12.3) , Use in Specific Populations (8.3) ] .

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AND PRECAUTIONS 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. ( 2.2 , 5.1 ) 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. ( 2.2 , 5.2 )

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 &lt;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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . von Hippel-Lindau (VHL) disease In LITESPARK-004, decreased hemoglobin occurred in 93% of patients and 7% had Grade 3 events <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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 [see Adverse Reactions (6.1) ] . 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 [see Adverse Reactions (6.1) ] . 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.

5.2 Hypoxia WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span>. Monitor oxygen saturation before initiation of, and periodically throughout, treatment with WELIREG. For decreased oxygen saturation with exercise (e.g., pulse oximeter &lt;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 &lt;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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

Advanced Renal Cell

Carcinoma (RCC) In LITESPARK- 005, hypoxia occurred in 15% of patients and 10% had Grade 3 events [see Adverse Reactions (6.1) ] . 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 [see Adverse Reactions (6.1) ] . 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.

5.3 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span>. 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span> .