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Anemia: WELIREG can cause severe anemia that can require blood transfusion.
In Study 004, anemia occurred in 90% of patients and 7% had Grade 3 anemia [see Clinical Trials Experience under Adverse Reactions]. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months). In another clinical trial [Study 001 (n=58)] in patients with advanced solid tumors who received the same dosage of WELIREG, anemia occurred in 76% of patients and 28% had Grade 3 anemia.
Monitor for anemia before initiation of, and periodically throughout, treatment with WELIREG. Closely monitor patients who are dual UGT2B17 and CYP2C19 poor metabolizers due to potential increases in exposure that may increase the incidence or severity of anemia [see Pharmacology: Pharmacogenomics under Actions].
Transfuse patients as clinically indicated. For patients with hemoglobin <9 g/dL, withhold WELIREG until ≥9 g/dL, then resume at 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 ≥9 g/dL, then resume at a reduced dose or permanently discontinue WELIREG [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
The use of erythropoiesis stimulating agents (ESAs) for treatment of anemia is not recommended in patients treated with WELIREG. For patients treated with WELIREG who develop anemia, the safety and effectiveness for use of ESAs have 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.
Hypoxia: WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
In Study 004, hypoxia occurred in 1.6% of patients [see Clinical Trials Experience under Adverse Reactions]. In another clinical trial [Study 001 (n=58)] in patients with advanced solid tumors who received the same dosage of WELIREG, hypoxia occurred in 29% of patients, including Grade 3 hypoxia in 16%.
Monitor oxygen saturation before initiation of, and periodically throughout, treatment with WELIREG. For decreased oxygen saturation with exercise (e.g., pulse oximeter <88% or PaO2 ≤55 mmHg), 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 mmHg) 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 [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Advise patients to report signs and symptoms of hypoxia immediately to a healthcare provider.
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 [see Effect of WELIREG on Other Drugs under Interactions]. 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 [see Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation].
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 [see Pharmacology: Pharmacokinetics under Actions]. 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) [see Pharmacology: Pharmacokinetics under Actions].
Dual UGT2B17 and CYP2C19 Poor Metabolizers: Patients who are dual UGT2B17 and CYP2C19 poor metabolizers have higher belzutifan exposures, which may increase the incidence and severity of adverse reactions of WELIREG. Closely monitor for adverse reactions in patients who are dual UGT2B17 and CYP2C19 poor metabolizers [see as previously mentioned; Adverse Reactions; Pharmacology: Pharmacogenomics under Actions].
Use in Children: Safety and effectiveness of WELIREG have not been established in pediatric patients.
Use in the Elderly: Of the patients who received WELIREG in Study 004, 3.3% were ≥65 years old [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. Clinical trials of WELIREG did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.
