WELIREG
Clinical safety rating: caution
Comprehensive clinical and safety monograph for WELIREG (WELIREG).
Hypoxia-inducible factor-2α (HIF-2α) inhibitor. Binds to HIF-2α, blocking its heterodimerization with HIF-1β, thereby reducing transcription of genes involved in cell proliferation, angiogenesis, and metabolism associated with tumor growth.
| Metabolism | Primarily metabolized by CYP3A4 and to a minor extent by CYP2C19 and UGT1A9. |
| Excretion | Primarily hepatic metabolism (CYP3A4) with 65% fecal excretion (mostly as metabolites) and 22% renal excretion (mostly unchanged drug). |
| Half-life | Terminal elimination half-life is approximately 14-18 hours in patients; supports once-daily dosing. |
| Protein binding | 99.7% bound to plasma proteins, primarily to albumin. |
| Volume of Distribution | Volume of distribution is 1.2 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 60-70%. |
| Onset of Action | Onset of clinical effect is observed within 2-4 weeks of oral administration. |
| Duration of Action | Duration of action is approximately 24 hours, allowing once-daily dosing; sustained exposure is necessary for continuous HIF-2α inhibition. |
| Molecular Weight | 422.5 |
120 mg orally once daily with or without food until disease progression or unacceptable toxicity.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment recommended for mild to moderate renal impairment (CrCl ≥30 mL/min). For severe renal impairment (CrCl 15-29 mL/min), reduce dose to 40 mg orally once daily. Not studied in ESRD (CrCl <15 mL/min). |
| Liver impairment | Mild hepatic impairment (Child-Pugh A): no dose adjustment. Moderate (Child-Pugh B): reduce dose to 80 mg orally once daily. Severe (Child-Pugh C): reduce dose to 40 mg orally once daily. |
| Pediatric use | Safety and effectiveness not established in pediatric patients; no recommended dose. |
| Geriatric use | No specific dose adjustment required; however, consider age-related renal impairment and monitor for adverse reactions. |
| 1st trimester | Avoid; teratogenic in animal studies, known to cause fetal harm. No adequate human data. |
| 2nd trimester | Avoid; potential for fetal harm based on mechanism and animal data. |
| 3rd trimester | Avoid; potential for fetal harm and risk of oligohydramnios due to VEGF inhibition. |
Clinical note
Comprehensive clinical and safety monograph for WELIREG (WELIREG).
| Placental transfer | Expected to cross the placenta based on molecular weight (less than 500 Da) and mechanism (inhibits VEGF, which is critical for fetal angiogenesis). No human data available. |
| Breastfeeding | Not recommended during treatment and for at least 1 week after the last dose due to potential for serious adverse reactions in nursing infants. No data on presence in human milk or effects on the breastfed child or milk production. |
■ FDA Black Box Warning
None.
| Serious Effects |
Hypersensitivity to belzutifan or any component of WELIREG
| Precautions | Anemia: Can cause severe anemia. Monitor hemoglobin before and during treatment., Hypoxia: May cause hypoxia. Monitor oxygen saturation; dose interruption or reduction may be required., Hepatotoxicity: Can cause elevated liver enzymes. Monitor liver function tests., Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of effective contraception. |
| Food/Dietary | No specific food interactions are known. However, avoid grapefruit and grapefruit juice as they may inhibit CYP2C19 and increase belzutifan exposure. Also avoid St. John's wort (a strong CYP2C19 inducer) which may decrease belzutifan efficacy. |
Loading safety data…
| Lactation Rating |
| L5 - Contraindicated |
| Teratogenic Risk | Welireg (belzutifan) is embryotoxic and teratogenic in animal studies at maternal exposures below the recommended human dose. No human data. First trimester: High risk of major congenital malformations and pregnancy loss. Second and third trimesters: Potential for impaired renal development and fetal hypoxia due to HIF-2α inhibition. Contraindicated in pregnancy. |
| Fetal Monitoring | Verify pregnancy status in females of reproductive potential prior to initiation. Monthly pregnancy testing during treatment and for 1 week after last dose. Monitor fetal growth and amniotic fluid volume by ultrasound if exposure occurs. |
| Fertility Effects | Based on animal studies, may impair female fertility (e.g., disrupted estrous cycles). No data on male fertility; however, HIF-2α inhibition may affect spermatogenesis. Advise patients on potential impact on fertility. |
| Clinical Pearls | WELIREG (belzutifan) is a HIF-2α inhibitor indicated for 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. Monitor for anemia and hypoxia due to HIF-2α inhibition; hemoglobin and pulse oximetry should be checked before and periodically during treatment. Dose reduction or interruption may be required for grade 3 or higher anemia or hypoxia. Avoid concomitant use with moderate or strong CYP2C19 inducers (e.g., rifampin) and strong CYP2C19 inhibitors (e.g., fluconazole) due to altered belzutifan exposure. |
| Patient Advice | Take WELIREG exactly as prescribed, usually once daily with or without food. · Do not crush, chew, or split the tablets; swallow whole. · Inform your healthcare provider if you experience new or worsening shortness of breath, fatigue, or pallor, which may be signs of anemia or low oxygen levels. · Avoid taking St. John's wort or certain stomach acid medications (e.g., omeprazole) without consulting your doctor as they may affect how WELIREG works. · Females of childbearing potential should use effective contraception during treatment and for at least 1 month after the last dose. Do not breastfeed while taking WELIREG and for 1 week after the last dose. · Keep all appointments for blood tests and oxygen level checks. |