Welireg Drug Information

Dosage Modifications for Adverse Reactions

Dosage modifications for WELIREG for adverse reactions are summarized in Table 2.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. von Hippel-Lindau (VHL) disease LITESPARK-004 The safety of WELIREG was evaluated in an open-label clinical trial (LITESPARK-004) in 61 patients with VHL disease who had at least one measurable solid tumor localized to the kidney. Patients received WELIREG 120 mg orally once daily until disease progression or unacceptable toxicity. The median duration of exposure to WELIREG was 68 weeks (range: 8.4 to 104.7 weeks).

Serious adverse reactions occurred in 15% of patients who received WELIREG, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each). Permanent discontinuation of WELIREG due to adverse reactions occurred in 3.3% of patients. Adverse reactions which resulted in permanent discontinuation of WELIREG were dizziness and opioid overdose (1.6% each).

Dosage interruptions of WELIREG due to an adverse reaction occurred in 39% of patients. Adverse reactions which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness. Dose reductions of WELIREG due to an adverse reaction occurred in 13% of patients.

The most frequently reported adverse reaction which required dose reduction was fatigue (7%). The most common (≥25%) adverse reactions, including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Table 3 summarizes the adverse reactions reported in patients treated with Table 4 summarizes the laboratory abnormalities in LITESPARK-004.

Table 4: Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients Who Received Renal Cell Carcinoma with a Clear Cell Component (ccRCC) LITESPARK-022 The safety of WELIREG in combination with intravenous pembrolizumab versus placebo in combination with intravenous pembrolizumab was investigated in LITESPARK-022, a randomized, double-blind trial in 1,828 patients who had undergone nephrectomy for ccRCC. The median duration of exposure to WELIREG was 12.4 months (range 1 day to 20.1 months). Serious adverse reactions occurred in 30% of patients who received WELIREG in combination with pembrolizumab.

Serious adverse reactions in ≥1% of patients included pneumonia (2%), hypoxia in combination with pembrolizumab, including sepsis (0.1%). The most common (≥25%) adverse reactions, including laboratory abnormalities, in patients who received WELIREG in combination with pembrolizumab were decreased hemoglobin, increased ALT, fatigue, increased AST, decreased lymphocytes, and increased alkaline phosphatase. Tables 5 and 6 summarize the adverse reactions and laboratory abnormalities, respectively, in LITESPARK-022.

Table 6: Select Laboratory Abnormalities (>20%) That Worsened from Baseline In Patients with ccRCC Who Received WELIREG in Combination With Pembrolizumab in LITESPARK-0 was evaluated in a randomized, active-controlled study (LITESPARK- 005) in 732 patients with advanced ccRCC that has progressed after prior PD-1 or PD-L1 checkpoint inhibitor and VEGF receptor targeted therapies. The median duration of exposure to WELIREG was 7.6 months (range 0.1 to 28.5 months). Adverse reactions which resulted in permanent discontinuation ≥ % of patients.

Adverse reactions which required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), % of patients. Adverse reactions which required dose reduction in ≥1% of patients were hypoxia (5%) and anemia (3.2%). The most common (≥25%) adverse reactions, including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin, fatigue, musculoskeletal pain, increased creatinine, decreased lymphocytes, increased alanine aminotransferase, decreased sodium, increased potassium, and increased aspartate aminotransferase.

Table 7 summarizes the adverse reactions in LITESPARK-005. Table 8 summarizes the laboratory abnormalities in LITESPARK-005. Table 8: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline In Patients with Advanced RCC who Received Pheochromocytoma or Paraganglioma LITESPARK-015 The safety of WELIREG was evaluated in an open-label clinical trial (LITESPARK-015) in 72 patients with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL).

The median duration of exposure to WELIREG was 20 months (range: 0.3 to 32.5 months). Serious adverse reactions occurring in ≥2% of patients treated with WELIREG were anemia and hypertension (4.2% each) and pyelonephritis, pneumonia, hypoxia, dyspnea and hemorrhage (2.8% each). Adverse reactions which resulted in permanent discontinuation of WELIREG were increased alanine aminotransferase and paraparesis (1.4% each).

Adverse reactions which required dosage interruption in >3% of patients were hypoxia, nausea and fatigue (4.2% each). The most frequently reported adverse reaction which required dose reduction was hypoxia (4.2%). Table 9 summarizes the adverse reactions reported in patients treated with summarizes the laboratory abnormalities in LITESPARK-015.

Table 10: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with PPGL Who Received 0

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.

Pregnancy Risk Summary 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 ( see Data ).

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Data Animal Data In a pilot embryo-fetal development study, pregnant rats received oral doses of 6, 60, or 200 mg/kg/day of belzutifan during the period of organogenesis. Belzutifan caused embryo-fetal lethality at doses ≥60 mg/kg/day (approximately 1 time the human exposure at the recommended dose based on AUC). Reduced fetal body weights, fetal rib malformations, and reduced skeletal ossification occurred at doses of 6 and 60 mg/kg/day (approximately ≥0.2 times the human exposure at the recommended dose based on AUC).

Pediatric Use The safety and effectiveness of WELIREG have been established in pediatric patients aged 12 years and older for the treatment of locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma. Use of WELIREG in pediatric patients aged 12 years and older is supported by evidence from an adequate and well-controlled study of WELIREG in adults with additional pharmacokinetic data demonstrating that belzutifan exposure is predicted to be within range of that observed in adults, and that the course of locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma is sufficiently similar in adults and pediatric patients to allow extrapolation of data in adults to pediatric patients. The safety and effectiveness of WELIREG have not been established in pediatric patients with VHL or ccRCC, or in pediatric patients younger than 12 years of age with PPGL.

There is no specific treatment for WELIREG overdose. In cases of suspected overdose, withhold WELIREG and institute supportive care.