Belzutifan

Coadministration of belzutifan with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan, which may increase the incidence and severity of adverse reactions of belzutifan. Monitor for anemia and hypoxia and reduce the dosage of belzutifan as recommended.

Coadministration of belzutifan 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. Avoid coadministration of belzutifan 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 belzutifan with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding.

Patients who are dual UGT2B17 and CYP2C19 poor metabolizers have higher belzutifan exposures, which may increase the incidence and severity of adverse reactions of belzutifan. Closely monitor for adverse reactions in patients who are dual UGT2B17 and CYP2C19 poor metabolizers.

Based on findings in animal studies, belzutifan can cause fetal harm when administered to a pregnant woman. There are no available data on the use of belzutifan 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. 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.

There are no data on the presence of belzutifan or its metabolites in human milk or their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with belzutifan and for 1 week after the last dose.

Carcinogenicity studies have not been conducted with belzutifan.

Belzutifan was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. Belzutifan was not clastogenic in either an in vitro micronucleus assay or an in vivo rat bone marrow micronucleus assay.

Fertility studies in animals have not been conducted with belzutifan. In repeat-dose toxicity studies up to 3-month duration, belzutifan-related findings included degeneration/atrophy of testes and hypospermia and cellular debris of the epididymis in rats administered ≥2 mg/kg/day (approximately 0.1 times the human exposure at the recommended dose of 120 mg daily). Findings in testes and epididymis were associated with decreased sperm count and motility and abnormal sperm morphology at ≥6 mg/kg/day (approximately 0.2 times the human exposure at the recommended dose of 120 mg daily) and did not reverse by the end of the recovery period. Belzutifan had no adverse effects on female reproductive organs in repeat-dose toxicity studies up to 3-month duration; however, belzutifan caused embryo-fetal lethality (post-implantation loss) in pregnant rats given oral doses ≥60 mg/kg/day (approximately 1 time the human exposure at the recommended dose based on AUC) during the period of organogenesis.

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 belzutifan 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 belzutifan 120 mg orally once daily. The median duration of exposure to belzutifan was 68 weeks (range: 8.4 to 104.7 weeks).

Serious adverse reactions occurred in 15% of patients who received belzutifan, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each).

Permanent discontinuation of belzutifan due to adverse reactions occurred in 3.3% of patients. Adverse reactions which resulted in permanent discontinuation of belzutifan were dizziness and opioid overdose (1.6% each).

Dosage interruptions of belzutifan 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 belzutifan 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 belzutifan were decreased hemoglobin, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea.

Table 1 summarizes the adverse reactions reported in patients treated with belzutifan in LITESPARK-004.

Table 1. Adverse Reactions Occurring in ≥10% of Patients Who Received Belzutifan in LITESPARK-004:

^* Graded per NCI CTCAE v4.0.
^† Includes other related terms.
^‡ Includes visual impairment, vision blurred, central retinal vein occlusion and retinal detachment.

Table 2 summarizes the laboratory abnormalities in LITESPARK-004.

Table 2. Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients Who Received Belzutifan in LITESPARK-004:

^* The denominator used to calculate the rate is based on all patients in the safety analysis population.

Advanced Renal Cell Carcinoma (RCC)

LITESPARK-005

The safety of belzutifan was evaluated in a randomized, active-controlled study (LITESPARK-005) in 732 patients with advanced RCC that has progressed after prior PD-1 or PD-L1 checkpoint inhibitor and VEGF receptor targeted therapies. Patients received 120 mg belzutifan (n=372) or 10 mg everolimus (n=360) by oral administration once daily. The median duration of exposure to belzutifan was 7.6 months (range 0.1 to 28.5 months).

Serious adverse reactions occurred in 38% of patients who received belzutifan. Serious adverse reactions in ≥2% of patients treated with belzutifan were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%), and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received belzutifan, including sepsis (0.5%) and hemorrhage (0.5%).

Permanent discontinuation of belzutifan due to adverse reactions occurred in 6% of patients. Adverse reactions which resulted in permanent discontinuation (≥0.5%) of belzutifan were hypoxia (1.1%), anemia (0.5%), and hemorrhage (0.5%).

Dosage interruptions of belzutifan due to an adverse reaction occurred in 39% of patients. Adverse reactions which required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%), and hemorrhage (2.2%).

Dose reductions of belzutifan due to an adverse reaction occurred in 13% 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 belzutifan were decreased hemoglobin, fatigue, musculoskeletal pain, increased creatinine, decreased lymphocytes, increased alanine aminotransferase, decreased sodium, increased potassium, and increased aspartate aminotransferase.

Table 3 summarizes the adverse reactions in LITESPARK-005.

Table 3. Adverse Reactions (≥10%) in Patients with Advanced RCC Receiving Belzutifan in LITESPARK-005:

^* Graded per NCI CTCAE v5.0.
^† Includes other related terms.

Clinically relevant adverse reactions in <10% of patients who received belzutifan in LITESPARK-005 included hemorrhage (9%) [including intracranial/cerebral hemorrhage (0.8%)], rash (8%), hypertension (6%), visual impairment [including vision blurred (4%), visual acuity decreased (1.1%), visual impairment (0.5%), and retinal detachment (0.3%)] (6%) and increased weight (5%).

Table 4 summarizes the laboratory abnormalities in LITESPARK-005.

Table 4. Select Laboratory Abnormalities (≥20%) That Worsened from Baseline In Patients with Advanced RCC who Received Belzutifan in LITESPARK-005:

^* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available belzutifan (range: 359 to 366 patients), and everolimus (range: 351 to 356 patients).
^† Graded per NCI CTCAE v5.0.