Chemical formula: C₁₇H₁₂F₃NO₄S Molecular mass: 383.044 g/mol PubChem compound: 117947097
Belzutifan interacts in the following cases:
Coadministration of belzutifan with inhibitors of UGT2B17 or CYP2C19 increases plasma exposures of belzutifan, which may increase the incidence and severity of adverse reactions of belzutifan. Patients should be monitored for anaemia and hypoxia and the dose of belzutifan should be reduced as recommended.
Coadministration of belzutifan with CYP3A4 substrates, including hormonal contraceptives, decreases concentrations of CYP3A4 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 metabolisers. Coadministration of belzutifan with sensitive CYP3A4 substrates, for which minimal decrease in concentration may lead to therapeutic failures of the substrate should be avoided. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dose in accordance with its summary of product characteristics.
Coadministration of belzutifan with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding. Patients using hormonal contraceptives should be advised to use an alternative non-hormonal contraceptive method or have their male partner use a condom during treatment with belzutifan.
Belzutifan is a CYP2B6 and CYP2C8 inducer in vitro. In vivo investigations have not been performed. Co-administration with belzutifan may result in a clinically relevant decrease in the plasma concentration of sensitive CYP2B6 and/or CYP2C8 substrates.
Belzutifan has not been studied in patients with severe hepatic impairment.
Based on findings in animals, belzutifan may impair fertility in males and females of reproductive potential. Patients should be advised of this potential risk. The reversibility of the effect on fertility is unknown.
There are no or limited amount of data from the use of belzutifan in pregnant women. Studies in animals have shown reproductive toxicity.
Belzutifan should not be used during pregnancy unless the clinical condition of the woman requires treatment with belzutifan.
Belzutifan is contraindicated during pregnancy. If pregnancy occurs during treatment with belzutifan, treatment should be discontinued.
There are no data on the presence of belzutifan or its metabolites in human milk, their effects on the breast-fed child, or on milk production. Because of the potential for serious adverse reactions in breast-fed children, advise women not to breast-feed during treatment with belzutifan and for 1 week after the last dose.
The pregnancy status of women of childbearing potential should be verified prior to initiating treatment with belzutifan.
Belzutifan may cause embryo-foetal harm, including foetal loss, when administered to a pregnant woman. Women of childbearing potential should be informed of the potential risk to a foetus.
Women of childbearing potential have to use highly effective contraception during treatment with belzutifan and for at least 1 week after the last dose. Use of bel zutifan may reduce the efficacy of hormonal contraceptives. Patients using hormonal contraceptives should be advised to use an alternative non-hormonal contraceptive method or have their male partner use a condom during treatment with belzutifan.
Based on findings in animals, belzutifan may impair fertility in males and females of reproductive potential. Patients should be advised of this potential risk. The reversibility of the effect on fertility is unknown.
Belzutifan has minor influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of belzutifan.
Patients should be advised not to drive and use machines, until they are reasonably certain belzutifan therapy does not affect them adversely.
The safety of belzutifan has been evaluated in 576 patients with advanced solid tumours and VHL disease-associated localised tumours treated with 120 mg belzutifan once daily in clinical studies. The median duration of exposure to belzutifan was 9.2 months (range: 0.1 to 55.4 months).
The most common adverse reactions under treatment with belzutifan were anaemia (84.2%), fatigue (42.7%), nausea (24.1%), dyspnoea (21.4%), dizziness (17.9%) and hypoxia (16.3%).
The most common Grade 3 or 4 adverse reactions were anaemia (28.8%) and hypoxia (12.2%). The most common serious adverse reactions were hypoxia (7.1%), anaemia (4.7%) and dyspnoea (1.2%).
The most common adverse reactions resulting in dose interruption of belzutifan were anaemia (7.1%), hypoxia (5.4%), fatigue (2.6%), nausea (2.4%), dyspnoea (1.7%) and dizziness (1.6%). The most common adverse reactions resulting in dose reduction of belzutifan were hypoxia (6.3%), anaemia (3.8%) and fatigue (1.7%). The most common adverse reaction resulting in discontinuation of belzutifan was hypoxia (1.4%).
Adverse reactions reported in the pooled dataset for patients treated with belzutifan (n=576) or reported from post-marketing use are listed in the table below. These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); and very rare (<1/10 000).
Adverse reactions in patients treated with belzutifan*:
| Adverse drug reaction | All Grades | Grade 3 – 4 |
|---|---|---|
| Blood and lymphatic system disorders | ||
| Anaemia† | Very common | Very common |
| Nervous system disorders | ||
| Dizziness | Very common | - |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnoea | Very common | Common |
| Hypoxia | Very common | Very common |
| Vascular disorders | ||
| Haemorrhage‡# | Very common | Common |
| Gastrointestinal disorders | ||
| Nausea | Very common | Uncommon |
| General disorders and administration site conditions | ||
| Fatigue | Very common | Common |
| Investigations | ||
| Weight increased | Common | Common |
*Adverse reaction frequencies presented in the table above may contain contributions from the underlying disease.
† Anaemia includes anaemia and haemoglobin decreased.
‡ Includes different bleeding events from different sites not listed individually.
Haemorrhage terms that occurred in 5 or more patients treated with be lzutifan were: haematuria, haemoptysis, contusion and epistaxis (any grade); and haematuria (grades 3-4).
# Includes CNS haemorrhage (a fatal case was observed).
Anaemia occurred in 83% of patients with advanced RCC receiving belzutifan, 32% had Grade 3 and 0.5% had Grade 4 anaemia. Median time to onset of anaemia was 29 days (range: 1 day to 27 months). Of the patients with anaemia, 22% received transfusions only, 20% of patients received ESAs only and 14% received both transfusion and ESAs. The median number of ESA doses administered to patients was 6.5 (range: 1-87). Patients received an ESA based on haemoglobin levels and physician discretion.
Anaemia occurred in 90.2% of patients with VHL disease-associated tumours receiving belzutifan, 11.5% of patients had Grade 3 anaemia. Median time to onset of all Grade anaemia events was 30 days (range: 1 day to 8 months). Of the patients with anaemia, 1.8% received transfusions only, 16.4% received ESAs only and 9.1% of patients received both transfusion and ESAs. The median number of ESA doses administered to patients was 5 (range: 1-35). Patients received an ESA based on haemoglobin levels and physician discretion.
The incidence of Grade 3 anaemia increased with higher belzutifan exposure in patients with baseline haemoglobin levels <12 g/dL.
Hypoxia occurred in 15% of patients with advanced RCC receiving belzutifan and 10% of patients had Grade 3 hypoxia and 0.3% patients had Grade 4 hypoxia. Of the patients with hypoxia, 70% were treated with oxygen therapy. Median time to o nset of hypoxia was 31 days (range: 1 day to 21 months).
Hypoxia (Grade 3) was reported in 1.6% of patients with VHL disease-associated tumours receiving belzutifan. Time to onset of hypoxia was 56 days.
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