WELIREG Film-coated tablet Ref.[114790] Active ingredients: Belzutifan

Anaemia

Anaemia has been reported in patients receiving belzutifan in clinical studies (see section 4.8). Patients should be monitored for anaemia before initiation of and periodically throughout treatment with belzutifan. For patients who develop Grade 3 anaemia, belzutifan should be withheld and patients should be treated according to standard medical practice, including erythropoiesis-stimulating agent (ESA) administration until resolved to ≤ Grade 2 (see the prescribing information for ESAs for more information). For recurrent Grade 3 anaemia, belzutifan should be discontinued. For patients who develop Grade 4 anaemia, belzutifan should be withheld and permanently discontinued for recurrent Grade 4 anaemia (see section 4.2).

Hypoxia

Hypoxia has been reported in patients receiv ing belzutifan in clinical studies (see section 4.8). Patients should be monitored for oxygen saturation with pulse oximetry before initiation of and periodically throughout treatment with belzutifan. For Grade 3 asymptomatic hypoxia, providing supplemental oxygen and continuing or withholding treatment should be considered. If withheld, belzutifan should be resumed at a reduced dose. For patients who have Grade 3 symptomatic hypoxia, belzutifan should be withheld, hypoxia should be treated, and belzutifan should be resumed at a reduced dose. If symptomatic hypoxia continues to recur, treatment should be discontinued. For Grade 4 hypoxia, treatment should be permanently discontinued (see section 4.2).

Embryo-foetal toxicity: Women of childbearing potential

Belzutifan may cause embryo -foetal harm, including foetal loss, in humans (see sections 4.6 and 5.3). The pregnancy status of women of childbearing potential should be verified prior to initiating treatment with belzutifan.

Women of childbearing potential have to use highly effective contraceptive methods during treatment with belzutifan and for at least 1 week after the last dose due to the potential risk to the foetus (see sections 4.5 and 4.6).

CNS haemorrhage in patients with VHL disease-associated CNS-haemangioblastomas (CNS-HB)

CNS haemorrhage, including with fatal outcome, has been observed in patients with VHL disease-associated CNS-HB. Physicians should be cautious of symptoms or signs of CNS haemorrhage in patients with VHL disease-associated CNS-HB being treated with belzutifan.

Information about excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

In vitro and pharmacogenomic studies indicate that belzutifan is metabolised by UGT2B17 and by CYP2C19, and that belzutifan induces CYP3A4 in a concentration dependent manner.

Effects of belzutifan on other medicinal products

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 (see section 5.2). 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 (see sections 4.4 and 4.6) 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.

In a clinical study, repeat administration of belzutifan 120 mg daily resulted in a 40% reduction in midazolam area under the curve (AUC), an effect consistent with a weak CYP3A4 inducer. Belzutifan may exhibit moderate CYP3A4 induction in patients who have higher belzutifan plasma exposures (see section 5.2).

Based on in vitro data, MATE-2K inhibition by belzutifan is expected at clinically relevant exposures, and inhibition of MATE1 cannot be excluded.

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.

Effects of other medicinal products on belzutifan

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.

Effects of strong CYP2C19 inducers on belzutifan expos ure have not yet been studied.

Women of childbearing potential / Contraception in males and females

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 (see sections 4.4 and 5.3). 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 (see secti on 4.5).

Pregnancy

There are no or limited amount of data from the use of belzutifan in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Renal cell carcinoma

Belzutifan should not be used during pregnancy unless the clinical condition of the woman requires treatment with belzutifan.

von Hippel-Lindau (VHL) disease-associated tumours

Belzutifan is contraindicated during pregnancy (see section 4.3). If pregnancy occurs during treatment with belzutifan, treatment should be discontinued.

Breast-feeding

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.

Fertility

Based on findings in animals, belzutifan may impair fertility in males and females of reproductive potential (see section 5.3). 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 (see section 4.8).

Patients should be advised not to drive and use machines, until they are reasonably certain belzutifan therapy does not affect them adversely.

Summary of the safety profile

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%).

Tabulated list of adverse reactions

Adverse reactions reported in the pooled dataset for patients treated with belzutifan (n=576) or reported from post-marketing use are listed in Table 2. 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).

Table 2. Adverse reactions in patients treated with belzutifan*:

^*Adverse reaction frequencies presented in Table 2 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) (see section 4.4).

Description of selected adverse reactions

Anaemia (see section 4.4)

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 (see section 5.1).

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 (see section 5.1).

The incidence of Grade 3 anaemia increased with higher belzutifan exposure in patients with baseline haemoglobin levels <12 g/dL (see section 4.4).

Hypoxia (see section 4.4)

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactio ns via the national reporting system listed in Appendix V.

Not applicable.