4.1. Therapeutic indications

von Hippel-Lindau (VHL) disease associated tumours

Welireg is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for VHL associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumours (pNET), and for whom localised procedures are unsuitable or undesirable.

Advanced Renal Cell Carcinoma (RCC) Welireg is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) whose disease has progressed on or after treatment with a programmed death receptor-1 (PD-1) / programmed death ligand (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI).

Pheochromocytoma or Paraganglioma (PPGL)

Welireg is indicated for the treatment of adult and paediatric (12 years and older) patients with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL).

4.2. Posology and method of administration

Therapy must be initiated and supervised by specialist physicians experienced in the treatment of cancer.

Posology

The recommended dose of Welireg is 120 mg (three 40 mg tablets) administered orally once daily, with or without food. Tablets should be swallowed whole.

Treatment should continue until disease progression or unacceptable toxicity occurs.

Missed dose

If a dose of Welireg is missed, it can be taken as soon as possible on the same day. The regular daily dose should be resumed the next day. Extra tablets should not be taken to make up for the missed dose.

If vomiting occurs any time after taking Welireg, the dose should not be retaken. The next dose should be taken the next day.

Dose Modifications

Dosage modifications for Welireg for adverse reactions are summarised in Table 1 (see section 4.4).

Table 1: Recommended Dose Modifications

Adverse Reactions

Severity*

Dose Modification

Anaemia

(see section 4.4)

Grade 3: Haemoglobin (Hgb < 8g /dL) transfusion indicated

• Withhold until resolved to ≤ Grade 2 (Hgb ≥ 8 g/dL).

• Resume at the same or reduced dose (reduce by 40 mg), consider discontinuing depending on the severity and persistence of anaemia.

Grade 4: Life-threatening or urgent intervention indicated

• Withhold until resolved to ≤ Grade 2 (Hgb ≥ 8 g/dL).

• Resume at a reduced dose (reduce by 40 mg) or permanently discontinue.

Hypoxia

(see section 4.4)

Grade 2: Decreased oxygen saturation with exercise (e.g. pulse oximeter < 88%) intermittent supplemental oxygen

• Consider withholding until resolved.

• Resume at the same dose or at a reduced dose depending on the severity of hypoxia.

Grade 3: Decreased oxygen saturation at rest (e.g. pulse oximeter <88% or PaO² <=55 mm Hg)

• Withhold until resolved to ≤ Grade 2

• Resume at reduced dose (reduce by 40 mg) or discontinue depending on the severity and persistence of hypoxia.

Grade 4: Life-threatening

• Permanently discontinue.

Other Adverse Reactions

(see section 4.8)

Grade 3

• Withhold dosing until resolved to ≤ Grade 2.

• Consider resuming at a reduced dose (reduce by 40 mg).

• Permanently discontinue upon recurrence of Grade 3.

Grade 4

• Permanently discontinue.

*Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0

Special Populations

Elderly (≥ 65 years old)

No dose adjustment is recommended for elderly patients. (see sections 5.1 and 5.2).

Renal impairment

No dose adjustment of Welireg is recommended in patients with mild or moderate renal impairment (eGFR ≥ 30 mL/minute/1.73 m2). Welireg has not been studied in patients with severe renal impairment (see section 5.2).

Hepatic impairment

No dose adjustment of Welireg is recommended in patients with mild hepatic impairment. Welireg has not been studied in patients with moderate or severe hepatic impairment (see section 5.2).

Paediatric population

The recommended dose of Welireg in paediatric PPGL patients 12 years and older is 120 mg administered orally once daily. The safety and efficacy in paediatric patients less than 15 years of age or weighing less than 40 kg with PPGL have not been established and may require dose reduction.

Method of administration

Welireg is for oral use.

It should be swallowed whole and may be taken with or without food.

4.3. Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Anaemia due to decreased erythropoietin

Anaemia occurred very commonly in patients receiving Welireg (see section 4.8). Patients should be monitored for anaemia before initiation of and periodically throughout treatment with belzutifan with more frequent monitoring within the first 6 months of treatment (see section 5.1). 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 and/or transfusion until resolved to ≤ Grade 2, then resume at the same or reduced dose. For recurrent Grade 3 anaemia, consider discontinuing belzutifan. For patients who develop Grade 4 anaemia, withhold belzutifan then resume at a reduced dose or permanently discontinue for recurrent Grade 4 anaemia (see section 4.2).

Hypoxia

Belzutifan can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalisation (see section 4.2).

Patients should be monitored for oxygen saturation with pulse oximetry before initiation of and periodically throughout treatment with belzutifan with more frequent monitoring within the first 6 months of treatment (see section 5.1). In light of the risk of hypoxia, smoking cessation is recommended.

For Grade 2 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 hypoxia, belzutifan should be withheld, hypoxia treated, and dose reduction should be considered. If Grade 3 hypoxia continues to recur, treatment should be discontinued. For Grade 4 hypoxia, treatment should be permanently discontinued (see section 4.2). Patients treated with belzutifan must be given the patient alert card.

Embryo-foetal toxicity

Based on findings in animals, belzutifan may cause foetal harm, including foetal loss, in humans. In a rat study, belzutifan caused embryo-foetal toxicity when administered during the period of organogenesis at maternal exposures that were lower than the human exposures at the recommended dose of 120 mg daily (see section 5.3).

Females of reproductive potential should be advised to use highly effective non-hormonal contraceptive methods during treatment with belzutifan and for 1 week after the last dose, since belzutifan can render some hormonal contraceptives ineffective (see sections 4.5 and 4.6). Advise male patients and their female partners of reproductive potential to use highly effective contraception during treatment with belzutifan and for 1 week after the last dose (see section 4.6). Advise male patients with female partners who are pregnant to use a barrier method of contraception during treatment with belzutifan and 1 week after the last dose.

Information about some of the ingredients

This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially 'sodium‑free'.

4.5. Interaction with other medicinal products and other forms of interaction

In vitro and pharmacogenomic studies indicate that belzutifan is metabolised by UGT2B17 and by CYP2C19.

Effects of belzutifan on other medicinal products

Coadministration of Welireg with CYP3A4 substrates, including hormonal contraceptives, decreases concentrations of CYP3A substrates (see sections 5.1 and 5.2), which may reduce the efficacy of these substrates. The magnitude of this reduction may be more pronounced in patients who are dual UGT2B17 and CYP2C19 poor metabolisers (see section 5.1).

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 summary of product characteristics.

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

Effects of other medicinal products on belzutifan

Co-administration 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. Monitor for anaemia and hypoxia and reduce the dosage of belzutifan as recommended.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of belzutifan in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Belzutifan is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether belzutifan or its metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with belzutifan and for 1 week after the last dose.

Women of child-bearing potential/ contraception in males and females

Pregnancy Testing

The pregnancy status of females of reproductive potential should be verified prior to initiating treatment with belzutifan.

Contraception

Belzutifan may cause embryo‑foetal harm, including foetal loss, when administered to a pregnant woman (see sections 4.4 and 5.3).

Females

Females of reproductive potential should be advised to use highly effective contraception during treatment with belzutifan and for at least 1 week after the last dose. Use of belzutifan 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 section 4.4).

Males

Male patients and their female partner of reproductive potential should be advised to use highly effective contraception during male patient treatment with belzutifan and for at least 1 week after the last dose (see section 4.4). Advise male patients with female partners who are pregnant to use barrier method of contraception during treatment with belzutifan and 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). Advise patients of this potential risk. The reversibility of the effect on fertility is unknown. Family planning should be discussed with patients as appropriate.

4.7. Effects on ability to drive and use machines

Belzutifan may have a 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.

4.8. Undesirable effects

von Hippel-Lindau (VHL) disease associated tumours

Summary of the safety profile

The safety of belzutifan was evaluated in an open‑label Phase 2 clinical study (LITESPARK-004), in 61 patients with VHL disease‑associated RCC and who did not require immediate nephrectomy or partial nephrectomy. Patients were treated with 120 mg belzutifan once daily. The median duration of exposure to belzutifan was 28.9 months (range: 1.9 to 37.5).

The most common adverse reactions with belzutifan were anaemia (90%), fatigue (71%), dizziness (44%) and nausea (36%).

The most common Grade 3 or 4 adverse reactions were anaemia (10%), and fatigue (5%).

Serious adverse reactions occurred in 5% of patients who received belzutifan, including anaemia, dyspnoea and hypoxia (1 patient each).

Dose interruption of belzutifan due to adverse reactions occurred in about 23% of patients. The most common adverse reactions resulting in dose interruption of belzutifan were fatigue (13.1%), nausea (8.2%), and anaemia (4.9%).

Dose reduction of belzutifan due to adverse reactions occurred in about 11.5% of patients. The adverse reactions resulting in dose reduction of belzutifan were fatigue (8.2%), anaemia, and hypoxia (one patient each 1.6%).

Tabulated list of adverse reactions.

Adverse reactions reported in clinical studies of belzutifan are listed in the table below by MedDRA 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) and not known (cannot be estimated from the available data).

Table 2: Adverse drug reactions in patients with VHL disease-associated tumours treated with belzutifan 120 mg Once Daily

Adverse Drug Reaction

All Grades

Grade 3 – 4

Blood and lymphatic disorders

Anaemia

Very common

Common

Nervous system disorders

Dizziness

Very common

Very rare

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Very common

Common

Hypoxia

Common

Common

Gastrointestinal disorders

Nausea

Very common

Very rare

General disorders and administration site disorders

Fatigue

Very common

Common

Investigations

Weight Increased

Very Common

Common

The safety of belzutifan was also evaluated in a Phase 1 clinical study (Study‑001), in 58 patients with non-VHL disease‑associated advanced solid tumours, treated with belzutifan 120 mg once daily. Study‑001 patients differed from VHL‑associated RCC patients (Study‑004). Study‑001 patients were older (median: 62.5 years old; range: 39 to 75 vs. 41.0; range: 19 to 66), had worse ECOG PS (scale 1: 63.8% in study-001 vs. 16.4% in study-004), had metastatic disease, had prior systemic therapies, had more comorbidities, and had lower baseline haemoglobin levels at treatment initiation (median: 119; range: 89 to 173 vs. 140; range 91 to 171). Study‑001 had a median duration of exposure to belzutifan of 25.4 weeks (range: 1.1 to 145.9 weeks). The adverse reactions with belzutifan in Study‑001 were anaemia (76%), fatigue (71%), dyspnoea (47%), nausea (35%), hypoxia (29%), dizziness (22%) and weight increased (10%). The adverse reactions resulting in dose interruption of belzutifan were hypoxia (10.3%), anaemia (8.6%), dyspnoea (5.2%), fatigue (1.7%) and nausea (1.7%). The adverse reactions resulting in dose reduction of belzutifan were hypoxia (3.4%), nausea (1.7%) and fatigue (1.7%). The adverse reactions resulting in discontinuation were hypoxia (3.4%) and fatigue (1.7%).

Advanced Renal Cell Carcinoma

Summary of the safety profile

The safety of belzutifan was evaluated in a Phase 3 clinical study (LITESPARK-005), in 372 patients with advanced RCC. Patients were treated with 120 mg belzutifan once daily. The median duration of exposure to belzutifan was 7.6 months (range 0.1 to 35.8 months).

The most common adverse reactions under treatment with belzutifan were anaemia (83%), fatigue (31%), dypsnoea (15%), hypoxia (15%) nausea (18%) and dizziness (12%).

Serious adverse reactions occurred in 13% of patients who received belzutifan. Serious adverse reactions occurring in ≥2% of patients were hypoxia (8%) and anaemia (5%).

The most common adverse reactions resulting in dose interruption of belzutifan were anaemia (8.6%), hypoxia (5.6%), fatigue (1.6%), dizziness (1.6%), dyspnoea (1.6%) and nausea (1.3%). The most common adverse reactions resulting in dose reduction of belzutifan were hypoxia (5.6%) and anaemia (3.0%). Belzutifan was discontinued due to adverse reaction in 5.9% of patients.

Tabulated list of adverse reactions

Adverse reactions observed in clinical studies of belzutifan are listed in Table 3. 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), and not known (cannot be estimated from the available data).

Table 3: Adverse reactions in patients treated with belzutifan 120 mg once daily in adult patients with advanced RCC

System Organ Class

All Grades

Grade 3-4

Blood and lymphatic disorders

Anemia*

Very Common

Very Common

Nervous system disorders

Dizziness

Very Common

Not Known

Headache

Very Common

Uncommon

Respiratory, thoracic and mediastinal disorders

Dypsnoea

Very Common

Common

Hypoxia

Very Common

Very Common

Gastrointestinal disorders

Nausea

Very Common

Uncommon

General disorders and administration site disorders

Fatigue

Very Common

Common

Investigations

Weight Increased

Common

Common

*Anaemia includes anaemia and haemoglobin decreased

Advanced Pheochromocytoma or Paraganglioma

Summary of the safety profile

The safety of belzutifan was evaluated in an open-label Phase 2 clinical study (LITESPARK-015), in 72 patients with advanced, unresectable, or metastatic PPGL. Patients were treated with 120 mg belzutifan once daily. The median duration of exposure to belzutifan was 20 months (range: 0.3 to 32.5 months).

The most common adverse reactions under treatment with belzutifan were anaemia (96%), fatigue (39%), dyspnea (31%), dizziness (25%), nausea (25%), oedema peripheral (22%), hypoxia (13%), and weight increased (13%).

The most common adverse reactions resulting in dose interruption of belzutifan were hypoxia (4.2%), nausea (4.2%), anaemia (2.8%), dizziness (2.8%), dyspnea (1.4%), and fatigue (1.4%). The most common adverse reactions resulting in dose reduction of belzutifan were hypoxia (4.2%), anaemia (2.8%), fatigue (2.8%), dizziness (1.4%), dyspnea (1.4%) and nausea (1.4%). Belzutifan was discontinued due to adverse reaction in 2 patients (2.8%).

Tabulated list of adverse reactions

Adverse reactions reported in clinical studies with belzutifan are listed in the table below by MedDRA 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 4: Adverse reactions for belzutifan 120 mg Once Daily in patients with PPGL

System Organ Class

All Grades

Grade 3-4

Blood and lymphatic disorders

anaemia*

Very Common

Very Common

Nervous system disorders

dizziness

Very Common

Common

Respiratory, thoracic and mediastinal disorders

dyspnea, hypoxia

Very Common

Common

Gastrointestinal disorders

nausea

Very Common

Common

General disorders and administration site disorders

fatigue

Very Common

Common

oedema peripheral

Very Common

Not Known

Investigations

weight increased

Very Common

Common

*Anaemia includes anaemia and haemoglobin decreased

Description of selected adverse reactions

Anaemia due to decreased erythropoietin

In LITESPARK-004 anaemia was reported in 90.2% of all patients with Grade 3 anaemia occurring in 9.8%. Median time to onset of all Grade anaemia events was 30 days (range: 1 day to 8.38 months). Most of the anaemia occurred in the first 3 months of treatment initiation and was not progressive. Three (4.9%) participants had anaemia events leading to study drug interruption and 1 participant (1.6%) had a dose reduction due to anaemia. No participant discontinued treatment due to anaemia. Of the 13 patients that were treated with an ESA, 4 received treatment with both an ESA and blood transfusions, while 9 received treatment with an ESA alone. Patients received an ESA based on haemoglobin levels and physician discretion. Anaemia was reported as resolved in 13 (21.3%) of participants and resolving or not yet resolved in 40 (65.6%) participants.

In LITESPARK-005, anaemia occurred in 83% of patients with advanced RCC receiving belzutifan, 119 patients (32%) had Grade 3 and 2 patients (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, 67 patients (22%) received transfusions only, 62 patients (20%) of patients received ESAs only and 42 patients (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.

In LITESPARK-015, anaemia was reported in 69 patients (96%). Grade 3 anaemia occurred in 16 patients (22%). Median time to onset of anaemia was 29 days (range: 1 day to 22 months). Of the 69 patients with anaemia, 14 patients (20%) received transfusions only, 18 patients (26%) received ESAs only and 4 patients (6%) received both transfusion and ESAs. The median number of ESA doses administered to patients was 11 (range: 1-110). Patients received an ESA based on haemoglobin levels and physician discretion. In another clinical study (Study‑001) for the treatment of non‑VHL disease-associated advanced solid tumours using the same dose of belzutifan, anaemia was reported in 44 patients (75.9%) with Grade 3 anaemia occurring in 16 patients (27.6%).

Hypoxia

In LITESPARK-004, Grade 3 hypoxia occurred in 1 patient (1.6%). This case of hypoxia occurred within 2 months of treatment initiation in a patient with previously undiagnosed restrictive lung disease and was asymptomatic. This patient did not receive supplemental oxygen and was managed with dose reduction to 80 mg once daily with no recurrence of hypoxia.

In LITESPARK- 005, hypoxia occurred in 15% of patients and 38 patients (10%) had Grade 3 hypoxia and 1 patient (0.3%) had Grade 4 hypoxia. Of the patients with hypoxia, 70% were treated with oxygen therapy. Median time to onset of hypoxia was 1 month (range: 1 day to 21 months).

In LITESPARK-015, hypoxia occurred in 9 patients (13%) and 7 patients (10%) had Grade 3 hypoxia. Of the patients with hypoxia, 67% were treated with oxygen therapy. Median time to onset of hypoxia was 35 days (range: 6 days to 24 months). In another clinical study (Study-001) for the treatment of non‑VHL disease-associated advanced solid tumours using the same dose of belzutifan, hypoxia occurred in 17 patients (29.3%), with Grade 3 hypoxia occurring in 9 patients (15.5%).

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 reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no specific treatment for belzutifan overdose. In cases of suspected overdose, withhold belzutifan and institute supportive care. The highest dose of belzutifan studied clinically was 240 mg daily (120 mg twice a day or 240 mg once a day). Adverse reactions observed in patients receiving more than 120 mg once a day were generally similar to those observed at other doses except for Grade 3 hypoxia observed at 120 mg twice a day and Grade 4 thrombocytopenia observed at 240 mg once daily.