Consumer medicine information

Welireg

Belzutifan

BRAND INFORMATION

Brand name

Welireg

Active ingredient

Belzutifan

Schedule

SUMMARY CMI

WELIREG^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new. Please report side effects. See the full CMI for further details.

1. Why am I using WELIREG?

WELIREG contains the active ingredient belzutifan. WELIREG is used to treat adults with von-Hippel Lindau (VHL) disease who need treatment for multiple tumour types. For more information, see Section 1. Why am I using WELIREG? in the full CMI.

2. What should I know before I use WELIREG?

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use WELIREG? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with WELIREG and affect how it works.

For more information, see Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use WELIREG?

Take your prescribed dose once per day. Take your prescribed dose at the same time each day. You can take WELIREG with or without food. Swallow the tablet whole. Do not break, crush or chew.

More instructions can be found in Section 4. How do I use WELIREG? in the full CMI.

5. What should I know while using WELIREG?

Things you should do	Tell your doctor if you get any symptoms of low red blood cell counts including tiredness, feeling cold, shortness of breath, chest pain, or fast heartbeat. Tell your doctor or get medical help right away if you get symptoms of low oxygen in your body, including shortness of breath or fast heart rate. For female patients who are able to become pregnant, your healthcare provider will do a pregnancy test before you start treatment with WELIREG. You should use an effective form of non-hormonal birth control (contraception) during treatment with WELIREG and for 1 week after your last dose. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with WELIREG and for 1 week after your last dose.
Driving or using machines	The effect of WELIREG on driving or using machines is not known. Be careful before you drive or use any machines or tools until you know how WELIREG affects you.
Looking after your medicine	Store below 30°C

For more information, see Section 5. What should I know while using WELIREG? in the full CMI.

6. Are there any side effects?

Common side effects of WELIREG include: feeling tired, headache, feeling dizzy, nausea, and weight gain.

WELIREG may decrease the oxygen level in your blood and red blood cell level. This may cause serious side effects including shortness of breath, trouble breathing, chest pain, or a very fast heartbeat. Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

FULL CMI

WELIREG^®

Active ingredient: belzutifan (bel-zu-ti-fan)

Consumer Medicine Information (CMI)

This leaflet provides important information about using WELIREG. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using WELIREG.

Where to find information in this leaflet:

1. Why am I using WELIREG?
2. What should I know before I use WELIREG?
3. What if I am taking other medicines?
4. How do I use WELIREG?
5. What should I know while using WELIREG?
6. Are there any side effects?
7. Product details

1. Why am I using WELIREG?

WELIREG contains the active ingredient belzutifan.

WELIREG is a hypoxia-inducible factor inhibitor, used to treat adults with von Hippel-Lindau (VHL) disease who need treatment for a type of kidney cancer called renal cell carcinoma (RCC), tumours in the brain and spinal cord called central nervous system haemangioblastomas, or a type of pancreatic cancer called pancreatic neuroendocrine tumours, that does not require surgery right away.

2. What should I know before I use WELIREG?

Warnings

Do not use WELIREG if:

you are allergic to belzutifan, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

have any other medical conditions such as breathing problems, heart problems/heart disease, low levels of red blood cells (anaemia), or, allergies
have any other medical conditions
Take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

WELIREG can harm your unborn baby and may also cause miscarriage.
Your doctor will do a pregnancy test before you start treatment with WELIREG.
You should use an effective form of non-hormonal birth control during treatment with WELIREG and for at least 1 week after your last dose.
WELIREG may cause hormonal forms of birth control to not work as well. Unplanned pregnancies can happen.
Talk with your doctor about birth control methods that may be right for you during this time
If you become pregnant or suspect you might be pregnant, tell your doctor right away.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known if WELIREG passes into your breast milk; it may harm your baby.
You and your doctor should decide together if you will take WELIREG or if you will breastfeed, but you should not do both at the same time.
If you intend to breastfeed, wait at least 1 week after your last dose of WELIREG before you start breastfeeding.

Men with female partners who are able to become pregnant

If you have a partner who is pregnant or could get pregnant:

Use an effective form of birth control during treatment with WELIREG and for 1 week after your last dose.
Talk to your doctor about birth control methods that may be right for you during this time.
Tell your doctor right away if your partner becomes pregnant or thinks she might be pregnant while you are taking WELIREG.

WELIREG may impair fertility. If you are planning to have a baby with your partner, talk to your doctor before taking WELIREG.

Children

It is not known if WELIREG is safe and effective for use in children.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Birth control methods that contain hormones (such as birth control pills, injections, or transdermal system patches) may not work as well during treatment with WELIREG.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect WELIREG.

4. How do I use WELIREG?

How much to take

The recommended dose is 120 mg (three 40 mg tablets)
Take WELIREG exactly as your doctor tells you to
Your doctor may change your dose if needed
You can take WELIREG with or without food
Swallow each tablet whole. Do not break, crush or chew

When to take WELIREG

Take your prescribed dose once a day
Take your prescribed dose at the same time each day

If you forget to take WELIREG

WELIREG should be taken at the same time each day.
If you miss a dose of WELIREG, take the missed dose as soon as possible on the same day. Take your next dose of WELIREG at your regular time the next day. Do not take extra tablets to make up for the missed dose.
If you vomit after taking WELIREG, do not take an extra dose. Take your next dose at your regular time the next day.
If you are not sure how to take WELIREG, call your doctor or pharmacist.

If you take too much WELIREG

If you think that you have taken too much WELIREG, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using WELIREG?

Things you should do

WELIREG may cause serious side effects, including:

Low red blood cell counts (anaemia). Low red blood cell counts are common with WELIREG and can be severe. You may need a blood transfusion if your red blood cell counts drop too low. Your doctor will do blood tests to check your red blood cell counts before you start and during treatment with WELIREG.
Tell your doctor if you get any symptoms of low red blood cell counts, including tiredness, feeling cold, shortness of breath, chest pain, or fast heartbeat.
Low oxygen levels in your body. WELIREG can cause low oxygen levels in your body that can be severe and may require you to stop treatment with WELIREG, receive oxygen therapy, or be hospitalised. Your doctor will monitor your oxygen levels before you start and during treatment with WELIREG.
Tell your doctor or get medical help right away if you get symptoms of low oxygen in your body, including shortness of breath or increased heart rate.

WELIREG may cause harm to unborn baby. Treatment with WELIREG during pregnancy can cause harm to your unborn baby. Birth control methods that contain hormones (such as birth control pills, injections, or transdermal system patches) may not work as well during treatment with WELIREG. Females who could get pregnant and males with female partners who are able to become pregnant should use effective contraception during treatment with WELIREG and for 1 week after your last dose. Tell your doctor right away if you, or your partner becomes pregnant or thinks she is pregnant while you are taking WELIREG.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how WELIREG affects you.

WELIREG may cause dizziness in some people.

Looking after your medicine

Follow the instructions on the bottle on how to take care of your medicine properly.

Store it below 30°C in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on windowsills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Serious side effects

Serious side effects	What to do
Low red blood cells (anaemia) Low oxygen levels in body which may cause: - shortness of breath or trouble breathing - chest pain - heart feels like it's beating very fast, skipping beats, racing or fluttering	Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Less serious side effects

Less serious side effects	What to do
Feeling like you're going to throw up Feeling tired Feeling dizzy Weight gain	Speak to your doctor if you have any of these less serious side effects and they worry you.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What WELIREG contains

Active ingredient (main ingredient)	belzutifan
Other ingredients (inactive ingredients)	croscarmellose sodium hypromellose acetate succinate magnesium stearate mannitol microcrystalline cellulose silicon dioxide indigo carmine aluminium lake macrogol polyvinyl alcohol purified talc titanium dioxide

What WELIREG looks like

WELIREG 40 mg tablet is a blue, oval, film-coated tablet, with “177” on one side (Aust R 355338).

Who distributes WELIREG

Merck Sharp & Dohme (Australia) Pty Limited
Level 1, Building A, 26 Talavera Road
Macquarie Park, NSW, 2113
msd-australia.com.au

This leaflet was prepared in August 2024.

RCN000025753

Published by MIMS October 2024

BRAND INFORMATION

Brand name

Welireg

Active ingredient

Belzutifan

Schedule

1 Name of Medicine

Belzutifan.

2 Qualitative and Quantitative Composition

Each Welireg tablet contains 40 mg of belzutifan.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Welireg 40 mg tablet is a blue oval shaped, film-coated tablet debossed with "177" on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Welireg (belzutifan) is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) haemangioblastomas, or pancreatic neuroendocrine tumours (pNET), not requiring immediate surgery.

4.2 Dose and Method of Administration

The recommended dose of Welireg is 120 mg (three 40 mg tablets) administered orally once daily, with or without food. Swallow tablets whole.
If a dose of Welireg is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for Welireg the next day. Extra tablets should not be taken to make up for the missed dose. If vomiting occurs any time after taking Welireg, do not retake the dose. The next dose should be taken the next day. Treatment should continue until disease progression or unacceptable toxicity occurs.

Dose modifications.

Dosage modifications for Welireg for adverse reactions are summarised in Table 1.

If a patient experiences a Grade 3 adverse reaction, not addressed in Table 1, withhold dosing until symptoms improve to ≤ Grade 2, then consider resuming at a reduced dose (reduce by 40 mg). Permanently discontinue Welireg if Grade 3 adverse reaction recurs (see Section 4.8 Adverse Effects (Undesirable Effects)). If a patient experiences a Grade 4 adverse reaction, not previously addressed in Table 1, permanently discontinue Welireg (see Section 4.8 Adverse Effects (Undesirable Effects)).

Paediatric patients.

Safety and efficacy of Welireg have not been established in paediatric patients less than 18 years of age (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Geriatric patients.

There are limited data available on the use of Welireg in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties). No dose adjustment of Welireg is recommended in elderly patients.

Renal impairment.

No dose adjustment of Welireg is recommended in patients with mild and moderate renal impairment. Welireg has not been studied in patients with severe renal impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

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 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

4.3 Contraindications

None.

4.4 Special Warnings and Precautions for Use

Anaemia due to decreased erythropoietin.

Welireg can cause severe anaemia that can require blood transfusion.
In a clinical trial (Study-004) with Welireg for the treatment of patients with VHL disease-associated RCC, anaemia was reported in 55 patients (90.2%). Grade 3 anaemia occurred in 6 patients (9.8%) (see Section 4.8 Adverse Effects (Undesirable Effects)). Median time to onset of all Grade anaemia events was 30 days (range: 1 day to 8.38 months). Of the 13 patients that were treated with an erythropoiesis-stimulating agent (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 (see Section 5.1 Pharmacodynamic Properties). In another clinical trial (Study-001) for the treatment of non-VHL disease-associated advanced solid tumours using the same dose of Welireg, anaemia was reported in 44 patients (75.9%). Grade 3 anaemia occurred in 16 patients (27.6%).
Monitor for anaemia before initiation of and periodically throughout treatment with Welireg. Closely monitor patients who are dual UGT2B17 and CYP2C19 poor metabolisers due to potential increases in exposure that may increase the incidence or severity of anaemia. For patients who develop Grade 3 anaemia, withhold Welireg and treat according to standard medical practice, until resolved to ≤ Grade 2. For recurrent Grade 3 anaemia, discontinue Welireg. For patients who develop Grade 4 anaemia, withhold Welireg and permanently discontinue for recurrent Grade 4 anaemia (see Section 4.2 Dose and Method of Administration).

Hypoxia.

Welireg can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalisation.
In a clinical trial (Study-004) with Welireg for the treatment of patients with VHL disease-associated RCC, Grade 3 hypoxia occurred in 1 patient (1.6%) (see Section 4.8 Adverse Effects (Undesirable Effects)). In another clinical trial (Study-001) for the treatment of non-VHL disease-associated advanced solid tumours using the same dose of Welireg, hypoxia occurred in 17 patients (29.3%), Grade 3 hypoxia occurred in 9 patients (15.5%).
Monitor oxygen saturation with pulse oximetry before initiation of and periodically throughout treatment with Welireg. For Grade 3 asymptomatic hypoxia (e.g. pulse oximetry < 88% or P_aO₂ ≤ 55 mmHg at rest), consider providing supplemental oxygen and consider continuing or withholding treatment. If withheld, resume at a reduced dose. For patients who have Grade 3 symptomatic hypoxia (e.g. pulse oximetry < 88% or P_aO₂ ≤ 55 mmHg at rest), withhold Welireg, treat hypoxia, and consider dose reduction. If symptomatic hypoxia continues to recur, discontinue treatment. For Grade 4 hypoxia (life-threatening airway compromise; urgent intervention indicated e.g. tracheotomy or intubation), permanently discontinue treatment (see Section 4.2 Dose and Method of Administration).
Advise patients to report signs and symptoms of hypoxia immediately to a healthcare provider.

Embryo-fetal toxicity.

Based on findings in animals, Welireg may cause fetal harm, including fetal loss, in humans. In a rat study, belzutifan caused embryo-fetal 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. Advise females of reproductive potential to use effective non-hormonal contraceptive during treatment with Welireg and for 1 week after the last dose due to the potential risk to the fetus. This is because the use of Welireg may reduce the efficacy of hormonal contraceptives. Advise male patients with female partners of reproductive potential to use highly effective contraception during treatment with Welireg and for 1 week after the last dose (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.6 Fertility, Pregnancy and Lactation).

Dual UGT2BI7 and CYP2C19 poor metabolisers.

Patients who are dual UGT2B17 and CYP2C19 poor metabolisers have higher belzutifan exposures, which may increase the incidence and severity of adverse reactions of belzutifan and should be closely monitored (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties).

Use in 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 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

No dose adjustment of Welireg is recommended in patients with mild or moderate renal impairment. Welireg has not been studied in patients with severe renal impairment (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

No dosage adjustment of Welireg is recommended in geriatric patients. Clinical trials of Welireg did not include sufficient numbers of patients aged 65 years and over to determine whether there is a difference in safety or effectiveness compared to younger patients (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties). Of the 61 patients with VHL disease-associated RCC (Study-004) treated with Welireg, only 2 patients were 65 years and over. Another clinical trial (Study-001) for the treatment of non-VHL disease-associated advanced solid tumours included 24 patients were 65 years and over.

Paediatric use.

Safety and effectiveness of Welireg in paediatric patients under 18 years of age have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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

Effects of Welireg on other drugs.

In vitro studies have shown that belzutifan induces CYP3A4.
Co-administration of Welireg with CYP3A4 substrates, including hormonal contraceptives, 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 metabolisers (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties).
Co-administration of Welireg with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding.
Belzutifan inhibits MATE2K (IC₅₀ 0.7 microM), OCT1 (IC₅₀ 47 microM) and MATE1 (IC₅₀ 39 microM) in vitro while the clinical unbound C_max is 1.8 microM. Welireg might increase plasma exposures of co-administered drugs that are predominantly cleared by these transporters.

Effects of other drugs on Welireg.

Co-administration with inhibitors of UGT2B17 or CYP2C19 is expected to increase plasma belzutifan exposure. Dose adjustment is not required on co-administration with inhibitors of UGT2B17 or CYP2C19. Drugs that induce CYP2C19 are expected to reduce plasma exposures of belzutifan.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No fertility studies in animals were conducted. Testicular atrophy and hypospermia, associated with decreased sperm count and motility and abnormal sperm morphology, were observed in general toxicology studies in rats at exposures lower than the human exposure at the recommended dose of 120 mg daily, and did not reverse at the end of a 26-week recovery period. Belzutifan caused post implantation loss in pregnant rats at exposures lower than the human exposure at the recommended dose of 120 mg daily. Based on findings in animals, Welireg may impair fertility in males and females of reproductive potential. Advise patients of this potential risk.
(Category D)
Based on findings in animal studies, Welireg may cause fetal harm, including fetal loss, when administered to a pregnant woman. There are no available data on the use of Welireg in pregnant women to evaluate drug-associated risk. In a rat embryo-fetal development study, administration of belzutifan during organogenesis caused embryo-fetal lethality, reduced fetal body weight, and fetal skeletal abnormalities at exposures similar to or below the human exposure at the recommended dose of 120 mg daily. Advise females of reproductive potential of the potential risk to a fetus.
There are no data on the presence of belzutifan or its metabolites in human milk, their effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Welireg and for 1 week after the last dose.

Females and males of reproductive potential.

Pregnancy testing. Verify the pregnancy status of females of reproductive potential prior to initiating treatment with Welireg.
Contraception. Welireg may cause embryo-fetal harm, including fetal loss, when administered to a pregnant woman (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Females.

Advise females of reproductive potential to use highly effective contraception during treatment with Welireg and for at least 1 week after the last dose. Use of Welireg may reduce the efficacy of hormonal contraceptives. Advise patients using hormonal contraceptives to use an alternative non-hormonal contraceptive method or add a barrier method of contraception (e.g. male condom) during treatment with Welireg (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Males.

Advise male patients with female partners of reproductive potential to use highly effective contraception during treatment with Welireg and for at least 1 week after the last dose.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials experience.

The safety of Welireg was evaluated in an open-label Phase 2 clinical trial (Study-004), in 61 patients with VHL disease who had at least one measurable solid tumour localised to the kidney as defined by Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1) and who did not require immediate surgery. Patients were treated with Welireg 120 mg once daily (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The median duration of exposure to Welireg was 125 weeks (range: 8.4 to 163.1 weeks).

Adverse events.

Welireg was discontinued due to adverse events in 3 patients (4.9%): 1 patient for Grade 1 dizziness; one patient for haemorrhage intracranial and 1 patient due to death from a concomitantly administered toxic agent. Adverse events leading to dose interruption of Welireg occurred in 27 patients (44.3%) and adverse events leading to dose reduction of Welireg occurred in 9 patients (14.8%). The most common (≥ 10%) adverse event resulting in dose interruption or reduction of Welireg was fatigue. Serious adverse events occurred in 14 patients (23.0%), of which 4 were determined to be drug-related (anaemia, urinary tract infection, haemorrhage intracranial, and hypoxia).
The most common adverse events (≥ 25%) that occurred in patients treated with Welireg were anaemia, fatigue, headache, dizziness, and nausea. Table 2 summarises the adverse events reported in patients treated with Welireg.

Adverse drug reactions.

The most common adverse reactions under treatment with belzutifan were anaemia (90%), fatigue (70%), dizziness (44%) and nausea (36%).
The most common adverse reactions resulting in dose interruption of belzutifan were fatigue (13.1%), nausea (8.2%) and anaemia (4.9%). The most common adverse reactions resulting in dose reduction of belzutifan were fatigue (8.2%), anaemia (1.6%) and hypoxia (1.6%). Belzutifan was discontinued due to adverse reaction in 1 patient (1.6%) (Grade 1 dizziness).

Tabulated list of adverse reactions.

Adverse reactions reported in clinical studies with belzutifan are listed in Table 3 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).

The safety of Welireg was also evaluated in a Phase 1 clinical trial (Study-001), in 58 patients with non-VHL disease-associated advanced solid tumours, treated with Welireg 120 mg once daily. Study-001 patients differed from VHL-associated RCC patients (Study-004). Study-001 patients were older, had worse ECOG PS, had metastatic disease, had prior therapies, had more comorbidities, and had lower baseline haemoglobin levels at treatment initiation. Study-001 had a median duration of exposure to Welireg of 25.4 weeks (range: 1.1 to 145.9 weeks). Welireg was discontinued due to adverse reactions in 6 patients (10.3%), most commonly due to hypoxia. Adverse reactions leading to dose interruption occurred in 24 patients (41.4%) and adverse reactions leading to dose reduction occurred in 6 patients (10.3%). The most common (≥ 10%) adverse reaction resulting in dose interruption or reduction was hypoxia. The most common adverse reactions (≥ 25%) that occurred in patients treated with Welireg were anaemia, fatigue, dyspnoea, nausea, hypoxia, cough, vomiting, and peripheral oedema.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no specific treatment for Welireg overdose. In cases of suspected overdose, if necessary, consider withholding Welireg and instituting supportive care. The highest dose of Welireg studied clinically was 240 mg total daily dose (120 mg twice a day or 240 mg once a day). Grade 3 hypoxia occurred at 120 mg twice a day and Grade 4 thrombocytopenia occurred at 240 mg once daily.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

Pharmacotherapeutic group: not yet assigned, ATC code: not yet assigned.

5.1 Pharmacodynamic Properties

Mechanism of action.

Belzutifan is an inhibitor of hypoxia-inducible factor 2 alpha (HIF-2α). HIF-2α is a transcription factor that plays a role in oxygen sensing by regulating genes that promote adaptation to hypoxia. Under normal oxygen levels, HIF-2α is targeted for ubiquitin-proteasomal degradation by VHL protein. Lack of functional VHL protein results in stabilization and accumulation of HIF-2α. Upon stabilization, HIF-2α translocates into the nucleus and interacts with hypoxia-inducible factor 1 beta (HIF-1β) domains to form a transcriptional complex that induces expression of downstream genes, including genes associated with cellular proliferation, angiogenesis, and tumour growth. Belzutifan binds to HIF-2α, and in conditions of hypoxia or impairment of VHL protein function, belzutifan blocks the HIF-2α-HIF-1β interaction, leading to reduced transcription and expression of HIF-2α target genes. In vivo, belzutifan has demonstrated anti-tumour activity in mouse xenograft models of clear cell renal cell carcinoma (ccRCC).
The pharmacodynamic effects of belzutifan were evaluated in patients with VHL disease-associated RCC (Study-004) and in patients with non-VHL disease-associated advanced solid tumours (Study-001). Circulating plasma levels of erythropoietin (EPO) were monitored in patients as a pharmacodynamic marker of HIF-2α inhibition. Treatment in patients with Welireg resulted in reductions in EPO at all dose levels. Reductions in EPO were observed to be dose/exposure dependent and showed a plateauing effect on reduction at exposures achieved with doses above 120 mg once daily. In patients with VHL disease-associated RCC receiving 120 mg once daily of Welireg, peak EPO suppression occurred at 2 weeks of treatment (mean percent decrease from baseline of approximately 60%). Mean EPO levels gradually returned to baseline values after 12 weeks of treatment.
The incidence of Grade 3 anaemia increased with higher belzutifan exposure in patients with baseline haemoglobin levels < 12 g/dL (see Section 4.4 Special Warnings and Precautions for Use).

Cardiac electrophysiology.

At the recommended dose (120 mg once daily) for Welireg, there were no clinically relevant effects on the QTc interval.

Pharmacogenomics.

Belzutifan is primarily metabolised by UGT2B17 and CYP2C19. The activity of these enzymes varies among individuals who carry different genetic variants, which may impact belzutifan concentrations. Poor metabolisers are individuals who are considered to have no enzyme activity. Approximately 15% of Caucasians, 11% of Latinos, 6% of African Americans, 38% of South Asians, and 70% of East Asians are UGT2B17 poor metabolisers. Approximately 2% of Caucasians, 1% of Latinos, 5% of African Americans, 8% of South Asians, and 13% of East Asians are CYP2C19 poor metabolisers. Approximately 0.3% of Caucasians, 0.1% of Latinos, 0.3% of African Americans, 3% of South Asians, and 9% of East Asians are dual UGT2B17 and CYP2C19 poor metabolisers. Expected frequencies in the Japanese population for the UGT2B17, CYP2C19, and dual UGT2B17 and CYP2C19 poor metabolisers are approximately 77%, 19%, and 15%, respectively. Expected frequencies in the United States population for the UGT2B17, CYP2C19, and dual UGT2B17 and CYP2C19 poor metabolisers are approximately 16%, 3%, and 0.5%, respectively based on the reported proportion of the US population represented by major racial/ethnic groups.
The impact of CYP2C19 and UGT2B17 poor metabolisers on belzutifan exposure was assessed in a population PK analysis. Based on the analysis, VHL disease-associated RCC patients who are UGT2B17, CYP2C19, or dual UGT2B17 and CYP2C19 poor metabolisers, are projected to have 1.5-, 1.6-, or 2.3-fold the exposures (steady state AUC_0-24hr), respectively, compared to a typical reference patient (UGT2B17 intermediate metaboliser, CYP2C19 non-poor metaboliser) for the recommended dose. No dose adjustment is recommended based on exposure-response analyses for efficacy and safety and the risk-benefit profile.

Clinical trials.

The efficacy of Welireg was investigated in Study-004, an open-label Phase 2 clinical trial in 61 patients with VHL disease who had at least one measurable solid tumour (as defined by RECIST v1.1) localised to the kidney and who did not require immediate surgery. Patients received Welireg at a dose of 120 mg once daily. Patients were evaluated radiologically approximately 12 weeks after initiation of treatment and every 12 weeks thereafter. Treatment was continued until progression of disease or unacceptable toxicity. The study excluded patients who had any evidence of metastatic disease, either RCC or other VHL disease-associated tumours, an immediate need for surgical intervention for tumour treatment, any major surgical procedure completed within 4 weeks prior to study enrollment, any major cardiovascular event within 6 months prior to study drug administration, or prior systemic treatments for VHL disease-associated RCC.
The study population characteristics were: median age of 41 years, 3.3% age 65 or over; 52.5% male; 90.2% White; and 82.0% had an ECOG PS of 0 and 16.4% had an ECOG PS of 1. Seventy-seven percent of patients had prior RCC surgical procedures. Other VHL disease-associated tumours in patients included pancreatic lesions (100.0%) of which 36.1% were pancreatic neuroendocrine tumours, CNS haemangioblastomas (82.0%), and retinal angiomas (19.7%).
The primary efficacy endpoint for the treatment of VHL disease-associated RCC was overall response rate (ORR) measured by Integrated Radiology and Oncology Assessment (IRO) assessment using RECIST v1.1 as assessed by a central independent review committee (IRC). Additional efficacy endpoints included disease control rate (DCR), response duration, time to response (TTR), and time to surgery (TTS). Radiographic endpoints were assessed by IRC using RECIST v1.1. The clinical benefit of Welireg in reducing RCC tumour size and slowing the growth of tumours was supported by pre-treatment and post-treatment linear growth rate of 3.52 and 3.37 mm/year respectively in Study-004. A total of 91.8% of participants (56/61) had a decrease in the sum of target tumour diameters, including 3.3% (2/61) achieved complete response (see Figure 1). After a median follow-up time of 29.2 months, one out of 61 (2%) patients required an RCC tumour reduction procedure during treatment. In a natural history study, RCC patients undergoing active surveillance have demonstrated linear tumour growth of 3.56 mm/year and showed that 28.7% of patients had their first tumour reduction procedure within 24 months of follow-up. Table 4 summarises the efficacy results for VHL disease-associated RCC tumours in Study-004.

Efficacy endpoints for the treatment of other VHL disease-associated tumours included ORR, DCR and response duration, as assessed by IRC using RECIST v1.1. These results are shown in Table 5.

5.2 Pharmacokinetic Properties

The pharmacokinetics of belzutifan are similar in healthy subjects and patients with solid tumours including advanced RCC. Based on a population-PK model analysis, the steady-state geometric mean (GCV%) for C_max and AUC_0-24hr for 120 mg once daily in patients with VHL disease-associated RCC are predicted to be 1.3 microgram/mL (42.2%) and 16.7 microgram.hr/mL (52.3%), respectively. Steady state is reached after approximately 3 days of once daily dosing with Welireg. Plasma C_max and AUC of belzutifan increased in a dose-proportional manner following doses up to the recommended dose.

Absorption.

Following single-dose oral administration of 120 mg of Welireg, peak plasma concentrations (median T_max) of belzutifan occurred at 1 to 2 hours postdose.

Effect of food.

A high-fat, high-calorie meal delayed peak belzutifan concentration by approximately 2 hours but, had no effect on exposure (AUC). There was a modest decrease of C_max by 35% following consumption of a high-fat, high-calorie meal, but this was not clinically meaningful. Therefore, Welireg can be taken without regard to food.

Distribution.

The mean steady-state apparent volume of distribution of belzutifan following an oral dose is 130 L. Plasma protein binding of belzutifan is 45%. The blood-to-plasma concentration ratio of belzutifan is 0.88.

Metabolism.

Belzutifan is primarily metabolised by UGT2B17 and CYP2C19 and to a lesser extent by CYP3A4. Both UGT2B17 and CYP2C19 display genetic polymorphisms (see Section 5.1 Pharmacodynamic Properties).

Excretion.

The mean apparent clearance of belzutifan is 7.3 L/hr and the mean elimination half-life is 14 hrs.

Special populations.

Renal impairment.

No relevant increase in exposure (AUC) was observed for subjects with mild or moderate renal impairment. Renal impairment (as evaluated by eGFR) was not identified as a significant covariate in the population pharmacokinetic analysis. The pharmacokinetics of belzutifan have not been studied in patients with severe renal impairment (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

No relevant increase in exposure (AUC) was observed for subjects with mild hepatic impairment (using NCI index) based on population pharmacokinetic analysis. The pharmacokinetics of belzutifan have not been studied in patients with moderate or severe hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Dual UGT2BI7 and CYP2C19 poor metabolisers.

Patients who are poor metabolisers of UGT2B17 and CYP2C19 had higher belzutifan AUC (see Section 5.1 Pharmacodynamic Properties).

Paediatric.

No studies with Welireg have been performed in pediatric patients.
Effects of age, gender, ethnicity, race, and bodyweight. Based on a population pharmacokinetic analysis, age, gender, ethnicity, race, and bodyweight do not have a clinically meaningful effect on the pharmacokinetics of belzutifan. Potential differences in exposure across races are possible due to different frequencies of metabolising enzymes (see Section 5.1 Pharmacodynamic Properties).
Drug interaction studies.

In vitro assessment of drug interactions.

Belzutifan is a substrate of UGT2B17, CYP2C19 and CYP3A4. Active transport is not an important determinant of belzutifan disposition. Belzutifan is not an inhibitor of CYP enzymes or transporters with the exception of MATE2K. Belzutifan does not induce CYP1A2 or CYP2B6, however, belzutifan induces CYP3A4 in a concentration dependent manner.

In vivo assessment of drug interactions.

In a clinical study, repeat administration of Welireg 120 mg QD resulted in a 40% reduction in midazolam AUC, an effect consistent with a weak CYP3A4 inducer. Based on PBPK modeling, Welireg may exhibit moderate CYP3A4 induction in patients who have higher belzutifan plasma exposures (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.1 Pharmacodynamic Properties).

5.3 Preclinical Safety Data

Genotoxicity.

Belzutifan was not genotoxic in in vitro bacterial mutagenicity assay and micronucleus assay in human lymphocytes, and an in vivo rat micronucleus assay.

Carcinogenicity.

Carcinogenicity studies have not been conducted with belzutifan.

6 Pharmaceutical Particulars

6.1 List of Excipients

Welireg tablets contain the inactive ingredients: croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, mannitol, microcrystalline cellulose, and silicon dioxide.
The film-coat contains indigo carmine aluminium lake, macrogol, polyvinyl alcohol, purified talc, titanium dioxide.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

HDPE bottle with child-resistant closure in pack size of 90 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Belzutifan is a white to light brown powder that is soluble in acetonitrile, dimethoxyethane and acetone, sparingly soluble in ethyl acetate, very slightly soluble in isopropanol and toluene, and insoluble in water.

Chemical structure.

The chemical name of belzutifan is 3-[[(1S,2S,3R)-2,3-Difluoro-2,3-dihydro-1-hydroxy-7- (methylsulfonyl)-1H-inden-4-yl]oxy]-5-fluorobenzonitrile. The molecular formula is C₁₇H₁₂F₃NO₄S and the molecular weight is 383.34 Daltons.
The chemical structure is:

CAS number.

1672668-24-4.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

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Belzutifan

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