Consumer medicine information

Veoza

Fezolinetant

BRAND INFORMATION

Brand name

Veoza

Active ingredient

Fezolinetant

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Veoza.

SUMMARY CMI

VEOZA™

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 or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using VEOZA?

VEOZA contains the active substance fezolinetant. VEOZA is not a hormone. This medicine is used in menopausal women to reduce moderate to severe vasomotor symptoms (VMS), associated with menopause. VMS are also known as hot flushes or night sweats.

For more information, see Section 1. Why am I using VEOZA? in the full CMI.

2. What should I know before I use VEOZA?

Talk to your doctor if you have any other medical conditions or if you take any other medicines.

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

3. What if I am taking other medicines?

Some medicines may interfere with VEOZA 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 VEOZA?

The recommended dose is one tablet by mouth once daily.

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

5. What should I know while using VEOZA?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using VEOZA.
Things you should not do
  • Do not stop taking this medicine unless your doctor tells you to do so.
Driving or using machines
  • VEOZA has no effect on the ability to drive or use machines.
Looking after your medicine
  • Store below 30°C.

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

6. Are there any side effects?

There are side effects associated with this medicine. It is important to be aware of them so that you can identify any symptoms if they occur (see the full CMI for more details). The most common side effects are diarrhoea, difficulty sleeping (insomnia), increased liver laboratory values and abdominal pain.

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

VEOZA™

Active ingredient(s): fezolinetant

Consumer Medicine Information (CMI)

This leaflet provides important information about using VEOZA. 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 VEOZA.

Where to find information in this leaflet:

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

1. Why am I using VEOZA?

VEOZA contains the active substance fezolinetant.

VEOZA is not a hormone.

This medicine is used in menopausal women to reduce moderate to severe vasomotor symptoms (VMS), associated with menopause. VMS are also known as hot flushes or night sweats.

Before menopause, there is a balance between oestrogen, a female sex hormone, and a brain chemical known as neurokinin B (NKB) that regulates your body's temperature control center located in a specific area of the brain. As your body goes through menopause, oestrogen declines and this balance is disrupted, which can lead to hot flushes and night sweats, also known as VMS. VEOZA helps to restore the balance by blocking NKB in your temperature control center to reduce the number and intensity of hot flushes. VEOZA is a non-hormonal medicine.

2. What should I know before I use VEOZA?

Warnings

Do not use VEOZA if:

  • you are allergic to fezolinetant, or any of the ingredients listed at the end of this leaflet.
  • you are taking certain medicines known as moderate or strong CYP1A2 inhibitors (e.g., ethinyl oestradiol containing contraceptives, mexiletine, enoxacin, fluvoxamine). These medicines can reduce the breakdown of Veoza in the body, leading to more side effects.
  • you have moderate or severe liver dysfunction.
  • you have severe kidney dysfunction.
  • Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • take any medicines for any other condition.
  • have any other medical conditions.
  • currently have or previously had breast cancer or another oestrogen-related cancer. During treatment, your doctor may not prescribe this medicine to you.
  • are taking hormone replacement therapy with oestrogens (medicines used to treat oestrogen deficiency symptoms). Your doctor may not prescribe this medicine to you.
  • have kidney problems, your doctor may not prescribe this medicine to you.
  • have liver problems, your doctor may want to monitor your liver enzymes periodically.

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

Do not take this medicine if you are pregnant or breast-feeding, or if you think you might be pregnant. This medicine is for use only by menopausal women.

Children and adolescents

Do not give this medicine to children and adolescents under 18 years of age, because this medicine is only for menopausal women.

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.

VEOZA may affect the way these medicines work, or these medicines may affect how VEOZA works. This includes medicines known to moderately and strongly reduce the activity of an enzyme (called cytochrome P450 1A2), such as fluvoxamine. If you normally take any of these medicines, your doctor might change it and prescribe a different medicine for you during your treatment with VEOZA.

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

4. How do I use VEOZA?

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

How much to take

The recommended dose is one tablet by mouth once daily.

When to take VEOZA

  • Take this medicine at about the same time each day.

How to take VEOZA

  • Swallow the tablet whole with liquids. Do not break, crush, or chew tablet.
  • Take with or without food.

If you forget to take VEOZA

VEOZA should be used regularly at the same time each day. If you miss your dose at the usual time, take the missed dose as soon as you remember on the same day, with at least 12 hours before the next scheduled dose. Return to your regular schedule the following day.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you miss several doses, tell your doctor and follow the advice given to you.

If you take too much VEOZA

If you think that you have used too much VEOZA, 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 VEOZA?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking VEOZA.

If you are going to have surgery, tell the surgeon or anesthetist that you are taking this medicine.

Keep all of your doctor's appointments so that your progress can be checked. Remind any doctor, dentist or pharmacist you visit that you are using VEOZA.

Things you should not do

  • Do not stop using this medicine suddenly.

Driving or using machines

VEOZA has no effect on the ability to drive or use machines.

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

Looking after your medicine

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

Store it in a cool dry place where the temperature stays below 30°C and 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 window sills.

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.

Less serious side effects

Less serious side effectsWhat to do
  • diarrhoea
  • difficulty sleeping (insomnia)
  • pain in the right upper stomach (abdomen) abdominal pain
  • headache
  • runny nose, sneezing, and coughing
  • feeling sick
  • sleepiness
  • joint pain
  • back pain
  • urinary tract infection
  • abnormal vaginal bleeding
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • signs and symptoms of increased liver laboratory values - nausea, vomiting, yellowing of the eyes or skin (jaundice)
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.

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 VEOZA contains

Active ingredient
(main ingredient)		fezolinetant
Other ingredients
(inactive ingredients)		mannitol
hyprolose
microcrystalline cellulose
magnesium stearate
hypromellose
purified talc
macrogol 8000
titanium dioxide
ferric oxide (iron oxide red)

Do not take this medicine if you are allergic to any of these ingredients.

What VEOZA looks like

VEOZA 45 mg tablets are round, light red, film-coated tablets debossed with the Astellas logo and ‘645’ on the same side.

(AUST R 401401).

Who distributes VEOZA

VEOZA is supplied in Australia by:

Astellas Pharma Australia Pty Ltd
Suite 2.01, 2 Banfield Road
Macquarie Park NSW 2113

Medical Information:

1800 751 755

VEOZA™ is a trademark of Astellas US LLC.

This leaflet was prepared in February 2024.

Published by MIMS April 2024

BRAND INFORMATION

Brand name

Veoza

Active ingredient

Fezolinetant

Schedule

S4

 

1 Name of Medicine

Fezolinetant.

2 Qualitative and Quantitative Composition

Each film-coated tablet contains 45 mg of fezolinetant and is formulated for oral administration.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablets.
Fezolinetant 45 mg tablets are round, light red, film-coated tablets debossed with the Astellas logo and '645' on the same side.

4 Clinical Particulars

4.1 Therapeutic Indications

Veoza is indicated for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Dosage.

The recommended dose of Veoza is 45 mg once daily.
The benefit and duration of treatment with Veoza should be periodically assessed based on the natural history and course of the vasomotor symptoms (VMS) associated with menopause. No clinical data beyond a treatment period of 12 months are available (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
A baseline and subsequent periodic evaluation of liver function is recommended (see Section 4.4 Special Warnings and Precautions for Use).

Special populations.

Elderly.

Clinical studies have not been conducted for safety and efficacy in women initiating Veoza treatment over 65 years of age.

Paediatric.

Veoza is not indicated for paediatric patients. No data are available.

Renal impairment.

No dose adjustment is required in patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m2) (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetic characteristics in special populations). There are no data for patients with end-stage renal disease. Veoza should not be used in patients with severe renal impairment or end-stage renal disease (eGFR < 30 mL/min/1.73 m2) (see Section 4.3 Contraindications).

Hepatic impairment.

No dose modification is recommended for individuals with Child-Pugh Class A (mild) chronic hepatic impairment (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetic characteristics in special populations).
Veoza should not be used in individuals with Child-Pugh Class B (moderate) or C (severe) chronic hepatic impairment (see Section 4.3 Contraindications).
Fezolinetant has not been studied in individuals with Child-Pugh Class C (severe) chronic hepatic impairment.

Method of administration.

Veoza should be administered orally once daily at about the same time each day with or without food, taken with liquids, and should be swallowed whole. Do not cut, crush, or chew tablets.
If a dose of Veoza is missed or not taken at the usual time, administer the missed dose as soon as possible, unless there is less than 12 hours before the next scheduled dose. Return to the regular schedule the following day.

4.3 Contraindications

Veoza is contraindicated in:
Patients with known hypersensitivity to fezolinetant or to any of the excipients in the formulation (see Section 6.1 List of Excipients).
Concomitant use of moderate or strong CYP1A2 inhibitors (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients with pre-existing Child-Pugh Class B (moderate) or Class C (severe) chronic hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).
Patients with severe or end stage renal impairment (eGFR < 30 mL/min/1.73 m2) (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Transaminase elevation and liver function monitoring.

A baseline and subsequent periodic evaluation of liver function (at least once within the first 3 months of treatment) is recommended to inform the individual benefit-risk assessment of treatment with Veoza.
Elevations in serum alanine aminotransferase (ALT) levels at least 3 times the upper limit of normal (ULN) occurred in 2.1% of women receiving fezolinetant compared to 0.8% of women receiving placebo. Elevations in serum aspartate aminotransferase (AST) levels at least 3 times the ULN occurred in 1.0% of women receiving fezolinetant compared to 0.4% of women receiving placebo (see Section 4.8 Adverse Effects (Undesirable Effects)). ALT and/or AST elevations were not accompanied by an increase in bilirubin greater than two times the ULN. In the clinical studies, there were no cases of Hy's law. Women with ALT or AST elevations were generally asymptomatic. Transaminase levels generally returned to pre-treatment levels (or close to these) without sequelae with dose continuation, and upon dose interruption or discontinuation.
In case of acute liver function test abnormalities, the cause should be investigated. A temporary or permanent discontinuation of Veoza may be required.

Patients with existing liver disease.

Patients with active liver disease, or Child-Pugh Class B (moderate) or C (severe) chronic hepatic impairment have not been included in the clinical efficacy and safety studies with fezolinetant.
The pharmacokinetics of fezolinetant have been studied in women with Child-Pugh Class A (mild) and B (moderate) chronic hepatic impairment (see Section 5.2 Pharmacokinetic Properties). Monitoring of liver function in women with known or suspected hepatic disorder is advised during treatment.

Patients with oestrogen-dependent tumours.

Fezolinetant has not been studied in patients with current or previous breast cancer or with other oestrogen-dependent tumours. A decision to treat these patients with Veoza should be based on an individual benefit-risk assessment.

Patients treated with anti-oestrogen therapy.

Fezolinetant has not been studied in patients undergoing treatment with anti-oestrogen therapy. Anti-oestrogen therapy can be associated with severe VMS and/or other symptoms of oestrogen deficiency. A decision to treat these patients with Veoza should be based on an individual benefit-risk assessment.

Concomitant use with hormone replacement therapy (local vaginal preparations excluded).

Concomitant use of fezolinetant with hormonal replacement therapy was not investigated and is not recommended.

Medicinally induced menopause.

Fezolinetant has been studied only in patients after natural or surgical menopause. No efficacy or safety data are available regarding the treatment of vasomotor symptoms in pharmacologically induced menopause (e.g. using GnRH analogues). A decision to treat these patients with Veoza should be based on an individual benefit-risk assessment.

Use in the elderly.

No data are available for commencing treatment in patients aged over 65 years.

Paediatric use.

Veoza is not indicated for paediatric patients. No data are available.

Effects on laboratory tests.

Elevated transaminases have been observed in patients receiving fezolinetant (see Section 4.4 Special Warnings and Precautions for Use, Transaminase elevation and liver function monitoring).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of other medicinal products on fezolinetant.

CYP1A2 inhibitors.

The concomitant use of moderate or strong CYP1A2 inhibitors with Veoza is contraindicated.
Fezolinetant is a substrate of CYP1A2. The concomitant use with drugs that are moderate or strong inhibitors of CYP1A2 (e.g. ethinyl oestradiol containing contraceptives, mexiletine, fluvoxamine) increase the plasma Cmax and AUC of fezolinetant.
In clinical studies, co-administration with fluvoxamine, a strong CYP1A2 inhibitor, resulted in an overall 1.8-fold increase in fezolinetant Cmax and a 9.4-fold increase in AUC; no change in tmax was observed.
Based on physiologically-based pharmacokinetic modelling, a typical weak CYP1A2 inhibitor (cimetidine) is predicted to increase the Cmax and AUC of fezolinetant by 42% and 75%, respectively. A typical moderate CYP1A2 inhibitor (mexiletine) is predicted to increase the Cmax of fezolinetant by 20% and the AUC 3.95-fold.
The predicted increase in fezolinetant exposure with concomitant use of weak CYP1A2 inhibitors is not considered to be clinically relevant.

CYP1A2 inducers.

In clinical studies, smoking (moderate inducer of CYP1A2) decreased fezolinetant Cmax to a geometric LS mean ratio of 71.74%, while AUC decreased to a geometric LS mean ratio of 48.29%.

Effect of fezolinetant on other medicinal products.

In vitro, fezolinetant is primarily catalysed by CYP1A2 and to a lesser extent by CYP2C9 and CYP2C19. Fezolinetant and its major metabolite, ES259564, are not inhibitors of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Fezolinetant and ES259564 are not inducers of CYP1A2, CYP2B6, and CYP3A4 at clinically relevant concentrations.
In vitro, fezolinetant, and its major metabolite, ES259564, are not inhibitors of P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1 or MATE2-K. ES259564, but not fezolinetant, is a substrate of P-glycoprotein (P-gp).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no human data on the effect of Veoza on fertility.
Fezolinetant did not affect fertility in female rats at oral doses up to 100 mg/kg/day (estimated to yield exposure to fezolinetant [plasma AUC] approximately 140-times higher than in patients at the maximum recommended human dose [MRHD] of 45 mg/day).
(Category B3)
The use of Veoza in pregnant women is not indicated. There are no data on the use of Veoza in pregnant women. It is recommended that perimenopausal women of childbearing potential use an effective non-hormonal contraceptive method.
Placental transfer of fezolinetant was demonstrated in rats. Embryofetal lethality was observed in pregnant rats and rabbits at oral doses of 100 and 125 mg/kg/day in the respective species (yielding exposure to fezolinetant [plasma AUC] more than 128-times higher than in patients at the MRHD). Fezolinetant did not produce malformations in either species. Decreased fetal weight, impaired ossification and an increased incidence of fetal skeletal variations were observed in rabbits at ≥ 75 mg/kg/day, occurring in the context of maternotoxicity. No adverse effects on embryofetal development were observed in rats at doses up to 50 mg/kg/day and in rabbits at 45 mg/kg/day (yielding exposure to fezolinetant 62- and 16-times higher than in patients).
 The use of Veoza in breastfeeding women is not recommended. There are no data to assess the effects of fezolinetant on the breastfed child or the effects on milk production. It is not known if fezolinetant is present in human milk.
Excretion of fezolinetant in milk was evident in rats following administration of radiolabelled drug, as well as subsequent absorption by infants via milk consumption. The concentration of radioactivity in milk was higher than in maternal plasma at all time points.

4.7 Effects on Ability to Drive and Use Machines

No formal studies on the effects of the ability to drive and use machines have been performed; however, fezolinetant is considered to have a negligible influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

The safety of Veoza was evaluated in three phase 3 studies (SKYLIGHT 1, 2, and 4). SKYLIGHT 1 and 2 were 12-week, randomised, placebo-controlled, double-blind studies, followed by a 40-week extension treatment period in women with moderate to severe VMS associated with menopause. SKYLIGHT 4 was a 52-week, randomised, placebo-controlled, double-blind long-term safety study in women with VMS associated with menopause. A total of 2203 women were administered Veoza once daily.

Adverse events.

See Table 1.
Across the phase 3 studies, the most common adverse reactions (≥ 3%) with Veoza 45 mg were diarrhoea and insomnia.
There were no serious adverse reactions reported at an incidence greater than 1% across the total study population.
The most frequent adverse reactions leading to discontinuation with Veoza 45 mg were alanine aminotransferase (ALT) increased (0.3%) and insomnia (0.2%).

Tabulated summary of adverse reactions.

Adverse reactions observed during clinical studies are listed below by frequency category in each system organ class. Frequency categories are defined as follows: 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); very rare (< 1/10,000); and not known (cannot be estimated from the available data). See Table 2.

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 experience with inadvertent fezolinetant overdose. Doses of fezolinetant up to 900 mg as a single dose and 720 mg as once daily for 7 days have been tested in clinical studies in healthy women. The maximum tolerated dose was determined to be 900 mg. At 900 mg, headache, nausea, and paraesthesia were observed.
In the case of overdose, the individual should be closely monitored, and supportive treatment should be considered based on signs and symptoms. The terminal half-life (t1/2) of fezolinetant is less than 15 hours.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fezolinetant is a nonhormonal selective NK3 receptor antagonist that blocks neurokinin B (NKB) binding on kisspeptin/neurokinin B/dynorphin (KNDy) neurons to modulate neuronal activity in the thermoregulatory centre.
The thermoregulatory centre in the hypothalamus is innervated by KNDy neurons, which are inhibited by oestrogen and stimulated by the neuropeptide NKB. Through the menopausal transition, declining oestrogen disrupts the balance with NKB. Unopposed, NKB signalling increases KNDy neuronal activity leading to hypertrophy of KNDy neurons and altered activity on the thermoregulatory centre, resulting in VMS, also known as hot flashes and night sweats.

Pharmacodynamic effects.

Fezolinetant treatment provided relief from VMS over 24 hours. Fezolinetant is not a hormone and treatment with fezolinetant did not show any clear trends or clinically relevant changes in sex hormones measured (follicle-stimulating hormone, testosterone, oestrogen, and dehydroepiandrosterone sulfate) in menopausal women. Transient decrease of luteinising hormone (LH) levels was observed at peak concentrations of fezolinetant.

Cardiac electrophysiology.

A model-based approach was conducted to assess the QT prolongation risk of fezolinetant. No clinically relevant prolongation of QTc interval was predicted by the model at the therapeutic or supratherapeutic concentrations.

Clinical trials.

Efficacy: effects on VMS.

SKYLIGHT 1 (2693-CL-0301) and SKYLIGHT 2 (2693-CL-0302) studies.

The efficacy of fezolinetant was evaluated in 1022 postmenopausal women with moderate to severe VMS in two 12-week, randomised, placebo-controlled, double-blind phase 3 studies of identical design, followed by a 40-week extension treatment period. In the initial 12-week period, 341 women received fezolinetant 45 mg daily, and 342 women received placebo.
In the study population, the mean age was 54 years (range: 40 to 65 years). The women self-identified as Caucasian (81%), Black (17%), and Asian (1%). The mean BMI was 28 kg/m2.
The study population included postmenopausal women with one or more of the following: prior hormone replacement therapy (HRT) use (19.9%), prior oophorectomy (21.6%), or prior hysterectomy (32.1%). The median time interval since amenorrhoea/menopause was between 57.2 and 69.2 months with a high variability (range: 2 to 442 months). The median time interval since onset of VMS was 54.8 months (range: 1 to 422 months). Women with a minimum average of 7 moderate to severe VMS per day were eligible to enroll. At baseline, the study participants had a mean 11 VMS episodes per day with a mean severity score of 2.4 points.
The co-primary efficacy endpoints for both studies were the change from baseline in moderate to severe VMS frequency and severity to weeks 4 and 12. Data from the studies showed a statistically significant and clinically meaningful (≥ 2 hot flashes per 24 hours) reduction from baseline in the frequency of moderate to severe VMS to weeks 4 and 12 for fezolinetant 45 mg compared to placebo. Data from the studies showed a statistically significant reduction from baseline in the severity of moderate to severe VMS to weeks 4 and 12 for fezolinetant 45 mg compared to placebo.
Results of the co-primary endpoint for change from baseline to weeks 4 and 12 in mean frequency of moderate to severe VMS per 24 hours from SKYLIGHT 1 and 2 and from pooled studies are shown in Table 3.
Figures 1 and 2 show the mean frequency of moderate to severe VMS per 24 hours in SKYLIGHT 1 and 2.
Results of the co-primary endpoint for change from baseline to weeks 4 and 12 in mean severity of moderate to severe VMS per 24 hours from SKYLIGHT 1 and 2 and from pooled studies are shown in Table 4.
The key secondary endpoint was the mean change from baseline to week 12 in Patient-Reported Outcomes Measurement Information System Sleep Disturbance - Short Form 8b (PROMIS SD SF). In SKYLIGHT 1, the LS mean difference compared to placebo was not statistically significant (-1.1 (95% CI: -2.5, 0.4)). In SKYLIGHT 2, the LS mean difference compared to placebo was statistically significant (-2.0 (95% CI: -3.5, -0.6)).
Safety: endometrial safety. The pivotal trials SKYLIGHT 1 and 2, and the long-term safety study SKYLIGHT 4 assessed the endometrial safety of fezolinetant 45 mg by transvaginal ultrasound and endometrial biopsies. 304 women had baseline and post-baseline endometrial biopsies during 52 weeks of treatment.
The endometrial biopsy assessments did not identify an increased risk of endometrial hyperplasia or malignancy according to pre-specified criteria for endometrial safety. The transvaginal ultrasound assessments did not identify a clinically relevant effect on endometrial thickness.

5.2 Pharmacokinetic Properties

In healthy women, fezolinetant Cmax and AUC increased proportionally with doses between 20 and 60 mg once daily.
After once-a-day dosing, steady-state plasma concentrations of fezolinetant were generally reached by day 2, with minimal fezolinetant accumulation. The pharmacokinetics of fezolinetant do not change over time.

Absorption.

Fezolinetant Cmax is usually achieved at 1 to 4 hours post-dose.

Effect of food.

Veoza may be administered with or without food. No clinically significant differences in fezolinetant pharmacokinetics were observed following administration with a high-calorie, high-fat meal.

Distribution.

The mean apparent volume of distribution (Vz/F) of fezolinetant is 189 L. The plasma protein binding of fezolinetant is low (51%). The distribution of fezolinetant into red blood cells is almost equal to plasma.

Metabolism.

Fezolinetant is primarily metabolised by CYP1A2 in humans to yield oxidised major metabolite ES259564. ES259564 is approximately 20-fold less potent against the human NK3 receptor with no significant off-target activities. The metabolite-to-parent ratio ranges from 0.7 to 1.8.

Excretion.

The apparent clearance at steady-state of fezolinetant is 10.8 L/h. Following oral administration, fezolinetant is mainly eliminated in urine (76.9%) and to a lesser extent in feces (14.7%). In urine, a mean of 1.1% of the administered fezolinetant dose was excreted unchanged and 61.7% of the administered dose was excreted as ES259564. The terminal elimination half-life (t1/2) of fezolinetant is less than 15 hours in healthy women.

Pharmacokinetic characteristics in special populations.

Effects of age, race, and body weight.

There are no clinically relevant effects of age (18 to 65 years), race (Black, Asian, Other), body weight (42 to 126 kg), or menopause status on the pharmacokinetics of fezolinetant.

Renal impairment.

Following single-dose administration of 30 mg fezolinetant, there was no clinically relevant effect on fezolinetant exposure (Cmax and AUC) in women with mild (eGFR 60 to less than 90 mL/min/1.73 m2) to severe (eGFR less than 30 mL/min/1.73 m2) renal impairment. The AUC of ES259564 was not changed in women with mild renal impairment but increased approximately 1.7- to 4.8-fold in moderate (eGFR 30 to less than 60 mL/min/1.73 m2) and severe renal impairment. Fezolinetant has not been studied in individuals with end-stage renal disease (eGFR less than 15 mL/min/1.73 m2).

Hepatic impairment.

Following single-dose administration of 30 mg fezolinetant in women with Child-Pugh Class A (mild) chronic hepatic impairment, mean fezolinetant Cmax increased by 23% and AUCinf increased by 56%, relative to women with normal hepatic function. In women with Child-Pugh Class B (moderate) chronic hepatic impairment, mean fezolinetant Cmax decreased by 15% and AUCinf increased by 96%. The Cmax of ES259564 decreased in both mild and moderate chronic hepatic impairment groups while AUCinf and AUClast slightly increased less than 15%. Fezolinetant has not been studied in individuals with Child-Pugh Class C (severe) chronic hepatic impairment.

Pharmacologically induced menopause.

Fezolinetant has not been studied in individuals with VMS induced by pharmacologic treatment of malignancy (e.g. breast cancer).

5.3 Preclinical Safety Data

Genotoxicity.

Fezolinetant showed no genotoxic potential in assays for bacterial reverse mutation (Ames test), chromosomal aberration in vitro (in human lymphocytes), or in the in vivo rat peripheral blood micronucleus test. ES259564, the major metabolite of fezolinetant, was also shown not to be mutagenic or clastogenic in vitro.

Carcinogenicity.

The carcinogenic potential of fezolinetant was investigated in a 6-month study in transgenic (Tg.rasH2) mice and in a 2-year study in female rats, both conducted by the oral route. Fezolinetant was not carcinogenic in transgenic mice up to the highest dose level tested (450 mg/kg/day, yielding exposure to fezolinetant [plasma AUC] in female animals 47-times higher than in patients at the MRHD of 45 mg/day). An increase in the incidence of thyroid follicular cell adenoma was noted in rats at 100 mg/kg/day (186-fold the plasma AUC in patients at the MRHD). The increase is considered to be a rat specific effect secondary to the induction of hepatic enzymes and, therefore, does not constitute a clinical carcinogenic risk. Furthermore, no treatment-related increase in tumour incidence was observed in rats at 30 mg/kg/day (yielding 75-times the clinical AUC).

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, hyprolose, microcrystalline cellulose, magnesium stearate, hypromellose, purified talc, macrogol 8000, titanium dioxide, and ferric oxide (iron oxide red).

6.2 Incompatibilities

None.

6.3 Shelf Life

36 months.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

PA/aluminium/PVC/aluminium unit dose blisters in cartons containing 10, 30 or 100 film-coated tablets.
(Note: not all pack sizes may be marketed).

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

Fezolinetant is a white powder. It is very slightly soluble in water (0.29 mg/mL).

Chemical structure.

The chemical name of fezolinetant is (4-Fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone having a molecular formula of C16H15FN6OS and a molecular weight of 358.39. The structural formula of fezolinetant is:

CAS number.

1629229-37-3.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes