Consumer medicine information

Ryeqo

Relugolix; Estradiol; Norethisterone acetate

BRAND INFORMATION

Brand name

Ryeqo

Active ingredient

Relugolix; Estradiol; Norethisterone acetate

Schedule

SUMMARY CMI

Ryeqo^® 40/1/0.5 (Ryeqo)

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about taking 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 taking Ryeqo?

Ryeqo contains the active ingredients, relugolix, estradiol hemihydrate and norethisterone acetate. Ryeqo is taken to treat adult women (over the age of 18 years) before they reach menopause for moderate to severe symptoms of uterine fibroids (commonly known as myomas), and for symptomatic treatment of endometriosis in women with a history of previous medical or surgical treatment for their endometriosis.

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

2. What should I know before I take Ryeqo?

Do not use if you have ever had an allergic reaction to Ryeqo or any of the ingredients listed at the end of the CMI.

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 take Ryeqo? in the full CMI.

3. What if I am taking other medicines?

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

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take Ryeqo?

Take one tablet each day.
The tablet must be taken orally every day, at about the same time, with or without food with a little liquid.

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

5. What should I know while taking Ryeqo?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are taking Ryeqo. Tell your doctor if you have any medical conditions, take any medicines for any other condition, or are planning on having surgery. Tell your doctor if you become pregnant whilst taking Ryeqo.
Things you should not do	Do not stop taking Ryeqo before talking to your doctor first.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how Ryeqo affects you. Ryeqo has no known effect on the ability to drive and use machines.
Drinking alcohol	Tell your doctor if you drink alcohol.
Looking after your medicine	Store Ryeqo in a cool dry place where the temperature is below 30°C. Store it in a cool dry place away from moisture, heat, or sunlight. Keep it where young children cannot reach it.

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

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. Ask your doctor or pharmacist if you have any further questions about side effects. The most common side effects are headaches, hot flushes, excessive, irregular, or prolonged bleeding from the womb (uterine bleeding), hair loss, decreased interest in sex, irritability, increased sweating, a lump in the breast tissue (breast cyst), indigestion, night sweats, back pain, joint pain, genital area dryness. Serious side effects include uterine myoma expulsion.

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

Ryeqo^® 40/1/0.5 (Ryeqo) (Re-echo)

Active ingredient(s): relugolix, estradiol, norethisterone acetate

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I taking Ryeqo?

Ryeqo contains the active ingredients relugolix, estradiol and norethisterone acetate.

It is used to treat adult women (over 18 years of age) before they reach menopause for:

moderate to severe symptoms of uterine fibroids (commonly known as myomas)
symptomatic treatment of endometriosis who have a history of previous medical or surgical treatment for their endometriosis
Endometriosis is an often painful disorder in which tissue similar to the tissue that normally lines the inside of your uterus (endometrium) grows outside of your uterus.

Relugolix reduces the production of hormones from the ovaries, reducing the amount of estrogen and progesterone circulating in the body.

Estradiol and norethisterone acetate are two types of female hormones added in Ryeqo to maintain a hormonal state similar to the beginning of your period.

Relugolix, estradiol, and norethisterone acts to relieve your symptoms of uterine fibroids or endometriosis.

2. What should I know before I take Ryeqo?

Warnings

Do not take Ryeqo if:

you are allergic to relugolix, estradiol or norethisterone or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
you have or previously have had a blood clot in a blood vessel in the legs (deep vein thrombosis), lungs (pulmonary embolism), heart (heart attack), brain (stroke), or any other parts of the body.
you have or previously had a disease caused by blood clots in the arteries, such as a heart attack, stroke or angina.
you have a blood clotting disorder (such as protein C deficiency, protein S deficiency, antithrombin-III deficiency, or Factor V Leiden).
you have osteoporosis.
you suffer from headaches with focal neurological symptoms such as paralysis or loss of muscle control, or migraine with visual disturbance.
you have had any tumour that is made worse by exposure to female sex hormones such as breast cancer or cancer of the genital organs.
you have or have had a liver disease and your liver function tests have not returned to normal.
you have or ever had liver tumour.
you are pregnant or think you may be pregnant.
you are breastfeeding.
you have any genital bleeding of unknown origin.
you are taking hormonal contraceptives and are unwilling to discontinue its use.

Your doctor will discuss your medical and family history with you. Your doctor will also need to check your blood pressure and make sure you are not pregnant.

You may also need a physical examination and additional checks, such as breast examination and a scan (called a DXA scan) to measure how strong your bones are, that will be specific to your medical needs and/or concerns.

Bone loss (decreased bone mineral density)

Taking Ryeqo can cause bone loss. For this reason, your doctor may order a DXA scan to check your bone mineral density when you start taking Ryeqo and periodically thereafter.

You may be at higher risk of experiencing bone loss under certain conditions, such as having a history of low-trauma fracture, having risk factors for osteoporosis or taking medications that decrease bone density (e.g. systemic or chronic inhaled corticosteroids, anticonvulsants, or chronic use of proton pump inhibitors).

Stop taking Ryeqo and get urgent medical attention if:

you notice any of the conditions mentioned in Section 2. What should I know before I take Ryeqo? under ‘Do not take Ryeqo if’.
you notice signs of liver disease:
- yellowing of your skin or the whites of your eyes (jaundice).
- nausea or vomiting, fever, severe tiredness.
- dark urine, itching or upper abdominal pain.
you notice migraine for the first time or unusually bad headaches occurring more often than before.
you notice possible signs of a blood clot that may mean you are suffering from a clot in the leg (i.e. deep vein thrombosis), or in the lung (i.e. pulmonary embolism), a heart attack or a stroke. For a description of the symptoms of these serious conditions, please go to Section 6. Are there any side effects? under Serious side effects.
you become pregnant.

Check with your doctor if you:

have any other medical conditions.
take any medicines for any other condition.

Tell your doctor if any of the following conditions apply to you:

if you have one or more of the risk factors for developing a blood clot listed below.
if you have high blood pressure.
if you have osteoporosis.
if you suffer from migraines.
if you think you might be pregnant. Treatment with Ryeqo usually leads to a significant reduction or may even stop your menstrual bleeding (your ‘period’), making it difficult to recognise pregnancy.
if you have or previously suffered from depression.
if you have renal (kidney) disease.

Ryeqo and risk of blood clots

The use of other medicines containing an estrogen and a progestogen increases the risk of blood clots. The risk of blood clots with Ryeqo has not been established. Ryeqo reduces the estrogen to levels similar to those at the beginning of your normal menstrual cycle.

Factors that can increase your risk of a blood clot in your vein and/or artery:

as you get older (particularly above about 35 years of age).
if you are overweight (body mass index > 30 kg/m²).
if you have had major surgery or prolonged time off your feet (e.g. your leg is in a cast).
if you have recently given birth.
if anyone in your close family has had a blood clot in the leg, lung or other organ, a heart attack or a stroke at a young age (e.g. below the age of 50 years).
if you smoke.
if you have a problem with your heart (valve disorder, disturbance of the rhythm called atrial fibrillation).
if you have diabetes.
if you have certain medical conditions, such as systemic lupus erythematous (SLE-a disease affecting your natural defence system), sickle cell disease (an inherited disease of the red blood cells), Crohn's disease or ulcerative colitis (chronic inflammatory bowel diseases), or cancer.

The risk of developing a blood clot increases the more factors you have.

The symptoms of a blood clot will depend on where the blood clot has occurred.

Go to Section 6. Are there any side effects? under Serious side effects for symptoms:

of a blood clot in your leg,
of a blood clot in your lung,
of a heart attack,
of a stroke.

Surgery

If you are going to have surgery, tell the surgeon that you are taking Ryeqo.

Liver tumours or liver disease

In rare cases, liver tumours or liver disease has been reported in women taking estrogens and progestogens. If you experience any symptoms of jaundice, contact your doctor for further medical advice.

Renal (kidney) impairment

If you experience any decrease in urine production or notice any fluid retention causing swelling in your legs, ankles or feet, please contact your doctor for further medical advice.

Change in menstrual bleeding pattern (your ‘period’)

Treatment with Ryeqo usually leads to a significant reduction or may even stop your menstrual bleeding (your ‘period’) within the first 30 days of treatment. However, if you continue to experience excessive bleeding, tell your doctor.

Depression

If you experience mood changes or any depressive symptoms contact your doctor for further medical advice.

Signs and symptoms of depression may include:

feeling overwhelmed by sadness that persists throughout the day for 2 weeks or more and often involves sleep and appetite changes.

Increased blood pressure

In rare cases, treatment with Ryeqo may lead to small increases in blood pressure. If you experience any symptoms of increased blood pressure, contact your doctor for further medical advice.

Uterine fibroid prolapse and expulsion

Uterine fibroids may develop anywhere within the muscular wall of the uterus, including the submucosa, a thin layer of tissue in the uterus. In some women, the uterine fibroid may protrude or slip through the cervix into the vagina and may lead to significant worsening of uterine bleeding or pain. If you re-experience severe uterine bleeding after your symptoms have improved while being treated with Ryeqo, contact your doctor for medical advice.

Gallbladder disorders

Some women taking estrogen and progestogen hormones, including Ryeqo, have reported gallbladder disorders (gallstones or inflammation of your gallbladder). If you experience unusually severe pain below your rib cage or in your upper abdomen, contact your doctor for medical advice.

Children and adolescents

Ryeqo should not be taken by children under 18 years of age since the safety and efficacy of Ryeqo has not been established in this age group.

Ryeqo contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, tell your doctor before taking this medicine.

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.

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

Do not take Ryeqo if you are pregnant or breast-feeding. If you think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. If you become pregnant, stop taking Ryeqo and contact your doctor.

Ryeqo stops ovulation and thus you are not likely to become pregnant while taking Ryeqo if used as recommended. Ovulation and menstrual bleeding will return rapidly after discontinuing Ryeqo and alternative birth control needs to be started immediately after discontinuation of Ryeqo. There are no data on fertility following treatment with Ryeqo in women with endometriosis.

Depending on when in your cycle you start taking Ryeqo, it may take time to obtain the full inhibition of ovulation by Ryeqo; therefore, non-hormonal birth control (e.g. condoms) should be used for the first month after starting Ryeqo.

If you miss your doses for 2 or more consecutive days, non-hormonal birth control (e.g. condoms) should be used for the next 7 days of treatment.

Do not take Ryeqo if you are breastfeeding.

You should know that most women have reduced or no periods during treatment and for a few weeks afterwards after medication is ceased.

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.

Talk to your doctor if you are taking any of the medicines listed below, as these medicines can affect Ryeqo or be affected by Ryeqo:

Certain medicines used to treat epilepsy (e.g. carbamazepine, topiramate, phenytoin, phenobarbital, primidone, oxcarbazepine)
Certain medicines used to treat human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) (e.g. ritonavir, efavirenz)
Certain medicines used to treat Hepatitis C Virus (HCV) (e.g. sofosbuvir, velpatasvir, voxilaprevir, glecaprevir)
Certain medicines used to treat fungal infections (e.g. ketoconazole, itraconazole, fluconazole, griseofulvin)
Certain medicines used to treat bacterial infections (e.g. rifampicin, rifabutin, clarithromycin, erythromycin, gentamicin, tetracycline, griseofulvin)
Certain medicine used to treat high blood pressure in the arteries in the lung (e.g. bosentan)
Certain medicines used to treat high blood pressure (e.g., diltiazem, carvedilol, verapamil)
Certain medicines used to treat irregular heartbeats (e.g. amiodarone, propafenone, quinidine, verapamil)
Certain medicines used to treat angina (e.g. ranolazine, carvedilol, verapamil)
Certain medicines to prevent organ rejection after transplantation (e.g. cyclosporine)
Herbal remedies containing St John's wort (Hypericum perforatum)

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

4. How do I take Ryeqo?

How much to take

Each daily dose is one tablet.
Follow the instructions provided and take Ryeqo until your doctor tells you to stop.

When to take Ryeqo

It is recommended that you start taking Ryeqo within the first 5 days after the start of bleeding due to your period. If you start at another time of your menstrual cycle, you may initially experience irregular or heavier bleeding.

How to take Ryeqo

The tablet must be taken orally every day, at about the same time, with or without food with a little liquid.

If you forget to take Ryeqo

Ryeqo should be taken regularly at about the same time each day. If you miss your dose at the usual time, take it as soon as you remember and then resume taking your tablet the next day as usual.

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 a dose for 2 or more consecutive days use nonhormonal contraception for the following 7 days.

If you take too much Ryeqo

If you think that you have taken too much Ryeqo, 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 taking Ryeqo?

Things you should do

Call your doctor straight away if you:

experience any of the side effects listed below and they worry you.
find out you are pregnant.

Remind any doctor, dentist, or pharmacist you visit that you are taking Ryeqo.

You should use a non-hormonal contraceptive for at least one month after starting treatment.

Things you should not do

Do not stop taking this medicine before talking to your doctor first. Your doctor will explain the effects of stopping treatment and discuss other possibilities with you.

Laboratory tests

If you need a blood or urine test, tell your doctor or the laboratory staff that you are taking Ryeqo because this medicine can affect the results of some tests.

Driving or using machines

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

Ryeqo has no known effect on the ability to drive and use machines.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

Store Ryeqo below 30°C

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

Store it 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 take this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not take 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 effects

What to do

General

headache
hot flush
excessive, irregular, or prolonged bleeding from the womb (uterine bleeding)
hair loss
decreased interest in sex
irritability
increased sweating
a lump in the breast tissue (breast cyst)
night sweats
back pain
joint pain
dryness of the genital area
hives

Gastrointestinal

indigestion

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Uterine myoma expulsion
(fibroid comes out either completely or partially through the vagina, usually with increased bleeding from the vagina).
Angioedema
(rapid swelling of the bottom layer of skin on the face (including eyelids, lips, swelling on the arms, legs, or genitals), or swelling of the tongue, or throat, potentially leading to breathing difficulties.
Blood clots
The signs of blood clots will depend on where the blood clot has occurred.
Symptoms of a blood clot in your leg (deep vein thrombosis)
The symptoms of a blood clot in the leg known as a deep vein thrombosis (DVT) can include:
- swelling in your leg and/or foot or along a vein in your leg.
- pain or tenderness in your leg which feels worse when you stand up or are walking.
- increased heat in the affected leg with red or discoloured skin.
Symptoms of a blood clot in your lung (pulmonary embolism)
The symptoms of a blood clot in the lung known as a pulmonary embolism (PE) can include:
- a sudden onset of unexplained shortness of breath or rapid breathing.
- sudden coughing which may be associated to a sharp pain in your chest.
- coughing up of blood.
- severe dizziness or feeling lightheaded.
- a rapid or irregular heartbeat.
Symptoms of a heart attack
The symptoms of a heart attack, also known as a myocardial infarction, may be temporary and can include:
- pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in your chest, arm, or below your breastbone.
- discomfort radiating to your back, jaw, throat, arm, stomach.
- feeling of being full, having indigestion or choking.
- sweating, nausea, vomiting or dizziness.
- extreme weakness, anxiety, or shortness of breath.
- rapid or irregular heartbeats.
Symptoms of a stroke
The symptoms of a stroke can include:
- a sudden numbness or weakness in your face, arm of leg, especially on one side of your body.
- sudden trouble walking, dizziness, loss of balance or coordination.
- sudden confusion, trouble seeing in one or both your eyes.
- sudden, severe or prolonged headache with no known cause.
- losing consciousness or fainting with or without a seizure.
Increased blood pressure
Symptoms of increased blood pressure may include headache, tiredness, dizziness.

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 Ryeqo contains

Active ingredients (main ingredients)	relugolix estradiol hemihydrate norethisterone acetate
Other ingredients (inactive ingredients)	lactose monohydrate mannitol (E421) sodium starch glycollate hyprolose (E463) magnesium stearate (E572) hypromellose type 2910 (E464) titanium dioxide (E171) triacetin (E1518) iron oxide yellow (E172)
Potential allergens	lactose monohydrate

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

What Ryeqo looks like

Ryeqo is a light yellow to yellow, round, film-coated tablet, with “415” on one side and plain faced on the other side.

Ryeqo is available in bottles of 28 film-coated tablets (1x bottle) or 84 film-coated tablets (3x bottles).

Not all pack sizes may be marketed.

The Australian Registration Number is AUST R 375414.

Who distributes Ryeqo?

Ryeqo is supplied in Australia by:

Gedeon Richter Australia Pty Ltd
Suite 902/15 Blue Street
North Sydney NSW 2060
Australia

Phone: 1300 GEDEON (1300 433 366)

This leaflet was prepared in January 2024.

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Ryeqo

Active ingredient

Relugolix; Estradiol; Norethisterone acetate

Schedule

1 Name of Medicine

Relugolix, estradiol (as hemihydrate) and norethisterone acetate.

2 Qualitative and Quantitative Composition

Each Ryeqo 40/1/0.4 (Ryeqo) film-coated tablet contains 40 mg relugolix, 1 mg estradiol (as hemihydrate) and 0.5 mg norethisterone acetate.
Each film-coated tablet contains approximately 80 mg of lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablet.
Light yellow to yellow, round film-coated tablet of 8 mm with "415" on one side and plain-faced on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Ryeqo is indicated in adult women of reproductive age for:
treatment of moderate to severe symptoms of uterine fibroids;
symptomatic treatment of endometriosis in women with a history of previous medical or surgical treatment for their endometriosis (see Section 5.1 Pharmacodynamic Properties).

4.2 Dose and Method of Administration

Dosage.

One tablet of Ryeqo must be taken once daily, at about the same time with or without food. Tablets should be taken with some liquid as needed (see Section 5.2 Pharmacodynamic Properties).

Bone mineral density (BMD) loss and osteoporosis.

Assessment of BMD by dual-energy X-ray absorptiometry (DXA) is recommended at baseline and after one year of treatment.
Use is recommended to be limited to 24 months, with extension of therapy conditional on stability of DXA and reassessment of risk/benefit in the individual patient by the treating physician.
Annual DXA is recommended while taking Ryeqo (see Section 4.4 Special Warnings and Precautions for Use).

Initiation of treatment.

Pregnancy must be ruled out prior to initiating treatment with Ryeqo.
When starting treatment, the first tablet must be taken within 5 days of the onset of menstrual bleeding. If treatment is initiated on another day of the menstrual cycle, irregular and/or heavy bleeding may initially occur.
Ryeqo can be taken without interruption. Discontinuation should be considered when the patient enters menopause, as the symptoms of both uterine fibroids and endometriosis are known to regress when menopause begins.

Contraceptive properties of Ryeqo.

Any hormonal contraception needs to be stopped prior to initiation of treatment, as concomitant use of hormonal contraceptives is contraindicated (see Section 4.3 Contraindications).
Nonhormonal methods of contraception must be used for at least 1 month after initiation of treatment.
After at least one month of Ryeqo use, Ryeqo inhibits ovulation in women taking the recommended dose and provides adequate contraception.
Women of childbearing potential must be advised that ovulation will return rapidly after discontinuing treatment. Therefore, a discussion with the patient, regarding appropriate contraceptive methods, must therefore take place prior to discontinuing treatment and alternative contraception needs to be started immediately after discontinuation of treatment (see Section 4.4 Special Warnings and Precautions for Use).

Method of administration.

Oral use. Ryeqo can be taken with or without food. Tablets should be taken with some liquid as needed.

Missed doses.

If a dose is missed, treatment must be taken as soon as possible and then continue the next day at the usual time.
If doses are missed for 2 or more consecutive days, a nonhormonal method of contraception is to be used for the next 7 days of treatment (see Section 4.6 Fertility, Pregnancy and Lactation).

Dosage adjustment.

Renal impairment.

No dose adjustment for Ryeqo in patients with mild, moderate, or severe renal impairment is required (see Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

No dose adjustment for Ryeqo in patients with mild or moderate hepatic impairment is required (see Section 5.2 Pharmacokinetic Properties). Ryeqo is contraindicated in women with severe liver disease if liver function values have not returned to normal (see Section 4.3 Contraindications).

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in Section 6.1 List of Excipients.
Venous thromboembolic disorder, past or present (e.g. deep venous thrombosis, pulmonary embolism).
Arterial thromboembolic cardiovascular disease, past or present (e.g. myocardial infarction, cerebrovascular accident, ischemic heart disease).
Known thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency or activated protein C (APC) resistance, including Factor V Leiden (see Section 4.4 Special Warnings and Precautions for Use)).
Known osteoporosis.
Headaches with focal neurological symptoms or migraine headaches with aura (see Section 4.4 Special Warnings and Precautions for Use).
Known or suspected sex steroid influenced malignancies (e.g. of the genital organs or the breasts).
Presence or history of liver tumours (benign or malignant) (see Section 4.4 Special Warnings and Precautions for Use).
Presence or history of severe hepatic disease as long as liver function values have not returned to normal.
Pregnancy or suspected pregnancy and breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation).
Genital bleeding of unknown aetiology.
Concomitant use of hormonal contraceptives.

4.4 Special Warnings and Precautions for Use

Ryeqo must only be prescribed after careful diagnosis.

Medical examination/consultation.

Prior to the initiation or reinstitution of Ryeqo, a complete medical history (including family history) must be taken. Blood pressure must be measured and a physical examination must be performed guided by the contraindications (see Section 4.3 Contraindications) and warnings for use (see Section 4.4 Special Warnings and Precautions for Use). During treatment, periodic check-ups must be carried out according to standard clinical practice.
Any hormonal contraception needs to be stopped prior to initiation of Ryeqo (see Section 4.3 Contraindications). Nonhormonal methods of contraception must be used for at least 1 month after initiation of treatment. Pregnancy must be ruled out prior to administering or re-initiation of Ryeqo.

Identified precautions.

Risk of thromboembolic disorders. The use of medicinal products containing an estrogen and a progestogen increases the risk of arterial or venous thromboembolism (ATE or VTE) compared with no use.
The risk of ATE/VTE with Ryeqo has not been established. Ryeqo contains doses of estrogen and progestogen lower than the doses used in combined hormonal contraceptives and are provided in combination with relugolix, a gonadotropin-releasing hormone (GnRH) receptor antagonist that suppresses ovarian production of estrogen and progesterone. Estradiol levels with Ryeqo are in the range observed in the early follicular phase of the menstrual cycle (see Section 5.1 Pharmacodynamic Properties).
If an ATE/VTE occurs, treatment must be discontinued immediately. Ryeqo is contraindicated in women with past or present venous or arterial thromboembolic disease (see Section 4.3 Contraindications).

Risk factors for venous thromboembolism (VTE).

The risk for venous thromboembolic complications in women using a product with an estrogen and progestogen may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see Table 1).

The increased risk of thromboembolism in pregnancy, and particularly the 6-week period of the puerperium, must be considered (for information on "Pregnancy and lactation" (see Section 4.6 Fertility, Pregnancy and Lactation)).

Symptoms of VTE (deep vein thrombosis and pulmonary embolism).

In the event of symptoms, women must be advised to get urgent medical attention and to inform the physician that she is taking Ryeqo.
Symptoms of deep vein thrombosis (DVT) can include:
unilateral swelling of the leg and/or foot or along a vein in the leg;
pain or tenderness in the leg which may be felt only when standing or walking;
increased warmth in the affected leg; red or discoloured skin on the leg.
Symptoms of pulmonary embolism (PE) can include:
sudden onset of unexplained shortness of breath or rapid breathing;
sudden coughing which may be associated with haemoptysis;
sharp chest pain;
severe light headedness or dizziness;
rapid or irregular heartbeat.
Some of these symptoms (e.g. "shortness of breath", "coughing") are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).

Risk factors for arterial thromboembolism (ATE).

Epidemiological studies have associated the use of estrogen/progestogen products with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (e.g. transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal.
The risk for arterial thromboembolic complications in women using a product with an estrogen and progestogen may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see Table 2).

Symptoms of ATE.

In the event of symptoms, women must be advised to get urgent medical attention and to inform the physician that she is taking Ryeqo.
Symptoms of a cerebrovascular accident can include:
sudden numbness or weakness of the face, arm or leg, especially on one side of the body;
sudden trouble walking, dizziness, loss of balance or coordination;
sudden confusion, trouble speaking or understanding;
sudden trouble seeing in one or both eyes;
sudden, severe or prolonged headache with no known cause;
loss of consciousness or fainting with or without seizure.
Temporary symptoms suggest the event is a transient ischaemic attack.
Symptoms of myocardial infarction can include:
pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone;
discomfort radiating to the back, jaw, throat, arm, stomach;
feeling of being full, having indigestion or choking;
sweating, nausea, vomiting or dizziness;
extreme weakness, anxiety, or shortness of breath;
rapid or irregular heartbeats.
Risk of bone loss. In some women treated with Ryeqo, who had normal bone mineral density (BMD) at start of treatment, a bone loss varying from > 3-8% was reported. Following an initial non-clinically relevant decrease in BMD, it stabilised after 12-24 weeks of treatment and thereafter remained stable (as measured up to 2 years). The mean decrease in BMD during the first year of treatment with Ryeqo was 0.69%. However, decreases of > 3% were seen in 21% of the patients.
Therefore, a DXA scan is recommended at baseline, after the first 52 weeks of treatment, and annually thereafter. Depending on the degree of change in BMD, the benefit and risks of Ryeqo may need to be reconsidered.
The benefits and risks of Ryeqo in patients with a history of a low trauma fracture or other risk factors for osteoporosis or bone loss, including those taking medications that may affect BMD, should be considered prior to initiating treatment. It is recommended to perform a DXA scan before commencing treatment with Ryeqo in these patients. Ryeqo should not be initiated if the risk associated with BMD loss exceeds the potential benefit of the treatment to verify that the patient does not have an unwanted degree of BMD loss, that exceeds the benefit of treatment with Ryeqo.
Liver tumours or liver disease. Ryeqo is contraindicated in women with liver tumours, benign or malignant; or liver disease as long as liver function values have not returned to normal (see Section 4.3 Contraindications). Treatment must be discontinued if jaundice develops.
In clinical trials, asymptomatic transient elevations of serum alanine aminotransferase (ALT) at least 3 times the upper limit of the reference range occurred in < 1% of participants treated with Ryeqo. Acute liver test abnormalities may necessitate the discontinuation of Ryeqo use until the liver tests return to normal.
Change in menstrual bleeding pattern. Patients must be informed that treatment with Ryeqo usually leads to a reduction in menstrual blood loss or amenorrhoea within the first 2 months of treatment.
Women receiving Ryeqo, for the treatment of uterine fibroids, were likely to have amenorrhoea (51.6%) or cyclic bleeding (15.4%), with the rest (31.9%) having an irregular bleeding pattern at the week 24 assessment. Furthermore, at the week 52 assessment 70.6% of women receiving Ryeqo were likely to have amenorrhoea. For those patients with endometriosis, the majority of patients (65.2%) are likely to have amenorrhoea at the week 24 assessment.
In case of persistent excessive bleeding, patients must notify their physician.
Contraceptive properties of Ryeqo. Ryeqo provides adequate contraception when used for at least 1 month (see Section 4.2 Dose and Method of Administration). However, women of childbearing potential must be advised that ovulation will return rapidly after discontinuing treatment. Therefore, alternative contraception needs to be started immediately after discontinuation of treatment.
Reduced ability to recognise pregnancy. Women who take Ryeqo commonly experience amenorrhoea or a reduction in the amount, intensity, or duration of menstrual bleeding.
This change in menstrual bleeding pattern may reduce the ability to recognise the occurrence of a pregnancy in a timely manner. Perform pregnancy testing if pregnancy is suspected and discontinue treatment if pregnancy is confirmed.
Uterine fibroid prolapse or expulsion. Submucosal uterine fibroids are common (15% to 20% of women with uterine fibroids) and some may prolapse through the cervix or be expelled, sometimes with transient worsening of uterine bleeding. Women known or suspected to have submucosal uterine fibroids must be advised regarding the possibility of uterine fibroid prolapse or expulsion when treated with Ryeqo and should contact their physician if severe bleeding reoccurs after bleeding symptoms have improved while being treated with Ryeqo.
Depression. Carefully observe women with a history of depression and discontinue Ryeqo if depression recurs to a serious degree. Data are limited on the association of Ryeqo or other products containing estradiol and progestins with onset of depression or exacerbation of existing depression. Women must be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.
Hypertension. Although small increases in blood pressure have been reported in women taking Ryeqo, clinically relevant increases are rare. However, if sustained clinically significant hypertension develops during the use of Ryeqo, hypertension should be treated, and the benefit of continued therapy should be assessed. If treatment with Ryeqo is discontinued, use may be resumed if normotensive values can be achieved with antihypertensive treatment.
Gallbladder disease. Conditions such as gallbladder disease, cholelithiasis and cholecystitis have been reported to occur or worsen with estrogen and progestogen use, including Ryeqo, but the evidence of an association with Ryeqo is inconclusive.
Lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Use in hepatic impairment.

See Section 4.4 Special Warnings and Precautions for Use, Liver tumours or liver disease.

Use in renal impairment.

The exposure to relugolix is increased in patients with moderate or severe renal impairment (see Section 5.2 Pharmacokinetic Properties), although no dose adjustment is required (see Section 4.2 Dose and Method of Administration). The amount of relugolix removed by haemodialysis is unknown.

Use in the elderly.

There is no relevant use of Ryeqo in the elderly population in the indications.

Paediatric use.

The safety and efficacy of Ryeqo in children and adolescents aged less than 18 years have not been established. No data are available.

Effects on laboratory tests.

The use of estrogens and progestogens may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Recommendations regarding interactions with Ryeqo are based on evaluations of interactions for the individual components.

Potential for other medicinal products to affect the components of Ryeqo.

Relugolix.

Oral P-glycoprotein (P-gp) inhibitors.

Concomitant use of Ryeqo with oral P-gp inhibitors is not recommended. Relugolix is a substrate of P-gp (see Section 5.2 Pharmacokinetic Properties) and in an interaction study with erythromycin, a P-gp and moderate cytochrome P450 (CYP) 3A4 inhibitor, the area under the curve (AUC) and maximum concentration (C_max) of relugolix were increased by 4.1-fold and 3.8-fold, respectively. Concomitant use of P-gp inhibitors may increase the exposure of relugolix, including certain anti-infective medicinal products (e.g. erythromycin, clarithromycin, gentamicin, tetracycline), anti-fungal medicinal products (ketoconazole, itraconazole), antihypertensive medicinal products (e.g. carvedilol, verapamil), antiarrhythmic medicinal products (e.g. amiodarone, propafenone, quinidine), antianginal medicinal products (e.g. ranolazine), cyclosporine, human immunodeficiency virus (HIV) or hepatitis C virus (HCV) protease inhibitors (e.g. ritonavir). If concomitant use with once or twice daily oral P-gp inhibitors is unavoidable (e.g. azithromycin), take Ryeqo first, and separate dosing with the P-gp inhibitor by at least 6 hours and monitor patients more frequently for adverse reactions.

Strong cytochrome P450 3A4 (CYP3A4) and/or P-gp inducers.

Co-administration of Ryeqo with strong CYP3A4 and/or P-gp inducers is not recommended. In a clinical interaction study with rifampicin, a strong CYP3A4 and P-gp inducer, the C_max and AUC of relugolix were reduced by 23% and 55%, respectively. Medicinal products that cause strong CYP3A4 and/or P-gp induction, such as anticonvulsants (e.g. carbamazepine, topiramate, phenytoin, phenobarbital, primidone, oxcarbazepine), anti-infective medicinal products (e.g. rifampicin, rifabutin, griseofulvin); St. John's wort (Hypericum perforatum); bosentan and HIV or HCV protease inhibitors (e.g. ritonavir,) and non-nucleoside reverse transcriptase inhibitors (e.g. efavirenz), may reduce the plasma concentrations of relugolix and may result in a decrease in therapeutic effects.

CYP3A4 inhibitors.

Concomitant use of relugolix with strong CYP3A4 inhibitors devoid of P-gp inhibition (voriconazole) did not increase the exposure of relugolix in a clinically meaningful manner. Furthermore, in a clinical interaction study, concomitant administration with atorvastatin, a weak CYP3A4 enzyme inhibitor, did not change the exposure of relugolix in a clinically meaningful manner.
Estradiol and norethisterone acetate.

CYP3A4 inhibitors.

Medicinal products that inhibit the activity of hepatic drug-metabolising enzymes, e.g. ketoconazole, may increase circulating concentrations of the estrogen and norethisterone components in Ryeqo.

CYP enzyme inducers.

The metabolism of estrogens and progestogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).
Ritonavir and nelfinavir, although known as strong inhibitors, are also inducers and may decrease the exposure of estrogens and progestogens.
Herbal preparations containing St John's Wort (Hypericum perforatum) may induce the metabolism of estrogens and progestogens. Clinically, an increase in estrogen metabolism may lead to decreased effectiveness with regard to protection of bone loss. Therefore, long-term concomitant use of liver enzyme inducers with Ryeqo is not recommended.

Potential for the components of Ryeqo to affect other medicinal products.

Relugolix.

Relugolix is a weak inducer of CYP3A4. After co-administration with daily 40 mg doses of relugolix, the AUC and C_max of midazolam, a sensitive CYP3A4 substrate, were decreased by 18% and 26%, respectively. However, based on the clinical study with midazolam, clinically meaningful effects of relugolix on other CYP3A4 substrates are not expected.
Relugolix is an inhibitor of breast cancer resistant protein (BCRP) in vitro, therefore, an interaction study was conducted with rosuvastatin, a BCRP and organic anion transporting polypeptide 1B1 (OATP1B1) substrate. After coadministration with daily 40 mg doses of relugolix, the AUC and C_max of rosuvastatin were decreased by 13% and 23%, respectively. The effects are not considered clinically meaningful and therefore no dose adjustments of rosuvastatin upon concomitant use are recommended. Clinical effects of Ryeqo on other BCRP substrates have not been evaluated and the relevance for other BCRP substrates is unknown.
Relugolix may cause saturation of intestinal P-gp at the 40 mg dose, as relugolix exhibits more than dose proportional pharmacokinetics over the dose range of 10-120 mg, which could result in increased absorption of co-administered medicines that are sensitive substrates of P-gp. No clinically significant differences in the pharmacokinetics of dabigatran etexilate (P-gp substrate) were observed upon co-administration with relugolix, clinically meaningful effects of relugolix on other P-gp substrates are not expected.

Estradiol and norethisterone acetate.

Estrogen and progestogen medicinal products may affect the metabolism of certain other active substances. Accordingly, plasma concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine) with use of Ryeqo. Dose adjustment of these medicinal products may be necessary.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Ryeqo inhibits ovulation and often causes amenorrhoea. Ovulation and menstrual bleeding will return rapidly after discontinuing treatment. There are no data on fertility following treatment with Ryeqo in women with endometriosis (see Section 5.1 Pharmacodynamic Properties).
Ryeqo inhibits ovulation in women taking the recommended dose and provides adequate contraception. A nonhormonal contraceptive method is recommended for use for 1 month after initiation of treatment and for 7 days following 2 or more missed consecutive doses. Concomitant use of hormonal contraceptives is contraindicated (see Section 4.3 Contraindications).
Women of childbearing potential must be advised that ovulation will return rapidly after discontinuing Ryeqo. A discussion with the patient, regarding appropriate contraceptive methods, must therefore take place prior to discontinuing treatment and alternative contraception needs to be started immediately after discontinuation of treatment (see Section 4.4 Special Warnings and Precautions for Use).
In a fertility and early embryonic development study in rats, oral administration of relugolix at doses up to 1000 mg/kg/day had no adverse effects on fertility, mating or early embryonic development. However, the binding affinity of relugolix for rat GnRH receptors is greater than 1000-fold less than for human GnRH, and the rat study only assessed non-pharmacological effects of relugolix. In a 39-week study in monkeys, relugolix did not induce toxicities in male reproductive organs but caused reversible decreases in ovary weight and corpora lutea in females at ≥ 5 mg/kg/day and decreased frequency of menses at 50 mg/kg/day (14 and 179 times the clinical exposure at the recommended clinical dose of 40 mg daily, based on AUC, respectively). In human GnRH-receptor knock-in mice, administration of relugolix at oral doses of ≥ 100 mg/kg twice daily to female mice induced a constant diestrus phase and decreased ovarian and uterine weights, which were reversible following cessation of treatment. In male knock-in mice, oral administration of relugolix decreased prostate and seminal vesicle weights at doses ≥ 3 mg/kg twice daily, which were reversible except for testis weight (not fully recovered in 28 days).
(Category D)
There is a limited amount of data from the use of relugolix in pregnant women. Studies in animals have shown that exposure to relugolix early in pregnancy may increase the risk of early pregnancy loss. Based on the pharmacological effects, an adverse effect on pregnancy cannot be excluded.
Ryeqo is contraindicated during pregnancy (see Section 4.3 Contraindications). Discontinue use of treatment if pregnancy occurs.
There appears to be little or no increased risk of harmful effects in children born to women who have used estrogens and progestogens as an oral contraceptive inadvertently during early pregnancy. The increased risk of VTE during the postpartum period must be considered when restarting Ryeqo (see Section 4.4 Special Warnings and Precautions for Use).
In an embryo-foetal development study in rabbits, oral administration of relugolix to pregnant rabbits during the period of organogenesis resulted in total litter loss and decreased number of live foetuses at 9 mg/kg/day (with an exposure comparable with the human exposure at the recommended clinical dose of 40 mg daily, based on AUC). No treatment related malformations were observed in surviving foetuses. No treatment related effects were observed at 3 mg/kg/day (about 0.2-fold the human exposure) or lower. The binding affinity of relugolix for rabbit GnRH receptors is unknown, although the affinity is likely greater in rabbits than in rats.
In a similar embryo-foetal development study in rats, oral administration of relugolix to pregnant rats during the period of organogenesis did not affect embryofetal development at up to 1,000 mg/kg/day (> 700 times the human exposure), a dose at which maternal toxicity (decreased body weight gain and food consumption) was observed. Since the binding affinity of relugolix for the rat GnRH receptor is more than 1,000-fold less than in humans, the rat is a pharmacologically unresponsive model, and the study represented an assessment of non-pharmacological targets of relugolix during pregnancy.
In animal studies, maternal administration of high doses of estrogens has produced urogenital malformations in the offspring. The relevance of these animal findings for the clinical use of estradiol is uncertain, but is considered likely to be low. Animal studies have also shown that high doses of progestogens can cause masculinisation of the female foetus.
Results from nonclinical studies indicate that relugolix is excreted into the milk of lactating rats. No data are available regarding the presence of relugolix or its metabolites in human milk or its effect on the breastfed infant. Detectable amounts of estrogen and progestogens have been identified in the breast milk of women receiving estrogen plus progestogen therapy. An effect on breastfeeding newborns/infants cannot be excluded.
Breastfeeding is contraindicated during the use of Ryeqo (see Section 4.3 Contraindications) and for 2 weeks following discontinuation of Ryeqo.
In lactating rats administered a single oral dose of 30 mg/kg radiolabelled relugolix on post-partum day 14, relugolix and/or its metabolites were present in milk at concentrations up to 10-fold higher than in plasma at 2 hours post-dose decreasing to low levels by 48 hours post-dose. The majority of relugolix-derived radioactivity in milk consisted of unchanged relugolix.

4.7 Effects on Ability to Drive and Use Machines

Ryeqo has no or negligible influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The most frequent adverse drug reactions in patients being treated for uterine fibroids were hot flush (8.3%) and uterine bleeding (4.7%). For those patients being treated for endometriosis, the most common adverse drug reactions were headache (17.0%) and hot flush (11.7%).
Adverse drug reactions listed in Table 3 and Table 4 are classified according to frequency and system organ class. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. 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), very rare (< 1/10,000), and not known (cannot be estimated from available data).
Tabulated list of adverse drug reactions in patients with uterine fibroids (see Table 3).

Tabulated list of adverse drug reactions in patients with endometriosis (see Table 4).

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

Single doses of relugolix up to 360 mg (9 times the recommended clinical dose of 40 mg) have been administered to healthy men and women and were generally well tolerated.
Overdoses up to 2 times the recommended dose have been reported during the clinical development of relugolix in combination with estradiol and norethisterone acetate without reports of adverse events.
Supportive care is recommended if an overdose occurs. The amount of relugolix, estradiol or norethisterone removed by haemodialysis is unknown.
Serious ill effects have not been reported following acute ingestion of large doses of estrogen containing drug products by young children. Overdose of estradiol and norethisterone acetate may cause nausea and vomiting, and withdrawal bleeding may occur in women.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, anti-gonadotrophin-releasing hormones:
ATC code: H01CC54

Mechanism of action.

Relugolix is a non-peptide GnRH receptor antagonist that binds to and inhibits GnRH receptors in the anterior pituitary gland. In humans, inhibition of GnRH receptor results in a dose dependent decrease in the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. As a result, circulating concentrations of LH and FSH are reduced. The reduction in FSH concentrations prevents follicular growth and development, thereby reducing the production of estrogen. Prevention of an LH surge inhibits ovulation and development of the corpus luteum, which precludes the production of progesterone. Therefore, Ryeqo provides adequate contraception when taken for at least 1 month (see Section 4.2 Dose and Method of Administration).
Estradiol is the same as the endogenously produced hormone and is a potent agonist of the nuclear estrogen receptor (ER) subtypes. Exogenously administered estradiol alleviates symptoms associated with a hypoestrogenic state, such as vasomotor symptoms and bone mineral density loss.
Norethisterone acetate is a synthetic progestogen. As estrogens promote the growth of the endometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen reduces the estrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Clinical trials.

Effects on pituitary and ovarian hormones. After administration of relugolix, rapid, dose-dependent decreases in circulating concentrations of LH, FSH, and estradiol are observed. Near maximum decreases in estradiol concentrations is noted with a 40 mg dose to within the postmenopausal range. Across clinical studies, average estradiol concentrations were consistently maintained at least 10 picogram/mL higher with Ryeqo compared with relugolix alone. In the phase 3 clinical studies, in patients with uterine fibroids, with Ryeqo, median estradiol pre-dose concentrations after 24 weeks were approximately 33 picogram/mL, and in those with endometriosis were approximately 38 picogram/mL corresponding with estradiol concentrations associated with the early follicular phase of the menstrual cycle. Progesterone levels in both populations were maintained at < 3.0 nanogram/mL with Ryeqo.
Effects on ovulatory function. In a single cohort study in healthy premenopausal women, administration of Ryeqo once daily for 84 days substantially suppressed follicular growth throughout the 84-day treatment period (mean dominant follicle size of approximately 6 mm) and ovulation was inhibited in 100% of women as assessed by the Hoogland Skouby score. After discontinuation of treatment, all women assessed (66 of 67) returned to ovulation within 43 days (mean 23.5 days).
Uterine fibroids.

Efficacy and safety over 24 weeks.

The efficacy and safety of Ryeqo once daily in patients with uterine fibroids was assessed in two replicate, 24 week, multinational, randomised, double blind, placebo-controlled studies in patients aged 18-50 with heavy menstrual bleeding associated with uterine fibroids (studies L1 and L2). Patients were required to have uterine fibroids confirmed by ultrasound and menstrual blood loss (MBL) volume of ≥ 80 mL, as assessed by the alkaline hematin method.
Both studies had 3 treatment groups: Women were randomised to receive relugolix 40 mg + estradiol 1 mg and norethisterone acetate 0.5 mg (E2/NETA) (Ryeqo) for 24 weeks, or placebo for 24 weeks, or relugolix 40 mg for 12 weeks followed by relugolix 40 mg co-administered with E2/NETA for 12 weeks. The median age of women was 42 years, and mean body mass index was 31.7 kg/m². Approximately 49.4% of women were Black, 44.7% were White, and 5.9% were of other races.

Reduction in heavy menstrual bleeding.

In both studies, a statistically significant higher percentage of responders, defined as MBL volume of < 80 mL and at least a 50% reduction from baseline in MBL volume, was observed in favour of women treated with Ryeqo compared with placebo (Table 5). Reductions in MBL volume were seen as early as the first assessment (week 4). The results for other secondary endpoints related to bleeding are as shown in Table 5. All key secondary endpoints were alpha controlled.

Bone mineral density (BMD) measurements over 104 weeks.

The effect of Ryeqo on BMD was evaluated by DXA every 12 weeks. A total of 477 women who completed the 24-week pivotal studies (Study L1 and L2) were enrolled into a 28 week, open-label, single arm extension study (Study L3), where all women received Ryeqo. A total of 228 women who completed the extension study were enrolled into an additional 52-week study (randomised withdrawal study) where they were re-randomised to receive either Ryeqo or placebo (see Table 6).

In the Ryeqo group, LS mean percent changes from baseline in BMD to week 36 and week 52 at the lumbar spine were -0.73% and -0.80%, respectively. While the upper bound of the 95% CI for week was below 0, the mean change from baseline was not considered clinically meaningful because the lower bound remained greater than -2.2%, the threshold considered clinically meaningful. The placebo group who subsequently received Ryeqo after 24 weeks of placebo treatment showed similar percent change in BMD, from baseline at the lumbar spine. During the randomised withdrawal study the LS mean percent change from the week 52 assessment in the Ryeqo group was 0.81%, whilst for those patients who completed 104 weeks of Ryeqo treatment the LS mean percent change from baseline was 0.04% (n = 32).

BMD measurements over 12 weeks in women with uterine fibroids treated with relugolix monotherapy.

In women treated with relugolix monotherapy for 12 weeks, in studies L1 and L2, BMD at the lumbar spine decreased by 2.0% and 1.92%, respectively from baseline. The difference in percent change in BMD between women treated with Ryeqo and relugolix monotherapy at week 12 was statistically significant, demonstrating the effectiveness of using relugolix in combination with E2/NETA (Ryeqo) to mitigate bone loss.
To compare effects of Ryeqo on percent change in BMD over 52 weeks treatment, an observational study of untreated age matched women with uterine fibroids was conducted to characterise longitudinal BMD of premenopausal women aged 18 to 50 years (natural history study). The percentage changes in BMD with Ryeqo for up to 52 weeks of treatment are consistent with those observed in this age-matched cohort of premenopausal women with uterine fibroids. Mean percent changes in BMD over 52 weeks indicated a slight decrease in BMD in age groups of 35 and older which was only slightly lower in women who received Ryeqo in comparison to women of this age group in the natural history study.

Effects on endometrium.

A subset of women underwent endometrial biopsy at baseline and at week 24 and at week 52. No cases of endometrial hyperplasia were identified in women with uterine fibroids.
Endometriosis.

Efficacy and safety over 24 weeks.

The efficacy and safety of Ryeqo once daily, in patients with endometriosis was assessed in two replicate, 24-week, multinational, randomised, double-blind, placebo-controlled studies in patients aged 18-50 with moderate to severe pain associated with endometriosis (Studies S1 and S2). Patients were required to have endometriosis confirmed by direct visualisation during surgery and/or histological confirmation and were required to have moderate to severe pain as assessed based on an 11-point numerical rating scale (NRS).
Both studies had three treatment arms: women were randomised to receive relugolix 40 mg + estradiol 1 mg and norethisterone acetate 0.5 mg (E2/NETA) (Ryeqo) for 24 weeks, or placebo for 24 weeks, or relugolix 40 mg for 12 weeks followed by relugolix 40 mg co-administered with E2/NETA for 12 weeks. Patients were eligible for inclusion if they had moderate to severe pain before the screening period until after the run-in period (i.e. at least two cycles). A high percentage (83.2%) of the study population of Studies S1 and S2 reported having undergone previous surgeries/procedures for endometriosis treatment. A low percentage (8%) of the study population did not report previous surgical or medical treatment before inclusion into the studies. At baseline, most patients (92.6%) used analgesics for pelvic pain, including 29.1% of patients in Study S1 and 48.4% of patients in Study S2 who used opioids. The most frequently reported other pharmacotherapies for endometriosis included dienogest (19.4%), estrogen progestin oral contraceptive (15.2%) and GnRH agonists (7.6%). The median age of women was 34 years, and mean body mass index was 26 kg/m². Approximately 91% of women were White, 6% were Black, and 3% were of other races.

Reduction in pain.

Studies S1 and S2 had two co-primary endpoints. The first co-primary endpoint was a responder analysis where a responder was defined as a woman who achieved a reduction from baseline in dysmenorrhea (DYS) NRS of at least 2.8 points over the last 35 days of treatment, without an increase in analgesic use (nonsteroidal anti-inflammatory drug or opioid). The second co-primary endpoint was a responder analysis where a responder was defined as a woman who achieved a reduction from baseline in non-menstrual pelvic pain (NMPP) NRS score of at least 2.1 points over the last 35 days of treatment, without an increase in analgesic use (nonsteroidal anti-inflammatory drug or opioid) for pain associated with endometriosis.
In both studies (S1 and S2), a statistically significant higher percentage of responders was observed in favour of women treated with Ryeqo compared with placebo (see Table 7).

Key secondary efficacy endpoints included changes from baseline in the Endometriosis Health Profile-30 (EHP-30) pain domain scores (a measure of the effect of pain on daily activities), dysmenorrhea NRS scores, NMPP NRS scores, dyspareunia NRS scores and opioid use. The results for the key secondary endpoints were generally similar between studies demonstrating statistically significant differences compared with placebo (see Table 8). All key secondary endpoints were alpha controlled.

Efficacy over 104 weeks.

Upon completion of the 24-week Studies S1 and S2, eligible participants could enroll in an 80-week, open-label, single-arm extension study (S3), where all women received Ryeqo. The primary efficacy endpoints for study S3 were defined in a manner analogous to the co-primary endpoints for Studies S1 and S2. For women originally randomised to Ryeqo in Studies S1 and S2, the reduction in dysmenorrhea and NMPP NRS scores were maintained for up to 104 weeks, whereas for women who were originally randomised to placebo, a reduction in their endometriosis-associated pain was observed after receiving Ryeqo during Study S3 (see Table 9).

Bone mineral density (BMD) measurements over 104 weeks.

The effect of Ryeqo on BMD was evaluated by DXA every 12 weeks. A total of 802 women who completed the 24-week pivotal studies (Study S1 and S2) were enrolled into the extension study (Study S3), where all patients received Ryeqo (see Table 10).

In the Ryeqo group, LS mean percent changes from baseline in BMD to week 52 and week 104 at the lumbar spine were -0.69% and -0.45%, respectively. In the placebo group (received placebo for 24 weeks followed by Ryeqo for 80 weeks) LS mean percent changes from baseline in BMD to week 52 and week 104 at the lumbar spine were -0.09% and -0.09%, respectively.
To compare effects of Ryeqo on percent change in BMD over 52 weeks treatment, an observational study of untreated age-matched women with endometriosis was conducted to characterise longitudinal BMD of premenopausal women aged 18-50 years (natural history study). Through 52 weeks of observation, there was minimal change in BMD with Ryeqo compared with those in an age-matched cohort of premenopausal women with endometriosis.

Effects on endometrium.

In the pivotal studies, no cases of endometrial hyperplasia or endometrial carcinoma assessed by biopsy were observed in women treated with Ryeqo for up to 52 weeks.

5.2 Pharmacokinetic Properties

The pharmacokinetic parameters of relugolix, estradiol (E2), total estrone (E1), and norethisterone (NET) following oral administration of a single Ryeqo tablet to healthy postmenopausal women under fasted conditions are summarized in Table 11.
The pharmacokinetic parameters of relugolix, estradiol (E2), total estrone (E1), and norethisterone (NET) at steady state after once daily administration of Ryeqo for 6 weeks to healthy premenopausal women are summarized in Table 12.

Absorption.

The absorption of relugolix after oral administration is primarily mediated by the P-gp efflux transporter, for which relugolix is a substrate. After oral administration, relugolix is rapidly absorbed, reaching an initial peak by 0.25 hours post dose followed by one or more subsequent absorption peaks through up to 12 hours post dose. The absolute bioavailability of relugolix is 11.6%. After administration of Ryeqo with a high fat, high-calorie meal, the AUC_0-∞ and C_max of relugolix were decreased by 38% and 55%, respectively, compared with the fasted state.
After oral administration of a single dose of Ryeqo in the fasted state, unconjugated estradiol concentrations increased slowly with mean concentrations reaching peak concentrations at 8 hours post dose. After administration of Ryeqo following consumption of a high-fat, high-calorie meal, no clinically meaningful effects of food on the exposure to estradiol or estrogenic metabolites were observed.
After oral administration, norethisterone acetate undergoes rapid biotransformation in the intestine and liver to norethisterone (NET). After oral administration of a single dose of Ryeqo in the fasted state, NET concentrations were initially quantifiable at 0.5 hours post dose, increasing rapidly thereafter with mean concentrations reaching peak concentrations within 1 hour.

Food effects.

Administration with food reduced the AUC and C_max of relugolix by 38% and 55%, respectively, relative to fasted conditions; however, the decrease in exposure to relugolix is considered not to be clinically meaningful. No clinically meaningful effects of food on the exposure to estradiol, estrogenic metabolites, or norethisterone were observed.

Distribution.

Relugolix is 68% to 71% bound to human plasma proteins with a mean whole blood-to-plasma ratio of 0.78. Estradiol and norethisterone circulating in the blood bind to a similar extent to sex hormone-binding globulin (SHBG; 36% to 37%) and to albumin (61%), while only approximately 1-2% are unbound. The value for apparent volume of distribution (Vz) of 19 x 10³ L derived from the absolute bioavailability study after intravenous administration indicates that relugolix distributes widely into tissues. The distribution of exogenous and endogenous estradiol is similar. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs.

Metabolism.

In vitro studies indicate that the primary CYP enzymes contributing to the overall hepatic oxidative metabolism of relugolix were CYP3A4/5 (45%) > CYP2C8 (37%) > CYP2C19 (< 1%) with the oxidative metabolites, metabolite A and metabolite B, formed by CYP3A4/5 and CYP2C8, respectively.
The metabolism of exogenous and endogenous estradiol is similar. Metabolism of estradiol occurs mainly in the liver and the gut but also in target organs and involves the formation of less active or inactive metabolites, including estrone, catechol estrogens and several estrogen sulphates and glucuronides. Estrogens are excreted with the bile, hydrolysed, and reabsorbed (enterohepatic circulation), and mainly eliminated in urine in biologically inactive form. Oxidation of estrone and estradiol involves cytochrome P450 enzymes, mainly CYP1A2, CYP1A2 (extra hepatic), CYP3A4, CYP3A5, and CYP1B1 and CYP2C9.
The most important metabolites of norethisterone are isomers of 5-alpha-dihydro-norethisterone and of tetrahydro-norethisterone, which are excreted mainly in the urine as sulphate or glucuronide conjugates.

Excretion.

Once absorbed, approximately 20% of relugolix is eliminated as unchanged active substance in the urine and 80% is eliminated through metabolism by multiple minor metabolic pathways and/or biliary secretion of unchanged active substance. Approximately 38% of the administered dose is excreted as metabolites (other than metabolite C) in the faeces and urine. Metabolite C, which is formed by intestinal microflora, is the primary metabolite in faeces (51%) and further reflects non absorbed active substance.
The mean terminal phase elimination half-life (t_1/2) of relugolix, estradiol, and norethisterone following single dose administration of the Ryeqo tablet are 61.5 hours, 16.6 hours, and 10.9 hours, respectively. Steady state of relugolix is reached after 12 to 13 days of once daily administration. The degree of accumulation of relugolix upon once daily administration is approximately 2-fold, reflecting an effective half-life of approximately 25 hours and supporting once daily administration of relugolix.
The accumulation for E2 and NET upon once daily administration are reported to be 33% to 47%, although when coadministered with relugolix, a weak inducer of intestinal (presystemic) CYP3A mediated metabolism, the accumulation for E2 is expected to be similar or slightly lower.

Linearity/nonlinearity.

Relugolix is associated with greater than proportional increases in exposure with respect to dose, within the dose range from 1 to 80 mg, which is most pronounced at doses greater than 20 mg; and thought to be related to the saturation of intestinal P-gp, resulting in an increase in oral bioavailability.
The pharmacokinetics of relugolix upon once daily administration of 40 mg relugolix is time independent.

Special populations.

The single dose pharmacokinetic parameters were not different between Japanese and Caucasian healthy subjects, indicating absence of ethnic sensitivity on the pharmacokinetics of relugolix. Population PK analysis suggests that there are no clinically meaningful differences in exposure of relugolix based on age, race or ethnicity, weight, or BMI. As both estradiol and norethisterone acetate are well known components of hormonal combination products, no studies in special populations were conducted.