RYEQO

Italy
Brand name RYEQO
Form tablets, film-coated
Active substance / Dosage
ESTRADIOL HEMIHYDRATE
NORETHISTERONE ACETATE
RELUGOLIX
Prescription type Restricted prescription – dispensable on hospital or specialist prescription
ATC code
H01CC54
Registration number 049616
Manufacturer GEDEON RICHTER PLC
RYEQO tablets, film-coated

Table of Contents

Package leaflet: Information for the user

Ryeqo 40 mg/1 mg/0.5 mg film-coated tablets

relugolix/estradiol/norethisterone acetate
This medicinal product is subject to additional monitoring. This will allow for rapid identification of new safety information. You can help by reporting any side effects you experience while taking this medicine. See the end of section 4 for information on how to report side effects.
Please read all of this leaflet carefully before you start taking this medicine, as it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
  • If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. See section 4.

Contents of this leaflet

  1. What Ryeqo is and what it is used for
  2. What you need to know before taking Ryeqo
  3. How to take Ryeqo
  4. Possible side effects
  5. How to store Ryeqo
  6. Contents of the pack and other information

1. What Ryeqo is and what it is used for

Ryeqo contains the active substances relugolix, estradiol and noretisterone acetate.
It is used to treat

  • moderate to severe symptoms of uterine fibroids (commonly known as fibroids), which are non-cancerous tumours of the uterus.
  • symptoms associated with endometriosis in women with a clinical history of previous pharmacological or surgical treatment for their endometriosis (endometriosis is a frequently painful disorder in which tissue similar to the tissue that normally lines the inside of the uterus – the endometrium – grows outside the uterus).

Ryeqo is used in adult women (over 18 years of age) before they reach menopause.
In some women, uterine fibroids can cause heavy menstrual bleeding (periods) and pelvic pain (pain below the navel). Ryeqo is used to treat fibroids to stop or reduce bleeding and to reduce pelvic pain and discomfort associated with uterine fibroids.
Women with endometriosis may experience pelvic or lower abdominal pain, pain during menstruation and pain during sexual intercourse. Ryeqo is used to treat endometriosis to reduce symptoms caused by the presence of uterine lining tissue growing outside its normal location.
This medicine contains relugolix, which blocks certain receptors in the brain, thereby reducing the production of hormones that stimulate the ovaries to produce estradiol and progesterone.
When these receptors are blocked, the levels of estrogen and progesterone circulating in the body are reduced. This medicine also contains two types of female hormones: estradiol, which belongs to a group of medicines called estrogens, and noretisterone, which belongs to a group of medicines called progestogens. The inclusion of these hormones in Ryeqo maintains a hormonal state similar to the early phase of the menstrual cycle, thus relieving symptoms while also helping to protect bone strength.

2. What you should know before taking Ryeqo

Do not take Ryeqo
Do not take Ryeqo if you have any of the conditions listed below.
If you have any of the conditions listed below, inform your doctor:

  • if you are allergic to relugolix, estradiol, norethisterone acetate, or any of the other components of this medicine (listed in section 6);
  • if you have or have previously had a blood clot in a blood vessel in your legs (deep vein thrombosis), lungs (pulmonary embolism), heart (heart attack), brain (stroke), or other parts of the body;
  • if you have or have previously had an arterial disease caused by blood clots, such as heart attack, stroke, or angina;
  • if you have a blood clotting disorder (such as protein C deficiency, protein S deficiency, antithrombin-III deficiency, or factor V Leiden);
  • if you suffer from osteoporosis;
  • if you suffer from headache with focal neurological symptoms such as paralysis or loss of muscle control, or migraine with visual disturbances;
  • if you have any type of tumour that could worsen due to exposure to female sex hormones, such as breast cancer or genital organ cancer;
  • if you have or have ever had liver tumours;
  • if you have or have ever had a liver disease and liver function tests have not returned to normal;
  • if you are pregnant, think you might be pregnant, or are breastfeeding;
  • if you have genital bleeding of unknown origin;
  • if you are taking hormonal contraceptives (e.g. contraceptive pill) and do not wish to discontinue their use.

If any of the above conditions occurs for the first time while taking Ryeqo,
stop treatment with Ryeqo immediately and consult your doctor without delay.
If you are unsure whether any of the conditions listed above apply to you, consult your doctor before
taking Ryeqo.
Warnings and precautions
Talk to your doctor or pharmacist before taking Ryeqo.
You should know that most women experience reduced or absent menstrual bleeding during
treatment and for several weeks after stopping it.
Your doctor will discuss your personal and family medical history with you. Your doctor will also check
your blood pressure and ensure you are not pregnant. You may also need a physical examination and additional tests, such as a breast examination and a scan to assess bone strength, tailored to your individual medical needs and concerns.
Stop taking Ryeqo and contact a doctor urgently if you notice:

  • any of the conditions mentioned in the section “Do not take Ryeqo”;
  • signs of liver disease:
  • yellowing of the skin or whites of the eyes (jaundice);
  • nausea or vomiting, fever, severe fatigue;
  • dark urine, itching, or upper abdominal pain;
  • a marked increase in blood pressure (symptoms may include headache, fatigue, dizziness);
  • migraine for the first time or unusually severe headache that occurs more frequently than before;
  • possible signs of a blood clot, which could indicate a clot in the leg (deep vein thrombosis) or lung (pulmonary embolism), heart attack, or stroke. For a description of symptoms of these serious conditions, see the section “Ryeqo and the risk of blood clots”.
  • If you become pregnant.

Inform 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 suffer from osteoporosis;
  • if you suffer from migraine;
  • if you think you might be pregnant. Treatment with Ryeqo usually leads to a significant reduction or cessation of menstrual bleeding (“period”), making it difficult to recognize pregnancy.
  • if you suffer or have previously suffered from depression;
  • if you have renal impairment.

Ryeqo and the risk of blood clots
The use of other medicines containing an oestrogen and a progestogen increases the risk of blood clots. The risk of blood clots associated with Ryeqo has not been established. Ryeqo reduces oestrogen levels to those similar to the beginning of a normal menstrual cycle.
Factors that may increase the risk of blood clots in a vein and/or an artery:

  • ageing (especially after age 35);
  • overweight (body mass index >30 kg/m²);
  • if you have had major surgery or prolonged immobility (e.g. leg in plaster);
  • recent childbirth;
  • a close family member who had a blood clot in the leg, lung, or another organ, a heart attack, or a stroke at a young age (e.g. before age 50);
  • if you are a smoker;
  • heart problems ( valve disorders, a heart rhythm disorder called atrial fibrillation);
  • diabetes;
  • certain diseases such as systemic lupus erythematosus (SLE – a disease affecting the natural defence system), sickle cell anaemia (an inherited disease affecting red blood cells), Crohn’s disease or ulcerative colitis (chronic inflammatory bowel diseases), or cancer.

The risk of developing a blood clot increases with the number of risk factors present.
Symptoms of a blood clot depend on where the clot has formed.
Symptoms of a blood clot in a leg ( deep vein thrombosis, DVT )
Symptoms of a blood clot in a leg, known as deep vein thrombosis (DVT), may include:

  • swelling of the leg and/or foot or along a vein in the leg;
  • pain or tenderness in the leg, which may only be felt when standing or walking;
  • increased warmth in the affected leg, with red or discoloured skin.

Symptoms of a blood clot in a lung ( pulmonary embolism, PE )
Symptoms of a blood clot in a lung, known as pulmonary embolism (PE), may include:

  • sudden and unexplained shortness of breath and rapid breathing;
  • sudden cough, possibly associated with sharp chest pain;
  • coughing up blood;
  • severe dizziness or lightheadedness;
  • rapid or irregular heartbeat.

Symptoms of a heart attack
Symptoms of a heart attack, also known as myocardial infarction, may be temporary and can include:

  • pain, discomfort, pressure, heaviness, crushing sensation, or fullness in the chest, arm, or below the breastbone;
  • discomfort radiating to the back, jaw, throat, arm, or stomach;
  • feeling of fullness, indigestion, or choking;
  • sweating, nausea, vomiting, or dizziness;
  • extreme weakness, anxiety, or shortness of breath;
  • rapid or irregular heartbeat.

Symptoms of a stroke
Symptoms of a stroke may include:

  • sudden numbness or weakness of the face, arm, or leg, especially on one side of the body;
  • sudden difficulty walking, dizziness, loss of balance or coordination;
  • sudden confusion, difficulty speaking or understanding speech;
  • sudden difficulty seeing with one or both eyes;
  • sudden severe or prolonged headache with no known cause;
  • loss of consciousness or fainting, with or without seizures.

Surgery
If you are scheduled for surgery, inform your doctor that you are taking Ryeqo.
Liver tumours or liver disease
In rare cases, liver tumours or liver disease have been reported in women taking oestrogens and progestogens. If you experience symptoms of jaundice, consult your doctor for advice.
Renal impairment (kidney)
If you notice a decrease in urine production or fluid retention causing swelling in your legs, ankles, or feet, consult your doctor for advice.
Changes in menstrual bleeding (“period”)
Treatment with Ryeqo usually leads to a significant reduction or cessation of menstrual bleeding (“period”) within the first 30 days of treatment. However, if you continue to experience excessive bleeding, consult your doctor.
Depression
If you experience mood changes or symptoms of depression, consult your doctor for advice.
Hypertension
In rare cases, treatment with Ryeqo may lead to small increases in blood pressure. If you experience symptoms of increased blood pressure, consult your doctor for advice.
Uterine fibroid prolapse and expulsion
Uterine fibroids can develop anywhere within the muscular wall of the uterus, including the submucosal layer, a thin tissue layer of the uterus. In some women, a uterine fibroid may protrude or slip through the cervix into the vagina, causing a significant worsening of uterine bleeding or pain. If you experience a recurrence of heavy uterine bleeding after an improvement in symptoms during treatment with Ryeqo, consult your doctor for advice.
Gallbladder disorders
Some women taking oestrogens and progestogens, including Ryeqo, have reported gallbladder disorders (gallstones or gallbladder inflammation). If you experience unusually severe pain below the ribcage or in the upper abdomen, contact your doctor for advice.
Children and adolescents
Ryeqo must not be taken by girls under 18 years of age, as the safety and efficacy of Ryeqo have not been established in this age group.
Other medicines and Ryeqo
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
Consult your doctor if you are taking any of the following medicines, as they may affect Ryeqo or be affected by Ryeqo:

  • Some medicines used to treat epilepsy (e.g. carbamazepine, topiramate, phenytoin, phenobarbital, primidone, oxcarbazepine, felbamate).
  • Some medicines used to treat HIV/AIDS virus infection (e.g. ritonavir, efavirenz).
  • Some medicines used to treat hepatitis C virus (HCV) (e.g. boceprevir, sofosbuvir, velpatasvir, voxilaprevir, telaprevir, glecaprevir).
  • Some medicines used to treat fungal infections (e.g. ketoconazole, itraconazole, fluconazole, griseofulvina).
  • Some medicines used to treat bacterial infections (e.g. rifampicin, rifabutin, clarithromycin, erythromycin, gentamicin, tetracycline, griseofulvina).
  • Some medicines used to treat pulmonary arterial hypertension (e.g. bosentan).
  • Some medicines used to treat hypertension (e.g. diltiazem, carvedilol, verapamil).
  • Some medicines used to treat irregular heartbeats (e.g. amiodarone, dronedarone, propafenone, quinidine, verapamil).
  • Some medicines used to treat angina (e.g. ranolazine, carvedilol, verapamil).
  • Some medicines used to prevent organ rejection after transplantation (e.g. ciclosporina).
  • St John’s wort or hypericum ( Hypericum perforatum ).

Pregnancy and breastfeeding
Do not take Ryeqo if you are pregnant or breastfeeding. If you suspect or are planning a pregnancy, consult your doctor before taking this medicine. If you become pregnant, stop taking Ryeqo and contact your doctor.
Ryeqo suppresses ovulation, so it is unlikely that you will become pregnant while taking it as directed. Ovulation and menstrual bleeding will return rapidly after stopping Ryeqo, and you will need to start an alternative method of birth control (contraception) immediately after stopping Ryeqo.
Depending on the point in your cycle when you start taking Ryeqo, it may take some time to achieve full ovulation suppression; therefore, you must use a non-hormonal contraceptive method (e.g. condoms) during the first month after starting Ryeqo.
If you miss two or more consecutive tablets, you must use a non-hormonal contraceptive method (e.g. condoms) for the next 7 days of treatment.
Driving and use of machines
Ryeqo has no known effects on the ability to drive or operate machinery.
Laboratory tests
If you are undergoing blood or urine tests, inform your doctor or laboratory staff that you are taking Ryeqo, as this medicine may affect the results of certain tests.
Ryeqo contains lactose
If your doctor has told you that you are intolerant to certain sugars, talk to your doctor before taking this medicine.

3. How to take Ryeqo

Take this medicine exactly as your doctor has told you. If you are unsure, consult your doctor or pharmacist.
The recommended dose is one tablet daily.
The tablet should be taken orally every day, approximately at the same time, with or without food, and with some liquid.
It is advisable to start taking Ryeqo within the first 5 days after the start of bleeding due to your period. If you start taking it at another time during your menstrual cycle, you may initially experience irregular or heavier bleeding.

If you take more Ryeqo than you should
There have been no reports of serious harmful effects related to taking several doses of this medicine at the same time. High doses of estrogens may cause nausea and vomiting, and vaginal bleeding. If you have taken too many Ryeqo tablets, contact your doctor or pharmacist for advice.

If you forget to take Ryeqo
If you miss a tablet, take it as soon as you remember, then take the next tablet at your usual time the following day. Do not take a double dose to make up for the forgotten tablet.
If you forget two or more consecutive tablets, consult your doctor and use a non-hormonal contraceptive method (e.g. condoms) for the next 7 days of treatment.

If you stop taking Ryeqo
If you wish to stop treatment with Ryeqo, speak to your doctor first. Your doctor will explain the effects of stopping treatment and discuss other options with you.
If you have any doubts about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
Contact a doctor immediately if you experience any of the following signs and symptoms of an
allergic reaction:

  • swelling of the lips, face or throat.

The following side effects have been reported with Ryeqo and are listed according to their frequency of
occurrence.
Very common side effects (may affect more than 1 in 10 people):

  • headache;
  • hot flush.

Common side effects (may affect up to 1 in 10 people):

  • irritability;
  • reduced sexual interest;
  • dizziness;
  • nausea;
  • hair loss;
  • increased sweating;
  • night sweats;
  • joint pain;
  • excessive, irregular or prolonged uterine bleeding (uterine bleeding);
  • dryness of the genital area.

Uncommon side effects (may affect up to 1 in 100 people):

  • indigestion;
  • itching (urticaria);
  • angioedema (rapid swelling of mucous membranes or skin, which may affect the face, mouth, tongue, abdomen, arms or legs);
  • breast lump (breast cyst);
  • expulsion of uterine fibroid (the fibroid completely or partially passes through the vagina, usually accompanied by increased vaginal bleeding).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, consult your doctor or pharmacist.
You may also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-
avverse. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Ryeqo

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the outer carton and on the bottle after Exp. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Ryeqo contains

  • The active substances are relugolix, estradiol and norethisterone acetate. One film-coated tablet contains relugolix 40 mg, estradiol 1 mg and norethisterone acetate 0.5 mg.
  • The other components are monohydrate lactose, mannitol (E421), sodium starch glycolate, hydroxypropylcellulose (E463), magnesium stearate (E572), hypromellose type 2910 (E464), titanium dioxide (E171), triacetin (E1518), iron oxide yellow (E172).

Description of the appearance of Ryeqo and package contents
Ryeqo is a round, film-coated tablet, light yellow to yellow in colour, 8 mm in diameter, marked with "415" on one side and plain on the other. It is available in high-density polyethylene (HDPE) bottles with desiccant, closed with a child-resistant polypropylene cap sealed by induction, or in PVC/Al blisters with desiccant packed in triplex pouches (PET/Al/PE). Each package contains one or three bottles with 28 tablets; or two or six blisters with 14 tablets.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
Gedeon Richter Plc.
Gyömrői út 19-21.
1103 Budapest
Hungary

Manufacturer (sites of batch release)
Gedeon Richter Plc.
Gyömrői út 19-21.
1103 Budapest
Hungary

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu