RYEQO 40mg / 1mg / 0.5mg tablets medication leaflet

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

Each film-coated tablet contains 40 mg relugolix, 1 mg estradiol (as hemihydrate), and 0.5 mgnorethisterone acetate.

Each film-coated tablet contains approximately 80 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Light yellow to yellow, round film-coated tablet of 8 mm with “415” on one side and plain-faced onthe other side.

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 orsurgical treatment for their endometriosis (see section 5.1).

Ryeqo treatment should be initiated and supervised by a physician experienced in the diagnosis andtreatment of uterine fibroids and/or endometriosis.

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

BMD loss and osteoporosis

A dual X ray absorptiometry (DXA) scan is recommended after 1 year of treatment. In patients withrisk factors for osteoporosis or bone loss, a DXA scan is recommended prior to starting Ryeqotreatment (see section 4.4).

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 menstrualbleeding. If treatment is initiated on another day of the menstrual cycle, irregular and/or heavybleeding may initially occur.

Ryeqo can be taken without interruption. Discontinuation should be considered when the patient entersmenopause, as the symptoms of both uterine fibroids and endometriosis are known to regress whenmenopause begins.

Any hormonal contraception needs to be stopped prior to initiation of treatment, as concomitant use ofhormonal contraceptives is contraindicated (see section 4.3).

Nonhormonal methods of contraception must be used for at least 1 month after initiation of Ryeqo.

After at least one month of Ryeqo use, Ryeqo inhibits ovulation in women taking the recommendeddose and provides adequate contraception.

Women of childbearing potential must be advised that ovulation will return rapidly after discontinuingtreatment. Therefore, a discussion with the patient, regarding appropriate contraceptive methods, musttherefore take place prior to discontinuing treatment and alternative contraception needs to be startedimmediately after discontinuation of treatment (see section 4.4).

Missed tablets

If one tablet is missed, the missed tablet must be taken as soon as possible and then continue the nextday by taking a tablet at the usual time.

If two or more tablets are missed for consecutive days, contraceptive protection may be reduced. Anonhormonal method of contraception is to be used for the next 7 days of treatment (see section 4.6).

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

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

No dose adjustment for Ryeqo in patients with mild or moderate hepatic impairment is required (seesection 5.2). Ryeqo is contraindicated in women with severe liver disease if liver function values havenot returned to normal (see section 4.3).

There is no relevant use of Ryeqo in children aged under 18 years for the treatment of symptoms ofuterine fibroids.

The safety and efficacy of Ryeqo in children aged under 18 years for the treatment of endometriosishas not been established. No data are available.

Oral use.

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

− Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.− Venous thromboembolic disorder, past or present (e.g. deep venous thrombosis, pulmonaryembolism).− 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 oractivated protein C (APC)-resistance, including Factor V Leiden (see section 4.4)).− Known osteoporosis.− Headaches with focal neurological symptoms or migraine headaches with aura (see section 4.4).− Known or suspected sex -steroid influenced malignancies (e.g. of the genital organs or thebreasts).− Presence or history of liver tumours (benign or malignant) (see section 4.4).− Presence or history of severe hepatic disease as long as liver function values have not returnedto normal.− Pregnancy or suspected pregnancy and breastfeeding (see section 4.6).− Genital bleeding of unknown aetiology.− Concomitant use of hormonal contraceptives.

Ryeqo must only be prescribed after careful diagnosis.

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 performedguided by the contraindications (see section 4.3) and warnings for use (see section 4.4). Duringtreatment, 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).

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.

The use of medicinal products containing an estrogen and a progestogen increases the risk of arterialor 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 andprogestogen lower than the doses used in combined hormonal contraceptives and are provided incombination with relugolix, a gonadotropin-releasing hormone (GnRH) receptor antagonist thatsuppresses ovarian production of estrogen and progesterone. Estradiol levels with Ryeqo are in therange observed in the early follicular phase of the menstrual cycle (see section 5.1).

If an ATE/VTE occurs, treatment must be discontinued immediately. Ryeqo is contraindicated inwomen with past or present venous or arterial thromboembolic disease (see section 4.3).

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

Table 1. Risk factors for VTE

Risk factor Comment

Obesity (body mass index [BMI] over 30 kg/m2) Risk increases substantially as BMI rises.

Prolonged immobilisation, major surgery or In these situations, it is advisable to discontinuemajor trauma use of the medicinal product (in the case ofelective surgery at least four weeks in advance)and not resume until two weeks after completeremobilisation.

Positive family history (VTE) ever in a sibling If a hereditary predisposition is suspected, theor parent especially at a relatively early age e.g. woman must be referred to a specialist forbefore 50 years. advice before using the medicinal product.

Other medical conditions associated with VTE Cancer, systemic lupus erythematosus,haemolytic uraemic syndrome, chronicinflammatory bowel disease (Crohn's disease orulcerative colitis) and sickle cell disease.

Increasing age Particularly above 35 years.

The increased risk of thromboembolism in pregnancy, and particularly the 6-week period of thepuerperium, must be considered (for information on “Pregnancy and lactation” see section 4.6).

In the event of symptoms, women must be advised to get urgent medical attention and to inform thephysician 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 bemisinterpreted as more common or less severe events (e.g. respiratory tract infections).

Epidemiological studies have associated the use of estrogen/progestogen products with an increasedrisk 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 andprogestogen may increase substantially in a woman with additional risk factors, particularly if thereare multiple risk factors (see Table 2 below).

Table 2. Risk factors for ATE

Risk factor Comment

Increasing age Particularly above 35 years.

Smoking Women are to be advised not to smoke if theywish to use the medicinal product.

Obesity (body mass index [BMI] over 30 kg/m2) Risk increases substantially as BMI increases.

Positive family history (ATE) ever in a sibling If a hereditary predisposition is suspected, theor parent especially at relatively early age e.g. woman must be referred to a specialist forbefore 50 years. advice before using the medicinal product.

Migraine An increase in frequency or severity of migraineduring use of the medicinal product (which maybe prodromal of a cerebrovascular event) maybe a reason for immediate discontinuation.

Other medical conditions associated with Diabetes mellitus, hyperhomocysteinaemia,adverse vascular events valvular heart disease and atrial fibrillation,dyslipoproteinaemia and systemic lupuserythematosus.

In the event of symptoms, women must be advised to get urgent medical attention and to inform thephysician 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, orbelow 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.

Following an initial non-clinically relevant decrease in bone mineral density (BMD), it stabilized after12-24 weeks of treatment and thereafter remained stable (as measured up to 2 years). The meandecrease 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 isrecommended after the first 52 weeks of treatment and as considered appropriate thereafter.

Depending on the degree of change in BMD, the benefit and risks of Ryeqo may need to bereconsidered.

The benefits and risks of Ryeqo in patients with a history of a low trauma fracture or other risk factorsfor osteoporosis or bone loss, including those taking medications that may affect BMD, should beconsidered prior to initiating treatment. It is recommended to perform a DXA scan beforecommencing treatment with Ryeqo in these patients. Ryeqo should not be initiated if the riskassociated with BMD loss exceeds the potential benefit of the treatment.

Ryeqo is contraindicated in women with liver tumours, benign or malignant; or liver disease as long asliver function values have not returned to normal (see section 4.3). Treatment must be discontinued ifjaundice develops.

In clinical trials, asymptomatic transient elevations of serum alanine aminotransferase (ALT) at least3 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 testsreturn to normal.

The exposure to relugolix is increased in patients with moderate or severe renal impairment (seesection 5.2), although no dose adjustment is required (see section 4.2). The amount of relugolixremoved by haemodialysis is unknown.

Patients must be informed that treatment with Ryeqo usually leads to a reduction in menstrual bloodloss 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 and Week 104 assessments 70.6%, and 58.3% ofwomen respectively receiving Ryeqo were likely to have amenorrhoea.

For those patients with endometriosis, the majority of patients (65.2%) were likely to haveamenorrhoea at the Week 24 assessment, with a subsequent 76.6% at the Week 52 assessment and82.3% at the Week 104 assessment.

In case of persistent excessive bleeding, patients must notify their physician.

Ryeqo provides adequate contraception when used for at least 1 month (see section 4.2). However,women of childbearing potential must be advised that ovulation will return rapidly after discontinuingtreatment. Therefore, alternative contraception needs to be started immediately after discontinuation oftreatment.

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 apregnancy in a timely manner. Perform pregnancy testing if pregnancy is suspected and discontinuetreatment, if pregnancy is confirmed.

Submucosal uterine fibroids are common (15% to 20% of women with uterine fibroids) and some mayprolapse 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 thepossibility of uterine fibroid prolapse or expulsion when treated with Ryeqo, and should contact theirphysician if severe bleeding reoccurs after bleeding symptoms have improved while being treatedwith Ryeqo.

Depression

Carefully observe women with a history of depression and discontinue Ryeqo if depression recurs to aserious degree. Data are limited on the association of Ryeqo or other products containing estradiol andprogestins with onset of depression or exacerbation of existing depression. Women must be advised tocontact their physician in case of mood changes and depressive symptoms, including shortly afterinitiating the treatment.

Although small increases in blood pressure have been reported in women taking Ryeqo, clinicallyrelevant increases are rare. However, if sustained clinically significant hypertension develops duringthe use of Ryeqo, hypertension should be treated, and the benefit of continued therapy should beassessed. If treatment with Ryeqo is discontinued, use may be resumed if normotensive values can beachieved with antihypertensive treatment.

Conditions such as gallbladder disease, cholelithiasis and cholecystitis have been reported to occur orworsen with estrogen and progestogen use, including Ryeqo, but the evidence of an association with

Ryeqo is inconclusive.

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

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

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

Concomitant use of Ryeqo with oral P-gp inhibitors is not recommended. Relugolix is a substrate of

P-gp (see section 5.2) and in an interaction study with erythromycin, a P-gp and moderatecytochrome P450 (CYP) 3A4 inhibitor, the area under the curve (AUC) and maximum concentration(Cmax) of relugolix were increased by 4.1-fold and 3.8-fold, respectively. Concomitant use of P-gpinhibitors 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, dronedarone, propafenone, quinidine),antianginal medicinal products (e.g. ranolazine), cyclosporine, human immunodeficiency virus (HIV)or hepatitis C virus (HCV) protease inhibitors (e.g. ritonavir, telaprevir). If concomitant use with onceor twice daily oral P-gp inhibitors is unavoidable (e.g. azithromycin), take Ryeqo first, and separatedosing with the P-gp inhibitor by at least 6 hours and monitor patients more frequently for adversereactions.

Co-administration of Ryeqo with strong CYP3A4 and/or P-gp inducers is not recommended. In aclinical interaction study with rifampicin, a strong CYP3A4 and P-gp inducer, the Cmax and AUC ofrelugolix were reduced by 23% and 55%, respectively. Medicinal products that cause strong CYP3A4and/or P-gp induction, such as anticonvulsants (e.g. carbamazepine, topiramate, phenytoin,phenobarbital, primidone, oxcarbazepine, felbamate), 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, boceprevir, telaprevir) and non-nucleoside reversetranscriptase inhibitors (e.g. efavirenz), may reduce the plasma concentrations of relugolix and mayresult in a decrease in therapeutic effects.

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 clinicalinteraction study, concomitant administration with atorvastatin, a weak CYP3A4 enzyme inhibitor, didnot change the exposure of relugolix in a clinically meaningful manner.

Effect of co-administered medicinal products on relugolix exposure from clinical trials andrecommendations are summarised in Table 3.

Table 3. Effect of co-administered medicinal products on relugolix exposure (AUC0-∞,Cmax; inorder of decreasing magnitude) from clinical trials and recommendations

Interacting drug dose Relugolix Change in Change in Recommendationregimen dose regimen relugolix relugolix

AUC0-∞ Cmaxerythromycin 40 mg single 4.1 -fold ↑ 3.8 -fold ↑ Concomitant use of Ryeqo500 mg QID, multiple dose with erythromycin anddoses other oral P-gp inhibitors isnot recommended.

azithromycin 120 mg 1.5 -fold ↑ 1.6 -fold ↑ If concomitant use with500 mg single dose single once or twice daily oral P-dose** gp inhibitors is unavoidable(e.g. azithromycin), take

Ryeqo first, followed byazithromycin 1.4 -fold ↑ 1.3 -fold ↑ administration of the P-gp500 mg single dose inhibitor at least 6 hours6 hours after thereafter and monitoradministration of patients more frequently forrelugolix adverse reactions.voriconazole 40 mg single 51% ↑ 21% ↑ No dose modifications200 mg BID, multiple dose recommended fordoses coadministration ofrelugolix and CYP3A4fluconazole 40 mg single 19% ↑ 44% ↑ inhibitors devoid of P-gp200 mg QD, multiple dose inhibition.dosesatorvastatin 40 mg single 5% ↓ 22% ↓80 mg QD, multiple dosedosesrifampicin 40 mg single 55% ↓ 23% ↓ Coadministration of Ryeqo600 mg QD, multiple dose with rifampicin and otherdoses combined P-gp and strong

CYP3A4 inducers is notrecommended as theefficacy of the relugolixcomponent of Ryeqo couldbe reduced.

*Data given as x-fold change represent a ratio between co-administration and relugolix alone. Data given as %change represent % difference relative to relugolix alone.

**For further details check Orgovyx SmPC, effect for the 40 mg dose not investigated, but expected to be larger.

Increase is indicated as “↑”, decrease as “↓”.

AUC = area under curve; Cmax= maximum concentration; QD = once daily; BID = twice daily; TID = three timesdaily; QID = four times daily

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.

The metabolism of estrogens and progestogens may be increased by concomitant use of substancesknown to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such asanticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin,rifabutin, nevirapine, efavirenz).

Ritonavir, telaprevir and nelfinavir, although known as strong inhibitors, are also inducers and maydecrease the exposure of estrogens and progestogens.

Herbal preparations containing St John's Wort (Hypericum perforatum) may induce the metabolism ofestrogens and progestogens. Clinically, an increase in estrogen metabolism may lead to decreasedeffectiveness with regard to protection of bone loss. Therefore, long-term concomitant use of liverenzyme inducers with Ryeqo is not recommended.

Relugolix is a weak inducer of CYP3A4. After co-administration with daily 40 -mg doses of relugolix,the AUC and Cmax of midazolam, a sensitive CYP3A4 substrate, were decreased by 18% and 26%,respectively. However, based on the clinical study with midazolam, clinically meaningful effects ofrelugolix on other CYP3A4 substrates are not expected.

Relugolix is an inhibitor of breast cancer resistant protein (BCRP) in vitro, therefore, an interactionstudy was conducted with rosuvastatin, a BCRP and organic anion transporting polypeptide 1B1(OATP1B1) substrate. After co-administration with daily 40-mg doses of relugolix, the AUC and Cmaxof rosuvastatin were decreased by 13% and 23%, respectively. The effects are not consideredclinically meaningful and therefore no dose-adjustments of rosuvastatin upon concomitant use arerecommended. Clinical effects of Ryeqo on other BCRP substrates have not been evaluated and therelevance for other BCRP substrates is unknown.

Relugolix may cause saturation of intestinal P-gp at the 40 mg dose, as relugolix exhibits more thandose proportional pharmacokinetics over the dose range of 10-120 mg, which could result in increasedabsorption of co-administered medicines that are sensitive substrates of P-gp. No clinically significantdifferences 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 arenot expected.

Estrogen and progestogen medicinal products may affect the metabolism of certain other activesubstances. 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.

Ryeqo inhibits ovulation in women taking the recommended dose and provides adequatecontraception. A nonhormonal contraceptive method is recommended for use for 1 month afterinitiation of treatment and for 7 days following 2 or more missed consecutive doses. Concomitant useof hormonal contraceptives is contraindicated (see section 4.3).

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 thereforetake place prior to discontinuing treatment and alternative contraception needs to be startedimmediately after discontinuation of treatment (see section 4.4).

There is a limited amount of data from the use of relugolix in pregnant women. Studies in animalshave shown that exposure to relugolix early in pregnancy may increase the risk of early pregnancy loss(see section 5.3). Based on the pharmacological effects, an adverse effect on pregnancy cannot beexcluded.

Ryeqo is contraindicated during pregnancy (see section 4.3). Discontinue use of treatment ifpregnancy occurs.

There appears to be little or no increased risk of harmful effects in children born to women who haveused estrogens and progestogens as an oral contraceptive inadvertently during early pregnancy. Theincreased risk of VTE during the postpartum period must be considered when re-starting Ryeqo (seesection 4.4).

Results from nonclinical studies indicate that relugolix is excreted into the milk of lactating rats (seesection 5.3). No data are available regarding the presence of relugolix or its metabolites in human milkor its effect on the breastfed infant. Detectable amounts of estrogen and progestogens have beenidentified in the breast milk of women receiving estrogen plus progestogen therapy. An effect onbreastfeeding newborns/infants cannot be excluded.

Breastfeeding is contraindicated during the use of Ryeqo (see section 4.3) and for 2 weeks followingdiscontinuation of Ryeqo.

Ryeqo inhibits ovulation and often causes amenorrhoea. Ovulation and menstrual bleeding will returnrapidly after discontinuing treatment (see section 5.1).

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

The most frequent adverse drug reactions, in patients being treated for uterine fibroids or endometriosis,were headache (13.2%), hot flush (10.3%) and uterine bleeding (5.8%).

Adverse drug reactions listed in Table 4 are classified according to frequency and system organ class.

Within each frequency grouping, adverse drug reactions are presented in order of decreasingseriousness. 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 notknown (cannot be estimated from available data).

Tabulated list of adverse drug reactions

Table 4. Adverse drug reactions in patients with uterine fibroids and endometriosis

Common Irritability

Libido decreased*

Very common Headache

Common Dizziness

Very common Hot flush

Common Nausea

Uncommon Dyspepsia

Common Alopecia

Hyperhidrosis

Night sweats

Uncommon Angioedema

Urticaria

Common Arthralgia

Common Uterine bleeding**

Vulvovaginal dryness

Uncommon Breast cyst

Uterine myoma expulsion

* includes libido decreased, libido loss and libido disorder.

** includes menorrhagia (heavy menstrual bleeding), metrorrhagia (intermenstrual bleeding), vaginalhaemorrhage, uterine haemorrhage, polymenorrhoea, and menstruation irregular

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Single doses of relugolix up to 360 mg (9 times the recommended clinical dose of 40 mg) have beenadministered 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 ofrelugolix 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 ornorethisterone removed by haemodialysis is unknown.

Serious ill effects have not been reported following acute ingestion of large doses ofestrogen-containing drug products by young children. Overdose of estradiol and norethisterone acetatemay cause nausea and vomiting, and withdrawal bleeding may occur in women.

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

Relugolix is a non-peptide GnRH receptor antagonist that binds to and inhibits GnRH receptors in theanterior pituitary gland. In humans, inhibition of GnRH receptor results in a dose dependent decreasein the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anteriorpituitary 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 ofestrogen. Prevention of an LH surge inhibits ovulation and development of the corpus luteum, whichprecludes the production of progesterone. Therefore, Ryeqo provides adequate contraception whentaken for at least 1 month (see section 4.2).

Estradiol is the same as the endogenously produced hormone and is a potent agonist of the nuclearestrogen receptor (ER) subtypes. Exogenously administered estradiol alleviates symptoms associatedwith a hypoestrogenic state, such as vasomotor symptoms and bone mineral density loss.

Norethisterone acetate is a synthetic progestogen. As estrogens promote the growth of theendometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. Theaddition of a progestogen reduces the estrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

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 a40-mg dose to within the postmenopausal range. Across clinical studies, average estradiolconcentrations were consistently maintained at least 10 pg/mL higher with Ryeqo compared withrelugolix alone. In the phase 3 clinical studies, in patients with uterine fibroids, with Ryeqo, medianestradiol predose concentrations after 24 weeks were approximately 33 pg/mL, and in those withendometriosis were approximately 38 pg/mL corresponding with estradiol concentrations associatedwith the early follicular phase of the menstrual cycle. Progesterone levels in both populations weremaintained at < 3.0 ng/mL with Ryeqo.

In a single cohort study in healthy premenopausal women, administration of Ryeqo once daily for84 days substantially suppressed follicular growth throughout the 84-day treatment period (meandominant follicle size of approximately 6 mm) and ovulation was inhibited in 100% of women asassessed 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

The efficacy and safety of Ryeqo once daily in patients with uterine fibroids was assessed in tworeplicate, 24-week, multinational, randomised, double-blind, placebo-controlled studies in patientsaged 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 receiverelugolix 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 mgco-administered with E2/NETA for 12 weeks. The median age of women was 42 years, and meanbody 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.

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 ofwomen treated with Ryeqo compared with placebo (Table 5). Reductions in MBL volume were seenas early as the first assessment (Week 4). The results for other secondary endpoints related to bleedingare as shown in Table 5. All key secondary endpoints were alpha -controlled.

Table 5. Results of primary and selected secondary efficacy assessments in study L1 and study

L2 (uterine fibroids)

Study L1 Study L2

Ryeqo Placebo Ryeqo Placebo(N = 128) (N = 127) (N = 125) (N = 129)

Number (%) ofrespondersa,b 94 (73.4%) 24 (18.9%) 89 (71.2%) 19 (14.7%)

Number (%) of patientswith MBL < 80 mL 97 (75.8%) 34 (26.8%) 97 (73.6%) 25 (19.4%)

Number (%) of patientswith ≥ 50% reduction in 101 (78.9%) 28 (22.1%) 96 (76.8%) 28 (21.7%)

MBL volume

Number (%) of patientswith amenorrhoeab,c 67 (52.3%) 7 (5.5%) 63 (50.4%) 4 (3.1%)

Number (%) of patientswith > 2 g/dLimprovement in 15 (50.0%) 5 (21.7%) 19 (61.3%) 2 (5.4%)haemoglobin levelsd

Number (%) of patientswho achieved NRS ≤ 1b,e 25 (43.1%) 7 (10.1%) 32 (47.1%) 14 (17.1%)

Percent change in primaryuterine fibroid volume -12.4 (5.62) -0.3 (5.40) -17.4 (5.93) -7.4 (5.92)

Percent change inuterine volume -12.9 (3.08) 2.2 (3.01) -13.8 (3.39) -1.5 (3.37)a A responder is defined as a woman who achieved both a MBL volume of < 80 mL and at least a 50% reductionfrom baseline in MBL volume over the last 35 days of treatment.b p-value < 0.0001 is comparison of Ryeqo vs placebo stratified by baseline MBL volume (< 225 mL, ≥ 225 mL)and geographic region (North America, Rest of World).c Amenorrhoea is defined as reported amenorrhoea, spotting, or negligible bleeding (MBL < 5 mL) withsupporting eDiary compliance at 2 consecutive visits.d In patients with a baseline Haemoglobin level ≤ 10.5 g/dLe In patients with moderate or severe pain at baseline

Abbreviations: MBL = menstrual blood loss; NRS = numerical rating scale; UFSQoL= uterine fibroid symptomand quality of life

Endometriosis

The efficacy and safety of Ryeqo once daily, in patients with endometriosis was assessed in tworeplicate, 24-week, multinational, randomised, double-blind, placebo-controlled studies in patientsaged 18-50 with moderate to severe pain associated with endometriosis (Studies S1 and S2). Patientswere required to have endometriosis confirmed by direct visualisation during surgery and/orhistological confirmation and were required to have moderate to severe pain as assessed based on an11-point numerical rating scale (NRS).

Both studies had three treatment groups: Women were randomised to receiverelugolix 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 mgco-administered with E2/NETA for 12 weeks. Patients were eligible for inclusion if they had moderateto severe pain before the screening period until after the run- in period (i.e. at least two cycles). A highpercentage (83.2%) of the study population of Studies S1 and S2 reported having undergone previoussurgeries/procedures for endometriosis treatment. A low percentage (8%) of the study population didnot report previous surgical or medical treatment before inclusion into the studies. At baseline, mostpatients (92.6%) used analgesics for pelvic pain, including 29.1% of patients in Study S1 and 48.4% ofpatients in Study S2 who used opioids. The most frequently reported other pharmacotherapies forendometriosis included dienogest (19.4%), estrogen progestin oral contraceptive (15.2%) and GnRHagonists (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 dysmenorrhoea and non-menstrual pelvic pain

Studies S1 and S2 had two co-primary endpoints, consisting of 2 responder analyses. In both studies, astatistically significantly higher percentage of responders was observed, defined as a reduction frombaseline in dysmenorrhea of at least 2.8 points over the last 35 days of treatment, without an increasein analgesic use (ibuprofen or opioid), defined as a reduction from baseline in non-menstrual pelvicpain score of at least 2.1 points over the last 35 days of treatment, without an increase in analgesic use(ibuprofen or opioid) (Table 6).

Table 6. Results of co-primary efficacy assessments in study S1 and study S2 (endometriosis)

Endpoint definition Study S1 Study S2

Ryeqo Placebo Ryeqo Placebo(N = 212) (N = 212) (N = 206) (N = 204)

Number (%) ofresponders for 158 (74.5%) 57 (26.9%) 155 (75.2%) 62 (30.4%)dysmenorrheaa,c

Number (%) ofresponders for non-menstrual pelvic pain 124 (58.5%) 84 (39.6%) 136 (66.0%) 87 (42.6%)(NMPP)b,ca Responders were patients whose NRS score for dysmenorrhea declined from baseline to Week 24/EOT by≥ 2.8 points, and the patient did not have increased use of study-specified analgesics for pelvic pain at Week24/EOT relative to baseline.b Responders were patients whose NRS score for NMPP declined from baseline to Week 24/EOT by ≥ 2.1points, and the patient did not have increased use of study specified analgesics for pelvic pain at Week 24/EOTrelative to baseline.c p-value < 0.0001 is comparison of Ryeqo vs placebo adjusted by baseline pain score, time since initial surgicaldiagnosis of endometriosis and geographic region.

Abbreviations: N = number of patients; NMPP = Non menstrual pelvic pain; NRS = Numerical Rating Scalescores (0=no pain, 10=worst pain as bad as you can imagine).

The results for the key secondary efficacy endpoints are shown in Table 7. All key secondaryendpoints were alpha controlled.

Table 7. Results of selected secondary efficacy assessments in study S1 and study S2(endometriosis)

Endpoint definition Study S1 Study S2

Ryeqo Placebo Ryeqo Placebo(N = 212) (N = 212) (N = 206) (N = 204)

Change in the EHP-30

Pain Domain score, LS -32.2 (1.68) -19.9 (1.69)

Mean (SE)a,b -33.8 (1.83) -18.7 (1.83)

Change in the meandysmenorrhea NRS score, -5.1 (0.19) -1.8 (0.19) -5.1 (0.19) -2.0 (0.19)

LS Mean (SE) a,b

Change in the mean

NMPP NRS score, LS -2.7 (0.17) -2.0 (0.17)

Mean (SE) a,b -2.9 (0.18) -2.0 (0.18)

Change in the meandyspareunia NRS score, -2.4 (0.21) -1.7 (0.22) -2.4 (0.19) -1.9 (0.19)

LS Mean (SE) a,b

Proportion of patientswho are not usingprotocol-specified opioids 182 (85.8%) 162 (76.4%) 169 (82.0%) 135 (66.2%)for endometriosis-associated pain, n (%)ca LS means were based on mixed-effects model with treatment, baseline value, visit, geographic region (North

America, Rest of World), time since initial surgical diagnosis of endometriosis (< 5 years, ≥ 5 years), andtreatment-by-visit interaction included as fixed effects; visit was also included in the model as random effectwithin each patient, and an unstructured covariance matrix was assumed.b Change from baseline to Week 24//EOTc At Week 24/EOT

Abbreviations: EOT = end-of-treatment; LS = least square; N = number of patients; NETA = norethisteroneacetate; NMPP = nonmenstrual pelvic pain; NRS = Numerical Rating Scale, SE = standard error.

The effect of Ryeqo on BMD was evaluated by DXA at week 12, 24, 36, 52 and 104. A total of 477women with uterine fibroids who completed the 24 week pivotal studies (Study L1 and L2) wereenrolled 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 52week study (randomised withdrawal study) where they were re randomised to receive either Ryeqo orplacebo A total of 802 women with endometriosis who completed the 24-week pivotal studies (Study

S1 and S2) were enrolled into the extension study (Study S3), where all patients received Ryeqo.

BMD measurements over 104 weeks in patients with uterine fibroids and endometriosis aresummarised in Table 8.

Table 8. Bone mineral density (BMD) measurements over 104 weeks in patients with uterinefibroids and endometriosis

Ryeqo Placebo(N = 672) (N = 672)

Lumbar spine (L1 - L4)

Study L1 & L2, S1 & S2

Week 12

N 553 545

LS means % changea -0.56 0.15(95% CI) (-0.77, -0.36) (-0.05, 0.36)

Week 24

N 528 516

LS means % changea -0.59 0.13(95% CI) (-0.82, -0.37) (-0.09, 0.36)

Study L3 and S3 Ryeqo Placebo Ryeqo

Week 36

N 387 379

LS means % changea -0.66 -0.00(95% CI) (-0.93; -0.40) (-0.27; 0.26)

Week 52

N 365 351

LS means % changea -0.69 -0.30(95% CI) (-1.00; -0.38) (-0.61; 0.01)

Randomised withdrawal study Ryeqo Placeboband Study S3

Week 104

N 221 229

LS means % changea -0.40 -0.18(95% CI) (-0.82; 0.02) (-0.60; 0.23)

Abbreviations: LS mean = least squares mean; CI = confidence interval, N = number of patientsa % change from baseline;b Majority of the patients randomised to the placebo group in the randomised withdrawal study were treated with

Ryeqo within about 2 cycles upon reassumption of HMB

In the Ryeqo group, LS mean percent changes from baseline in BMD to week 52 and week 104 at thelumbar spine were -0.69% and -0.40%, respectively.

Over a period of 12 months after cessation of Ryeqo, in those endometriosis patients who met BMDloss criteria, evidence of recovery or trend towards recovery was observed in 100% of women at thelumbar spine.

BMD measurements over 12 weeks in women with uterine fibroids and endometriosis treated withrelugolix monotherapy

In women treated with relugolix monotherapy for 12 weeks, in studies L1 and L2, S1 and S2, BMD atthe lumbar spine decreased by -1.86% from baseline. The difference in percent change in BMDbetween women treated with Ryeqo and relugolix monotherapy at Week 12 was statisticallysignificant, demonstrating the effectiveness of using relugolix in combination with E2/NETA (Ryeqo)to mitigate bone loss.

To provide context for the effects of Ryeqo on percent change in BMD over 52 weeks treatment, anobservational study of untreated age-matched women with uterine fibroids and endometriosis wasconducted to characterise longitudinal BMD of premenopausal women aged 18-50 years (naturalhistory study). Through 52 weeks of observation, there was minimal change in BMD with Ryeqocompared with those in an age-matched cohort of premenopausal women with uterine fibroids andendometriosis.

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

The European Medicines Agency has waived the obligation to submit the results of studies with

Ryeqo in all subsets of the paediatric population in treatment of leiomyoma of the uterus orendometriosis (see section 4.2 for information on paediatric use).

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 underfasted conditions are summarized in Table 9.

Table 9. Single dose pharmacokinetic parameters of relugolix, estradiol, total estrone, andnorethisterone in post-menopausal women

Unconjugated Norethisterone

Relugolix Estradiol (E2) Estrone (E1) (NET)

AUC0-∞(ng*hr/mL or pg*hr/mL) 198.1 (111.6) 818.7 (334.4) 4126 (1650) 17.5 (8.46)

Cmax (ng/mL or pg/mL) 25.99 (18.21) 27.95 (19.15) 188.4 (59.09) 3.57 (1.43)

T (hr) 2.00 7.00 6.00 1.01max (0.25, 5.00) (0.25, 24.00) (2.00, 12.00) (0.50, 4.00)

Terminal t1/2 (hr) 61.5 (13.2) 16.6 (7.67) 15.9 (6.52) 10.9 (3.05)

Abbreviations: AUC0-∞ = area under the concentration-time curve from time 0 extrapolated to infinity;

Cmax = maximum observed concentration; E1 = estrone; E2 =estradiol; NET = norethisterone; Tmax = time to themaximum observed concentration; t1/2 = half-life

Note: Baseline-adjusted pharmacokinetic parameters for estradiol and unconjugated E1 are presented in thistable. Arithmetic means and standard deviations are shown except for tmax, where median and range (minimum,maximum) are shown. AUC0-∞ is presented in ng*hr/mL for relugolix and NET and in pg*hr/mL forunconjugated E2 and unconjugated E1. Cmax is presented in ng/mL for relugolix and NET and in pg/mL forunconjugated E2 and unconjugated E1.

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 premenopausalwomen are summarized in Table 10.

Table 10. Multi-dose pharmacokinetic parameters of relugolix, estradiol, total estrone, andnorethisterone in pre-menopausal women

Unconjugated Norethisterone

Relugolix Estradiol (E2) Estrone (E1) (NET)

AUC0-24(ng*hr/mL or pg*hr/mL) 157 (94.7) 784 (262) 4450 (1980) 25.5 (11.4)

Cmax (ng/mL or pg/mL) 26 (21.4) 46.8 (17.3) 303 (137) 5.21 (1.53)

Tmax (hr) 3 (0.5, 6) 3 (0.50, 12.00) 4 (1, 8.08) 1 (1, 2)

Effective t1/2 (hr) ~25 17.1 (4.03) 13.9 (4.14) 8.28 (1.87)

Abbreviations: AUC0-24 = area under the concentration-time curve during a dosing interval (24);

Cmax = maximum observed concentration; E1 = estrone; E2 =estradiol; NET = norethisterone; tmax = time to themaximum observed concentration.

Note: arithmetic means and standard deviations are shown except for tmax, where median and range (minimum,maximum) are shown. AUC0-24 is presented in ng*hr/mL for relugolix and NET and in pg*hr/mL forunconjugated E2 and unconjugated E1. Cmax is presented in ng/mL for relugolix and NET and in pg/mL forunconjugated E2 and unconjugated E1. Effective half-life for relugolix is estimated from accumulation ratiosbased on AUC values after multiple-dose administration of relugolix at 40 mg.

The absorption of relugolix after oral administration is primarily mediated by the P-gp effluxtransporter, for which relugolix is a substrate. After oral administration, relugolix is rapidly absorbed,reaching an initial peak by 0.25 hours postdose followed by one or more subsequent absorption peaksthrough up to 12 hours postdose. The absolute bioavailability of relugolix is 11.6%. Afteradministration of Ryeqo with a high-fat, high-calorie meal, the AUC0-∞ and Cmax of relugolix weredecreased by 38% and 55%, respectively, compared with the fasted state.

After oral administration of a single dose of Ryeqo in the fasted state, unconjugated estradiolconcentrations increased slowly with mean concentrations reaching peak concentrations at 8 hourspostdose. After administration of Ryeqo following consumption of a high-fat, high-calorie meal, noclinically meaningful effects of food on the exposure to estradiol or estrogenic metabolites wereobserved.

After oral administration, norethisterone acetate undergoes rapid biotransformation in the intestine andliver 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 postdose, increasing rapidly thereafter withmean concentrations reaching peak concentrations within 1 hour.

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

Relugolix is 68% to 71% bound to human plasma proteins with a mean whole blood-to-plasma ratioof 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% areunbound. The value for apparent volume of distribution (Vz) of 19 × 103 L derived from the absolutebioavailability study after intravenous administration indicates that relugolix distributes widely intotissues. The distribution of exogenous and endogenous estradiol is similar. Estrogens are widelydistributed in the body and are generally found in higher concentrations in the sex hormone targetorgans.

In vitro studies indicate that the primary CYP enzymes contributing to the overall hepatic oxidativemetabolism of relugolix were CYP3A4/5 (45%) > CYP2C8 (37%) > CYP2C19 (< 1%) with theoxidative 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 occursmainly in the liver and the gut but also in target organs and involves the formation of less active orinactive metabolites, including estrone, catecholestrogens and several estrogen sulphates andglucuronides. Estrogens are excreted with the bile, hydrolysed and reabsorbed (enterohepaticcirculation), and mainly eliminated in urine in biologically inactive form. Oxidation of estrone andestradiol involves cytochrome P450 enzymes, mainly CYP1A2, CYP1A2 (extra hepatic), CYP3A4,

CYP3A5, and CYP1B1 and CYP2C9.

The most important metabolites of norethisterone are isomers of 5alpha-dihydro-norethisterone andtetrahydro-norethisterone, which are excreted mainly in the urine as sulphate or glucuronideconjugates.

Once absorbed, approximately 20% of relugolix is eliminated as unchanged active substance in theurine and 80% is eliminated through metabolism by multiple minor metabolic pathways and/or biliarysecretion of unchanged active substance. Approximately 38% of the administered dose is excreted asmetabolites (other than metabolite-C) in the faeces and urine. Metabolite-C, which is formed byintestinal microflora, is the primary metabolite in faeces (51%) and further reflects non-absorbedactive substance.

The mean terminal phase elimination half-life (t1/2) of relugolix, estradiol, and norethisteronefollowing 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. Thedegree of accumulation of relugolix upon once daily administration is approximately 2-fold, reflectingan 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 co-administered with relugolix, a weak inducer of intestinal (pre-systemic)

CYP3A-mediated metabolism, the accumulation for E2 is expected to be similar or slightly lower.

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; andthought 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 timeindependent.

The single-dose pharmacokinetic parameters were not different between Japanese and Caucasianhealthy subjects, indicating absence of ethnic sensitivity on the pharmacokinetics of relugolix.

Population PK analysis suggests that there are no clinically meaningful differences in exposure ofrelugolix based on age, race or ethnicity, weight, or BMI. As both estradiol and norethisterone acetateare well known components of hormonal combination products, no studies in special populationswere conducted.

After administration of a single 40-mg dose of relugolix to patients with severe renal impairment, theexposure AUC0-∞ and Cmax of relugolix were increased by 1.5- and 1.1-fold, respectively, comparedwith healthy control subjects with normal renal function. After administration of a single 40-mg doseof relugolix to patients with moderate renal impairment, the exposure AUC0-∞ and Cmax of relugolixboth were increased by 1.5-fold compared with healthy control subjects with normal renal function.

Mild renal impairment was not a significant covariate for any of the pharmacokinetic parameters ofrelugolix in a population pharmacokinetic model. Although caution should be used to treat patientswith moderate or severe renal impairment (see section 4.4), no dose adjustments with Ryeqo inpatients with mild, moderate or severe renal impairment are required (see section 4.2).

The effect of end-stage renal disease with or without haemodialysis on the pharmacokinetics ofestradiol, norethisterone and relugolix, the components of Ryeqo, in premenopausal women have notbeen evaluated. The amount of relugolix, estradiol or norethisterone removed by haemodialysis isunknown.

Ryeqo must not be used in patients with severe hepatic impairment (see section 4.3). No doseadjustments for Ryeqo in patients with mild or moderate hepatic impairment are required (seesection 4.2). After administration of a single 40-mg dose of relugolix to patients with mild hepaticimpairment, the AUC0-∞ and Cmax of relugolix were decreased by 31% and 24%, respectively,compared with healthy control subjects with normal hepatic function. After administration of a single40-mg dose of relugolix to patients with moderate hepatic impairment, the AUC0-∞ and Cmax ofrelugolix were decreased by 5% and increased by 1.2-fold, respectively, compared with healthycontrol subjects with normal hepatic function.

Non-clinical studies have not been conducted with relugolix in combination with estradiol andnorethisterone acetate. Non-clinical data reveal no special hazard for humans based on conventionalstudies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.

In pregnant rabbits orally dosed with relugolix during the period of organogenesis, spontaneousabortion and total litter loss were observed at exposure levels (AUC) comparable to that achieved atthe recommended human dose of 40 mg/day. No effects on embryofoetal development were observedin rats; however, relugolix does not interact significantly with GnRH receptors in that species.

In experimental animals, estradiol or estradiol valerate displayed an embryo lethal effect already atrelatively low doses; malformations of the urogenital tract and feminisation of male foetuses wereobserved.

Norethisterone, like other progestogens, caused virilisation of female foetuses in rats and monkeys.

After high doses of norethisterone, embryo lethal effects were observed.

In lactating rats administered a single oral dose of 30 mg/kg radiolabelled relugolix on post-partumday 14, relugolix and/or its metabolites were present in milk at concentrations up to 10-fold higherthan in plasma at 2 hours post-dose decreasing to low levels by 48 hours post-dose. The majority ofrelugolix-derived radioactivity in milk consisted of unchanged relugolix.

Environmental risk assessment studies have shown that this medicinal product may pose a risk for theaquatic compartment (see section 6.6).

Lactose monohydrate

Mannitol (E421)

Sodium starch glycolate

Hydroxypropylcellulose (E463)

Magnesium stearate (E572)

Hypromellose type 2910 (E464)

Titanium dioxide (E171)

Triacetin (E1518)

Iron oxide yellow (E172)

Not applicable.

3 years

This medicinal product does not require any special storage condition.

High-density polyethylene (HDPE) bottles with desiccant, closed with an induction-sealedchild-resistant polypropylene cap containing 28 film-coated tablets. Each pack contains 28 or 84 film-coated tablets.

PVC/Al blister with desiccant packed in PET/Al/PE triplex foil sachet containing 14 film-coatedtablets. Each pack contains 28 or 84 film-coated tablets.

Not all pack sizes may be marketed.

This medicinal product may pose a risk to the environment (see section 5.3). Any unused medicinalproduct or waste material should be disposed of in accordance with local requirements.

Gedeon Richter Plc.

Gyömrői út 19-21,1103 Budapest,

Hungary

EU/1/21/1565/001

EU/1/21/1565/002

EU/1/21/1565/003

EU/1/21/1565/004

Date of first authorisation: 16 July 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.