- − 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, 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)).
- − 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 the breasts).
- − 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 returned to normal.
- − Pregnancy or suspected pregnancy and breastfeeding (see section 4.6).
- − 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.
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) and warnings for use (see section 4.4). 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). 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.
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).
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).
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 below).
Table 1. Risk factors for VTE
|Obesity (body mass index [BMI] over 30 kg/m2)||Risk increases substantially as BMI rises.|
|Prolonged immobilisation, major surgery or major trauma||In these situations, it is advisable to discontinue use of the medicinal product (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation.|
|Positive family history (VTE) ever in a sibling or parent especially at a relatively early age e.g. before 50 years.||If a hereditary predisposition is suspected, the woman must be referred to a specialist for advice before using the medicinal product.|
|Other medical conditions associated with VTE||Cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative 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 the puerperium, must be considered (for information on “Pregnancy and lactation” see section 4.6).
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 below).
Table 2. Risk factors for ATE
|Increasing age||Particularly above 35 years.|
|Smoking||Women are to be advised not to smoke if they wish 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 or parent especially at relatively early age e.g. before 50 years.||If a hereditary predisposition is suspected, the woman must be referred to a specialist for advice before using the medicinal product.|
|Migraine||An increase in frequency or severity of migraine during use of the medicinal product (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation.|
|Other medical conditions associated with adverse vascular events||Diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus.|
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.
Therefore, a DXA scan is recommended after the first 52 weeks of treatment to verify that the patient does not have an unwanted degree of BMD loss, that exceeds the benefit of treatment with Ryeqo.
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.
Liver tumors 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). 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.
The exposure to relugolix is increased in patients with moderate or severe renal impairment (see section 5.2), although no dose adjustment is required (see section 4.2). The amount of relugolix removed by haemodialysis is unknown.
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 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.
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). 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.
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.
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.
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.
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.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
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
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) 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 (Cmax) of relugolix were both increased by 6.2-fold. 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, 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 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 Cmax and AUC and 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, 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 reverse transcriptase inhibitors (e.g. efavirenz), may reduce the plasma concentrations of relugolix and may result 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 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
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, telaprevir 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 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 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 co-administration with daily 40-mg doses of relugolix, the AUC and Cmax 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 clinical interaction studies have been conducted with P-gp substrates such as dabigatran etexilate or fexofenadine. Therefore, co-administration with sensitive P-gp substrates is not recommended.
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
Women of childbearing potential
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).
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).
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 (see section 5.3). Based on the pharmacological effects, an adverse effect on pregnancy cannot be excluded.
Ryeqo is contraindicated during pregnancy (see section 4.3). 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 re-starting Ryeqo (see section 4.4).
Results from nonclinical studies indicate that relugolix is excreted into the milk of lactating rats (see section 5.3). 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) and for 2 weeks following discontinuation of Ryeqo.
Ryeqo inhibits ovulation and often causes amenorrhoea. Ovulation and menstrual bleeding will return rapidly after discontinuing treatment (see section 5.1).
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 Undesirable effects
Summary of the safety profile
The most frequent adverse drug reactions were hot flush (8.3%) and uterine bleeding (4.7%).
Tabulated list of adverse drug reactions
Adverse drug reactions listed in Table 3 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).
Table 3. Adverse drug reactions
|Skin and subcutaneous tissue disorders|
|Reproductive system and breast disorders|
|Uncommon||Uterine myoma expulsion|
* includes menorrhagia and metrorrhagia
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed in Appendix V.
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.