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Ryeqo (relugolix, estradiol hemihydrate and norethisterone acetate) UK PI

Ryeqo▼ UK Prescribing Information

Please refer to the Summary of Product Characteristics (SmPC) before prescribing

Presentation: film coated tablets containing 40 mg relugolix, 1 mg estradiol hemihydrate and 0.5 mg norethisterone acetate.

Indications: treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age.

Dosage and administration: one tablet, taken orally, once daily, at about the same time with or without food, with some liquid as needed. When starting treatment, the first tablet must be taken within 5 days of the onset of menstrual bleeding. If treatment is initiated on another day of the menstrual cycle, irregular and/or heavy bleeding may initially occur. Prior to starting Ryeqo treatment (1) in patients with risk factors for osteoporosis or bone loss, a dual X ray absorptiometry (DXA) is recommended (2) pregnancy must be ruled out. Ryeqo can be taken without interruption. Discontinuation should be considered when the patient enters menopause, as uterine fibroids are known to regress when menopause begins. A DXA scan is recommended after 1 year of treatment. Contraceptive properties of Ryeqo: Any hormonal contraception needs to be stopped prior to initiation of treatment, as concomitant use of hormonal contraceptives is contraindicated. Non-hormonal methods of contraception must be used for at least 1 month after initiation of treatment. After at least one month of Ryeqo use, Ryeqo inhibits ovulation in women taking the recommended dose and provides adequate contraception. Women of childbearing potential must be advised that ovulation will return rapidly after discontinuing treatment. Therefore, a discussion with the patient, regarding appropriate contraceptive methods, must therefore take place prior to discontinuing treatment and alternative contraception needs to be started immediately after discontinuation of treatment. Missed doses If a dose is missed, treatment must be taken as soon as possible and then continue the next day at the usual time. If doses are missed for 2 or more consecutive days, a nonhormonal method of contraception is to be used for the next 7 days of treatment. Elderly: no relevant use of Ryeqo in the elderly population. Renal impairment: No dose adjustment required. Hepatic impairment: No dose adjustment required in patients with mild or moderate hepatic impairment. Contraindicated in women with severe liver disease if liver function values have not returned to normal. Paediatric population: no relevant use of Ryeqo in children aged under 18 years for the indication of the treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age.

Contraindications: hypersensitivity to the active substance(s) or to any of the excipients, venous thromboembolic disorder, past or present (e.g. deep venous thrombosis, pulmonary embolism), arterial thromboembolic cardiovascular disease, past or present (e.g. myocardial infarction, cerebrovascular accident, ischemic heart disease), known thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency or activated protein C (APC) resistance, including Factor V Leiden), known osteoporosis, headaches with focal neurological symptoms or migraine headaches with aura, 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), presence or history of severe hepatic disease as long as liver function values have not returned to normal, pregnancy or suspected pregnancy and breastfeeding, genital bleeding of unknown aetiology, concomitant use of hormonal contraceptives.

Warnings and precautions: Ryeqo must only be prescribed after careful diagnosis. Medical examination/ consultation: prior to the initiation or reinstitution of Ryeqo, a complete medical history (including family history) must be taken. Blood pressure must be measured, and a physical examination must be performed guided by the contraindications and warnings for use. During treatment, periodic check-ups must be carried out according to standard clinical practice. Risk of thromboembolic disorders: the use of medicinal products containing an oestrogen 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 oestrogen and progestogen lower than the doses used in combined hormonal contraceptives. Estradiol levels with Ryeqo are in the range observed in the early follicular phase of the menstrual cycle. If an ATE/VTE occurs, treatment must be discontinued immediately. Ryeqo is contraindicated in women with past or present venous or arterial thromboembolic disease. VTE and ATE: for risk factors of VTE and ATE and symptoms of VTE and ATE see SmPC for details. 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 tumours or liver disease: treatment must be discontinued if jaundice develops. In clinical trials, asymptomatic transient elevations of serum alanine aminotransferase (ALT) at least 3 times the upper limit of the reference range occurred in < 1% of participants treated with Ryeqo. Acute liver test abnormalities may necessitate the discontinuation of Ryeqo use until the liver tests return to normal. Change in menstrual bleeding pattern: Patients must be informed that treatment usually leads to a reduction in menstrual blood loss or amenorrhoea within the first 2 months of treatment; 51.6% were likely to have amenorrhoea or cyclic bleeding (15.4%), with the rest (31.9%) having an irregular bleeding pattern at the Week 24 assessment. 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. Reduced ability to recognise pregnancy: amenorrhoea or a reduction in the amount, intensity, or duration of menstrual bleeding is common during treatment; this may reduce the ability to recognise the occurrence of a pregnancy in a timely manner. Perform pregnancy testing if pregnancy is suspected and discontinue treatment, if pregnancy is confirmed. Uterine fibroid prolapse or expulsion: Submucosal uterine fibroids are common (15% to 20% of women with uterine fibroids) and some may prolapse through the cervix or be expelled, sometimes with transient worsening of uterine bleeding. Women known or suspected to have submucosal uterine fibroids must be advised regarding the possibility of uterine fibroid prolapse or expulsion when treated with Ryeqo and should contact their physician if severe bleeding reoccurs after bleeding symptoms have improved while being treated with Ryeqo. Depression: carefully observe women with a history of depression and discontinue Ryeqo if depression recurs to a serious degree. Women must be advised to contact their physician in case of mood changes and depressive symptoms. Hypertension: although small increases in blood pressure have been reported in women taking Ryeqo, clinically relevant increases are rare. However, if sustained clinically significant hypertension develops during the use of Ryeqo, hypertension should be treated, and the benefit of continued therapy should be assessed. If treatment with Ryeqo is discontinued, use may be resumed if normotensive values can be achieved with antihypertensive treatment. Gallbladder disease: 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. Laboratory tests: the use of estrogens and progestogens may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range. Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take Ryeqo.

Interactions: concomitant use with oral P glycoprotein (P-gp) inhibitors, strong cytochrome P450 3A4 (CYP3A4) and/or P gp inducers is not recommended. CYP3A4 inhibitors may increase circulating concentrations of the estrogen and norethisterone components in Ryeqo. CYP enzyme inducers-metabolism of estrogens and progestogens may be increased by concomitant use; long term concomitant use is not recommended. Plasma concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine) with use of Ryeqo; dose adjustment of these medicines may be necessary. Consult SmPC for further details.

Undesirable effects: Common: irritability, hot flush, dyspepsia, alopecia, hyperhidrosis, night sweats, uterine bleeding, breast cyst, libido decreased. Uncommon): uterine myoma expulsion

Legal category: POM

Pack size and NHS price: Ryeqo 40 mg/1 mg/0.5 mg film-coated tablets x 28 – £72.00. Ryeqo 40 mg/1 mg/0.5 mg film-coated tablets x 84 – £216.00.

Marketing Authorization Number: EU/1/21/1565/001 and PLGB 04854/0186

Marketing Authorization Holder: Gedeon Richter Plc. Gyömrői út 19-21, 1103 Budapest, Hungary

Further information available from: Gedeon Richter UK Ltd, 127 Shirland Road, London W9 2EP. Tel: +44 (0) 207 604 8806. Email: medinfo.uk@gedeonrichter.eu

Date of Authorisation:  9 Aug 2021

UK-REL-2100050 – December 2021

Adverse events should be reported. Reporting forms and information can be found at https://yellowcard.mhra.gov.uk/. Adverse events should also be reported to Gedeon Richter (UK) Ltd on +44 (0) 207 604 8806 or drugsafety.uk@gedeonrichter.eu