GnRH Antagonist + HRT Add-Back Combination
Pregnancy: Contraindicated during pregnancy and breastfeeding. Pregnancy must be ruled out before initiating treatment, and treatment discontinued if pregnancy occurs — animal studies show that exposure to relugolix early in pregnancy may increase the risk of early pregnancy loss. Breastfeeding is contraindicated during use and for 2 weeks following discontinuation. Ryeqo inhibits ovulation and often causes amenorrhoea; ovulation and menstrual bleeding return rapidly after discontinuation, so alternative contraception must be started immediately on stopping.
Relugolix/Estradiol/Norethisterone (Combination)
Brand names: Ryeqo
This relugolix, estradiol and norethisterone combination is the same once-daily oral GnRH antagonist plus hormonal add-back product, used for heavy bleeding from uterine fibroids and for endometriosis-associated pain.
Adult dose
Dose: Uterine fibroids and/or endometriosis in women of reproductive age: one tablet of Ryeqo 40 mg/1 mg/0.5 mg (relugolix 40 mg with estradiol 1 mg and norethisterone acetate 0.5 mg) once daily
Route: Oral. Can be taken with or without food; tablets should be taken with some liquid as needed
Frequency: Once daily, at about the same time each day. Ryeqo can be taken without interruption
Max: One tablet daily. The SPC states a single fixed-strength tablet taken once daily, with no up-titration and no higher dose anywhere in its posology; it also states that if two or more tablets are missed on consecutive days the missed tablets are not doubled up, only that a non-hormonal contraceptive method is used for the next 7 days
Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of uterine fibroids and/or endometriosis. INITIATION, verbatim: 'Pregnancy must be ruled out prior to initiating treatment with Ryeqo. When starting treatment, the first tablet must be taken within 5 days of the onset of menstrual bleeding. If treatment is initiated on another day of the menstrual cycle, irregular and/or heavy bleeding may initially occur.' DISCONTINUATION: 'Discontinuation should be considered when the patient enters menopause, as the symptoms of both uterine fibroids and endometriosis are known to regress when menopause begins.' CONTRACEPTION: any hormonal contraception must be stopped before initiation, as concomitant use of hormonal contraceptives is contraindicated; non-hormonal methods of contraception must be used for at least 1 month after initiation, after which Ryeqo inhibits ovulation at the recommended dose and provides adequate contraception. Ovulation returns rapidly after discontinuation, so alternative contraception must be started immediately on stopping. MISSED TABLETS, verbatim: 'If one tablet is missed, the missed tablet must be taken as soon as possible and then continue the next day by taking a tablet at the usual time. If two or more tablets are missed for consecutive days, contraceptive protection may be reduced. A nonhormonal method of contraception is to be used for the next 7 days of treatment.' ELDERLY: 'There is no relevant use of Ryeqo in the elderly population in the indications.' The strengths quoted above are those of the exact product fetched: 'Ryeqo 40mg/1mg/0.5mg film-coated tablets'.
Paediatric dose
Route: Not applicable — no relevant use under 18 years
Frequency: Not applicable
NO PAEDIATRIC DOSE IS PUBLISHED BECAUSE THE SPC GIVES NONE. Verbatim paediatric population text: 'There is no relevant use of Ryeqo in children aged under 18 years for the treatment of symptoms of uterine fibroids. The safety and efficacy of Ryeqo in children aged under 18 years for the treatment of endometriosis has not been established. No data are available.' dosePerKg is null — this is a fixed-dose combination tablet and is never dosed by weight.
Dose adjustments
Renal
No dose adjustment is required in patients with mild, moderate or severe renal impairment.
Hepatic
No dose adjustment is 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.
Dose independently re-sourced from UK Summary of Product Characteristics (SPC) via the eMC — clinician-reviewed. Always confirm against the product SmPC and your local formulary before prescribing.
Contraindications
- Hypersensitivity to the active substances 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, ischaemic heart disease)
- Known thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency, or activated protein C 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
Side effects
- Very common: headache (13.2%)
- Very common: hot flush (10.3%)
- Common: uterine bleeding (5.8%), including heavy menstrual bleeding, intermenstrual bleeding, vaginal haemorrhage, uterine haemorrhage, polymenorrhoea and irregular menstruation
- Common: irritability, decreased libido
- Common: dizziness
- Common: nausea
- Common: alopecia, hyperhidrosis, night sweats
- Common: arthralgia
- Common: vulvovaginal dryness
- Uncommon: dyspepsia
- Uncommon: angioedema, urticaria
- Uncommon: breast cyst, uterine myoma expulsion
Monitoring
- Bone mineral density — a dual X-ray absorptiometry (DXA) scan is recommended after 1 year of treatment, and in patients with risk factors for osteoporosis or bone loss a DXA scan is recommended prior to starting treatment
- Pregnancy must be ruled out prior to administering or re-initiating treatment
- A complete medical history (including family history) must be taken prior to initiation or reinstitution; blood pressure must be measured and a physical examination performed, guided by the contraindications and warnings
- During treatment, periodic check-ups must be carried out according to standard clinical practice
- Arterial or venous thromboembolism — if an event occurs, treatment must be discontinued immediately; risk factors include obesity (BMI over 30 kg/m2), prolonged immobilisation, major surgery or major trauma, positive family history of VTE in a sibling or parent especially before 50 years, other conditions associated with VTE (cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease, sickle cell disease) and increasing age, particularly above 35 years
- In elective surgery, discontinue at least four weeks in advance and do not resume until two weeks after complete remobilisation
- This list may be incomplete — check the full SPC.
Clinical monograph
How it works
Relugolix antagonises pituitary GnRH receptors to suppress ovarian sex hormones, and the bundled estradiol and norethisterone acetate act as add-back to mitigate bone loss and menopausal-type symptoms.
Prescribing in practice
- Reduction in bone mineral density is the principal safety issue, so treatment duration is restricted and bone density monitoring considered with longer courses or where osteoporosis risk is high.
- The oestrogen-progestogen content means combined-hormone cautions apply, with contraindications including hormone-sensitive cancers, a history of thromboembolism, and undiagnosed vaginal bleeding.
- Non-hormonal contraception is recommended as contraceptive cover should not be assumed, and the product must be discontinued if pregnancy is suspected.
Monitoring
Evaluate thromboembolic and cardiovascular risk and blood pressure at baseline and on review, with bone mineral density monitoring during prolonged use.
Counselling the patient
- Take the tablet once daily at a consistent time.
- Use non-hormonal contraception and report any signs of pregnancy.
- Seek urgent advice for chest pain, breathlessness, or a painful swollen leg.
Evidence & guidelines
NICE supports relugolix combination therapy for uterine fibroids and endometriosis, based on the LIBERTY and SPIRIT randomised trials.
Reference: LIBERTY 1 & 2 trials (Watts et al. NEJM 2020); NICE TA826; MHRA SPC Ryeqo 2022; Al-Hendy et al. NEJM 2021 (replicate trial); Drug verified in RxNorm (NLM); confirm dosing against the manufacturer SPC (eMC). Verify against your local formulary and current prescribing references before prescribing. The structured dose values shown have been reviewed by a clinician. Monograph status: clinician-reviewed (2026-07-04).
Related
Curated clinical cross-links plus same-class fallbacks.