Approved indication: treatment of moderate to severe symptoms of uterine fibroids in adult females of reproductive age
Ryeqo (Gedeon Richter)
40 mg+1 mg+0.5 mg film coated tablets

The combination of relugolix, estradiol and norethisterone (relugolix combination therapy) is a treatment option for symptomatic uterine fibroids (e.g. for heavy menstrual bleeding) in adult females of reproductive age. Relugolix is not available in Australia as monotherapy. Other pharmacological options for symptomatic fibroids include various hormonal contraceptive types and regimens (e.g. oral, intravaginal and depot contraceptives), tranexamic acid and nonsteroidal anti-inflammatory drugs.1 Use of gonadotropin-releasing hormone (GnRH) agonists (e.g. leuprorelin; approved in the US and Europe) or selective progesterone modulators (e.g. ulipristal; approved in Europe only) has been described for this indication.2 These medicines are available in Australia but are not approved for this indication.

Relugolix is a GnRH antagonist that suppresses pituitary release of luteinising hormone and follicle-stimulating hormone, and subsequent ovarian release of estradiol and progesterone. It induces a menopause-like state, substantially decreasing menstrual bleeding and other symptoms of uterine fibroids such as pelvic pain, dysmenorrhoea, blood clots and secondary iron deficiency anaemia.3 The addition of low-dose estradiol aims to limit menopausal symptoms (e.g. hot flushes) and loss of bone mineral density, while low-dose norethisterone reduces estrogen-induced endometrial hyperplasia.2-4

A 2021 phase-2 dose-finding randomised controlled trial (RCT) (n=216) showed relugolix monotherapy was generally well tolerated and resulted in dose-dependent reduction of heavy menstrual bleeding associated with fibroids.5

The Phase 3 LIBERTY trials6 (2 multicentre, double-blind, 24-week RCTs; total n=770) evaluated daily relugolix combination therapy versus relugolix monotherapy (to compare the effects on bone mineral density) versus placebo. Once-daily relugolix combination therapy and relugolix monotherapy groups both showed:

  • significant reduction in the primary outcome of menstrual bleeding, compared with placebo (p<0.001)
  • significant improvement in 6 of 7 key secondary endpoints (measures of menstrual blood loss including amenorrhea, pain, distress from bleeding, pelvic discomfort, anaemia, and uterine volume on ultrasound), but not fibroid volume.

Relugolix combination therapy and placebo groups had greater bone mineral density preservation compared with the relugolix monotherapy group. The incidence of non-serious adverse events was similar in all groups (e.g. hot flush, headache, arthralgia, nausea, fatigue). There were very few serious adverse events (total 0.09%) and no deaths.

The recommended dosage is one tablet (40 mg relugolix, 1 mg estradiol [as hemihydrate] and 0.5 mg norethisterone acetate) orally, taken at the same time daily. It should be commenced within 5 days of the start of a menstrual period, to prevent irregular bleeding.4

Females who have risk factors for osteoporosis and bone loss should have baseline dual energy X-ray absorptiometry (DXA) before starting therapy, and be reassessed at 2 years.

Relugolix combination therapy is not safe during pregnancy (Category D) and pregnancy must be excluded prior to starting therapy.4

Hormonal contraception should be ceased, and a nonhormonal method of contraception (e.g. condoms) used, for at least one month before commencing relugolix therapy. After one month of therapy, ovulation will be suppressed and this confers effective contraception, unless 2 or more doses are missed, in which case nonhormonal contraception is advised for 7 days.4

Contraindications to relugolix combination therapy include:4

  • arterial and venous thromboembolic disorders (past or present), or thrombophilias
  • headaches with focal neurological symptoms or migraines with aura
  • known osteoporosis
  • known or suspected sex hormone–influenced malignancy
  • liver tumour (present or past) or severe liver disease
  • pregnancy, concomitant use of hormonal contraceptives, genital bleeding
  • hypersensitivity to any of the 3 drug components.

An important consideration for prescribing is that, as there are 3 components to the combination medicine, each one may be affected by, or affect, other drugs whose metabolism involves cytochrome P450 enzymes or p-glycoprotein. The relevance of this is many other drugs potentially can influence contraceptive efficacy of relugolix combination therapy if co-prescribed. For a full list of precautions and drug interactions, refer to the product information.

After 24 months of relugolix combination therapy, patients should be reassessed and decisions individualised as to its continuation.4

In summary, relugolix+estradiol+norethisterone combination therapy is potentially a valuable nonsurgical option for females with moderate to severe symptomatic uterine fibroids.

This new drug comment was finalised on 29 January 2024. 

🅃 manufacturer provided the product information. The Transparency Score is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.

At the time the comment was prepared, information about this drug was available on the websites of the Food and Drug Administration in the USA, the European Medicines Agency and the Therapeutic Goods Administration.


Australian Prescriber welcomes Feedback.


 The new drug commentaries in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Advisory Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.