Free special edition 2023

MARKETING AUTHORISATIONS

NEW SUBSTANCE, NEW COMBINATION Relugolix + estradiol + norethisterone ( ryeqo °) in uterine fibroids A risky hormone cocktail

EDITORS’ OPINION

Cascade An imaginary scenario: when the fictional pharmaceutical company

MultiCombin suggested preventing the adverse effects of gizmoline by adding noxiozine , they still needed to prevent noxiozine ’s adverse effects. They soon found a solution: adding a third drug! It may sound far-fetched, yet that was the thinking behind the development and author isation of the combination of relugolix + estra diol + norethisterone (Ryeqo°) as a treatment for uterine fibroids (see opposite). To prevent the adverse effects of the hypoestrogenism caused by the GnRH antagonist relugolix , the company added the oestrogen estradiol . And to prevent the adverse effects of oestrogen on the endometrium, in particular the risk of cancer, it added the progestogen norethis terone . As a result, pre-menopausal women taking this combination are at risk of both the adverse effects of hypoestrogenism, which are similar to the effects of menopause, and those of postmenopausal hormone replace ment therapy with an oestrogen + progesto gen combination. Piling up drugs in this way, and the ensuing cascade of adverse effects, might be accept able if efficacy had been demonstrated and outweighed the risks. But that is far from the case for this three-drug combination. It is sometimes in patients’ interests to take a drug to relieve the adverse effects of another, very useful, drug. But before layering drug upon drug, the first step is to carefully consider how useful the first drug in the pile is to patients. Surely forgoing a drug of little value, rather than attempting to mitigate its adverse effects, is less dangerous and more beneficial for patients. ©Prescrire

NOT ACCEPTABLE The three-drug combination of relugolix + estradiol + norethisterone was mainly evaluated in two placebo-­ controlled trials. It markedly reduced

menstrual bleeding inmost women, but not fibroids, and no conclusive evidence of effects on other symptoms was obtained. Its adverse effects were mostly symptoms of menopause, including loss of bone mineral density, as well as hypertension and alopecia. Nothing is known of the long-termeffects of this treatment: in clinical trials, only 32 patients were treated for 2 years. In practice, it is more prudent to continue using treatments with better-established harms and benefits (despite their limitations), and to avoid exposing patients to this risky hormone cocktail. RYEQO° - relugolix + estradiol + norethisterone tablets • 40mg of relugolix + 1mg of estradiol + 0.5mg of norethisterone per tablet Gedeon Richter ■ Gonadorelin (GnRH) receptor antagonist + oestrogen progestogen hormone replacement ■ Indication : “ moderate to severe symptoms of uterine fibroids in adult women of reproductive age ”. [EUmarketing authorisation, cen tralised procedure] ■ Dosage : 1 tablet perday. “ The first tabletmust be takenwithin 5days of the onset of menstrual bleeding ”, given the risk of irregular heavy bleeding at the start of treatment when initiated on other days of the menstrual cycle.

Excerpt from Prescrire Int January 2023 Full article (4 pages) available to subscribers at english.prescrire.org

Prescrire Int • January 2023

Prescrire International Special Edition 2023 • Page 5