GnRH Antagonist + HRT Add-Back Combination Pregnancy: CONTRAINDICATED — GnRH suppression + HRT combination; effective contraception must be used if pregnancy is possible (relugolix monotherapy does not reliably prevent pregnancy)

Relugolix/Estradiol/Norethisterone (Combination)

Brand names: Ryeqo

Adult dose

Dose: 1 tablet once daily (relugolix 40 mg + estradiol 1 mg + norethisterone acetate 0.5 mg)

Route: Oral

Frequency: Once daily

Max: 1 tablet/day

Moderate-severe symptoms of uterine fibroids in premenopausal women; continuous add-back HRT incorporated into single tablet — no bone loss issue; MHRA 2022 approved

Paediatric dose

Dose: Not applicable — premenopausal adult women only N/A/kg

Route: N/A

Frequency: N/A

Max: N/A

Not licensed in paediatrics

Dose adjustments

Renal

No dose adjustment required

Hepatic

Contraindicated in liver disease or history of hormone-related liver tumour

Paediatric weight-based calculator

Patient weight (kg)

Not licensed in paediatrics

Clinical pearls

LIBERTY trials (Watts et al. NEJM 2020): relugolix combination tablet significantly reduced heavy menstrual bleeding and fibroid-related pain vs placebo over 24 weeks with preservation of bone density — pivotal for MHRA 2022 approval
Innovative fixed-dose combination concept: GnRH antagonist (relugolix) provides rapid, non-flare oestrogen suppression while incorporated add-back (E2 + NET) maintains bone protection and reduces vasomotor symptoms — single tablet daily improves adherence
Bone mineral density: maintained at near-baseline throughout treatment duration (unlike GnRH agonist monotherapy) — suitable for extended treatment beyond 6 months without DEXA monitoring requirement
Immediate reversibility: GnRH antagonist property — menstrual cycles return promptly after stopping (median 35 days); allows flexible fertility planning around treatment
MHRA 2022: first combination GnRH antagonist + add-back HRT in single tablet licensed for fibroids in the UK; NICE TA826 positive appraisal; represents significant advance over Esmya (liver injury) and injectable GnRH agonists

Contraindications

Undiagnosed vaginal bleeding
Thromboembolic disorders (current or history)
Known/suspected hormone-dependent cancers
Severe hepatic impairment
Pregnancy or breastfeeding

Side effects

Hot flushes (substantially reduced vs GnRH agonist monotherapy due to add-back)
Headache
Nausea
Hair loss (norethisterone component)
Irregular breakthrough bleeding (first 3 months)
Thromboembolic risk (norethisterone component)

Interactions

P-gp and CYP3A4 inhibitors — avoid with strong P-gp inhibitors; may increase relugolix exposure
P-gp inducers (rifampicin, carbamazepine) — reduce relugolix levels; avoid
Antacids — take relugolix separately from antacids

Monitoring

Fibroid size response (ultrasound at 3 months if symptomatic)
Blood pressure
Menstrual pattern
VTE risk factors (norethisterone component)
BMD (only if additional risk factors)

Reference: BNFc; BNF 90; LIBERTY 1 & 2 trials (Watts et al. NEJM 2020); NICE TA826; MHRA SPC Ryeqo 2022; Al-Hendy et al. NEJM 2021 (replicate trial). Verify against your local formulary and the latest BNF before prescribing.

Curated clinical cross-links plus same-class fallbacks.

Calculators