What are the risks associated with Relugolix (GnRH receptor antagonist)?

Relugolix Risks and Safety Profile

Relugolix as monotherapy causes significant hypoestrogenic effects including hot flashes, headaches, hypertension, and bone mineral density loss, but when combined with low-dose estrogen and progestin (add-back therapy), these risks are substantially mitigated while maintaining therapeutic efficacy. 1

Primary Hypoestrogenic Risks

Bone Mineral Density Loss

• Relugolix monotherapy causes dose-dependent bone loss, with the 40-mg dose resulting in a mean BMD decrease of 4.9% over 24 weeks, comparable to leuprorelin's 4.4% decrease 2
• Without add-back therapy, approximately 1% of bone mass is lost per month after onset of hypoestrogenism 3
• Combination treatment with low-dose estrogen and progestin (add-back therapy) minimizes BMD loss over time and is FDA-approved for fibroid-related heavy menstrual bleeding 1, 3

Vasomotor and Systemic Effects

• Hot flashes occur frequently with relugolix monotherapy, with incidence similar to leuprorelin 2, 4
• Headaches are a common hypoestrogenic effect 1
• Hypertension can develop during treatment 1
• These symptoms are substantially reduced with add-back therapy 3, 5

Reproductive and Fertility Risks

Active Fertility Suppression

• Fertility is actively suppressed during relugolix treatment, though the medication is often chosen by patients interested in uterus-preserving therapy or future fertility preservation 6
• Male patients with female partners of reproductive potential must use effective contraception during treatment and for 2 weeks after the last dose 7
• Relugolix may impair fertility in males of reproductive potential based on animal studies and mechanism of action 7

Menstrual Irregularities

• Metrorrhagia (irregular uterine bleeding) and menorrhagia (heavy menstrual bleeding) occur with relugolix treatment 2, 4
• Irregular menstruation is a common adverse event 4

Pregnancy and Lactation Risks

Fetal Harm

• Relugolix can cause fetal harm and loss of pregnancy when administered to pregnant females based on animal studies 7
• In animal reproduction studies, oral administration to pregnant rabbits during organogenesis caused embryo-fetal lethality at maternal exposures 0.3 times the human exposure at 120 mg daily 7
• Abortion, total litter loss, or decreased number of live fetuses occurred in animal studies 7

Lactation Concerns

• Relugolix and/or its metabolites were present in milk of lactating rats at concentrations up to 10-fold higher than plasma at 2 hours post-dose 7
• No human data exist on presence in breast milk or effects on breastfed children 7

Drug Interaction Risks

P-glycoprotein (P-gp) Inhibitors

• Co-administration with oral P-gp inhibitors increases relugolix exposure, which may increase the risk of adverse reactions 7
• Avoid co-administration with oral P-gp inhibitors; if unavoidable, take relugolix first and wait at least 6 hours before taking the P-gp inhibitor 7
• If an oral P-gp inhibitor will only be administered for up to 2 weeks, relugolix may be interrupted while the P-gp inhibitor is being administered 7

Combined P-gp and Strong CYP3A Inducers

• Co-administration decreases relugolix exposure, which may reduce therapeutic effects 7
• Avoid co-administration; if unavoidable, increase the relugolix dose 7

Common Adverse Events

Gastrointestinal Effects

• Diarrhea occurs in 12% of patients (Grade 3-4: 0.2%) 7
• Constipation occurs in 12% of patients 7

Musculoskeletal Effects

• Musculoskeletal pain occurs in 30% of patients (Grade 3-4: 1.1%) 7

General Effects

• Fatigue and asthenia occur in 26% of patients (Grade 3-4: 0.3%) 7

Less Common but Clinically Relevant

• Increased weight, insomnia, gynecomastia, hyperhidrosis, depression, and decreased libido occur in <10% of patients 7

Laboratory Abnormalities

Metabolic Changes

• Glucose increased in 44% of patients (Grade 3-4: 2.9%) 7
• Triglycerides increased in 35% of patients (Grade 3-4: 2%) 7
• ALT increased in 27% of patients (Grade 3-4: 0.3%) 7
• AST increased in 18% of patients 7

Hematologic Changes

• Hemoglobin decreased in 28% of patients (Grade 3-4: 0.5%) 7

Postmarketing Adverse Reactions

Hypersensitivity Reactions

• Angioedema and urticaria have been reported in post-approval use 7

Critical Clinical Pitfalls

Rapid Symptom Recurrence

• Cessation of therapy leads to rapid recurrence of symptoms, making relugolix unsuitable as a definitive long-term solution without add-back therapy 1
• Transition to definitive therapy (surgical options or UAE) should be considered if symptoms recur rapidly after discontinuation 6

Duration Limitations

• Relugolix is commonly used for short courses to decrease fibroid size in preparation for surgery rather than indefinite management 1

Cost Considerations

• Add-back regimens increase the overall cost of therapy but are essential for long-term management to mitigate hypoestrogenic effects 3