How should I manage a 29‑year‑old woman with endometriosis who has been on Orilissa (elagolix) for 11 months and now presents with 3 days of heavy vaginal bleeding and cramping, a negative urine pregnancy test, and a normal pelvic ultrasound performed 20 days ago?

Management of Heavy Vaginal Bleeding in a Patient on Orilissa

This patient's heavy bleeding after 11 months of amenorrhea on Orilissa requires immediate evaluation for pregnancy (already done), structural pathology, and consideration of breakthrough bleeding from the medication itself, with NSAIDs as first-line treatment if no underlying pathology is identified. 1

Initial Evaluation

Although the pelvic ultrasound was normal 20 days ago, you must re-evaluate for new pathologic uterine conditions given the acute change in bleeding pattern after prolonged amenorrhea. 2 The differential diagnosis includes:

• IUD displacement (if applicable) - verify proper placement 2
• Pregnancy complications - already appropriately ruled out with negative urine HCG
• Sexually transmitted infections or pelvic inflammatory disease - obtain cervical cultures 2
• New uterine pathology (polyps, fibroids, adenomyosis) - consider repeat imaging if clinically indicated 2
• Breakthrough bleeding from Orilissa - a known adverse effect 1

Understanding Orilissa's Bleeding Profile

Elagolix (Orilissa) causes dose-dependent changes in menstrual bleeding patterns. 1 Key facts about this medication:

• At 150 mg once daily: 6-17% of women experience amenorrhea during the first 6 months, increasing to 11-15% during months 6-12 1
• At 200 mg twice daily: 13-52% experience amenorrhea during the first 6 months, increasing to 46-57% during months 6-12 1
• Breakthrough bleeding can occur even after prolonged amenorrhea, though this represents a change from her established pattern 1

The fact that this patient was amenorrheic for 11 months and now has heavy bleeding suggests either a medication-related breakthrough bleed or new underlying pathology. 1

Treatment Algorithm

Step 1: Rule Out Serious Pathology

• Perform pelvic examination to assess for cervical/vaginal lesions
• Obtain STI testing (gonorrhea, chlamydia) 2
• Consider repeat pelvic ultrasound if examination is abnormal or bleeding persists beyond 7 days
• Check hemoglobin/hematocrit if bleeding is truly heavy

Step 2: Medical Management if No Pathology Found

NSAIDs are the recommended first-line treatment for heavy bleeding in women on hormonal medications. 2, 3 Specifically:

• Mefenamic acid 500 mg three times daily for 5-7 days 2, 3
• Alternative: Ibuprofen 600-800 mg three times daily for 5-7 days 2

Important: Tranexamic acid should NOT be used in this patient because she is on Orilissa, which can affect lipid metabolism and potentially increase thrombosis risk. 1, 4 The FDA label notes dose-dependent increases in LDL-C and triglycerides with Orilissa, and tranexamic acid carries thrombosis concerns. 1

Step 3: If NSAIDs Fail

Consider short-term combined oral contraceptives (10-20 days) to stabilize the endometrium if the patient has no contraindications to estrogen. 3 However, note that:

• Orilissa is a weak to moderate CYP3A inducer and may decrease effectiveness of hormonal contraceptives 1, 4
• This is a temporizing measure only

Step 4: Reassess Orilissa Continuation

If bleeding persists despite treatment and is unacceptable to the patient, counsel about alternative endometriosis management options. 2 Consider:

• Switching to alternative GnRH therapy (though leuprolide may be more effective for some patients) 5
• Other hormonal options (progestins, oral contraceptives) 6
• Surgical consultation if medical management fails 6

Critical Considerations

Duration of Orilissa therapy matters: The FDA label indicates that the 150 mg once daily dose can be used for up to 24 months, while the 200 mg twice daily dose should be limited to 6 months due to bone mineral density concerns. 1 At 11 months, this patient is within safe duration limits for the lower dose.

Hepatic monitoring: Check liver function tests if not recently done, as Orilissa can cause dose-dependent ALT elevations (1.1% with 200 mg twice daily). 1

Return of menses after stopping: If you decide to discontinue Orilissa, counsel that 77-95% of women resume menses within 1-2 months after stopping the 150 mg dose. 1

Common Pitfalls to Avoid

• Do not assume this is "normal" breakthrough bleeding without excluding new pathology, given the acute change after 11 months of amenorrhea 2
• Do not use tranexamic acid due to thrombosis risk in the context of Orilissa's lipid effects 1
• Do not prescribe aspirin, as it may increase blood loss 3
• Do not ignore the possibility of medication interactions if she started any new medications, particularly strong CYP3A inhibitors (ketoconazole, clarithromycin) which can increase Orilissa levels 2-fold 1, 4