Can a patient (e.g., a man with metastatic prostate cancer or a woman with endometriosis or uterine fibroids) safely switch from leuprolide (leuprorelin) to relugolix without a wash‑out period, and what dosing and monitoring are needed?

Switching from Leuprolide to Relugolix

Patients can safely switch directly from leuprolide to relugolix without a washout period, as relugolix provides rapid testosterone suppression within 24 hours and avoids the testosterone surge associated with GnRH agonists. 1, 2

Direct Switching Protocol

Timing of Transition

• Initiate relugolix at the time the next leuprolide injection would be due (i.e., when the previous depot formulation is expected to lose efficacy) 2
• Administer relugolix loading dose of 360 mg on day 1, followed by 120 mg once daily 1, 2
• No washout period is required because relugolix achieves castrate testosterone levels (<50 ng/dL) within 24-48 hours, preventing any testosterone rebound 2

Key Advantages of This Approach

• Relugolix is a GnRH receptor antagonist that causes immediate testosterone suppression without the initial testosterone surge (flare phenomenon) seen with GnRH agonists like leuprolide 2
• The rapid onset eliminates the risk of disease flare during transition that could occur with a washout period 2
• Oral administration improves convenience and eliminates injection-site complications (such as the subcutaneous abscess risk documented with leuprolide) 3

Monitoring Requirements

Testosterone Levels

• Measure serum testosterone at 4 weeks after switching to confirm castrate levels (<50 ng/dL) 1, 2
• Continue monitoring testosterone every 3-6 months to ensure sustained castration 1

PSA Monitoring

• Check PSA at 4-8 weeks after switching, then every 3 months 1, 3
• PSA should remain stable or continue declining; any rise suggests treatment failure or progression to castration-resistant disease 4

Cardiovascular Assessment

• Relugolix demonstrates significantly lower risk of major adverse cardiovascular events compared to leuprolide (HR 0.46,95% CI 0.24-0.88) 1, 2
• Monitor blood pressure regularly, as hypertension can occur with androgen deprivation 5
• Assess cardiovascular risk factors at baseline and periodically, particularly in patients with pre-existing cardiac disease 1, 2

Disease-Specific Considerations

Metastatic Prostate Cancer

• Castration resistance-free survival is equivalent between relugolix and leuprolide (74.3% vs 75.3% at 48 weeks, HR 1.03) 4
• Continue concurrent therapies (abiraterone, enzalutamide, apalutamide, or darolutamide) without interruption during the switch 1, 3
• The combination of relugolix plus enzalutamide has demonstrated sustained PSA suppression and good tolerability 3

Endometriosis or Uterine Fibroids (Women)

• Switch timing follows the same principle: start relugolix when the next leuprolide injection is due 1
• Add-back therapy with low-dose estrogen and progestin is FDA-approved and essential for long-term use to prevent bone mineral density loss and mitigate hypoestrogenic symptoms 1, 5, 6
• Without add-back therapy, bone mineral density decreases by 4.9% over 24 weeks 5

Critical Clinical Pitfalls to Avoid

Do Not Create a Washout Gap

• Avoid any gap between stopping leuprolide and starting relugolix, as this allows testosterone recovery and potential disease flare in prostate cancer or symptom recurrence in gynecologic conditions 2
• The traditional washout periods recommended when switching between biologics or immunosuppressives (4 times the terminal half-life) do not apply here because relugolix's mechanism prevents testosterone surge 1

Bone Health Management

• Initiate calcium (1200 mg daily) and vitamin D (800-1000 IU daily) supplementation at the time of switch 5
• Consider baseline DEXA scan if planning long-term therapy (>6-12 months), particularly in women or men with additional osteoporosis risk factors 5
• For women, add-back therapy substantially mitigates bone loss while maintaining therapeutic efficacy 5, 6

Medication Adherence

• Oral daily administration requires different adherence patterns than quarterly injections 2
• Counsel patients that missing doses can lead to rapid testosterone recovery (within 4 days of discontinuation) and loss of disease control 2
• Consider pill organizers, smartphone reminders, or pharmacy adherence programs 2

Cost Considerations

• Relugolix costs approximately $11,550-12,858 per 6 months compared to leuprolide depot at $1,235 per 6 months 1
• Verify insurance coverage and prior authorization requirements before switching 1
• For women requiring add-back therapy, factor in additional costs of estrogen-progestin combination 5

Contraindications and Special Populations

When NOT to Switch

• Patients with documented poor oral medication adherence should remain on injectable depot formulations 2
• Pregnancy (both medications are contraindicated; verify negative pregnancy test in women of childbearing potential before switching) 1

Patients Who Benefit Most from Switching

• Those with cardiovascular disease or high cardiovascular risk (relugolix shows superior cardiac safety profile) 1, 2
• Patients experiencing injection-site reactions or complications with leuprolide 3
• Those preferring oral over injectable therapy 2
• Women requiring long-term therapy who can benefit from add-back regimens 5, 6