relugolix (Rx)

>10%

All grades

• Hot flush (54%)
• Glucose increased (44%)
• Triglycerides increased (35%)
• Musculoskeletal pain (30%)
• Hemoglobin decreased (28%)
• ALT increased (27%)
• Fatigue (26%)
• AST increased (18%)
• Diarrhea (12%)
• Constipation (12%)

1-10%

All grades

• Increased weight (<10%)
• Insomnia (<10%)
• Gynecomastia (<10%)
• Hyperhidrosis (<10%)
• Depression (<10%)
• Decreased libido (<10%)

Grade 3-4

• Glucose increased (2.9%)
• Triglycerides increased (2%)
• Musculoskeletal pain (1.1%)

<1%

Grade 3-4

• Hot flush
• Fatigue
• Diarrhea
• ALT increased
• Hemoglobin increased

Postmarketing Reports

Immune system disorders: Hypersensitivity, including angioedema and urticaria

Contraindications

None

Cautions

Based animal studies and mechanism of action, fetal harm may occur

Therapy suppresses pituitary gonadal system; results of diagnostic tests conducted during and after treatment may be affected; monitor therapeutic effect of relugolix by measuring serum concentrations of prostate specific antigen (PSA) periodically; if PSA increases, measure serum testosterone concentrations

Hypersensitivity reactions, including pharyngeal edema and other serious cases of angioedema, reported; advise patients who experience any symptoms of hypersensitivity to temporarily discontinue therapy and promptly seek medical care; discontinue therapy for severe hypersensitivity reactions and manage as clinically indicated

QT/QTc interval prolongation

• Androgen deprivation therapy may prolong QT/QTc interval
• Consider benefits and risks in patients with congenital long QT syndrome, congestive heart failure, or frequent electrolyte abnormalities, and those taking drugs known to prolong QT interval
• Correct electrolyte abnormalities
• Consider periodic ECG and electrolyte monitoring

Drug interaction overview

• CYP enzymes: Substrate of CYP3A (primarily) and CYP2C8 (minor)
• Transporter systems: Substrate of P-gp; inhibitor of BCRP and P-gp

• P-gp inhibitors

  • Avoid coadministration
  • Coadministration increases relugolix AUC and peak plasma concentration; if unable to avoid, adjust time between dosing relugolix and the P-gp inhibitor

• Combined P-gp and strong CYP3A inducers

  • Avoid coadministration
  • Coadministration decreases relugolix AUC and peak plasma concentration; if unable to avoid, adjust relugolix dose

Pregnancy

Based on findings in animals and mechanism of action, can cause fetal harm and loss of pregnancy when administered to pregnant females

Human data are unavailable

Animal studies

• Administration to pregnant rabbits during organogenesis caused embryofetal lethality at maternal exposures that were 0.3 times the human exposure at the recommended dose of 120 mg daily based on AUC

Contraception

• Males with female partners of reproductive potential: Use effective contraception during treatment and for 2 weeks after last dose

Infertility

• Based on findings in animals and mechanism of action, may impair fertility in males of reproductive potential

Lactation

Data are unavailable on presence in human milk, effects on breastfed children, or effects on milk production

Relugolix and/or its metabolites were present in milk of lactating rats at concentrations up to 10-fold higher than in plasma at 2 hr post dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Gonadotropin-releasing hormone (GnRH) receptor antagonist; binds to and blocks GnRH receptors in the anterior pituitary gland

Blocking GnRH receptors decreases the release of gonadotropins (ie, luteinizing hormone, follicle stimulating hormone), thereby decreasing the downstream production of testosterone by the testes in men

Absorption

Absolute bioavailability: ~12%

Peak plasma time: 2.25 hr

Peak plasma concentration

• 360 mg: 215 ng/mL
• 120 mg: 70 ng/mL

AUC

• 360 mg: 985 nghr/mL
• 120 mg: 407 nghr/mL

Distribution

Protein bound: 68-71%; albumin (primarily), alpha1-acid glycoprotein (less extent)

Blood/plasma ratio: 0.78

Metabolism

Metabolized primarily by CYP3A and to lesser extent by CYP2C8 in vitro

Elimination

Half-life: 25 hr; terminal half-life 60.8 hr

Total clearance: 29.4 L/hr

Renal clearance: 8 L/hr

Excretion: Feces (81%; 4.2 unchanged); urine (4.1%; 2.2 unchanged)

Oral Administration

Take at approximately the same time each day

May take with or without food

Swallow tablets whole; do not crush or chew

Patients treated with GnRH receptor agonists and antagonists for prostate cancer is usually continued upon development of nonmetastatic or metastatic castration-resistant prostate cancer

Missed dose

• Take missed dose as soon as remembered
• Dose missed by >12 hours: Do not take missed dose; resume with next scheduled dose
• Treatment interrupted for >7 days: Restart with 360-mg loading dose on first day, and then continue 120 mg qDay

Storage

Store at room temperature; not to exceed 30ºC (86ºF)

Dispense in original container only

For bottles, keep container tightly closed after first opening