Relugolix (Monograph)

Brand name: Orgovyx
Drug class: Antigonadotropins
Chemical name: 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea
Molecular formula: C₂₉H₂₇F₂N₇O₅S
CAS number: 737789-87-6

Medically reviewed by Drugs.com on Nov 6, 2023. Written by ASHP.

Introduction

Antineoplastic agent; gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone [LHRH], gonadorelin) antagonist.

Uses for Relugolix

Prostate Cancer

Treatment of advanced prostate cancer.

Medical castration (defined as serum total testosterone concentration <50 ng/dL) achieved sooner with relugolix compared with leuprolide.

Relugolix Dosage and Administration

General

Pretreatment Screening

Weigh benefits of androgen deprivation therapy against potential risks in patients with congenital long QT syndrome, CHF, or frequent electrolyte abnormalities, and in patients receiving drugs known to prolong the QT interval.
Correct electrolyte abnormalities.

Patient Monitoring

Consider periodic monitoring of ECGs and electrolytes.
Periodically measure prostate-specific antigen (PSA) concentrations to monitor response to the drug.
If serum PSA concentrations increase, measure serum testosterone concentrations.

Administration

Oral Administration

Administer orally once daily at approximately the same time each day without regard to food. Swallow tablets whole; do not crush or chew.

If a dose is missed, administer the missed dose as soon as it is remembered. If a dose is missed by >12 hours, do not administer the missed dose; instead, resume therapy with the next scheduled dose.

If concomitant therapy with an oral P-glycoprotein (P-gp) inhibitor is unavoidable, administer relugolix at least 6 hours before administration of the P-gp inhibitor.

Dosage

Adults

Prostate Cancer

Oral

Initial loading dose of 360 mg, followed by 120 mg once daily. Following development of nonmetastatic or metastatic castration-resistant prostate cancer, therapy with GnRH receptor agonists and antagonists usually is continued.

If relugolix therapy is interrupted for >7 days, reinitiate treatment with 360 mg on the first day, followed by 120 mg once daily.

May interrupt relugolix therapy for up to 2 weeks if short-term P-gp inhibitor therapy is required.

Dosage adjustment required if used concomitantly with a combined P-gp inducer and potent CYP3A inducer. Increase relugolix dosage to 240 mg once daily; following discontinuance of concomitant therapy, reduce relugolix dosage to 120 mg daily.

Special Populations

Manufacturer makes no special population dosage recommendations.

Cautions for Relugolix

Contraindications

Manufacturer states none known.

Warnings/Precautions

Prolongation of QT Interval

Androgen deprivation therapy may prolong the QT interval.

Weigh benefits of androgen deprivation therapy against potential risks in patients with congenital long QT syndrome, CHF, or frequent electrolyte abnormalities and in patients receiving drugs known to prolong the QT interval.

Correct electrolyte abnormalities and consider periodic monitoring of ECGs and electrolytes.

In a study in healthy individuals, no increase in mean QT interval corrected for rate (QT_c) of >10 msec observed following single 60- or 360-mg dose of relugolix.

Fetal/Neonatal Morbidity and Mortality

Safety and efficacy of relugolix not established in females. May cause fetal harm and loss of pregnancy; embryofetal lethality (abortion, total litter loss, decreased number of live fetuses) demonstrated in animals.

Advise patients of potential for fetal harm and loss of pregnancy. Advise men who have female partners of reproductive potential to use effective methods of contraception during relugolix therapy and for 2 weeks after the last dose of the drug.

Laboratory Monitoring

Periodically measure prostate-specific antigen (PSA) concentrations to monitor response to the drug. If serum PSA concentrations increase, measure serum testosterone concentrations.

Laboratory Test Interferences

Relugolix therapy suppresses pituitary-gonadal system; may affect results of diagnostic tests of pituitary gonadotropic and gonadal functions performed during and after therapy.

Effects on Fertility

Based on animal studies and mechanism of action, relugolix may impair fertility in males of reproductive potential.

Specific Populations

Pregnancy

Safety and efficacy not established in females. No data on use in pregnant women; however, based on animal studies and mechanism of action, relugolix can cause fetal harm.

Lactation

Safety and efficacy at recommended dosage of 120 mg daily not established in females. Not known whether relugolix distributes into human milk, affects breast-fed infants, or affects milk production. Relugolix and/or its metabolites distribute into milk in rats.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

In primary prostate cancer efficacy study, 81% of patients receiving relugolix were ≥65 years of age and 35% were ≥75 years of age. No overall differences in safety or efficacy observed between geriatric patients and younger adults.

Population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses in men 45–91 years of age revealed no clinically important effects of age on pharmacokinetics or testosterone response to therapy.

Hepatic Impairment

No clinically important differences in pharmacokinetics of relugolix observed in patients with mild to moderate hepatic impairment (Child-Pugh class A or B). Effect of severe hepatic impairment (Child-Pugh class C) on pharmacokinetics of relugolix not established.

Renal Impairment

No clinically important differences in pharmacokinetics of relugolix observed in patients with mild to severe renal impairment (Cl_cr15–89 mL/minute). Effect of end-stage renal disease with or without hemodialysis on pharmacokinetics of relugolix not established.

Common Adverse Effects

Adverse effects or laboratory abnormalities reported in ≥10 or ≥15%, respectively: Hot flush, musculoskeletal pain, fatigue, constipation, increased glucose concentrations, increased triglyceride concentrations, decreased hemoglobin, increased ALT and AST concentrations.

Drug Interactions

Substrate of CYP3A and CYP2C8. Does not inhibit CYP isoenzyme 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4. Induces CYP3A and CYP2B6; does not induce CYP1A2.

Substrate and inhibitor of P-gp. Inhibitor but not a substrate of breast cancer resistance protein (BCRP). Does not inhibit organic anion transport protein (OATP) 1B1 or 1B3, organic anion transporter (OAT) 1 or 3, organic cation transporter (OCT) 2, multidrug and toxin extrusion transporter (MATE) 1 or 2-K, or bile salt export pump (BSEP).

Drugs Affecting P-gp Transport System

Oral P-gp inhibitors: Increased peak plasma concentrations and AUC of relugolix, which may increase risk of adverse effects. Intestinal P-gp efflux is the primary determinant of relugolix absorption and oral bioavailability. Inhibition of intestinal P-gp efflux appears to be primarily responsible for the increase in relugolix exposure following simultaneous administration of an oral P-gp inhibitor. Avoid concomitant use; if concomitant use cannot be avoided, administer relugolix at least 6 hours before the P-gp inhibitor and monitor more frequently for adverse effects. May interrupt relugolix therapy for up to 2 weeks if short-term P-gp inhibitor therapy required.

Drugs Affecting Hepatic Microsomal Enzymes and P-gp Transport System

Combined P-gp inducer and potent CYP3A inducer: Decreased relugolix exposure, which may reduce efficacy. Avoid concomitant use. If concomitant use cannot be avoided, increase relugolix dosage to 240 mg once daily; following discontinuance of concomitant therapy, reduce relugolix dosage to 120 mg daily.

Specific Drugs

Drug	Interaction	Comments
Acid suppressants (e.g., proton-pump inhibitors, histamine H₂-receptor antagonists)	No clinically important effects on pharmacokinetics of relugolix
Atorvastatin	No clinically important effects of atorvastatin (weak CYP3A inhibitor) on pharmacokinetics of relugolix
Enzalutamide	No clinically important effects on pharmacokinetics of relugolix
Erythromycin	Erythromycin (potent P-gp inhibitor and moderate CYP3A inhibitor) increased AUC and peak plasma concentration of relugolix by 6.2-fold	Avoid concomitant use; if concomitant use required, administer relugolix at least 6 hours before oral erythromycin and monitor more frequently for adverse effects May interrupt relugolix therapy for up to 2 weeks if short-term P-gp inhibitor therapy required
Midazolam	No clinically important effects on pharmacokinetics of midazolam (CYP3A substrate)
Rifampin	Rifampin (P-gp inducer and potent CYP3A inducer) decreased AUC and peak plasma concentrations of relugolix by 55 and 23%, respectively	Avoid concomitant use; if concomitant use required, increase relugolix dosage to 240 mg once daily; following discontinuance of rifampin, reduce relugolix dosage to 120 mg once daily
Rosuvastatin	No clinically important effects on pharmacokinetics of rosuvastatin (BCRP substrate)
Voriconazole	No clinically important effects of voriconazole (potent CYP3A inhibitor without P-gp inhibitory activity) on pharmacokinetics of relugolix

Relugolix Pharmacokinetics

Absorption

Bioavailability

Intestinal P-gp efflux is primary determinant of relugolix absorption and oral bioavailability. Following oral administration, mean absolute bioavailability is approximately 12%; peak concentrations are achieved at a median of 2.25 hours.

With once-daily oral administration, accumulation of relugolix is approximately twofold.

Food

Administration with high-calorie, high-fat meal decreases relugolix absorption by approximately 20%; effect not considered clinically important.

Distribution

Extent

Distributes into milk in rats.

Plasma Protein Binding

68–71% bound to plasma proteins (mainly albumin and to a lesser extent α₁-acid glycoprotein).

Elimination

Metabolism

Metabolized mainly by CYP3A and to a lesser extent by CYP2C8 and other minor pathways.

Elimination Route

Excreted mainly as metabolites in feces (81%) and urine (4.1%); only about 6.4% of dose is recovered as unchanged drug.

Half-life

Mean effective half-life: 25 hours.

Mean terminal elimination half-life: Approximately 61 hours.

Special Populations

Age (45–91 years), race/ethnicity, body weight (41–193 kg), mild to severe renal impairment (Cl_cr 15–89 mL/minute), and mild to moderate hepatic impairment (Child-Pugh class A or B) have no clinically important effects on pharmacokinetics.

Stability

Storage

Oral

Tablets

Room temperature (≤30°C). Dispense in original container only. Keep bottle tightly closed after first opening.

Actions

Oral nonpeptide GnRH antagonist.
Rapidly, competitively, and reversibly binds to and blocks GnRH receptors in the pituitary, thereby reducing the release of gonadotropins (i.e., LH, FSH) and, consequently, testosterone without initial stimulation of the hypothalamic-pituitary-gonadal axis and the associated testosterone surge.

Advice to Patients

Importance of reading the manufacturer's patient information for relugolix.
Advise patients that relugolix may prolong the QT interval and that they should contact their clinician immediately if signs or symptoms of QT-interval prolongation (e.g., dizziness, fainting, palpitations, chest pain) occur.
Risk of hot flushes, flushing of the skin, weight gain, decreased sex drive, and difficulties with erectile function.
Potential for relugolix to cause fetal harm and loss of pregnancy. Advise male patients with female partners of reproductive potential that they should use effective methods of contraception during relugolix therapy and for 2 weeks after the last dose of the drug.
Inform patients that relugolix may cause infertility in males.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.