AHFS Class:

• Antigonadotropins 68:18.04

Generic Name(s):

• Relugolix

Relugolix, a gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone [LHRH], gonadorelin) antagonist, is used as an antineoplastic agent.1,2,3,4

Prostate Cancer

Relugolix is used for the treatment of advanced prostate cancer in adults.1,2

Clinical Experience

Efficacy of relugolix for this indication was established in a randomized, open-label study (HERO) in 930 men, 47-97 years of age, with advanced prostate cancer who required at least one year of continuous androgen deprivation therapy.1,2 The study included patients with evidence of biochemical (i.e., increasing prostate-specific antigen [PSA] concentration) or clinical relapse after local primary intervention with curative intent, newly diagnosed hormone-sensitive metastatic disease, or advanced localized disease unlikely to be cured by local primary intervention.1,2 Patients were randomized in a 2:1 ratio to receive oral relugolix (initial dose of 360 mg, followed by 120 mg once daily) or leuprolide acetate (22.5 mg [or 11.25 mg in Japan and Taiwan] by subcutaneous injection every 3 months) for 48 weeks.1,2 Prostate cancer was metastatic, locally advanced, or localized at baseline in 32, 31, or 28%, respectively, of patients; the median baseline testosterone concentration was 408 ng/dL.1 The primary end point was sustained suppression of testosterone to castration levels (defined as testosterone concentration less than 50 ng/dL) from day 29 through week 48.1,2

Sustained medical castration was achieved in 96.7% of patients receiving relugolix and 88.8% of those receiving leuprolide.1,2 Patients receiving relugolix attained medical castration sooner than those receiving leuprolide.1,2 Medical castration was attained by day 4, 8, 15, or 29 of treatment in 56, 91, 99, or 99%, respectively, of relugolix-treated patients compared with 0, 0, 12, or 82%, respectively, of leuprolide-treated patients.1 PSA concentrations decreased by 65, 83, or 92% following 2 weeks, 4 weeks, or 3 months, respectively, of therapy with relugolix and remained suppressed throughout 48 weeks of treatment; however, PSA results should be interpreted with caution because of the heterogeneity of the study population and because the rapidity of the reduction in PSA concentrations has not been shown to correlate with clinical benefit.1 At 90 days after relugolix therapy was discontinued, testosterone concentrations exceeded the lower limit of normal (i.e., greater than 280 ng/dL) or baseline values in 55% of patients who received no androgen deprivation therapy during the 90-day period following discontinuance of relugolix.1

General

Pretreatment Screening

• Weigh benefits of androgen deprivation therapy against potential risks in patients with congenital long QT syndrome, congestive heart failure (CHF), or frequent electrolyte abnormalities, and in patients receiving drugs known to prolong the QT interval.1
• Correct electrolyte abnormalities.1

Patient Monitoring

• Consider periodic monitoring of ECGs and electrolytes.1
• Periodically measure prostate-specific antigen (PSA) concentrations to monitor response to the drug.1
• If serum PSA concentrations increase, measure serum testosterone concentrations.1

Administration

Relugolix is administered orally with a loading dose on the first day followed by once daily dosing at approximately the same time each day without regard to food.1

The tablets should be swallowed whole and not crushed or chewed.1

If a dose is missed, the missed dose should be taken as soon as it is remembered.1 However, if a dose is missed by more than 12 hours, the missed dose should not be taken and therapy should be resumed with the next scheduled dose.1

The tablets should be stored at room temperature (not above 30ºC).1

Dosage

Prostate Cancer

The recommended adult dosage of relugolix for the treatment of advanced prostate cancer is an initial loading dose of 360 mg, followed by 120 mg once daily.1 If relugolix therapy is interrupted for more than 7 days, treatment should be reinitiated with a loading dose of 360 mg on the first day, followed by 120 mg once daily.1 Following development of nonmetastatic or metastatic castration-resistant prostate cancer, therapy with gonadotropin-releasing hormone (GnRH) receptor agonists and antagonists usually is continued.1

Dosage Modifications with P-gp Inhibitor Use

Concomitant use of relugolix with oral P-gp inhibitors should be avoided.1 If concomitant use is unavoidable, relugolix should be administered first and separated from the P-gp inhibitor by at least 6 hours.1 Relugolix therapy may be interrupted for up to 2 weeks if short-term therapy with a P-gp inhibitor is required.1

Dosage Modifications with Combined P-gp and Strong CYP3A Inducer Use

Concomitant use of relugolix with a combined P-gp and strong cytochrome P-450 isoenzyme 3A (CYP3A) inducer should be avoided.1 If concomitant use is unavoidable, relugolix dosage should be increased to 240 mg once daily.1 The recommended relugolix dosage of 120 mg once daily should be resumed after discontinuation of the combined P-gp and strong CYP3A inducer.1

Special Populations

The manufacturer makes no special population dosage recommendations at this time.1

Contraindications

• Severe hypersensitivity to relugolix or any of its components.1

Warnings/Precautions

Prolongation of QT Interval

Androgen deprivation therapy, such as relugolix therapy, may prolong the QT interval.1 The benefits of androgen deprivation therapy should be weighed against the potential risks in patients with congenital long QT syndrome, congestive heart failure, or frequent electrolyte abnormalities, and in those taking drugs known to prolong the QT interval.1 Electrolyte abnormalities should be corrected, and periodic monitoring of electrocardiograms (ECGs) and electrolytes should be considered.1

Hypersensitivity Reactions

In the postmarketing setting, hypersensitivity reactions (e.g., pharyngeal edema and other serious cases of angioedema) have been reported with relugolix therapy.1 In the HERO study, angioedema was reported in 0.2% of patients.1 Patients who experience any symptoms of angioedema should temporarily discontinue relugolix and seek immediate medical care.1 If a severe hypersensitivity reaction occurs, discontinue relugolix and manage as clinically indicated.1

Fetal/Neonatal Morbidity and Mortality

Safety and efficacy of relugolix have not been established in females.1 Based on findings in animals and the drug's mechanism of action, relugolix can cause fetal harm and loss of pregnancy when administered to pregnant women.1 In an animal reproduction study, oral administration of relugolix to pregnant rabbits during the period of organogenesis caused embryofetal lethality (abortion, total litter loss, decreased number of live fetuses) at maternal exposures of 0.3 times the human exposure at the recommended dosage of 120 mg daily.1

Patients should be advised of the potential for fetal harm and loss of pregnancy.1 Men who have female partners of reproductive potential should be advised to use effective methods of contraception during relugolix therapy and for 2 weeks after the last dose of the drug.1

Laboratory Testing

Relugolix therapy results in suppression of the pituitary-gonadal system; results of diagnostic tests of pituitary gonadotropic and gonadal functions performed during and after relugolix therapy may be affected.1 To monitor response to relugolix, serum prostate-specific antigen (PSA) concentrations should be measured periodically.1 If serum PSA concentrations increase, serum testosterone concentrations should be measured.1

Specific Populations

Pregnancy

Safety and efficacy of relugolix have not been established in females.1 There are no data on use of relugolix in pregnant women to inform the drug-associated risk; however, based on animal findings and the drug's mechanism of action, relugolix can cause fetal harm.1

Lactation

Safety and efficacy of relugolix at the recommended dosage of 120 mg daily have not been established in females.1 It is not known whether relugolix distributes into human milk, affects breast-fed infants, or affects milk production.1 Relugolix and/or its metabolites are distributed into milk in rats at concentrations up to 10 times higher than 2-hour postdose plasma concentrations.1

Females and Males of Reproductive Potential

Patients should be advised of the potential for fetal harm and loss of pregnancy.1 Men who have female partners of reproductive potential should be advised to use effective methods of contraception during relugolix therapy and for 2 weeks after the last dose.1

Based on findings in animals and the drug's mechanism of action, relugolix may impair fertility in males of reproductive potential.1

Pediatric Use

Safety and efficacy of relugolix in pediatric patients have not been established.1

Geriatric Use

In the primary efficacy study of relugolix for treatment of prostate cancer, 81% of patients receiving relugolix were 65 years of age or older, while 35% were 75 years of age or older.1 No overall differences in safety or efficacy were observed between geriatric patients and younger adults.1 Population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses in men 45-91 years of age revealed no clinically important effects of age on the pharmacokinetics of relugolix or on testosterone response to therapy.1

Hepatic Impairment

No clinically important differences in the pharmacokinetics of relugolix have been observed in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).1 The effect of severe hepatic impairment (Child-Pugh class C) on the pharmacokinetics of relugolix has not been established.1

Renal Impairment

No clinically important differences in the pharmacokinetics of relugolix have been observed in patients with mild to severe renal impairment (creatinine clearance 15-89 mL/minute).1 The effect of end-stage renal disease with or without hemodialysis on the pharmacokinetics of relugolix has not been established.1

Common Adverse Effects

Adverse effects reported in 10% or more of patients receiving relugolix include hot flush, musculoskeletal pain, fatigue, constipation, and diarrhea.1 Laboratory abnormalities reported in 15% or more of patients receiving the drug include increased glucose concentrations, increased triglyceride concentrations, decreased hemoglobin, and increased ALT and AST concentrations.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Relugolix is a substrate of cytochrome P-450 (CYP) isoenzymes 3A and 2C8.1 Relugolix is not an inhibitor of CYP isoenzyme 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4.1 Relugolix induces CYP3A and CYP2B6, but does not induce CYP1A2.1

Concomitant administration of relugolix with voriconazole (potent CYP3A inhibitor without P-gp inhibitory activity) or atorvastatin (weak CYP3A inhibitor) did not result in clinically important effects on the pharmacokinetics of relugolix.1,3

Concomitant administration of relugolix with midazolam (sensitive CYP3A substrate) did not result in clinically important effects on the pharmacokinetics of midazolam.1,3

Drugs Affecting or Affected by Transport Systems

Relugolix is a substrate and an inhibitor of P-glycoprotein (P-gp).1 Relugolix also is an inhibitor but not a substrate of breast cancer resistance protein (BCRP).1 Relugolix 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).1

Concomitant administration of relugolix with rosuvastatin (BCRP substrate) did not result in clinically important effects on the pharmacokinetics of rosuvastatin.1

P-glycoprotein Inhibitors

Intestinal P-gp efflux is the primary determinant of relugolix absorption and oral bioavailability.3 Concomitant administration of relugolix and an oral P-gp inhibitor increases peak plasma concentration and area under the serum concentration-time curve (AUC) of relugolix, which may increase the risk of adverse effects.1 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.3

Concomitant use of relugolix and oral P-gp inhibitors should be avoided.1,3 If such concomitant use cannot be avoided, relugolix should be administered at least 6 hours before administration of the P-gp inhibitor, and the patient should be monitored more frequently for adverse effects.1,3 Relugolix therapy may be interrupted for up to 2 weeks if short-term therapy with a P-gp inhibitor is required.1,3

Drugs Affecting Hepatic Microsomal Enzymes and Transport Systems

Concomitant administration of relugolix with erythromycin (a potent P-gp inhibitor and moderate CYP3A inhibitor) increased the AUC and peak plasma concentration of relugolix by 6.2-fold.1,3

Concomitant use of relugolix with combined P-gp inducers and potent CYP3A inducers decreases exposure to relugolix, which may reduce efficacy of the drug.1 When relugolix was administered concomitantly with rifampin (P-gp inducer and potent CYP3A inducer), the AUC and peak plasma concentration of relugolix were decreased by 55 and 23%, respectively.1 Concomitant use of relugolix with combined P-gp inducers and potent CYP3A inducers should be avoided.1,3 If relugolix must be used concomitantly with both a P-gp inducer and a potent CYP3A inducer, relugolix dosage should be increased to 240 mg once daily; following discontinuance of such concomitant therapy, dosage of relugolix should be reduced to 120 mg once daily.1,3

Drugs Affecting Gastric Acidity

Concomitant administration of relugolix with drugs that reduce gastric acidity (e.g., proton-pump inhibitors, histamine H₂-receptor antagonists) did not result in clinically important effects on the pharmacokinetics of relugolix.1,3

Enzalutamide

Concomitant administration of relugolix and enzalutamide did not result in clinically important effects on the pharmacokinetics of relugolix.1,3

Description

Relugolix is an oral nonpeptide gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone, gonadorelin) antagonist.1,2,3,4 The drug rapidly, competitively, and reversibly binds to and blocks GnRH receptors in the pituitary, thereby reducing the release of gonadotropins (i.e., luteinizing hormone [LH], follicle-stimulating hormone [FSH]) and, consequently, testosterone without initial stimulation of the hypothalamic-pituitary-gonadal axis and the associated testosterone surge.1,2,3,4

Relugolix is a substrate for intestinal P-glycoprotein (P-gp).1 Intestinal P-gp efflux is the primary determinant of relugolix absorption and oral bioavailability.3 Following oral administration, mean absolute bioavailability of relugolix is approximately 12%, and peak concentrations are achieved at a median of 2.25 hours.1 With once-daily oral administration, accumulation of relugolix is approximately twofold.1 Although administration with a high-calorie, high-fat meal decreases relugolix absorption by approximately 20%, the effect is not considered clinically important.1,3 Relugolix is 68-71% bound to plasma proteins, mainly to albumin and to a lesser extent to α₁-acid glycoprotein.1 The mean effective half-life of relugolix is 25 hours, and the mean terminal elimination half-life is approximately 61 hours.1 Relugolix is metabolized mainly by CYP3A and to a lesser extent by CYP2C8 and other minor pathways.1,3 Following oral administration of a single 80-mg dose of radiolabeled relugolix, the drug was excreted in feces (81%) and urine (4.1%), mainly as metabolites; unchanged drug accounted for only about 6.4% of the recovered dose.1,3 Age (45-91 years), race/ethnicity, and body weight (41-193 kg) do not have clinically important effects on the pharmacokinetics of relugolix.1

Advice to Patients

• Advise patients to read the manufacturer's patient information for relugolix.1
• 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.1
• Inform patients that relugolix may cause serious hypersensitivity reactions including angioedema.1 Advise patients to discontinue relugolix if hypersensitivity symptoms occur and to promptly contact their clinician.1
• Inform patients of the risk of hot flushes, flushing of the skin, weight gain, decreased sex drive, and difficulties with erectile function.1
• Potential for relugolix to cause fetal harm and loss of pregnancy.1 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.1
• Inform patients that relugolix may cause infertility in males.1
• Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Sumitomo Pharma America, Inc. Orgovyx^® (relugolix) tablets prescribing information. Marlborough, MA. 2023 Aug.

2. Shore ND, Saad F, Cookson MS et al. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med . 2020; 382:2187-2196. [PubMed 32469183]

3. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 214621Orig1s000: Multi-discipline review. From FDA website. [Web]

4. MacLean DB, Shi H, Faessel HM et al. Medical Castration Using the Investigational Oral GnRH Antagonist TAK-385 (Relugolix): Phase 1 Study in Healthy Males. J Clin Endocrinol Metab . 2015; 100:4579-87. [PubMed 26502357]