ORGOVYX Film-coated tablet Ref.[27984] Active ingredients: Relugolix

5.1 QT/QTc Interval Prolongation

Androgen deprivation therapy, such as ORGOVYX may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, or frequent electrolyte abnormalities and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes [see Clinical Pharmacology (12.2)].

5.2 Embryo-Fetal Toxicity

The safety and efficacy of ORGOVYX have not been established in females. Based on findings in animals and mechanism of action, ORGOVYX can cause fetal harm and loss of pregnancy when administered to a pregnant female. In an animal reproduction study, oral administration of relugolix to pregnant rabbits during the period of organogenesis caused embryo-fetal lethality at maternal exposures that were 0.3 times the human exposure at the recommended dose of 120 mg daily based on area under the curve (AUC). Advise males with female partners of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose of ORGOVYX [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

5.3 Laboratory Testing

Therapy with ORGOVYX results in suppression of the pituitary gonadal system. Results of diagnostic tests of the pituitary gonadotropic and gonadal functions conducted during and after ORGOVYX may be affected. The therapeutic effect of ORGOVYX should be monitored by measuring serum concentrations of prostate specific antigen (PSA) periodically. If PSA increases, serum concentrations of testosterone should be measured.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• QT/QTc Interval Prolongation [see Warnings and Precautions (5.1)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ORGOVYX was evaluated in HERO, a randomized (2:1), open-label, clinical study in patients with advanced prostate cancer [see Clinical Studies (14)]. Patients received orally administered ORGOVYX as a loading dose of 360 mg on the first day followed by 120 mg taken orally once daily (n=622) or received leuprolide acetate administered by depot injection at doses of 22.5 mg (n=264) or 11.25 mg (n=44) per local guidelines every 12 weeks (n=308). Leuprolide acetate 11.25 mg is a dosage regimen that is not recommended for this indication in the US. Among patients who received ORGOVYX, 91% were exposed for at least 48 weeks. Ninety-nine (16%) patients received concomitant radiotherapy and 17 (3%) patients received concomitant enzalutamide with ORGOVYX.

Serious adverse reactions occurred in 12% of patients receiving ORGOVYX. Serious adverse reactions in ≥0.5% of patients included myocardial infarction (0.8%), acute kidney injury (0.6%), arrhythmia (0.6%), hemorrhage (0.6%), and urinary tract infection (0.5%). Fatal adverse reactions occurred in 0.8% of patients receiving ORGOVYX including metastatic lung cancer (0.3%), myocardial infarction (0.3%), and acute kidney injury (0.2%). Fatal and non-fatal myocardial infarction and stroke were reported in 2.7% of patients receiving ORGOVYX.

Permanent discontinuation of ORGOVYX due to an adverse reaction occurred in 3.5% of patients. Adverse reactions which resulted in permanent discontinuation of ORGOVYX in ≥0.3% of patients included atrioventricular block (0.3%), cardiac failure (0.3%), hemorrhage (0.3%), increased transaminases (0.3%), abdominal pain (0.3%), and pneumonia (0.3%).

Dosage interruptions of ORGOVYX due to an adverse reaction occurred in 2.7% of patients. Adverse reactions which required dosage interruption in ≥0.3% of patients included fracture (0.3%).

The most common adverse reactions (≥10%) and laboratory abnormalities (≥15%), were hot flush (54%), glucose increased (44%), triglycerides increased (35%), musculoskeletal pain (30%), hemoglobin decreased (28%), alanine aminotransferase increased (ALT) (27%), fatigue (26%), aspartate aminotransferase increased (AST) (18%), constipation (12%), and diarrhea (12%).

Table 1 summarizes the adverse reactions in HERO.

Table 1. Adverse Reactions (≥10%) of Patients with Advanced Prostate Cancer Who Received ORGOVYX in HERO:

^* Includes arthralgia, back pain, pain in extremity, musculoskeletal pain, myalgia, bone pain, neck pain, arthritis, muculoskeletal stiffness, non-cardiac chest pain, musculoskeletal chest pain, spinal pain, and musculoskeletal discomfort.
^† Includes fatigue and asthenia.
^‡ Includes diarrhea and colitis.

Clinically relevant adverse reactions in <10% of patients who received ORGOVYX included increased weight, insomnia, gynecomastia, hyperhidrosis, depression, and decreased libido.

Table 2 summarizes the laboratory abnormalities in HERO.

Table 2. Select Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with Advanced Prostate Cancer Who Received ORGOVYX in HERO:

^* The denominator used to calculate the rate varied from 611 to 619 in the ORGOVYX arm and from 301 to 306 in the leuprolide arm based on the number of patients with a baseline value and at least one post-treatment value.

7.1 Effect of Other Drugs on ORGOVYX

P-gp Inhibitors

Co-administration of ORGOVYX with a P-gp inhibitor increases the AUC and the maximum concentration (C_max) of relugolix [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions associated with ORGOVYX. Avoid co-administration of ORGOVYX with oral P-gp inhibitors.

If co-administration is unavoidable, take ORGOVYX first, separate dosing by at least 6 hours, and monitor patients more frequently for adverse reactions [see Dosage and Administration (2.2)].

Treatment with ORGOVYX may be interrupted for up to 2 weeks for a short course of treatment with certain P-gp inhibitors.

If treatment with ORGOVYX is interrupted for more than 7 days, resume administration of ORGOVYX with a 360 mg loading dose on the first day, followed by 120 mg once daily.

Combined P-gp and Strong CYP3A Inducers

Co-administration of ORGOVYX with a combined P-gp and a strong CYP3A inducer decreases the AUC and C_max of relugolix [see Clinical Pharmacology (12.3)], which may reduce the effects of ORGOVYX. Avoid co-administration of ORGOVYX with combined P-gp and strong CYP3A inducers.

If co-administration is unavoidable, increase the ORGOVYX dose [see Dosage and Administration (2.3)]. After discontinuation of the combined P-gp and strong CYP3A inducer, resume the recommended dose of ORGOVYX once daily.

Risk Summary

The safety and efficacy of ORGOVYX have not been established in females.

Based on findings in animals and mechanism of action, ORGOVYX can cause fetal harm and loss of pregnancy when administered to a pregnant female [see Clinical Pharmacology (12.1)]. There are no human data on the use of ORGOVYX in pregnant females to inform the drug-associated risk. In an animal reproduction study, oral administration of relugolix to pregnant rabbits during organogenesis caused embryo-fetal lethality at maternal exposures that were 0.3 times the human exposure at the recommended dose of 120 mg daily based on AUC (see Data). Advise patients of the potential risk to the fetus.

Data

Animal Data

In an embryo-fetal development study, oral administration of relugolix to pregnant rabbits during the period of organogenesis resulted in abortion, total litter loss, or decreased number of live fetuses at a dose of 9 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose of 120 mg daily based on AUC).

Risk Summary

The safety and efficacy of ORGOVYX at the recommended dose of 120 mg daily have not been established in females. There are no data on the presence of relugolix in human milk, the effects on the breastfed child, or the effects on milk production. Relugolix and/or its metabolites were present in milk of lactating rats (see Data).

Data

Animal Data

In lactating rats administered a single oral dose of 30 mg/kg radiolabeled relugolix on post-partum day 14, relugolix and/or its metabolites were present in milk at concentrations up to 10-fold higher than in plasma at 2 hours post-dose.

Contraception

Males

Based on findings in animals and mechanism of action, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose of ORGOVYX [see Use in Specific Populations (8.1)].

Infertility

Males

Based on findings in animals and mechanism of action, ORGOVYX may impair fertility in males of reproductive potential [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)].

The safety and efficacy of ORGOVYX in pediatric patients have not been established.

Of the 622 patients who received ORGOVYX in the HERO study, 81% were 65 years of age or older, while 35% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. There was no clinically relevant impact of age on the pharmacokinetics of ORGOVYX or testosterone response based on population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses in men 45 to 91 years of age.