DRUG INTERACTIONS- Summary

­ P-gp Inhibitors: Avoid co-administration. If unavoidable, take ORGOVYX first, separate dosing by at least 6 hours, and monitor patients more frequently for adverse reactions 

Combined P-gp and Strong CYP3A Inducers: Avoid co-administration. If unavoidable, increase the ORGOVYX dose to 240 mg once daily 

BRIEF SUMMARY

RELUGOLIX-(Dec 2020)

Indn-  To treat  advanced Prostrate Cancer

Comp- • Tablets: 120 mg- • Recommended Dosage:                                                                                                           A loading dose of 360 mg on the first day of treatment followed by 120 mg taken orally once daily, at approximately the same time each day • ORGOVYX can be taken with or without 

CI- • None

WARNINGS-

­ • QT/QTc Interval Prolongation: Androgen deprivation therapy may prolong the QT interval

 • Embryo-Fetal Toxicity: ORGOVYX can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception 

Pat Inform-

QT/QTc Interval Prolongation                                                                                              • Advise patients that androgen deprivation therapy treatment  may prolong the QT interval. Inform patients of the signs and symptoms of QT prolongation. Advise patients to contact their healthcare provider immediately for signs or symptoms of QT prolongation 

Androgen Deprivation                                                                                                         • Inform patients about adverse reactions related to androgen deprivation therapy, including hot flashes, flushing of the skin, increased weight, decreased sex drive, and difficulties with erectile function 

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U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  51

ADVERSE REACTIONS

­ The most common adverse reactions (= 10%) and laboratory abnormalities (= 15%) were hot flush, glucose increased, triglycerides increased, musculoskeletal pain, hemoglobin decreased, alanine aminotransferase (ALT) increased, fatigue, aspartate aminotransferase (AST) increased, constipation, and diarrhea

WARNINGS AND PRECAUTIONS

­ • QT/QTc Interval Prolongation: Androgen deprivation therapy may prolong the QT interval

 • Embryo-Fetal Toxicity: ORGOVYX can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

QT/QTc Interval Prolongation                                                                                                  • Advise patients that androgen deprivation therapy treatment with ORGOVYX may prolong the QT interval. Inform patients of the signs and symptoms of QT prolongation. Advise patients to contact their healthcare provider immediately for signs or symptoms of QT prolongation 

Androgen Deprivation                                                                                                               • Inform patients about adverse reactions related to androgen deprivation therapy with ORGOVYX, including hot flashes, flushing of the skin, increased weight, decreased sex drive, and difficulties with erectile function 

Embryo-Fetal Toxicity                                                                                                                   • Inform patients that ORGOVYX can be harmful to a developing fetus and can cause loss of pregnancy.

• 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

Infertility                                                                                                                                           • Inform patients that ORGOVYX may cause infertility 

Manufactured by Bushu Pharmaceuticals, Ltd, Kawagoe, Saitama, Japan Manufactured for Myovant Sciences, Inc., Brisbane, CA 94005 Reference ID: 4

 CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                                        Relugolix is a nonpeptide GnRH receptor antagonist that competitively binds to pituitary GnRH receptors, thereby, reducing the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and consequently testosterone.

2. Pharmacodynamics -                                                                                                         Pituitary and Gonadal Hormones-                                                                                  Relugolix reduced LH, FSH , and testosterone concentrations after oral administration of the recommended loading dose of 360 mg and a 120 mg dose once daily. Out of 622 patients, 56% had testosterone concentrations at castrate levels (< 50 ng/dL) by the first sampling timepoint at Day 4, and 97% maintained castrate levels of testosterone through 48 weeks.

Follicle-Stimulating Hormone and Luteinizing Hormone-                                     Concentrations over Time in HERO Cardiac Electrophysiology- In a randomized, double-blind, placebo- and positive-controlled (open-label moxifloxacin), parallelgroup thorough QT/QTc study, no increase in mean QTc interval > 10 ms was identified after administration of single 60 or 360 mg doses of relugolix (0.2 or 1 times the recommended loading dose, respectively).

3. Pharmacokinetics-                                                                                                               After administration of single doses ranging from 60 mg to 360 mg (0.17 to 1 times the recommended loading dose), the AUC from time zero extrapolated to infinity (AUC0-inf) and the maximum observed plasma concentration (Cmax) of relugolix increase approximately proportionally with dose.

Absorption-                                                                                                                             Relugolix is a substrate for intestinal P-gp. The mean (CV%) absolute bioavailability of relugolix is approximately 12% (62%). The median (range) Tmax of relugolix is 2.25 hours (0.5 to 5.0 hours).

Effect of Food -                                                                                                                          No clinically meaningful differences in the pharmacokinetics of relugolix were observed following consumption of a high-calorie, high-fat meal (approximately 800 to 1000 calories with 500, 220, and 124 from fat, carbohydrate, and protein, respectively).

Distribution-                                                                                                                              Plasma protein binding of relugolix is 68 to 71%, primarily to albumin and to a lesser extent to a1-acid glycoprotein. The mean blood-to-plasma ratio is 0.78.

Elimination-                                                                                                                            The mean effective half-life of relugolix is 25 hours and the mean (CV%) terminal elimination half-life is 60.8 (11%) hours. The mean (CV%) total clearance of relugolix is 29.4 (15%) L/h and the renal clearance is 8 L/h.

Metabolism-                                                                                                                               Relugolix is metabolized primarily by CYP3A and to a lesser extent by CYP2C8 in vitro.

Excretion-                                                                                                                                After oral administration of a single 80-mg radiolabeled dose of relugolix, approximately 81% of the radioactivity was recovered in feces (4.2% as unchanged) and 4.1% in urine (2.2% as unchanged).

Specific Populations -                                                                                                                 No clinically meaningful differences in the pharmacokinetics of relugolix were observed based on age (45 to 91 years), race/ethnicity (Asian [19%], White [71%], Black/African American [6%]), body weight (41 to 193 kg), mild to severe renal impairment (creatinine clearance [CLcr] 15 to 89 mL/min, as estimated by the Cockcroft-Gault equation), or mild to moderate hepatic impairment (Child-Pugh A or B).

The effect of end-stage renal disease with or without hemodialysis or severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of relugolix has not been evaluated.

Drug Interactions Studies-                                                                                               Clinical Studies Combined P-gp and Moderate CYP3A Inhibitor: Co-administration with erythromycin (P-gp and moderate CYP3A inhibitor) increased the AUC and Cmax of relugolix by 6.2-fold.

Combined P-gp and Strong CYP3A Inducer: Co-administration with rifampin (P-gp and strong CYP3A inducer) decreased the AUC and Cmax of relugolix by 55% and 23%, respectively.

Other Drugs: No clinically significant differences in the pharmacokinetics of relugolix were observed when co-administered with voriconazole (strong CYP3A inhibitor), atorvastatin, enzalutamide, or acidreducing agents.

No clinically significant differences in the pharmacokinetics of midazolam (sensitive CYP3A substrate) or rosuvastatin (BCRP substrate) were observed upon co-administration with relugolix.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy 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 

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 

Advise patients of the potential risk to the fetus.

2.Lactation 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.

3. Females and Males of Reproductive Potential-                                                 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..

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)].

4. Pediatric Use -                                                                                                                    The safety and efficacy of ORGOVYX in pediatric patients have not been established.

5. Geriatric Use -                                                                                                                          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.