Orgovyx

ORGOVYX is indicated for the treatment of adult patients with advanced prostate cancer.

• 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 (
  2.1 Recommended Dosage

  Initiate treatment of ORGOVYX with a loading dose of 360 mg on the first day and continue treatment with a 120 mg dose taken orally once daily at approximately the same time each day.

  ORGOVYX can be taken with or without food

  [see Clinical Pharmacology ]

  . Instruct patients to swallow tablets whole and not to crush or chew tablets.

  Advise patients to take a missed dose of ORGOVYX as soon as they remember. If the dose was missed by more than 12 hours, patients should not take the missed dose and resume with the next scheduled dose.

  If treatment with ORGOVYX is interrupted for greater than 7 days, restart ORGOVYX with a loading dose of 360 mg on the first day, and continue with a dose of 120 mg once daily.

  In patients treated with GnRH receptor agonists and antagonists for prostate cancer, treatment is usually continued upon development of nonmetastatic or metastatic castration-resistant prostate cancer.
  ).
• ORGOVYX can be taken with or without food (
  2.1 Recommended Dosage

  Initiate treatment of ORGOVYX with a loading dose of 360 mg on the first day and continue treatment with a 120 mg dose taken orally once daily at approximately the same time each day.

  ORGOVYX can be taken with or without food

  [see Clinical Pharmacology ]

  . Instruct patients to swallow tablets whole and not to crush or chew tablets.

  Advise patients to take a missed dose of ORGOVYX as soon as they remember. If the dose was missed by more than 12 hours, patients should not take the missed dose and resume with the next scheduled dose.

  If treatment with ORGOVYX is interrupted for greater than 7 days, restart ORGOVYX with a loading dose of 360 mg on the first day, and continue with a dose of 120 mg once daily.

  In patients treated with GnRH receptor agonists and antagonists for prostate cancer, treatment is usually continued upon development of nonmetastatic or metastatic castration-resistant prostate cancer.
  ,
  12.3 Pharmacokinetics

  After administration of single doses ranging from 60 mg to 360 mg (0.17 to 1 times the recommended loading dose), total systemic exposure (AUC) and the maximum concentration (C_max) of relugolix increases in an approximately dose proportional manner. After administration of multiple doses of relugolix once daily, the AUC of relugolix increases in an approximately dose proportional manner while the C_maxincrease is greater than dose proportional for doses from 20 mg to 180 mg (0.17 to 1.5 times the recommended daily dose).

  After administration of a single 360 mg loading dose, the mean (± standard deviation [± SD]) AUC and C_maxof relugolix are 985 (± 742) ng.hr/mL and 215 (± 184) ng/mL, respectively. After administration of 120 mg once daily, the mean (± SD) AUC and C_maxof relugolix at steady-state are 407 (± 168) ng.hr/mL and 70 (± 65) ng/mL, respectively. The accumulation of relugolix upon once daily administration is approximately 2-fold.

  Absorption

  Relugolix is a substrate for intestinal P-gp. The mean (CV%) absolute bioavailability of relugolix is 12% (62%). The median (min, max) time to maximum concentration (T_max) of relugolix is 2.25 (0.5, 5.0) hours.

  Effect of Food

  No clinically significant differences in the pharmacokinetics of relugolix were observed following administration 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 α₁-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 61 (11%) hours. The mean (CV%) total clearance of relugolix is 29 (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.

  Excretion

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

  Specific Populations

  No clinically significant 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 Inhibitors:

  Co-administration with erythromycin (P-gp and moderate CYP3A inhibitor) increased the AUC and C_maxof relugolix by 3.5- and 2.9-fold respectively.

  Combined P-gp and Strong CYP3A Inducers:

  Co-administration of relugolix with rifampin (P-gp and strong CYP3A inducer) decreased the AUC and C_maxof 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 acid-reducing agents. No clinically significant differences in the pharmacokinetics of midazolam (sensitive CYP3A substrate) or rosuvastatin (BCRP substrate), or dabigatran etexilate (P-gp substrate) were observed upon co-administration with relugolix.

  In Vitro Studies

  Cytochrome P450 (CYP) Enzymes:

  Relugolix is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Relugolix is an inducer of CYP3A and CYP2B6, but not an inducer of CYP1A2.

  Transporter Systems:

  Relugolix is a substrate of P-gp, but not a substrate of BCRP. Relugolix is an inhibitor of BCRP and P-gp, but not an inhibitor of OATP1B1, OATP1B3, OATP2B1, OAT1, OAT3, OCT2, MATE1, MATE2-K, or BSEP.
  ). Instruct patients to swallow tablets whole and not to crush or chew tablets (
  2.1 Recommended Dosage

  Initiate treatment of ORGOVYX with a loading dose of 360 mg on the first day and continue treatment with a 120 mg dose taken orally once daily at approximately the same time each day.

  ORGOVYX can be taken with or without food

  [see Clinical Pharmacology ]

  . Instruct patients to swallow tablets whole and not to crush or chew tablets.

  Advise patients to take a missed dose of ORGOVYX as soon as they remember. If the dose was missed by more than 12 hours, patients should not take the missed dose and resume with the next scheduled dose.

  If treatment with ORGOVYX is interrupted for greater than 7 days, restart ORGOVYX with a loading dose of 360 mg on the first day, and continue with a dose of 120 mg once daily.

  In patients treated with GnRH receptor agonists and antagonists for prostate cancer, treatment is usually continued upon development of nonmetastatic or metastatic castration-resistant prostate cancer.
  ).

Tablets: 120 mg, light red, almond-shaped, film-coated, and debossed with “R” on one side and “120” on the other side.

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

• QT/QTc Interval Prolongation: Androgen deprivation therapy may prolong the QT interval (
  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 ].
  ).
• Hypersensitivity: ORGOVYX can cause hypersensitivity reactions, including angioedema. Withhold ORGOVYX in patients who experience symptoms of hypersensitivity. Discontinue ORGOVYX for severe hypersensitivity reactions and manage as clinically indicated (
  5.2 Hypersensitivity Reactions

  ORGOVYX is contraindicated in patients with severe hypersensitivity to relugolix or any of the product components

  [see Contraindications ]

  . Hypersensitivity reactions, including pharyngeal edema and other serious cases of angioedema, have been reported postmarketing in patients treated with ORGOVYX.

  In HERO, patients treated with relugolix reported angioedema (0.2%)

  [see Clinical Trials Experience ]

  .

  Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue ORGOVYX and promptly seek medical care.

  Discontinue ORGOVYX for severe hypersensitivity reactions and manage as clinically indicated.
  ).
• Embryo-Fetal Toxicity: ORGOVYX can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception (
  5.3 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 and Clinical Pharmacology ]

  .
  ,
  8.1 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

  [see Clinical Pharmacology ]

  . 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).
  ,
  8.3 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

  [see Use in Specific Populations ].

  Infertility

  Males

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

  [see Clinical Pharmacology and Nonclinical Toxicology ].
  ).