HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights
do not include all the information needed to use ORGOVYX safely and effectively. See full prescribing information
for
ORGOVYX.
ORGOVYX (relugolix) tablets, for oral use Initial U.S. Approval: 2020
-----------------------------INDICATIONS AND USAGE-------------------------
ORGOVYX is
a gonadotropin-releasing hormone (GnRH)
receptor antagonist indicated for the treatment of adult
patients with advanced prostate cancer (1).
------------------------DOSAGE AND
ADMINISTRATION---------------------
•
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).
• ORGOVYX can
be
taken with or
without food
(2.1, 12.3). Instruct patients to
swallow tablets
whole
and not to crush
or
chew tablets (2.1).
---------------------DOSAGE FORMS AND
STRENGTHS---------------------
•
Tablets: 120 mg (3).
--------------------------------CONTRAINDICATIONS----------------------------
•
None (4).
------------------------WARNINGS AND
PRECAUTIONS----------------------
• QT/QTc
Interval Prolongation:
Androgen deprivation therapy may prolong the
QT
interval (5.1).
•
Embryo-Fetal Toxicity: ORGOVYX can cause fetal harm. Advise
males with
female partners of reproductive potential to
use
effective contraception
(5.2, 8.1, 8.3).
-------------------------------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 (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Myovant Sciences, Inc., at
1-833-MYOVANT (1-833-696-8268) or FDA at 1
800-FDA-1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS------------------------------
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 (2.2, 7.1).
Combined P-gp
and
Strong CYP3A Inducers: Avoid co-administration. If unavoidable, increase the
ORGOVYX dose to 240 mg once
daily (2.3, 7.1).
See 17 for PATIENT COUNSELING
INFORMATION and
FDA-approved patient labeling.
Revised: 12/2020
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND
USAGE
2 DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage
2.2
Dose Modification for
Use
with
P-gp Inhibitors
2.3
Dose Modification for
Use
with
Combined P-gp and
Strong
CYP3A Inducers
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND
PRECAUTIONS
5.1
QT/QTc
Interval Prolongation
5.2
Embryo-Fetal Toxicity
5.3
Laboratory Testing
6 ADVERSE REACTIONS
6.1
Clinical Trials Experience
7 DRUG INTERACTIONS
7.1
Effect of Other
Drugs on ORGOVYX
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and
Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2
Animal Toxicology
and/or Pharmacology
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND
HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections
omitted from the full prescribing information are
not
listed.
FUL
L PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
ORGOVYX is indicated for the treatment of
adult
patients with advanced
prostate cancer.
2 DOSAG
E AND ADMINISTRATION
2.1
Re
commended 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
(12.3)]. 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.
2.2
Dos
e Modification for
Use
with P-gp Inhibitors
Avoid co-administration of ORGOVYX with oral P-gp inhibitors. If co-administration is
unavoidable, take ORGOVYX first
and
separate dosing by at least 6 hours[see Drug Interactions (7.1) and Clinical
Pharmacology (12.3)]. Treatment with ORGOVYX may be interrupted for up to two weeks
if a short course of
treatment with a P-gp inhibitor is required.
2.3
Dos
e Modification for
Use
with Combined P-gp
and Strong CYP3A Inducers
Avoid co-administration of ORGOVYX with combined P-gp and strong CYP3A inducers.
If co-administration is
unavoidable,
increase the ORGOVYX dose to 240 mg once daily.
After
discontinuation of
the
combined P-gp and strong CYP3A inducer,
resume the recommended
ORGOVYX dose of
120
mg once daily[see Drug Interactions (7.1)andClinical
Pharmacology
(12.3)].
3 DOSAG
E FORMS AND
STRENGTHS
Tablets: 120 mg,
light
red, almond-shaped, film-coated, and debossed with “R” on one side and “120” on the other side.
4
CONTRAINDICATIONS
None.
5 WARNING
S AND
PRECAUTIONS
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
Labora
tory 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.
6
ADVERS
E REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
•
QT/QTc Interval Prolongation[see Warnings and Precautions (5.1)].
6.1
Clinica
l Trials Experience
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.
T
able 1: Adverse Reactions ( ≥
10%) of Patients with Advanced Prostate Cancer Who Received ORGOVYX in
HERO
|
Adverse Reaction
|
ORGOVYX N = 622
|
Leuprolide Acetate N = 308
|
|
All Grades (%)
|
Grade 3-4 (%)
|
All Grades (%)
|
Grade 3-4 (%)
|
|
Vascular disorders
|
|
|
|
|
|
Hot flush
|
54
|
0.6
|
52
|
0
|
|
Musculoskeletal and connective tissue disorders
|
|
|
|
|
|
Musculoskeletal paina
|
30
|
1.1
|
29
|
1.6
|
|
General
|
|
|
|
|
|
Fatigueb
|
26
|
0.3
|
24
|
0
|
|
Gastrointestinal disorders
|
|
|
|
|
|
Diarrheac
|
12
|
0.2
|
7
|
0
|
|
Constipation
|
12
|
0
|
10
|
0
|
a 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.
b Includes fatigue and asthenia.
c 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.
|
|
|
ORGOVYXa
|
|
|
Leuprolide Acetatea
|
|
|
|
|
|
|
|
|
(%)
|
|
(%)
|
(%)
|
(%)
|
|
Chemistry
|
|
Glucose increased
|
44
|
|
2.9
|
54
|
|
6
|
|
Triglycerides increased
|
35
|
|
2
|
36
|
|
0.7
|
|
ALT increased
|
27
|
|
0.3
|
28
|
|
0
|
|
AST increased
|
18
|
|
0
|
19
|
|
0.3
|
|
Hematology
|
|
Hemoglobin decreased
|
28
|
|
0.5
|
29
|
|
0.7
|
|
|
Table 2: Select Laboratory Abnormalities ( ≥ 1
5%) That Worsened
from Baseline in
Patients with Advanced
Prostate Cancer Who Received
ORGOVYX in HERO
Laboratory Test
All Grades
Grade 3-4
All Grades
Grade 3-4
a 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 DRU
G INTERACTIONS
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 (Cmax) 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 Cmax 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.
8 US
E IN SPECIFIC
POPULATIONS
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
(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).
8.2
Lac
tation
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.
8.3
Female
s 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
(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)].
8.4
Pedia
tric Use
The safety and efficacy of ORGOVYX in pediatric patients have not been established.
8.5
Geria
tric 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.
11
D
ESCRIPTION
Relugolix is a nonpeptide small molecule,
GnRH
receptor antagonist. The chemical name is N-(4-{1 [(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4 tetrahydrothieno[2,3-d]pyrimidin-6-yl}phenyl)-N’-methoxyurea.
The molecular weight is
623.63 daltons and the molecular formula is
C29H27F2N7O5S. The structural formula is:
Relugolix is a white to off-white to slightly yellow solid with a solubility of 0.04 mg per mL in water at 25°C.
ORGOVYX is
provided as film-coated tablets for oral administration. Each tablet contains 120 mg of
relugolix. The inactive ingredients are mannitol,
sodium starch glycolate, hydroxypropyl cellulose,
magnesium stearate, hypromellose, titanium dioxide, ferric
oxide red, and carnauba wax.
12 CLINICA
L PHARMACOLOGY
12.1 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.
12.2 Pharmacodynamic
s
Pituitary and Gonadal Hormones
Relugolix reduced
LH, FSH (Figure 1), 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.
In a
substudy of 137 patients who did not receive subsequent
androgen deprivation therapy for at least
90
days after discontinuation of
relugolix,
the cumulative incidence rate of
achieving testosterone concentrations above the lower limit of
the
normal range (> 280 ng/dL) or baseline at 90 days
was 55% [see Clinical
Studies
(14)].
F
igure 1: Mean (±
95% CI) 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), parallel- group 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).
12.3 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. After administration of multiple 20 mg to 180 mg doses
of relugolix once daily (0.17 to 1.5 times the
recommended once daily dose), the
AUCtau of relugolix increases approximately proportionally with dose
and the Cmax increases greater than proportionally to dose.
After administration of a single 360 mg loading dose in patients, the mean (± standard deviation [± SD]) of AUC0-24 and Cmax of relugolix
were 985 (±
742)
ng.hr/mL and 215 (± 184) ng/mL,
respectively.
After administration of
a 120 mg
dose once daily in patients, the mean (± SD) of AUC0-24 and Cmax of relugolix at steady-state were 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 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 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
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 acid- reducing agents.
No
clinically significant
differences in the pharmacokinetics
of midazolam (sensitive CYP3A substrate) or rosuvastatin (BCRP substrate) were observed upon co-administration with relugolix.
In Vitro Studies
Cytochrome P450 (CYP) Enzymes: Relugolix is
a substrate of CYP3A and CYP2C8. 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, OAT1, OAT3,
OCT2, MATE1,
MATE2-K, or
BSEP.
13 NONCLINICA
L TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis,
Impairment of Fertility
Two-year carcinogenicity studies were conducted in mice at oral relugolix doses
up to 100 mg/kg/day
and in rats at doses up to 600 mg/kg/day. Relugolix was
not carcinogenic in mice or rats at exposures
up to approximately 75 or 224 times,
respectively, the human exposure at the recommended dose of 120 mg daily based on AUC.
Relugolix was
not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic
in the in vitro chromosomal aberration assay in Chinese hamster lung cells
or the in vivo rat bone marrow micronucleus assay.
In human GnRH-receptor knock-in male mice,
oral administration of
relugolix decreased prostate and seminal
vesicle weights at doses ≥ 3 mg/kg twice daily for 28 days. The effects
of relugolix
were
reversible, except for testis weight,
which did not fully recover within 28 days
after drug withdrawal. In a
39-week repeat-dose toxicity study in monkeys, there were no significant effects
on
male reproductive organs at oral relugolix doses
up to 50 mg/kg/day (approximately 53 times
the
human exposure at the recommended dose of 120 mg daily based on AUC).
13.2 Anima
l Toxicology and/or Pharmacology
Phospholipidosis (intracellular phospholipid accumulation) was
observed in multiple organs and
tissues (e.g., liver, pancreas, spleen, kidney, lymph nodes, lung, bone marrow, gastrointestinal tract or
testes) after repeated oral
administration of
relugolix in rats
and monkeys. In a rat 26-week toxicity
study, phospholipidosis was observed at doses ≥ 100 mg/kg (approximately 18 times the human exposure at the recommended dose based on AUC). In
a monkey 39-week toxicity study, this
effect was observed at doses ≥ 1.5 mg/kg (approximately 0.6 times the human exposure at the
recommended dose based on AUC) and demonstrated evidence of reversibility after cessation of treatment. The significance of this finding in humans
is unknown.
14 CLINICA
L STUDIES
HERO Study
The safety and efficacy of ORGOVYX was evaluated in HERO
(NCT03085095),
a randomized,
open label study in men with advanced prostate cancer requiring at least 1 year of androgen deprivation
therapy and defined as biochemical (PSA) or clinical relapse following local
primary intervention,
newly diagnosed castration-sensitive metastatic
disease, or advanced localized disease.
A total
of 934 patients were randomized to receive ORGOVYX or leuprolide in a 2:1 ratio for 48
weeks:
a) ORGOVYX at a loading dose of 360 mg on the first
day followed by daily doses of
120
mg orally
b) Leuprolide acetate 22.5 mg injection (or 11.25 mg in Japan and Taiwan) subcutaneously every
3 months. Leuprolide acetate 11.25 mg is a dosage regimen that is not recommended for this indication in the US.
Serum testosterone concentrations
were measured at
screening; on Days
1, 4, 8, 15, and 29 in the
first month; then monthly until
the end of the study.
The population (N
= 930) across
both
treatment groups had a median age of
71
years (range 47 to 97
years). The ethnic/racial distribution was 68%
White, 21%
Asian, 4.9% Black, and 5% other.
Disease stage was distributed as
follows: 32% metastatic
(M1),
31% locally advanced (T3/4 NX M0 or any T N1 M0), 28% localized (T1 or T2 N0 M0), and 10% not
classifiable. The median testosterone
concentration at baseline across the treatment
groups
was 408 ng/dL.
The major efficacy outcome measure was
medical
castration rate defined as achieving and maintaining serum testosterone suppression to castrate levels
(< 50 ng/dL) by Day 29 through 48 weeks
of treatment. Other endpoints
included castration rates on
Day 4 and 15 and castration rates with testosterone < 20 ng/dL at Day 15.
The efficacy results
are
shown in Table 3 and the timecourse of
percent change from baseline in testosterone suppression by ORGOVYX and leuprolide during the 48 week treatment period are shown in Figure 2.
T
able 3: Medical Castration Rates (Testosterone Concentrations < 50 ng/dL) from Day 29
through
Week
48 in HERO
|
|
ORGOVYX
360/120 mg (N = 622)b
|
Leuprolide Acetate
22.5 or 11.25 mga
(N = 308)b
|
|
Castration Rate (95% CI)c
|
96.7%
(94.9%, 97.9%)
|
88.8%
(84.6%, 91.8%)
|
a 11.25 mg is a dosage regimen that is not recommended for this indication in the US. The castration rate of the subgroup
of patients receiving 22.5 mg leuprolide (n = 264) was 88.0% (95% CI: 83.4%, 91.4%). b Two patients in each arm did not receive the study treatment and were not included. c Kaplan-Meier estimates within group.
F
igure 2: Mean
(95% CI) Percent Change from
Baseline in
Testosterone Concentrations from
Baseline to Week 49 by Treatment Group
in HERO
Mean (±95% CI) Percent Change from Baseline
in Testosterone (%)
|
100
50
0
-50
-100
Relugolix Leuprolide
End
of Treatment
|
Baseline 1 3 5 9 13 17 21 25 29 33 37 41 45 49
|
|
Evaluable
|
|
|
|
|
|
Time (Week)
|
|
|
|
|
|
|
Patients, n
|
|
Relugolix
|
605 599 606
|
599
|
594
|
588
|
587
|
584
|
580
|
569
|
561
|
557
|
554
|
547
|
|
Leuprolide
|
292 293 295
|
294
|
293
|
289
|
291
|
283
|
275
|
275
|
274
|
268
|
263
|
257
|
The percentages of
patients
who
attained the medical
castration levels
of
testosterone < 50 ng/dL
and < 20 ng/dL within the first
29
days of treatment
are
summarized in Table 4 and the cumulative
incidences of time to testosterone < 50 ng/dL or < 20 ng/dL are shown in Figure 3.
T
able 4: Percentage of Patients Attaining
Testosterone Decreases within the First 29 Days in HEROa
|
|
Testosterone < 50 ng/dL
|
Testosterone < 20 ng/dL
|
|
ORGOVYX (N = 622)
|
Leuprolide Acetate (N = 308)
|
ORGOVYX (N = 622)
|
Leuprolide Acetate (N = 308)
|
|
Day 4
|
56%
|
0%
|
7%
|
0%
|
|
Day 8
|
91%
|
0%
|
27%
|
0%
|
|
Day 15
|
99%
|
12%
|
78%
|
1%
|
|
Day 29
|
99%
|
82%
|
95%
|
57%
|
a Kaplan-Meier estimates within group.
F
igure 3: Cumulative Incidence of Time to Testosterone < 50 ng/dL and < 20 ng/dL in HERO
In the clinical trial, PSA levels
were monitored and were lowered on average by 65%
two
weeks after administration of
ORGOVYX, 83% after 4 weeks, 92%
after 3 months and remained suppressed throughout
the
48 weeks of treatment. These PSA results should be interpreted with caution because
of
the heterogeneity of
the patient population studied.
No
evidence has shown that
the
rapidity of
PSA decline is related to a clinical benefit.
A substudy was conducted in 137 patients
who
did not receive subsequent androgen deprivation
therapy for at least 90 days
after discontinuation of ORGOVYX. Based on Kaplan-Meier analyses,
55% of patients
achieved testosterone levels
above the lower limit
of the normal range (> 280 ng/dL)
or baseline at
90
days after discontinuation of ORGOVYX.
16 HO
W SUPPLIED/STORAGE AND HANDLING
The 120 mg tablets
are
film-coated, light red, almond shaped,
and
debossed with “R” on one side and
“120” on the other side and are supplied in two configurations, bottles and blister
packs. Each bottle (NDC
72974-120-01) contains 30
tablets and a desiccant and is
closed with a child-resistant induction
seal cap. The blister
cards contain nine tablets packaged in a carton (NDC 72974-120-02). Each ORGOVYX tablet contains
120
mg of relugolix.
• Store ORGOVYX at
room temperature. Do not
store above 30°C
(86°F).
• Dispense to patients in original
container only.
• For bottles,
keep
container tightly closed after first opening.
• Keep out of
reach of children.
17 PATIEN
T 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 [see Warnings
and
Precautions (5.1)].
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 [see Adverse Reactions
(6.1)].
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[see
Warnings
and
Precautions (5.2) and Use in Specific
Populations
(8.1, 8.3)].
Infertility
•
Inform patients that
ORGOVYX may cause infertility[see Use in Specific
Populations
(8.3)].
Manufactured by Bushu Pharmaceuticals,
Ltd, Kawagoe, Saitama,
Japan
Manufactured for Myovant Sciences, Inc., Brisbane,
CA
94005
Issued: December 2020 214621-MS-000
|
PATIENT INFORMATION
ORGOVYX (or-GO-vix)
(relugolix) Tablets
|
|
What is ORGOVYX?
ORGOVYX is a prescription medicine used in adults for the treatment of advanced prostate cancer. It is not known if ORGOVYX is safe or effective in females.
It is not known if ORGOVYX is safe or effective in children.
|
|
Before taking ORGOVYX, tell your healthcare provider about all of your medical conditions, including if you:
• have any heart problems, including a condition called long QT syndrome.
• are pregnant or plan to become pregnant. ORGOVYX can harm your unborn baby and cause loss of pregnancy (miscarriage).
• have a partner who is pregnant or may become pregnant.
o Males who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with ORGOVYX and for 2 weeks after the last dose of ORGOVYX.
• are breastfeeding or plan to breastfeed. It is not known if ORGOVYX passes into your breast milk.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking ORGOVYX with certain other medicines can affect how ORGOVYX works or may cause side effects.
You should not start or stop any medicine before you talk with your healthcare provider who prescribed ORGOVYX. Know the medicines you take. Keep a list of them with you to show to your healthcare provider and pharmacist when you get a new medicine.
|
|
How should I take ORGOVYX?
• Take ORGOVYX exactly as your healthcare provider tells you.
• Take 3 ORGOVYX tablets on your first day of treatment. After that, take 1 ORGOVYX tablet each day.
• Take ORGOVYX at about the same time each day.
• Take ORGOVYX with or without food.
• Swallow ORGOVYX tablets whole. Do not crush or chew tablets.
• Your healthcare provider may change your dose if needed.
• Do not change your dose or stop taking ORGOVYX without talking with your healthcare provider first.
• If you miss a dose of ORGOVYX, take it as soon as you remember. If the dose was missed by more than 12 hours, the missed dose should not be taken. Take your next dose at your regular time the next day.
|
|
What are the possible side effects of ORGOVYX? ORGOVYX may cause serious side effects, including:
• Changes in the electrical activity of your heart (QT prolongation). Your healthcare provider may check your
body salts (electrolytes) and the electrical activity of your heart during treatment with ORGOVYX. Tell your healthcare provider right away if you get any signs or symptoms of QT prolongation, including:
o dizziness o feeling that your heart is pounding or racing (palpitations)
o fainting o chest pain
The most common side effects of ORGOVYX include:
• hot flushes • increasedliverenzymes
• increased blood sugar levels • tiredness
• increased blood fat (triglyceride) levels • constipation
• muscle and joint pain • diarrhea
• decreased blood hemoglobin levels
Other side effects include weight gain, decreased sex drive, and erectile function problems.
ORGOVYX may cause fertility problems in males, which may affect your ability to father children. Talk to your healthcare provider if this is a concern for you.
These are not all the possible side effects of ORGOVYX.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
|
|
How should I store ORGOVYX?
• Store ORGOVYX at room temperature. Do not store ORGOVYX above 86°F (30°C).
• Keep the bottle tightly closed after you first open it.
• The ORGOVYX bottle contains a desiccant to help keep your medicine dry (protect it from moisture). Do not remove the desiccant from the bottle.
Keep ORGOVYX and all medicines out of the reach of children.
|
General information about the safe and effective use of ORGOVYX.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ORGOVYX for a condition for which it was not prescribed. Do not give ORGOVYX to other people, even if they have the same symptoms that you have. It may harm them. You can ask
your pharmacist or healthcare provider for information about ORGOVYX that is written for health professionals.
What are the ingredients in ORGOVYX? Active ingredient: relugolix
Inactive ingredients: mannitol, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hypromellose,
titanium dioxide, ferric oxide red, and carnauba wax.
Manufactured by: Bushu Pharmaceuticals, Ltd, Kawagoe, Saitama, Japan
Manufactured for: Myovant Sciences, Inc., Brisbane, CA 94005
For more information, go to www.orgovyx.com or call 1-833-MYOVANT (1-833-696-8268).
This Patient Information has been
approved by the U.S. Food and Drug Administration. Issued: December 2020
214621-MS-000
