ORGOVYX 120mg tablets medication leaflet

Orgovyx 120 mg film-coated tablets

Each film-coated tablet contains 120 mg of relugolix.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Light red, almond-shaped, film-coated tablet (11 mm [length] × 8 mm [width]) with “R” onone side and “120” on the other side.

Orgovyx is indicated for the treatment of adult patients with advanced hormone-sensitiveprostate cancer.

Treatment with Orgovyx should be initiated and supervised by specialist physiciansexperienced in the medical treatment of prostate cancer.

Treatment with Orgovyx should be initiated with a loading dose of 360 mg (three tablets) onthe first day, followed by a 120 mg (one tablet) dose taken once daily at approximately thesame time each day.

Because relugolix does not induce an increase in testosterone concentrations, it is notnecessary to add an anti-androgen as surge protection at initiation of therapy.

Dose modification for use with P-gp inhibitors

Co-administration of Orgovyx with oral P-glycoprotein (P-gp) inhibitors is not recommended.

If co-administration is required, Orgovyx should be taken first and dosing should be separatedby at least 6 hours (see section 4.5). Treatment with Orgovyx may be interrupted for up to2 weeks if a short course of treatment with a P-gp inhibitor is required.

Dose modification for use with combined P-gp and strong CYP3A inducers

Co-administration of Orgovyx with combined P-gp and strong cytochrome P450 (CYP) 3Ainducers is not recommended. If co-administration is required, the dose of Orgovyx must beincreased to 240 mg once daily. After discontinuation of the combined P-gp and strong

CYP3A inducer, the recommended 120 mg dose of Orgovyx once daily must be resumed (seesection 4.5).

If a dose is missed, Orgovyx must be taken as soon as the patient remembers. If the dose wasmissed by more than 12 hours, the missed dose must not be taken and regular dosing scheduleshould be resumed the following day.

If treatment with Orgovyx is interrupted for greater than 7 days, Orgovyx must be restartedwith a loading dose of 360 mg on the first day, followed with a dose of 120 mg once daily.

No dose adjustment in elderly patients is required (see section 5.2).

No dose adjustment in patients with mild, or moderate renal impairment is required. Cautionis warranted in patients with severe renal impairment (see sections 4.4 and 5.2).

No dose adjustment in patients with mild or moderate hepatic impairment is required (seesections 4.4 and 5.2).

There is no relevant use of Orgovyx in children and adolescents under 18 years of age for theindication of treatment of advanced hormone-sensitive prostate cancer.

Oral use.

Orgovyx can be taken with or without food (see section 5.2). Tablets should be taken withsome liquid as needed and should be swallowed whole.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Effect on QT/QTc interval prolongation

In patients with a history of or risk factors for QT prolongation and in patients receivingconcomitant medicinal products that might prolong the QT interval (see section 4.5),physicians should assess the benefit-risk ratio including the potential for Torsade de pointesprior to initiating Orgovyx.

A thorough QT/QTc study showed that there was no intrinsic effect of relugolix onprolongation of the QTc interval (see section 4.8).

Cardiovascular disease such as myocardial infarction and stroke has been reported in themedical literature in patients with androgen deprivation therapy. Therefore, all cardiovascularrisk factors should be taken into account.

Long-term suppression of testosterone in men who have had orchiectomy or who have beentreated with a GnRH receptor agonist or GnRH antagonist is associated with decreased bonedensity. Decreased bone density, in patients with additional risk factors, may lead toosteoporosis and increased risk of bone fracture.

Patients with known or suspected hepatic disorder have not been included in long-termclinical trials with relugolix. Mild, transient increases in alanine aminotransferase (ALT) andaspartate aminotransferase (AST) have been observed but were not accompanied by anincrease in bilirubin or associated with clinical symptoms (see section 4.8). Monitoring ofliver function in patients with known or suspected hepatic disorder is advised duringtreatment. The pharmacokinetics of relugolix in patients with severe hepatic impairment hasnot been evaluated (see section 5.2).

The exposure to relugolix in patients with severe renal impairment may be increased by up to2-fold (see section 5.2). Because a lower dose of relugolix is not available, caution in patientswith severe renal impairment is warranted upon administration of a 120-mg dose of relugolixonce daily. The amount of relugolix removed by haemodialysis is unknown.

Prostate-specific antigen (PSA) monitoring

The effect of Orgovyx should be monitored by clinical parameters and prostate-specificantigen (PSA) serum levels.

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, thatis to say essentially ‘sodium-free’.

Potential for other medicinal products to affect the exposure to relugolix

Clinical interaction studies with P-gp inhibitors (erythromycin and azithromycin) andcombined P-gp and strong CYP3A4 inducers (rifampicin) have shown to affect the exposureof relugolix to a clinically relevant extent. Effect of co-administration on the exposure torelugolix and associated dosing recommendations are summarised in Table 1. This list alsoincludes expected effect and recommendations with other potentially interacting medicinalproducts.

Co-administration of Orgovyx and oral P-gp inhibitors is not recommended. Relugolix is a

P-gp substrate (see section 5.2).

If co-administration with once or twice daily oral P-gp inhibitors is required, Orgovyx shouldbe taken first, with the oral P-gp inhibitor taken 6 hours thereafter, and patients should bemonitored more frequently for adverse reactions. Alternatively, treatment with Orgovyx maybe interrupted for up to 2 weeks for a short course of treatment with a P-gp inhibitor (e.g. forcertain macrolide antibiotics). 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 by120 mg once daily (see section 4.2).

Combined P-gp and strong CYP3A inducers

Co-administration of Orgovyx with combined P-gp and strong CYP3A inducers is notrecommended.

If co-administration is required, the Orgovyx dose should be increased (see section 4.2). Afterdiscontinuation of the combined P-gp and strong CYP3A inducer, the recommended dose of

Orgovyx should be resumed once daily.

Other medicinal products

No clinically significant differences in the pharmacokinetics of relugolix were observed uponco-administration of relugolix with acid-reducing agents.

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of

Orgovyx with medicinal products known to prolong the QT interval or medicinal productsable to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III(e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone,moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).

Table 1. Effect of co-administered medicinal products on relugolix exposure (Cmax, AUC0-inf) and recommendations

Interacting drug dose Relugolix Change in Change in Recommendationregimen dose relugolix relugolixregimen AUC0-inf Cmax

Medicinal products that are oral P gp inhibitorserythromycin 120 mg 3.5 -fold ↑ 2.9 -fold ↑ Concomitant use ofsingle dose Orgovyx with500 mg QID, multiple erythromycin,doses azithromycin andother oral P-gp(P-gp and moderate inhibitors is not

CYP3A4 inhibitor) recommendedazithromycin 120 mg *1.5 -fold ↑ *1.6 -fold ↑single dose If concomitant use500 mg single dose with once or twicedaily oral P-gp(P-gp inhibitor) inhibitors is required(e.g. azithromycin),azithromycin 1.4 -fold ↑ 1.3 -fold ↑ take Orgovyx first,and separate dosing500 mg single dose 6 with the P-gphours inhibitor by at least 6hours and monitorafter administration of patients morerelugolix frequently foradverse reactions.

(P-gp inhibitor)

Other medicinal Therapeutic Expected: ↑ Expected: ↑products that are P-gp dose forinhibitor include (but Orgovyxnot limited to):

See also See alsoclinical study clinical study

Anti infectivesresults with results withazithromycin,erythromycin erythromycinerythromycin,and andclarithromycin,azithromycin azithromycingentamicin,(above). (above).

tetracycline.

Antifungal agentsketoconazole,itraconazole.

Antihypertensivescarvedilol,verapamil.

Antiarrhythmicsamiodarone,dronedarone,propafenone,quinidine.

Antianginal agentsranolazine

Immunosupressiveagentscyclosporine.

HIV or HCV proteaseinhibitorsritonavir,telaprevir.

Medicinal products that are CYP3A4 inhibitorsvoriconazole 120 mg 12% ↑ 18% ↓ No dosesingle dose modifications200 mg BID, multiple recommended for co-doses administration ofrelugolix and(strong CYP3A4 CYP3A4 inhibitorsinhibitor) devoid of P-gpinhibitionfluconazole 40 mg 19%↑ 44% ↑single dose200 mg QD, multipledoses(moderate CYP3A4inhibitor)atorvastatin 40 mg 5%↓ 22%↓single dose80 mg QD, multipledoses(weak CYP3A4inhibitor)

Medicinal products that are combined P gp and strong CYP3A4 inducersrifampicin 40 mg 55%↓ 23%↓ Co-administration ofsingle dose Orgovyx with600 mg QD, multiple rifampicin and otherdosesstrong CYP3A4 and

P-gp inducers is notrecommended, asthis may decrease the

AUC and Cmax ofrelugolix and maytherefore reduce thetherapeutic effects of

Orgovyx.

An increased dose isrecommended if co-administration isrequired (seesection 4.2).

Medicinal products Therapeutic Expected: ↓ Expected: ↓that are combined P dose forgp and strong Orgovyx

See also See alsoinclude (but notclinical study clinical studylimited to):results with results witherythromycin erythromycin

Androgen receptorand andinhibitorazithromycin azithromycinapalutamide.(above). (above).

Anticonvulsantscarbamazepine,phenytoin,phenobarbital.

Anti infectivesrifampicin,rifabutin.

Medicinal herb

St. John’s Wort(Hypericumperforatum).

HIV or HCV proteaseinhibitors

Non nucleosidereverse transcriptaseinhibitors efavirenz.

Combination with other medicines for advanced hormone-sensitive prostate cancer

Abiraterone Therapeutic Expected: ↔ Expected: ↔ Abiraterone anddose for docetaxel are not

Orgovyx known(not an inhibitors/inducers ofinhibitor/inducer of enzymes and

CYP3A4 and/or P-gp) transporterscontributing to the

Docetaxel Therapeutic Expected: ↔ Expected: ↔metabolism anddose for

Orgovyx transport ofrelugolix.(not aninhibitor/inducer of

CYP3A4 and/or P-gp)

No clinicallymeaningfulinteraction isexpected and no doseadjustment of

Orgovyx is required.

Darolutamide Therapeutic Expected: ↔ Expected: ↔ Darolutamide is adose for weak inducer of

Orgovyx CYP3A4. However(weak inducer of the potential

CYP3A4) decrease in exposureis not expected to beclinicallymeaningful.

No dose adjustmentof Orgovyx isrequired.

Enzalutamide Therapeutic Expected: ↔ Expected: ↔ Enzalutamide maydose for decrease (CYP3A4

Orgovyx induction) and/or(strong CYP3A4 increase (P-gpinducer and P-gp inhibition) theinhibitor) relugolix exposure.

Based on limiteddata (n=20) in menwho received a 120mg dose of relugolixand 80 to 160 mgdoses ofenzalutamideconcomitantly for upto 266 days in thephase 3 study,plasma relugolixtroughconcentrations didnot change to aclinically significantextent upon addingenzalutamide to therelugolixmonotherapy.

Therefore, no dosemodifications arerecommended for co-administration ofrelugolix andenzalutamide.

Apalutamide Therapeutic Expected: ↓ Expected: ↓ Co-administration ofdose for Orgovyx with

Orgovyx apalutamide is not(P-gp and strong recommended, as

CYP3A4 inducer) apalutamide is acombined P-gp andstrong CYP3A4inducer.

In a clinical study ,

Orgovyx 120 QD(withoutapalutamide) and

Orgovyx 240 QD(with 240 QDapalutamide)resulted in similar

Ctrough values.

An increased dose of

Orgovyx isrecommended if co-administration withapalutamide isrequired (seesection 4.2).

Abbreviations: QD: once a day, BID: twice a day, QID: four times a day, HIV: humanimmunodeficiency virus, HCV: hepatitis C virus.

*: Upon co-administration of azithromycin and relugolix, relugolix exposure increases up to5-fold were observed in the first 3 hours after dosing in the median concentration-time curves.

After a dose separation window of 6 hours, the increase in relugolix exposure in the medianconcentration-time curves was maximally 1.6-fold in the first 3 hours after dosing.

Potential for relugolix to affect the exposure to other medicinal products

Relugolix is a weak inducer of CYP3A mediated metabolism, and an inhibitor of BCRP and

P-gp in vitro. Effect of co-administration of relugolix on the exposure of midazolam,rosuvastatin and dabigatran and associated dosing recommendations are summarised in Table2. This list also includes expected potential interacting effect of relugolix on other medicinalproducts.

Cytochrome P450 (CYP) enzymes: Relugolix is not an inhibitor of CYP1A2, CYP2B6,

CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 nor an inducer of CYP1A2 or CYP2B6at clinically relevant plasma concentrations.

Transporter systems: Relugolix is not an inhibitor of OATP1B1, OATP1B3, OATP2B1,

OAT1, OAT3, OCT2, MATE1, MATE2-K, or BSEP at clinically relevant plasmaconcentrations.

Table 2. Effect of relugolix on exposure (Cmax, AUC0-inf) of co-administered medicinalproducts and recommendations

Relugolix dose Drug dose Change in Change in Recommendationregimen regimen drug AUC0- drug Cmaxinf

Medicinal products that are CYP3A substrates120 mg QD, multiple Midazolam 22% ↓ 14% ↓ No dose adjustmentdoses 5mg single of midazolam anddose other CYP3Asubstrates is(sensitiverequired.

CYP3Asubstrate) Clinicallymeaningfulinteractions withother CYP3Asubstrates thanmidazolam are notexpected. If adecrease in thetherapeutic effectsoccur, medicinalproducts (e.g. statins)may be titrated toachieve desiredtherapeutic effects

Medicinal products that are BCRP substrates120 mg QD, multiple Rosuvastatin 27% ↓ 34% ↓ The decrease indoses 10mg single exposure todose rosuvastatin is notconsidered clinically(sensitivemeaningful;

BCRP andhowever,

OATP1B1rosuvastatin may besubstrate)titrated to achievedesired therapeuticeffects. The effect ofrelugolix on other

BCRP substrates hasnot been evaluatedand the relevance forother BCRPsubstrates isunknown.

Medicinal products that are P-gp substrates120mg single dose Dabigatran 17% ↑ 18% ↑ The increase inexetilate dabigatran exposure150mg single is not considered todose be clinicallymeaningful.(P-gp

Therefore, clinicallysubstrate)meaningful effects ofa 120 mg dose ofrelugolix on other

P-gp substrates arenot expected.

Considering that the360 mg loading doseof relugolix has notbeen tested, doseseparation of theloading dose ofrelugolix fromadministration ofother P-gp substratesis advised.

Combination with other medicines for advanced hormone-sensitive prostate cancer

Therapeutic dose for Abiraterone Expected: Expected: No clinically

Orgovyx ↔ ↔ meaningful changes(CYP3A4in exposure aresubstrate)expected and no doseadjustments arenecessary for

Therapeutic dose for Docetaxel Expected: Expected:

abiraterone,

Orgovyx ↔ ↔(CYP3A enzalutamide,substrate) apalutamide,darolutamide ordocetaxel when co-administered withrelugolix.

Therapeutic dose for Darolutamide Expected: Expected:

Orgovyx ↔ ↔(CYP3A, P-gp and BCRPsubstrate)

Therapeutic dose for Enzalutamide Expected: Expected:

Orgovyx ↔ ↔(CYP2C8and CYP3A4substrate)

Therapeutic dose for Apalutamide Expected: Expected:

Orgovyx ↔ ↔(CYP2C8and CYP3A4substrate)

Abbreviations: QD: once a day

This medicinal product is not indicated in women of childbearing potential. It is not to beused in women who are, or may be, pregnant or breast-feeding (see section 4.1).

It is not known whether relugolix or its metabolites are present in semen. Based on findings inanimals and mechanism of action, if a patient engages in sexual intercourse with a woman ofchildbearing potential, effective contraception during treatment and for 2 weeks after the lastdose of Orgovyx must be used.

There is a limited amount of data from the use of relugolix in pregnant women. Studies inanimals have shown that exposure to relugolix in early pregnancy may increase the risk ofearly pregnancy loss (see section 5.3). Based on the pharmacological effects, an adverse effecton pregnancy cannot be excluded.

Results from nonclinical studies indicate that relugolix is excreted into the milk of lactatingrats (see section 5.3). No data are available regarding the presence of relugolix or itsmetabolites in human milk or its effect on the breast-fed infant. An effect on breast-feedingnewborns/infants cannot be excluded.

Based on findings in animals and mechanism of action, Orgovyx may impair fertility in malesof reproductive potential (see section 5.3).

Orgovyx has no or negligible influence on the ability to drive and use machines. Fatigue anddizziness are very common (fatigue) and common (dizziness) adverse reactions that mayinfluence the ability to drive and use machines.

The most commonly observed adverse reactions during relugolix therapy are physiologicaleffects of testosterone suppression, including hot flushes (54%), musculoskeletal pain (30%),and fatigue (26%). Other very common adverse reactions include diarrhoea and constipation(12% each).

Adverse reactions listed in Table 3 are classified according to frequency and system organclass. Within each frequency grouping, adverse drug reactions are presented in order ofdecreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare(< 1/10 000), and not known (cannot be estimated from available data).

Table 3. Adverse reactions reported in clinical trials and during post-marketingexperience

Common Anaemia

Common Gynaecomastia

Common Insomnia

Depression

Common Dizziness

Uncommon Myocardial infarction

Unknown QT prolonged (see sections 4.4 and 4.5)

Very common Hot flush

Common Hypertension

Very common Diarrhoeaa

Common Nausea

Common Hyperhidrosis

Uncommon Urticaria

Very common Musculoskeletal painb

Uncommon Osteoporosis/osteopenia

Reproductive and breast disorders

Common Libido decreased

General disorder and administration site conditions

Very common Fatiguec

Common Weight increased

Glucose increasedd

Triglyceride increasedd

Blood cholesterol increasede

Uncommon Aspartate aminotransferase increased

Alanine aminotransferase increasedda Includes diarrhoea and colitisb Includes arthralgia, back pain, pain in extremity, musculoskeletal pain, myalgia, bone pain, neck pain, arthritis,musculoskeletal stiffness, non-cardiac chest pain, spinal pain, and musculoskeletal discomfortc Includes fatigue and astheniad Grade 3/4 increases identified through clinical laboratory test monitoring (see below)e There were no reported cholesterol increases > grade 2

Changes in laboratory parameters

Changes in laboratory values observed during up to 1 year of treatment in the phase 3 study(N = 622) were in the same range for Orgovyx and a GnRH agonist (leuprorelin) used asactive comparator. ALT and/or AST concentrations > 3x upper limit of normal (ULN) werereported for 1.4% of patients with normal values prior to treatment, following treatment with

Orgovyx. An increase to grade 3/4 ALT was observed in 0.3% of patients and to grade 3/4

AST in 0% of patients treated with Orgovyx, respectively. No events were associated withincreased bilirubin.

Haemoglobin concentration decreased by 10 g/L during up to 1 year of treatment. Markeddecrease in haemoglobin (≤ 105 g/L) was observed in 4.8% following treatment with

Orgovyx, with decreases to grade 3/4 in 0.5%. Glucose increased to grade 3/4 in 2.9% andtriglycerides increased to grade 3/4 in 2.0% of patients observed.

Reporting suspected adverse reactions after authorisation of the medicinal product isimportant. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via the nationalreporting system listed in Appendix V.

There is no known specific antidote for overdose with Orgovyx. In the event of an overdose,

Orgovyx should be stopped and general supportive measures should be undertaken until anyclinical toxicity has diminished or resolved, taking into consideration the half-life of61.5 hours. Adverse reactions in the event of an overdose have not yet been observed; it isexpected that such reactions would resemble the adverse reactions listed in section 4.8. It isnot known if relugolix is removed by haemodialysis.

Pharmacotherapeutic group: Endocrine therapy, other hormone antagonists and related agents,

ATC code: L02BX04

Relugolix is a nonpeptide GnRH receptor antagonist that competitively binds to GnRHreceptors in the anterior pituitary gland preventing native GnRH from binding and signallingthe secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

Consequently, the production of testosterone from the testes is reduced. In humans, FSH and

LH concentrations rapidly decline upon initiating treatment with Orgovyx and testosteroneconcentrations are suppressed to below physiologic concentrations. Treatment is notassociated with the initial increases in FSH and LH concentrations and subsequentlytestosterone (“potential symptomatic flare”) observed upon initiation of treatment with a

GnRH analogue. Following discontinuation of treatment, pituitary and gonadal hormoneconcentrations return to physiologic concentrations.

The safety and efficacy of Orgovyx was evaluated in HERO, a randomised, open-label studyin adult men with androgen-sensitive advanced prostate cancer requiring at least 1 year ofandrogen deprivation therapy and who were not candidates for surgical or radiation therapywith curative intent. Eligible patients had either evidence of biochemical (PSA) or clinicalrelapse following local primary intervention with curative intent and were not candidates forsalvage surgery, had newly diagnosed androgen-sensitive metastatic disease, or had advancedlocalized disease unlikely to be cured by primary intervention with either surgery or radiation.

Eligible patients had to have an Eastern Cooperative Oncology Group (ECOG) performancestatus of 0 or 1. Patients with disease progression during the treatment period wereencouraged to remain on study and, if indicated, may have received radiotherapy asprescribed by the investigator. If PSA levels rose, patients were allowed to receiveenzalutamide after the confirmation of PSA progression or docetaxel during the study.

The primary efficacy outcome measure was medical castration rate defined as achieving andmaintaining serum testosterone suppression to castrate levels (< 50 ng/dL) by day 29 through48 weeks of treatment, plus non-inferiority of relugolix compared to leuprorelin was assessed(see Table 4). Other key secondary endpoints included castration rates on day 4 and 15,castration rates with testosterone < 20 ng/dL at day 15, and PSA response rate at day 15 (see

Table 5).

A total of 934 patients were randomised to receive Orgovyx or leuprorelin 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 of120 mg orally.

b) Leuprorelin 22.5 mg injection (or 11.25 mg in Japan, Taiwan, and China)subcutaneously every 3 months.

The population (N = 930) across both treatment groups had a median age of 71 years (range47 to 97 years). The ethnic/racial distribution was 68% White, 21% Asian, 4.9% Black, and5% other. Disease stage was distributed as follows: 32% metastatic (M1), 31% locallyadvanced (T3/4 NX M0 or any T N1 M0), 28% localized (T1 or T2 N0 M0), and 10% notclassifiable.

The primary efficacy results of Orgovyx to leuprorelin on achieving and maintaining serumtestosterone at castrate levels (T< 50 ng/dL) are shown in Table 4 and Figure 1. The baselinetestosterone levels and the time-course of testosterone suppression by Orgovyx andleuprorelin during the 48 week treatment period are shown in Figure 2.

Table 4. Medical castration rates (testosterone concentrations < 50 ng/dL) from week 5 day 1(day 29) through week 49 day 1 (day 337) in HERO

Orgovyx Leuprorelin360/120 mg 22.5 or 11.25 mga

No. treated 622b 308b

Responder rate (95% CI)c 96.7% 88.8%(94.9%, 97.9%) (84.6%, 91.8%)

Difference from leuprorelin (95% CI) 7.9%(4.1%, 11.8%)dp-value < 0.0001a 22.5 mg dosed in Europe and North America; 11.25 mg dosed in Asia. The castration rate of the subgroup ofpatients receiving 22.5 mg leuprorelin (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.

d Non-inferiority was tested with a margin of -10%.

Figure 1: Cumulative incidence of testosterone concentrations < 50 ng/dL in HEROError! Nodocument variable supplied.

1.00.80.60.40.2 Relugolix

Leuprorelin0.00 1 3 5 9 13 17 21 25 29 33 37 41 45 49

Number of Time (Week)

Patients at Risk

Relugolix 622 96 5 4 3 1 0 0 0 0 0 0 0 0 0

Leuprorelin 308 307 252 24 13 11 3 1 1 1 1 0 0 0 0

Figure 2: Testosterone concentrations from baseline to week 49 (mean and 95% CI) in HERO500 Relugolix (N = 622)

Leuprorelin (N = 308)

End of

Baselin0e 1 3 5 9 13 17 21 25 29 33 37 41 45 49

Time (Week)

Evaluable

Patients, n

Relugolix 612 615 609 616 609 604 598 597 594 590 579 571 567 564 557

Leuprorelin 300 300 301 303 302 301 297 299 291 283 283 282 276 271 264

A summary of the results of the key secondary endpoints are shown in Table 5.

Table 5. Summary of key secondary endpoints

Orgovyx Leuprorelin

Secondary endpoint (N = 622) (N = 308) p-Value

Cumulative probability of testosterone 56.0 0.0 <0.0001suppression to < 50 ng/dL prior to dosing onday 4

Cumulative probability of testosterone 98.7 12.1 <0.0001suppression to < 50 ng/dL prior to dosing onday 15

Mean (95% CI) Testosterone Concentration (ng/dL)

Cumulative Incidence

Proportion of patients with PSA response at 79.4 19.8 <0.0001

Day 15 followed with confirmation at day 29

Cumulative probability of testosterone 78.4 1.0 <0.0001suppression to < 20 ng/dL prior to dosing onday 15

Abbreviations: PSA = prostate-specific antigen.

The European Medicines Agency has waived the obligation to submit the results of studieswith Orgovyx in all subsets of the paediatric population in treatment of advanced hormone-sensitive prostate cancer (see section 4.2 for information on paediatric use).

After oral administration of a single 360 mg loading dose, 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, the mean (± SD), Cmax, Cavg(average plasma concentration over the 24-hour dosing interval), and Ctrough of relugolix atsteady-state were 70 (± 65) ng/mL, 17.0 (± 7) ng/mL and 10.7 (± 4) ng/mL, respectively.

The accumulation of exposure to relugolix upon once daily administration of a 120-mg doseof relugolix is approximately 2-fold. After once daily administration of relugolix following a360-mg loading dose on the first day of administration, steady state of relugolix is achievedby day 7.

The absorption of relugolix after oral administration is primarily mediated by intestinal P-gp,for which relugolix is a substrate. After oral administration, relugolix is rapidly absorbed,reaching quantifiable concentration by 0.5 hours post-dose followed by one or moresubsequent absorption peaks. The median (range) time to Cmax (tmax) of relugolix is 2.25 hours(0.5 to 5.0 hours). The absolute bioavailability of relugolix is 11.6%.

After administration of a single 120-mg dose of relugolix following consumption of a high-calorie, high-fat meal (approximately 800 to 1 000 calories with 500, 220, and 124 from fat,carbohydrate, and protein, respectively), the AUC0-∞ and Cmax were decreased 19% and 21%,respectively. The decreases in exposure to relugolix with food are not considered to beclinically meaningful and therefore Orgovyx may be administered without regard to food (seesection 4.2).

Relugolix is 68 to 71% bound to plasma proteins, primarily to albumin and to a lesser extentto α1-acid glycoprotein. The mean blood-to-plasma ratio is 0.78. Based on the apparentvolume of distribution (Vz), relugolix distributes widely to tissues. The estimated volume ofdistribution at steady state (Vss) is 3 900 L.

In vitro studies indicate that the primary CYP enzymes contributing to the overall hepaticoxidative metabolism of relugolix were CYP3A4/5 (45%) > CYP2C8 (37%) > CYP2C19(< 1%) with the oxidative metabolites, Metabolite-A and Metabolite-B, formed by CYP3A4/5and CYP2C8, respectively.

Once absorbed, approximately 19% of relugolix is eliminated as unchanged active substancein the urine and approximately 80% is eliminated through multiple biotransformationpathways, including CYP3A and CYP2C8 and multiple other minor metabolic pathways, witha minor contribution from biliary secretion of unchanged medicinal product and/ormetabolites. Approximately 38% of the administered dose is excreted as metabolites (otherthan Metabolite-C) in the faeces and urine. Metabolite-C, which is formed by intestinalmicroflora, is the primary metabolite in faeces (51%) and further reflects non-absorbed drug.

Relugolix is associated with greater than dose-proportional increases in exposure at dosesbelow approximately 80 mg, which is consistent with the dose-dependent saturation ofintestinal P-gp and the corresponding decreasing contribution of intestinal P-gp efflux to theoral bioavailability of relugolix as the dose is increased. Upon saturation of intestinal P-gp, agreater proportion of the absorption of relugolix is governed by passive diffusion, and theexposure to relugolix increases in proportion to dose within the 80- to 360-mg dose range.

The saturation of intestinal P-gp with higher doses of relugolix is demonstrated by the dose-related increases in exposure to relugolix associated with erythromycin, a strong P-gpinhibitor (and moderate CYP3A inhibitor), where the increases in exposure was less for a120-mg dose compared with lower doses of relugolix (20 or 40 mg) (see section 4.5).

Population PK (PopPK) and PopPK/PD analyses suggest that there are no clinicallymeaningful differences in exposure of relugolix or testosterone concentrations based on age,race or ethnicity, body size (body weight or body mass index) or stage of cancer.

Based upon the dedicated renal impairment studies with 40 mg relugolix, the exposure torelugolix (AUC0-t) was increased by 1.5-fold in patients with moderate renal impairment andby up to 2.0-fold in patients with severe renal impairment as compared to subjects withnormal renal function. The increases in patients with moderate renal impairment are notconsidered to be clinically meaningful. With respect to patients with severe renal impairment,caution is warranted upon once daily administration of a 120-mg dose of relugolix (seesection 4.4).

The effect of end stage renal disease with or without haemodialysis on the pharmacokineticsof relugolix has not been evaluated. The amount of relugolix removed by haemodialysis isunknown.

After administration of a single 40-mg dose of relugolix to patients with mild or moderatehepatic impairment, the total exposure to relugolix (AUC0-∞) was decreased by 31% or wascomparable, respectively, compared to subjects with normal hepatic function. The meanelimination half-life of relugolix in patients with mild or moderate hepatic impairment andhealthy control subjects was comparable.

No dose adjustment for Orgovyx in patients with mild or moderate hepatic impairment isrequired (see section 4.2). The effects of severe hepatic impairment on the pharmacokineticsof relugolix have not been evaluated.

Non-clinical data based on conventional studies of safety pharmacology, repeated dosetoxicity, genotoxicity, or carcinogenic potential reveal no special hazard for humans beyondthose discussed below.

In human GnRH-receptor knock-in male mice, oral administration of relugolix decreasedprostate and seminal vesicle weights at doses ≥ 3 mg/kg twice daily for 28 days. The effectsof relugolix were reversible, except for testis weight, which did not fully recover within28 days after drug withdrawal. These effects in knock-in male mice are likely associated withthe pharmacodynamics of relugolix; however, the relevance of these findings to humans isunknown. In a 39-week repeat dose toxicity study in monkeys, there were no significanteffects on male reproductive organs at oral relugolix doses up to 50 mg/kg/day(approximately 36 times the human exposure at the recommended dose of 120 mg daily basedon AUC). Relugolix (doses of ≥ 1 mg/kg) suppressed LH concentrations in castrated malecynomolgus monkeys; however, the suppressive effect of relugolix on LH and sex hormoneswas not evaluated in the 39-week toxicity study in intact monkeys. Therefore, the relevance ofthe lack of effect on reproductive organs in intact male monkeys to humans is unknown.

In pregnant rabbits orally dosed with relugolix during the period of organogenesis,spontaneous abortion and total litter loss were observed at exposure levels (AUC) less thanthat achieved at the recommended human dose of 120 mg/day. No effects on embryofoetaldevelopment were observed in rats; however, relugolix does not interact significantly with

GnRH receptors in that species.

In lactating rats administered a single oral dose of 30 mg/kg radiolabelled relugolix on post-partum day 14, relugolix and/or its metabolites were present in milk at concentrations up to10-fold higher than in plasma at 2 hours post-dose decreasing to low levels by 48 hours post-dose. The majority of relugolix-derived radioactivity in milk consisted of unchangedrelugolix.

Environmental risk assessment studies have shown that relugolix may pose a risk for theaquatic compartment (see section 6.6).

Mannitol (E421)

Sodium starch glycolate (E468)

Hydroxypropyl cellulose (E463)

Magnesium stearate (E572)

Hypromellose (E464)

Titanium dioxide (E171)

Iron oxide red (E172)

Carnauba wax (E903)

Not applicable.

4 years

This medicinal product does not require any special storage conditions.

Orgovyx film-coated tablets are supplied in a bottle. Each high-density polyethylene (HDPE)bottle contains 30 or 90 film-coated tablets and a desiccant and is closed with a child-resistantinduction seal polypropylene (PP) cap.

Pack sizes of 30 and 90 (3 packs of 30 or 1 pack of 90) film-coated tablets.

Orgovyx film-coated tablets also supplied in Alu/Alu blisters containing 30 and 90 film-coated tablets.

Not all pack sizes may be marketed.

This medicinal product may pose a risk to the environment (see section 5.3). Any unusedmedicinal product or waste material should be disposed of in accordance with localrequirements.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n,

Edifici Est 6ª planta,08039 Barcelona,

Spain

EU/1/22/1642/001

EU/1/22/1642/002

EU/1/22/1642/003

EU/1/22/1642/004

EU/1/22/1642/005

Date of first authorisation: 29 April 2022

Detailed information on this medicinal product is available on the website of the European

Medicines Agency https://www.ema.europa.eu.