ORGOVYX Film-coated tablet Ref.[50889] Active ingredients: Relugolix

Effect on QT/QTc interval prolongation

Androgen deprivation therapy may prolong the QT interval. In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant 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 pointes prior to initiating Orgovyx.

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

Cardiovascular disease

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

Changes in bone density

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

Hepatic impairment

Patients with known or suspected hepatic disorder have not been included in long-term clinical trials with relugolix. Mild, transient increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been observed but were not accompanied by an increase in bilirubin or associated with clinical symptoms (see section 4.8). Monitoring of liver function in patients with known or suspected hepatic disorder is advised during treatment. The pharmacokinetics of relugolix in patients with severe hepatic impairment has not been evaluated (see section 5.2).

Severe renal impairment

The exposure to relugolix in patients with severe renal impairment may be increased by up to 2-fold (see section 5.2). Because a lower dose of relugolix is not available, caution in patients with severe renal impairment is warranted upon administration of a 120-mg dose of relugolix once 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-specific antigen (PSA) serum levels.

Sodium

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

Potential for other medicinal products to affect the exposure to relugolix

P-gp inhibitors

Co-administration of Orgovyx and oral P-gp inhibitors should be avoided. Relugolix is a P-gp substrate (see section 5.2). Upon co-administration of a 120-mg dose of relugolix following administration of 500-mg doses of erythromycin four times daily for 8 days, a P-gp and moderate CYP3A inhibitor, the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C_max) of relugolix was increased by 3.5- and 2.9-fold, respectively, due to inhibition of intestinal P-gp by erythromycin, which resulted in an increase in the oral bioavailability of relugolix. Co-administration of Orgovyx with other oral P-gp inhibitors also may increase the AUC and C_max of relugolix and may therefore increase the risk of adverse reactions associated with Orgovyx. Medicinal products that are oral P-gp inhibitors include certain anti-infectives (e.g. azithromycin, erythromycin, clarithromycin, gentamicin, tetracycline), antifungal agents (ketoconazole, itraconazole), antihypertensives (e.g. carvedilol, verapamil), antiarrhythmics (e.g. amiodarone, dronedarone, propafenone, quinidine), antianginal agents (e.g. ranolazine), cyclosporine, human immunodeficiency virus (HIV) or hepatitis C virus (HCV) protease inhibitors (e.g. ritonavir, telaprevir).

If co-administration with once or twice daily oral P-gp inhibitors cannot be avoided (e.g. azithromycin), Orgovyx should be taken first, with the oral P-gp inhibitor taken 6 hours thereafter, and patients should be monitored more frequently for adverse reactions. Alternatively, treatment with Orgovyx may be interrupted for up to 2 weeks for a short course of treatment with a P-gp inhibitor (e.g. for certain 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 by 120 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 should be avoided. Upon co-administration of a 40-mg dose of relugolix following administration of 600-mg doses of rifampicin once daily for 13 days, a P-gp and strong CYP3A inducer, the AUC and C_max of relugolix were decreased by 55% and 23%, respectively, due to induction of intestinal P-gp (and CYP3A) by rifampicin, which resulted in a decrease in the oral bioavailability of relugolix. Co-administration of Orgovyx with other combined P-gp and strong CYP3A inducers also may decrease the AUC and C_max of relugolix and may therefore reduce the therapeutic effects of Orgovyx. Medicinal products that are combined P-gp and strong CYP3A4 inducers include the androgen receptor inhibitor apalutamide, certain anticonvulsants (e.g. carbamazepine, phenytoin, phenobarbital), anti-infectives (e.g. rifampicin, rifabutin), St. John’s Wort (Hypericum perforatum), HIV or HCV protease inhibitors (e.g. ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g. efavirenz).

If co-administration cannot be avoided, the Orgovyx dose should be increased (see section 4.2). After discontinuation 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 upon co-administration of relugolix with voriconazole (strong CYP3A inhibitor; 400-mg doses twice daily on the first day followed by 200-mg doses twice daily for 8 days), atorvastatin (80-mg doses once daily for 10 days), or acid-reducing agents. No clinically significant differences in the pharmacokinetics of a single 5-mg dose of midazolam (sensitive CYP3A substrate) or a single dose of 10-mg of rosuvastatin (breast cancer resistance protein [BCRP] substrate) were observed upon co-administration with relugolix. Based on limited data (n=20) in men who received a 120-mg dose of relugolix and 80- to 160-mg doses of enzalutamide (an androgen receptor signalling inhibitor that is a strong CYP3A inducer and P-gp inhibitor) concomitantly for up to 266 days in the phase 3 study, plasma relugolix trough and serum testosterone concentrations did not change to a clinically significant extent upon adding enzalutamide to the relugolix monotherapy. Therefore, the same dose of relugolix may be maintained during combination treatment.

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 products able 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).

Potential for relugolix to affect the exposure to other medicinal products

Relugolix is a weak inducer of CYP3A-mediated metabolism. Upon co-administration of a single 5-mg dose of midazolam, a sensitive CYP3A substrate, following once daily administration of 120-mg doses of Orgovyx to steady state, the AUC_0-inf and C_max of midazolam was decreased by 22% and 14%, respectively, which is not considered to be clinically meaningful. Clinically meaningful effects on other CYP3A4 substrates are not expected; however, if a decrease in the therapeutic effects occur, medicinal products (e.g. statins) may be titrated to achieve desired therapeutic effects.

Relugolix is an inhibitor of BCRP in vitro. Upon co-administration of a single 10-mg dose of rosuvastatin, a BCRP and OATP1B1 substrate, following once daily administration of 120-mg doses of relugolix to steady state, the AUC_0-inf and C_max of rosuvastatin were decreased by 27% and 34%, respectively. The decrease in exposure to rosuvastatin is not considered clinically meaningful; however, rosuvastatin may be titrated to achieve desired therapeutic effects. The effect of relugolix on other BCRP substrates has not been evaluated and the relevance for other BCRP substrates is unknown.

Relugolix is an inhibitor of P-gp in vitro, indicating the potential for clinically relevant inhibition of P-gp with a 120-mg dose of relugolix. However, the in vitro inhibitory potency is less than that observed for BCRP and, therefore, a clinically meaningful interaction with P-gp substrates is not expected. No clinical drug interaction studies with a P-gp substrate have been performed.

In vitro studies

Cytochrome P450 (CYP) enzymes

Relugolix is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 nor an inducer of CYP1A2 or CYP2B6 at clinically relevant plasma concentrations.

Transporter systems

Relugolix is not an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, MATE2-K, or BSEP at clinically relevant plasma concentrations.

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

Contraception

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

Pregnancy

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

Breast-feeding

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

Fertility

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

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

Summary of the safety profile

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

Tabulated list of adverse reactions

Adverse reactions listed in Table 1 are classified according to frequency and system organ class. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. Frequencies are defined as very common (≥1/10), common (≥1/100 to <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). Within each frequency group, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions reported in the HERO study:

^a Includes diarrhoea and colitis
^bIncludes arthralgia, back pain, pain in extremity, musculoskeletal pain, myalgia, bone pain, neck pain, arthritis, musculoskeletal stiffness, non-cardiac chest pain, spinal pain, and musculoskeletal discomfort
^c Includes fatigue and asthenia
^d Grade ¾ increases identified through clinical laboratory test monitoring (see below)
^e There were no reported cholesterol increases > grade 2

Description of selected adverse reactions

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 as active comparator. ALT and/or AST concentrations >3x upper limit of normal (ULN) were reported for 1.4% of patients with normal values prior to treatment, following treatment with Orgovyx. An increase to grade ¾ ALT was observed in 0.3% of patients and to grade ¾ AST in 0% of patients treated with Orgovyx, respectively. No events were associated with increased bilirubin.

Haemoglobin concentration decreased by 10 g/L during up to 1 year of treatment. Marked decrease in haemoglobin (≤105 g/L) was observed in 4.8% following treatment with Orgovyx, with decreases to grade ¾ in 0.5%. Glucose increased to grade ¾ in 2.9% and triglycerides increased to grade ¾ in 2.0% of patients observed.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. 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 national reporting system listed in Appendix V.

Not applicable.