relugolix: prescribing information – dosing, contraindications, interactions, side effects

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

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

Posology

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

Because relugolix does not induce an increase in testosterone concentrations, it is not necessary 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 separated by at least 6 hours (see section 4.5). Treatment with Orgovyx may be interrupted for up to 2 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) 3A inducers is not recommended. If co-administration is required, the dose of Orgovyx must be increased 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 (see section 4.5).

Missed doses

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

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

Special populations

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

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

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

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

Method of administration

Oral use.

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

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

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 3 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).

Table 3. Adverse reactions reported in clinical trials and during post-marketing experience Blood and lymphatic system disorders Common Anaemia Endocrine disorders Common Gynaecomastia Psychiatric disorders Common Insomnia Depression Nervous system disorders Common Dizziness Headache Cardiac disorders Uncommon Myocardial infarction Unknown QT prolonged (see sections 4.4 and 4.5) Vascular disorders Very common Hot flush Common Hypertension Gastrointestinal disorders Very common Diarrhoeaa Constipation Common Nausea Skin and subcutaneous tissue disorders Common Hyperhidrosis Rash Uncommon Urticaria Angioedema Musculoskeletal and connective tissue disorders Very common Musculoskeletal painb Uncommon Osteoporosis/osteopenia Reproductive and breast disorders Common Libido decreased General disorder and administration site conditions Very common Fatiguec Investigations Common Weight increased Glucose increasedd Triglyceride increasedd Blood cholesterol increasede Uncommon Aspartate aminotransferase increased Alanine aminotransferase increasedd a Includes diarrhoea and colitis b 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 discomfort c Includes fatigue and asthenia d Grade 3/4 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 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 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 3/4 in 0.5%. Glucose increased to grade 3/4 in 2.9% and triglycerides increased to grade 3/4 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.

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

Clinical interaction studies with P-gp inhibitors (erythromycin and azithromycin) and combined P-gp and strong CYP3A4 inducers (rifampicin) have shown to affect the exposure of relugolix to a clinically relevant extent. Effect of co-administration on the exposure to

relugolix and associated dosing recommendations are summarised in Table 1. This list also includes expected effect and recommendations with other potentially interacting medicinal products.

P-gp inhibitors

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 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 is not recommended.
If co-administration is required, 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 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 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).

Table 1. Effect of co-administered medicinal products on relugolix exposure (Cmax, AUC0- inf) and recommendations Interacting drug dose regimen Relugolix dose regimen Change in relugolix AUC0-inf Change in relugolix Cmax Recommendation Medicinal products that are oral P gp inhibitors erythromycin

500 mg QID, multiple doses

(P-gp and moderate
CYP3A4 inhibitor)
120 mg single dose

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.

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 any clinical toxicity has diminished or resolved, taking into consideration the half-life of 61.5 hours. Adverse reactions in the event of an overdose have not yet been observed; it is expected that such reactions would resemble the adverse reactions listed in section 4.8. It is not known if relugolix is removed by haemodialysis.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Endocrine therapy, other hormone antagonists and related agents, ATC code: L02BX04

Mechanism of action

Relugolix is a nonpeptide GnRH receptor antagonist that competitively binds to GnRH receptors in the anterior pituitary gland preventing native GnRH from binding and signalling the 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 testosterone concentrations are suppressed to below physiologic concentrations. Treatment is not associated with the initial increases in FSH and LH concentrations and subsequently testosterone (“potential symptomatic flare”) observed upon initiation of treatment with a GnRH analogue. Following discontinuation of treatment, pituitary and gonadal hormone concentrations return to physiologic concentrations.

Clinical efficacy and safety

The safety and efficacy of Orgovyx was evaluated in HERO, a randomised, open-label study in adult men with androgen-sensitive advanced prostate cancer requiring at least 1 year of androgen deprivation therapy and who were not candidates for surgical or radiation therapy with curative intent. Eligible patients had either evidence of biochemical (PSA) or clinical relapse following local primary intervention with curative intent and were not candidates for salvage surgery, had newly diagnosed androgen-sensitive metastatic disease, or had advanced localized disease unlikely to be cured by primary intervention with either surgery or radiation.
Eligible patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with disease progression during the treatment period were encouraged to remain on study and, if indicated, may have received radiotherapy as prescribed by the investigator. If PSA levels rose, patients were allowed to receive enzalutamide after the confirmation of PSA progression or docetaxel during the study.

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

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 at steady-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 dose of relugolix is approximately 2-fold. After once daily administration of relugolix following a 360-mg loading dose on the first day of administration, steady state of relugolix is achieved by day 7.

Absorption

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 more subsequent 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 be clinically meaningful and therefore Orgovyx may be administered without regard to food (see section 4.2).

Distribution