Relugolix

Relugolix is a non-peptide, orally active antagonist of the gonadotropin-releasing hormone (GnRH) receptor. Prostate cancer growth depends largely on testosterone, which the testes make under the control of luteinising hormone (LH) from the pituitary gland, and the pituitary releases LH in response to GnRH. Relugolix blocks the GnRH receptor itself, so testosterone falls below physiological levels without the temporary surge, or ‘flare’, that GnRH agonists can cause.

Mechanism of Action

• Receptor blockade: relugolix binds competitively to GnRH receptors in the anterior pituitary gland and prevents native GnRH from binding and triggering the release of luteinising hormone (LH) and follicle-stimulating hormone (FSH).
• Testosterone suppression: with less LH, the testes produce less testosterone. In patients, FSH and LH fall rapidly after treatment starts and testosterone is suppressed to below physiological concentrations. In clinical data, about 56% of patients reached castrate-level testosterone (below 50 ng/dL) by day 4, and about 97% kept castrate levels through 48 weeks of treatment.
• No flare: treatment is not associated with the initial rise in FSH, LH and testosterone seen when a GnRH agonist is started, so an anti-androgen is not needed as surge protection at the start.
• Reversible effect: after treatment stops, pituitary and gonadal hormone concentrations return to physiological levels. Once-daily dosing is needed to keep testosterone suppressed.
• QT interval: androgen deprivation therapy as a class may prolong the QT interval, but a thorough QT/QTc study found no intrinsic effect of relugolix on the QTc interval.

Pharmacokinetics

• Absorption: absorption is mediated mainly by intestinal P-glycoprotein (P-gp), of which relugolix is a substrate. Quantifiable levels appear within 0.5 hours, followed by one or more further absorption peaks; the median time to peak concentration is 2.25 hours (range 0.5 to 5.0 hours). Absolute bioavailability is about 11.6%. A high-calorie, high-fat meal lowered AUC by 19% and peak concentration by 21%, which is not clinically meaningful, so the tablets can be taken with or without food.
• Accumulation and steady state: exposure about doubles with once-daily 120 mg dosing, and steady state is reached by day 7 when treatment starts with the 360 mg loading dose.
• Linearity: exposure rises more than in proportion to dose below about 80 mg, because intestinal P-gp becomes saturated as the dose increases. Between 80 and 360 mg, exposure rises in proportion to dose.
• Distribution: 68–71% bound to plasma proteins, mainly albumin and to a lesser extent alpha-1-acid glycoprotein. The volume of distribution at steady state is about 3,900 L, indicating wide distribution into tissues.
• Metabolism: in vitro, oxidative metabolism in the liver is mainly through CYP3A4/5 (about 45%) and CYP2C8 (about 37%), with CYP2C19 contributing under 1%.
• Elimination: about 19% of absorbed drug is excreted unchanged in urine and about 80% is cleared through multiple metabolic pathways, with a minor contribution from biliary secretion. The main metabolite in faeces (about 51%) is formed by intestinal bacteria and reflects drug that was not absorbed. The effective half-life is about 25 hours and the terminal half-life about 61 hours.
• Special populations: age, race or ethnicity, body size and stage of cancer have no clinically meaningful effect on exposure. In moderate and severe renal impairment, exposure was about 1.5-fold and up to 2-fold higher (studies with a 40 mg dose); in mild hepatic impairment exposure was 31% lower, and in moderate impairment it was comparable to normal. Severe hepatic impairment and end-stage renal disease have not been evaluated.

• Advanced hormone-sensitive prostate cancer: treatment of adult patients.

This page covers the single-ingredient 120 mg tablet only. Relugolix is also an ingredient of a separate combination tablet authorised for gynaecological conditions such as uterine fibroids; that is a different medicinal product with its own indications and dosing and is not described here.

• Hypersensitivity to relugolix or to any of the excipients.

The most common side effects reflect the lowering of testosterone: hot flushes (54%), musculoskeletal pain (30%) and fatigue (26%). Diarrhoea and constipation each occur in about 12% of patients.

Very common (≥1/10): hot flush, diarrhoea (includes colitis), constipation, musculoskeletal pain, fatigue (includes asthenia).

Common (≥1/100 to <1/10): anaemia, gynaecomastia, insomnia, depression, dizziness, headache, hypertension, nausea, hyperhidrosis, rash, decreased libido, weight increased, increased glucose, increased triglycerides, increased blood cholesterol.

Uncommon (≥1/1,000 to <1/100): myocardial infarction, urticaria, angioedema, osteoporosis or osteopenia, increased aspartate aminotransferase, increased alanine aminotransferase.

Not known: QT prolongation.

Musculoskeletal pain covers joint, back, limb, bone, neck and spinal pain, myalgia, arthritis, stiffness, non-cardiac chest pain and musculoskeletal discomfort. Grade 3 or 4 increases in glucose, triglycerides and alanine aminotransferase were found through laboratory monitoring; no cholesterol increase above grade 2 was reported. Myocardial infarction, angioedema and QT prolongation are the serious reactions to watch for, and long-term testosterone suppression also lowers bone density (see Special Instructions).

Relugolix is a P-gp substrate and is cleared partly by CYP3A and CYP2C8, so P-gp inhibitors and combined P-gp and strong CYP3A inducers matter most.

• Oral P-gp inhibitors: the combination is not recommended. Erythromycin (a P-gp and moderate CYP3A4 inhibitor) raised relugolix exposure (AUC) 3.5-fold and peak concentration 2.9-fold after a single dose; azithromycin raised them 1.5-fold and 1.6-fold. Other oral P-gp inhibitors include clarithromycin, ketoconazole, itraconazole, verapamil, carvedilol, amiodarone, ciclosporin and ritonavir. If the combination is required, Orgovyx is taken first, the P-gp inhibitor at least 6 hours later, and patients are monitored more often for side effects; alternatively, Orgovyx can be interrupted for up to 2 weeks during a short course (for example certain macrolide antibiotics).
• Combined P-gp and strong CYP3A inducers (rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital, apalutamide, efavirenz, St John’s wort): not recommended, because exposure falls (rifampicin lowered AUC by 55% and peak concentration by 23%). If the combination is required, the Orgovyx dose is increased to 240 mg once daily, and returned to 120 mg once daily after the inducer is stopped.
• CYP3A4 inhibitors that do not inhibit P-gp: no dose change is recommended (studied with voriconazole, fluconazole and atorvastatin).
• Acid-reducing agents: no clinically significant difference in relugolix pharmacokinetics.
• Medicines that prolong the QT interval: because androgen deprivation therapy may prolong the QT interval, combination with medicines known to prolong it or to cause torsade de pointes should be carefully evaluated. The SmPC names class IA antiarrhythmics (quinidine, disopyramide), class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin and antipsychotics.
• Effect of relugolix on other medicines: relugolix is a weak CYP3A inducer and, in vitro, an inhibitor of BCRP and P-gp. A sensitive CYP3A probe substrate fell by 22% in AUC, with no dose adjustment needed. Rosuvastatin (a BCRP and OATP1B1 substrate) fell by 27% in AUC and 34% in peak concentration, which is not considered meaningful, although the statin dose may be titrated to effect. Dabigatran etexilate (a P-gp substrate) rose by 17% in AUC and 18% in peak concentration, which is not considered meaningful. Because the 360 mg loading dose has not been tested, it should be taken apart from other P-gp substrates.
• Other prostate cancer medicines: no clinically meaningful interaction is expected, and no dose adjustment is needed, with abiraterone, docetaxel, darolutamide or enzalutamide (in limited data from 20 men, relugolix trough levels did not change meaningfully when enzalutamide was added). Apalutamide is a P-gp and strong CYP3A4 inducer, so the Orgovyx dose is increased to 240 mg once daily; in a clinical study this gave trough levels similar to 120 mg alone.
• Food: no clinically meaningful effect; Orgovyx can be taken with or without food.

Treatment should be started and supervised by a specialist physician experienced in the medical treatment of prostate cancer. The tablets are taken by mouth, swallowed whole with some liquid if needed, with or without food, at about the same time each day.

Recommended Dose

• Loading dose: 360 mg (three 120 mg tablets) on the first day.
• Maintenance dose: 120 mg (one tablet) once daily, taken at about the same time each day.
• No anti-androgen is needed as surge protection when starting, because relugolix does not raise testosterone.
• The effect of treatment is followed with clinical assessment and serum prostate-specific antigen (PSA) levels.

Dose Adjustments

• Oral P-gp inhibitors: not recommended. If unavoidable, take Orgovyx first and give the P-gp inhibitor at least 6 hours later, or interrupt Orgovyx for up to 2 weeks during a short course of the inhibitor.
• Combined P-gp and strong CYP3A inducers: not recommended. If unavoidable, increase the dose to 240 mg once daily, and return to 120 mg once daily after the inducer is stopped.

Missed Doses and Interruptions

• A missed dose is taken as soon as the patient remembers. If it is more than 12 hours late, it is skipped and the usual schedule resumes the next day.
• If treatment is interrupted for more than 7 days, restart with the 360 mg loading dose on the first day, then 120 mg once daily.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no adjustment in mild or moderate impairment; caution in severe impairment.
• Hepatic impairment: no adjustment in mild or moderate impairment; severe impairment has not been evaluated.
• Children and adolescents: no relevant use under 18 years of age in advanced hormone-sensitive prostate cancer.

QT Interval

Androgen deprivation therapy may prolong the QT interval. In patients with a history of, or risk factors for, QT prolongation, and in those taking medicines that might prolong it, the doctor should weigh benefit against risk, including the potential for torsade de pointes, before starting Orgovyx. A thorough QT/QTc study showed no intrinsic effect of relugolix itself on the QTc interval.

Cardiovascular Disease

Myocardial infarction and stroke have been reported in the medical literature in men on androgen deprivation therapy. All cardiovascular risk factors should be taken into account.

Bone Density

Long-term suppression of testosterone, whether by orchiectomy, a GnRH agonist or a GnRH antagonist, is associated with decreased bone density. In patients with additional risk factors this may lead to osteoporosis and a higher risk of fracture.

Liver Function

Patients with known or suspected liver disease were not included in long-term clinical trials. Mild, transient rises in alanine and aspartate aminotransferase were seen without a rise in bilirubin or symptoms. Liver function should be monitored in patients with known or suspected hepatic disorder, and the pharmacokinetics in severe hepatic impairment have not been evaluated.

Severe Renal Impairment

Exposure may be up to 2-fold higher in severe renal impairment. Because a lower dose is not available, caution is needed with the 120 mg daily dose. The amount of relugolix removed by haemodialysis is unknown.

Monitoring of Treatment

The effect of Orgovyx should be monitored by clinical parameters and serum PSA levels.

Pregnancy, Contraception, Breastfeeding and Fertility

• Women: Orgovyx is not indicated in women of childbearing potential and must not be used by women who are, or may be, pregnant or breastfeeding.
• Contraception: it is not known whether relugolix or its metabolites are present in semen. If a patient has sexual intercourse with a woman of childbearing potential, effective contraception must be used during treatment and for 2 weeks after the last dose.
• Pregnancy: data are limited; animal studies showed that exposure in early pregnancy may increase the risk of early pregnancy loss, and an adverse effect on pregnancy cannot be excluded.
• Breastfeeding: relugolix passes into the milk of lactating rats; there are no human data, and an effect on a breastfed infant cannot be excluded.
• Fertility: Orgovyx may impair fertility in men of reproductive potential.

Sodium

Each tablet contains less than 1 mmol (23 mg) of sodium, so it is essentially sodium-free.

Effect on Driving

Orgovyx has no or negligible influence on the ability to drive and use machines. Fatigue (very common) and dizziness (common) may affect it.

Orgovyx tablets need no special storage conditions. They are supplied in plastic bottles (30, 33, 90 or 95 tablets, with a desiccant and a child-resistant cap) or aluminium blisters (30 and 90 tablets); not all pack sizes may be marketed. Keep them in the original container, out of the sight and reach of children.

4 years. Do not use after the expiry date on the pack.

Prescription only (Rx), subject to restricted medical prescription (Annex II B), on the prescription of a specialist physician experienced in the medical treatment of prostate cancer. Orgovyx is a tablet taken at home, so it is supplied to the patient or to the treating clinic on prescription.