Relugolix

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, physicians should assess the benefit-risk ratio including the potential for Torsade de pointes prior to initiating relugolix.

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

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. 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.

Co-administration of relugolix 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 relugolix 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 relugolix. 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 relugolix dose should be increased. After discontinuation of the combined P-gp and strong CYP3A inducer, the recommended dose of relugolix should be resumed once daily.

Co-administration of relugolix and oral P-gp inhibitors should be avoided. Relugolix is a P-gp substrate.

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 relugolix 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 relugolix. 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), relugolix 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 relugolix 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 relugolix is interrupted for more than 7 days, resume administration of relugolix with a 360 mg loading dose on the first day followed by 120 mg once daily.

The exposure to relugolix in patients with severe renal impairment may be increased by up to 2-fold. 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.

Based on findings in animals and mechanism of action, relugolix may impair fertility in males of reproductive potential.

Relugolix is not to be used in women who are, or may be, pregnant.

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. Based on the pharmacological effects, an adverse effect on pregnancy cannot be excluded.

Relugolix is not to be used in women who are breast-feeding.

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. Based on the pharmacological effects, an adverse effect on pregnancy cannot be excluded.

Relugolix is not indicated in women of childbearing potential.

Fertility

Based on findings in animals and mechanism of action, relugolix may impair fertility in males of reproductive potential.

Relugolix 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 the following table 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.

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 relugolix 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 relugolix. An increase to grade ¾ ALT was observed in 0.3% of patients and to grade ¾ AST in 0% of patients treated with relugolix, 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 relugolix, 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.