Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Gedeon Richter Plc., Gyömrői út 19-21, 1103 Budapest, Hungary
Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, anti-gonadotrophinreleasing hormones
ATC code: H01CC54
Relugolix is a non-peptide GnRH receptor antagonist that binds to and inhibits GnRH receptors in the anterior pituitary gland. In humans, inhibition of GnRH receptor results in a dose dependent decrease in the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. As a result, circulating concentrations of LH and FSH are reduced. The reduction in FSH concentrations prevents follicular growth and development, thereby reducing the production of estrogen. Prevention of an LH surge inhibits ovulation and development of the corpus luteum, which precludes the production of progesterone. Therefore, Ryeqo provides adequate contraception when taken for at least 1 month (see section 4.2).
Estradiol is the same as the endogenously produced hormone and is a potent agonist of the nuclear estrogen receptor (ER) subtypes. Exogenously administered estradiol alleviates symptoms associated with a hypoestrogenic state, such as vasomotor symptoms and bone mineral density loss.
Norethisterone acetate is a synthetic progestogen. As estrogens promote the growth of the endometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen reduces the estrogen-induced risk of endometrial hyperplasia in nonhysterectomised women.
After administration of relugolix, rapid, dose-dependent decreases in circulating concentrations of LH, FSH, and estradiol are observed. Near maximum decreases in estradiol concentrations is noted with a 40-mg dose to within the postmenopausal range. Across clinical studies, average estradiol concentrations were consistently maintained at least 10 pg/mL higher with Ryeqo compared with relugolix alone. In the phase 3 clinical studies, in patients with uterine fibroids, with Ryeqo, median estradiol predose concentrations after 24 weeks were approximately 33 pg/mL, and in those with endometriosis were approximately 38 pg/mL corresponding with estradiol concentrations associated with the early follicular phase of the menstrual cycle. Progesterone levels in both populations were maintained at <3.0 ng/mL with Ryeqo.
In a single cohort study in healthy premenopausal women, administration of Ryeqo once daily for 84 days substantially suppressed follicular growth throughout the 84-day treatment period (mean dominant follicle size of approximately 6 mm) and ovulation was inhibited in 100% of women as assessed by the Hoogland-Skouby score. After discontinuation of treatment, all women assessed (66 of 67) returned to ovulation within 43 days (mean 23.5 days).
The efficacy and safety of Ryeqo once daily in patients with uterine fibroids was assessed in two replicate, 24-week, multinational, randomised, double-blind, placebo-controlled studies in patients aged 18-50 with heavy menstrual bleeding associated with uterine fibroids (Studies L1 and L2). Patients were required to have uterine fibroids confirmed by ultrasound and menstrual blood loss (MBL) volume of ≥80 mL, as assessed by the alkaline hematin method.
Both studies had 3 treatment groups: Women were randomised to receive relugolix 40 mg + estradiol 1 mg and norethisterone acetate 0.5 mg (E2/NETA) (Ryeqo) for 24 weeks, or placebo for 24 weeks, or relugolix 40 mg for 12 weeks followed by relugolix 40 mg co-administered with E2/NETA for 12 weeks. The median age of women was 42 years, and mean body mass index was 31.7 kg/m². Approximately 49.4% of women were Black, 44.7% were White, and 5.9% were of other races.
In both studies, a statistically significant higher percentage of responders, defined as MBL volume of <80 mL and at least a 50% reduction from baseline in MBL volume, was observed in favour of women treated with Ryeqo compared with placebo (Table 5). Reductions in MBL volume were seen as early as the first assessment (Week 4). The results for other secondary endpoints related to bleeding are as shown in Table 5. All key secondary endpoints were alpha-controlled.
Table 5. Results of primary and selected secondary efficacy assessments in study L1 and study L2 (uterine fibroids):
| Study L1 | Study L2 | |||
|---|---|---|---|---|
| Ryeqo (N=128) | Placebo (N=127) | Ryeqo (N=125) | Placebo (N=129) | |
| Number (%) of respondersa,b | 94 (73.4%) | 24 (18.9%) | 89 (71.2%) | 19 (14.7%) |
| Number (%) of patients with MBL <80 mL | 97 (75.8%) | 34 (26.8%) | 97 (73.6%) | 25 (19.4%) |
| Number () of patients with ≥50 reduction in MBL volume | 101 (78.9%) | 28 (22.1%) | 96 (76.8%) | 28 (21.7%) |
| Number (%) of patients with amenorrhoeab,c | 67 (52.3%) | 7 (5.5%) | 63 (50.4%) | 4 (3.1%) |
| Number (%) of patients with >2 g/dL improvement in haemoglobin levelsd | 15 (50.0%) | 5 (21.7%) | 19 (61.3%) | 2 (5.4%) |
| Number (%) of patients who achieved NRS ≤1b,e | 25 (43.1%) | 7 (10.1%) | 32 (47.1%) | 14 (17.1%) |
| Percent change in primary uterine fibroid volume | -12.4 (5.62) | -0.3 (5.40) | -17.4 (5.93) | -7.4 (5.92) |
| Percent change in uterine volume | -12.9 (3.08) | 2.2 (3.01) | -13.8 (3.39) | -1.5 (3.37) |
a A responder is defined as a woman who achieved both a MBL volume of <80 mL and at least a 50% reduction from baseline in MBL volume over the last 35 days of treatment.
b p-value <0.0001 is comparison of Ryeqo vs placebo stratified by baseline MBL volume (<225 mL, ≥225 mL)
and geographic region (North America, Rest of World).
c Amenorrhoea is defined as reported amenorrhoea, spotting, or negligible bleeding (MBL <5 mL) with supporting eDiary compliance at 2 consecutive visits.
d In patients with a baseline Haemoglobin level ≤10.5 g/dL
e In patients with moderate or severe pain at baseline
Abbreviations: MBL = menstrual blood loss; NRS = numerical rating scale; UFSQoL= uterine fibroid symptom and quality of life
The efficacy and safety of Ryeqo once daily, in patients with endometriosis was assessed in two replicate, 24-week, multinational, randomised, double-blind, placebo-controlled studies in patients aged 18–50 with moderate to severe pain associated with endometriosis (Studies S1 and S2). Patients were required to have endometriosis confirmed by direct visualisation during surgery and/or histological confirmation and were required to have moderate to severe pain as assessed based on an 11-point numerical rating scale (NRS).
Both studies had three treatment groups: Women were randomised to receive relugolix 40 mg + estradiol 1 mg and norethisterone acetate 0.5 mg (E2/NETA) (Ryeqo) for 24 weeks, or placebo for 24 weeks, or relugolix 40 mg for 12 weeks followed by relugolix 40 mg co-administered with E2/NETA for 12 weeks. Patients were eligible for inclusion if they had moderate to severe pain before the screening period until after the run- in period (i.e. at least two cycles). A high percentage (83.2%) of the study population of Studies S1 and S2 reported having undergone previous surgeries/procedures for endometriosis treatment. A low percentage (8%) of the study population did not report previous surgical or medical treatment before inclusion into the studies. At baseline, most patients (92.6%) used analgesics for pelvic pain, including 29.1% of patients in Study S1 and 48.4% of patients in Study S2 who used opioids. The most frequently reported other pharmacotherapies for endometriosis included dienogest (19.4%), estrogen progestin oral contraceptive (15.2%) and GnRH agonists (7.6%). The median age of women was 34 years, and mean body mass index was 26 kg/m². Approximately 91% of women were White, 6% were Black, and 3% were of other races.
Studies S1 and S2 had two co-primary endpoints, consisting of 2 responder analyses. In both studies, a statistically significantly higher percentage of responders was observed, defined as a reduction from baseline in dysmenorrhea of at least 2.8 points over the last 35 days of treatment, without an increase in analgesic use (ibuprofen or opioid), defined as a reduction from baseline in non-menstrual pelvic pain score of at least 2.1 points over the last 35 days of treatment, without an increase in analgesic use (ibuprofen or opioid) (Table 6).
Table 6. Results of co-primary efficacy assessments in study S1 and study S2 (endometriosis):
| Endpoint definition | Study S1 | Study S2 | ||
|---|---|---|---|---|
| Ryeqo (N=212) | Placebo (N=212) | Ryeqo (N=206) | Placebo (N=204) | |
| Number (%) of responders for dysmenorrheaa,c | 158 (74.5%) | 57 (26.9%) | 155 (75.2%) | 62 (30.4%) |
| Number (%) of responders for non- menstrual pelvic pain (NMPP)b,c | 124 (58.5%) | 84 (39.6%) | 136 (66.0%) | 87 (42.6%) |
a Responders were patients whose NRS score for dysmenorrhea declined from baseline to Week 24/EOT by ≥2.8 points, and the patient did not have increased use of study-specified analgesics for pelvic pain at Week 24/EOT relative to baseline.
b Responders were patients whose NRS score for NMPP declined from baseline to Week 24/EOT by ≥2.1 points, and the patient did not have increased use of study specified analgesics for pelvic pain at Week 24/EOT relative to baseline.
c p-value <0.0001 is comparison of Ryeqo vs placebo adjusted by baseline pain score, time since initial surgical diagnosis of endometriosis and geographic region.
Abbreviations: N = number of patients; NMPP = Non menstrual pelvic pain; NRS = Numerical Rating Scale scores (0=no pain, 10=worst pain as bad as you can imagine).
The results for the key secondary efficacy endpoints are shown in Table 7. All key secondary endpoints were alpha controlled.
Table 7. Results of selected secondary efficacy assessments in study S1 and study S2 (endometriosis):
| Endpoint definition | Study S1 | Study S2 | ||
|---|---|---|---|---|
| Ryeqo (N=212) | Placebo (N=212) | Ryeqo (N=206) | Placebo (N=204) | |
| Change in the EHP-30 Pain Domain score, LS Mean (SE)a,b | -33.8 (1.83) | -18.7 (1.83) | -32.2 (1.68) | -19.9 (1.69) |
| Change in the mean dysmenorrhea NRS score, LS Mean (SE)a,b | -5.1 (0.19) | -1.8 (0.19) | -5.1 (0.19) | -2.0 (0.19) |
| Change in the mean NMPP NRS score, LS Mean (SE)a,b | -2.9 (0.18) | -2.0 (0.18) | -2.7 (0.17) | -2.0 (0.17) |
| Change in the mean dyspareunia NRS score, LS Mean (SE)a,b | -2.4 (0.21) | -1.7 (0.22) | -2.4 (0.19) | -1.9 (0.19) |
| Proportion of patients who are not using protocol-specified opioids for endometriosis- associated pain, n (%)c | 182 (85.8%) | 162 (76.4%) | 169 (82.0%) | 135 (66.2%) |
a LS means were based on mixed-effects model with treatment, baseline value, visit, geographic region (North America, Rest of World), time since initial surgical diagnosis of endometriosis (<5 years, ≥5 years), and treatment-by-visit interaction included as fixed effects; visit was also included in the model as random effect within each patient, and an unstructured covariance matrix was assumed.
b Change from baseline to Week 24//EOT
c At Week 24/EOT
Abbreviations: EOT = end-of-treatment; LS = least square; N = number of patients; NETA = norethisterone acetate; NMPP = nonmenstrual pelvic pain; NRS = Numerical Rating Scale, SE = standard error.
The effect of Ryeqo on BMD was evaluated by DXA at week 12, 24, 36, 52 and 104. A total of 477 women with uterine fibroids who completed the 24 week pivotal studies (Study L1 and L2) were enrolled into a 28 week, open-label, single arm extension study (Study L3), where all women received Ryeqo. A total of 228 women who completed the extension study were enrolled into an additional 52 week study (randomised withdrawal study) where they were re randomised to receive either Ryeqo or placebo A total of 802 women with endometriosis who completed the 24-week pivotal studies (Study S1 and S2) were enrolled into the extension study (Study S3), where all patients received Ryeqo. BMD measurements over 104 weeks in patients with uterine fibroids and endometriosis are summarised in Table 8.
Table 8. Bone mineral density (BMD) measurements over 104 weeks in patients with uterine fibroids and endometriosis:
| Ryeqo (N=672) | Placebo (N=672) | |
|---|---|---|
| Lumbar spine (L1 – L4) | ||
| Study L1 & L2, S1 & S2 | ||
| Week 12 | ||
| N | 553 | 545 |
| LS means % changea | \<> -0.56 | 0.15 |
| (95% CI) | (-0.77, -0.36) | (-0.05, 0.36) |
| Week 24 | ||
| N | 528 | 516 |
| LS means % changea | -0.59 | 0.13 |
| (95% CI) | (-0.82, -0.37) | (-0.09, 0.36) |
| Study L3 and S3 | Ryeqo | Placebo → Ryeqo |
| Week 36 | ||
| N | 387 | 379 |
| LS means % changea | -0.66 | -0.00 |
| (95% CI) | (-0.93; -0.40) | (-0.27; 0.26) |
| Week 52 | ||
| N | 365 | 351 |
| LS means % changea | -0.69 | -0.30 |
| (95% CI) | (-1.00; -0.38) | (-0.61; 0.01) |
| Randomised withdrawal study and Study S3 | Ryeqo | Placebob |
| Week 104 | ||
| N | 221 | 229 |
| LS means % changea | -0.40 | -0.18 |
| (95% CI) | (-0.82; 0.02) | (-0.60; 0.23) |
Abbreviations: LS mean = least squares mean; CI = confidence interval, N = number of patients
a % change from baseline;
b Majority of the patients randomised to the placebo group in the randomised withdrawal study were treated with Ryeqo within about 2 cycles upon reassumption of HMB
In the Ryeqo group, LS mean percent changes from baseline in BMD to week 52 and week 104 at the lumbar spine were -0.69% and -0.40%, respectively.
Over a period of 12 months after cessation of Ryeqo, in those endometriosis patients who met BMD loss criteria, evidence of recovery or trend towards recovery was observed in 100% of women at the lumbar spine.
In women treated with relugolix monotherapy for 12 weeks, in studies L1 and L2, S1 and S2, BMD at the lumbar spine decreased by -1.86% from baseline. The difference in percent change in BMD between women treated with Ryeqo and relugolix monotherapy at Week 12 was statistically significant, demonstrating the effectiveness of using relugolix in combination with E2/NETA (Ryeqo) to mitigate bone loss.
To provide context for the effects of Ryeqo on percent change in BMD over 52 weeks treatment, an observational study of untreated age-matched women with uterine fibroids and endometriosis was conducted to characterise longitudinal BMD of premenopausal women aged 18-50 years (natural history study). Through 52 weeks of observation, there was minimal change in BMD with Ryeqo compared with those in an age-matched cohort of premenopausal women with uterine fibroids and endometriosis.
In the clinical studies, no cases of endometrial hyperplasia or endometrial carcinoma assessed by biopsy were observed in women treated with Ryeqo for up to 52 weeks.
The European Medicines Agency has waived the obligation to submit the results of studies with Ryeqo in all subsets of the paediatric population in treatment of leiomyoma of the uterus or endometriosis (see section 4.2 for information on paediatric use).
The pharmacokinetic parameters of relugolix, estradiol (E2), total estrone (E1), and norethisterone (NET) following oral administration of a single Ryeqo tablet to healthy postmenopausal women under fasted conditions are summarized in Table 9.
Table 9. Single dose pharmacokinetic parameters of relugolix, estradiol, total estrone, and norethisterone in post-menopausal women:
| Relugolix | Estradiol (E2) | Unconjugated Estrone (E1) | Norethisterone (NET) | |
|---|---|---|---|---|
| AUC0-∞ (ng*hr/mL or pg*hr/mL) | 198.1 (111.6) | 818.7 (334.4) | 4126 (1650) | 17.5 (8.46) |
| Cmax (ng/mL or pg/mL) | 25.99 (18.21) | 27.95 (19.15) | 188.4 (59.09) | 3.57 (1.43) |
| Tmax (hr) | 2.00 (0.25, 5.00) | 7.00 (0.25, 24.00) | 6.00 (2.00, 12.00) | 1.01 (0.50, 4.00) |
Terminal t1/2 (hr) 61.5 (13.2) 16.6 (7.67) 15.9 (6.52) 10.9 (3.05)
Abbreviations: AUC0-∞ = area under the concentration-time curve from time 0 extrapolated to infinity; Cmax = maximum observed concentration; E1 = estrone; E2 =estradiol; NET = norethisterone; Tmax = time to the maximum observed concentration; t1/2 = half-life
Note: Baseline-adjusted pharmacokinetic parameters for estradiol and unconjugated E1 are presented in this table. Arithmetic means and standard deviations are shown except for tmax, where median and range (minimum, maximum) are shown. AUC0-∞ is presented in ng*hr/mL for relugolix and NET and in pg*hr/mL for unconjugated E2 and unconjugated E1. Cmax is presented in ng/mL for relugolix and NET and in pg/mL for unconjugated E2 and unconjugated E1.
The pharmacokinetic parameters of relugolix, estradiol (E2), total estrone (E1), and norethisterone (NET) at steady state after once daily administration of Ryeqo for 6 weeks to healthy premenopausal women are summarized in Table 10.
Table 10. Multi-dose pharmacokinetic parameters of relugolix, estradiol, total estrone, and norethisterone in pre-menopausal women:
| Relugolix | Estradiol (E2) | Unconjugated Estrone (E1) | Norethisterone (NET) | |
|---|---|---|---|---|
| AUC0-24 (ng*hr/mL or pg*hr/mL) | 157 (94.7) | 784 (262) | 4450 (1980) | 25.5 (11.4) |
| Cmax (ng/mL or pg/mL) | 26 (21.4) | 46.8 (17.3) | 303 (137) | 5.21 (1.53) |
| Tmax (hr) | 3 (0.5, 6) | 3 (0.50, 12.00) | 4 (1, 8.08) | 1 (1, 2) |
| Effective t1/2 (hr) | ~25 | 17.1 (4.03) | 13.9 (4.14) | 8.28 (1.87) |
Abbreviations: AUC0-24 = area under the concentration-time curve during a dosing interval (24); Cmax = maximum observed concentration; E1 = estrone; E2 =estradiol; NET = norethisterone; tmax = time to the maximum observed concentration.
Note: arithmetic means and standard deviations are shown except for tmax, where median and range (minimum, maximum) are shown. AUC0-24 is presented in ng*hr/mL for relugolix and NET and in pg*hr/mL for unconjugated E2 and unconjugated E1. Cmax is presented in ng/mL for relugolix and NET and in pg/mL for unconjugated E2 and unconjugated E1. Effective half-life for relugolix is estimated from accumulation ratios based on AUC values after multiple-dose administration of relugolix at 40 mg.
The absorption of relugolix after oral administration is primarily mediated by the P-gp efflux transporter, for which relugolix is a substrate. After oral administration, relugolix is rapidly absorbed, reaching an initial peak by 0.25 hours postdose followed by one or more subsequent absorption peaks through up to 12 hours postdose. The absolute bioavailability of relugolix is 11.6%. After administration of Ryeqo with a high-fat, high-calorie meal, the AUC0-∞ and Cmax of relugolix were decreased by 38% and 55%, respectively, compared with the fasted state.
After oral administration of a single dose of Ryeqo in the fasted state, unconjugated estradiol concentrations increased slowly with mean concentrations reaching peak concentrations at 8 hours postdose. After administration of Ryeqo following consumption of a high-fat, high-calorie meal, no clinically meaningful effects of food on the exposure to estradiol or estrogenic metabolites were observed.
After oral administration, norethisterone acetate undergoes rapid biotransformation in the intestine and liver to norethisterone (NET). After oral administration of a single dose of Ryeqo in the fasted state, NET concentrations were initially quantifiable at 0.5 hours postdose, increasing rapidly thereafter with mean concentrations reaching peak concentrations within 1 hour.
Administration with food reduced the AUC and Cmax of relugolix by 38% and 55%, respectively, relative to fasted conditions; however, the decrease in exposure to relugolix is considered not to be clinically meaningful. No clinically meaningful effects of food on the exposure to estradiol, estrogenic metabolites, or norethisterone were observed.
Relugolix is 68% to 71% bound to human plasma proteins with a mean whole blood-to-plasma ratio of 0.78. Estradiol and norethisterone circulating in the blood bind to a similar extent to sex hormonebinding globulin (SHBG; 36% to 37%) and to albumin (61%), while only approximately 1-2% are unbound. The value for apparent volume of distribution (Vz) of 19 × 103 L derived from the absolute bioavailability study after intravenous administration indicates that relugolix distributes widely into tissues. The distribution of exogenous and endogenous estradiol is similar. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs.
In vitro studies indicate that the primary CYP enzymes contributing to the overall hepatic oxidative metabolism of relugolix were CYP3A4/5 (45%) > CYP2C8 (37%) > CYP2C19 (<1%) with the oxidative metabolites, metabolite-A and metabolite-B, formed by CYP3A4/5 and CYP2C8, respectively.
The metabolism of exogenous and endogenous estradiol is similar. Metabolism of estradiol occurs mainly in the liver and the gut but also in target organs and involves the formation of less active or inactive metabolites, including estrone, catecholestrogens and several estrogen sulphates and glucuronides. Estrogens are excreted with the bile, hydrolysed and reabsorbed (enterohepatic circulation), and mainly eliminated in urine in biologically inactive form. Oxidation of estrone and estradiol involves cytochrome P450 enzymes, mainly CYP1A2, CYP1A2 (extra hepatic), CYP3A4, CYP3A5, and CYP1B1 and CYP2C9.
The most important metabolites of norethisterone are isomers of 5alpha-dihydro-norethisterone and tetrahydro-norethisterone, which are excreted mainly in the urine as sulphate or glucuronide conjugates.
Once absorbed, approximately 20% of relugolix is eliminated as unchanged active substance in the urine and 80% is eliminated through metabolism by multiple minor metabolic pathways and/or biliary secretion of unchanged active substance. Approximately 38% of the administered dose is excreted as metabolites (other than metabolite-C) in the faeces and urine. Metabolite-C, which is formed by intestinal microflora, is the primary metabolite in faeces (51%) and further reflects non-absorbed active substance.
The mean terminal phase elimination half-life (t1/2) of relugolix, estradiol, and norethisterone following single-dose administration of the Ryeqo tablet are 61.5 hours, 16.6 hours, and 10.9 hours, respectively. Steady state of relugolix is reached after 12 to 13 days of once daily administration. The degree of accumulation of relugolix upon once daily administration is approximately 2-fold, reflecting an effective half-life of approximately 25 hours and supporting once daily administration of relugolix.
The accumulation for E2 and NET upon once daily administration are reported to be 33% to 47%, although when co-administered with relugolix, a weak inducer of intestinal (pre-systemic) CYP3A-mediated metabolism, the accumulation for E2 is expected to be similar or slightly lower.
Relugolix is associated with greater than proportional increases in exposure with respect to dose, within the dose range from 1 to 80 mg, which is most pronounced at doses greater than 20 mg; and thought to be related to the saturation of intestinal P-gp, resulting in an increase in oral bioavailability. The pharmacokinetics of relugolix upon once daily administration of 40 mg relugolix is time independent.
The single-dose pharmacokinetic parameters were not different between Japanese and Caucasian healthy subjects, indicating absence of ethnic sensitivity on the pharmacokinetics of relugolix. Population PK analysis suggests that there are no clinically meaningful differences in exposure of relugolix based on age, race or ethnicity, weight, or BMI. As both estradiol and norethisterone acetate are well known components of hormonal combination products, no studies in special populations were conducted.
After administration of a single 40-mg dose of relugolix to patients with severe renal impairment, the exposure AUC0-∞ and Cmax of relugolix were increased by 1.5- and 1.1-fold, respectively, compared with healthy control subjects with normal renal function. After administration of a single 40-mg dose of relugolix to patients with moderate renal impairment, the exposure AUC0-∞ and Cmax of relugolix both were increased by 1.5-fold compared with healthy control subjects with normal renal function. Mild renal impairment was not a significant covariate for any of the pharmacokinetic parameters of relugolix in a population pharmacokinetic model. Although caution should be used to treat patients with moderate or severe renal impairment (see section 4.4), no dose adjustments with Ryeqo in patients with mild, moderate or severe renal impairment are required (see section 4.2). The effect of end-stage renal disease with or without haemodialysis on the pharmacokinetics of estradiol, norethisterone and relugolix, the components of Ryeqo, in premenopausal women have not been evaluated. The amount of relugolix, estradiol or norethisterone removed by haemodialysis is unknown.
Ryeqo must not be used in patients with severe hepatic impairment (see section 4.3). No dose adjustments for Ryeqo in patients with mild or moderate hepatic impairment are required (see section 4.2). After administration of a single 40-mg dose of relugolix to patients with mild hepatic impairment, the AUC0-∞ and Cmax of relugolix were decreased by 31% and 24%, respectively, compared with healthy control subjects with normal hepatic function. After administration of a single 40-mg dose of relugolix to patients with moderate hepatic impairment, the AUC0-∞ and Cmax of relugolix were decreased by 5% and increased by 1.2-fold, respectively, compared with healthy control subjects with normal hepatic function.
Non-clinical studies have not been conducted with relugolix in combination with estradiol and norethisterone acetate. Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.
In pregnant rabbits orally dosed with relugolix during the period of organogenesis, spontaneous abortion and total litter loss were observed at exposure levels (AUC) comparable to that achieved at the recommended human dose of 40 mg/day. No effects on embryofoetal development were observed in rats; however, relugolix does not interact significantly with GnRH receptors in that species.
In experimental animals, estradiol or estradiol valerate displayed an embryo lethal effect already at relatively low doses; malformations of the urogenital tract and feminisation of male foetuses were observed.
Norethisterone, like other progestogens, caused virilisation of female foetuses in rats and monkeys. After high doses of norethisterone, embryo lethal effects were observed.
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 to 10-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 unchanged relugolix.
Environmental risk assessment studies have shown that relugolix may pose a risk for the aquatic compartment (see section 6.6).
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