Rieko film-coated tablets 40 mg+1 mg+0.5 mg No. 28

Instructions for Rijeko film-coated tablets 40 mg + 1 mg + 0.5 mg No. 28

Composition

active ingredients: relugolix, estradiol (as estradiol hemihydrate), norethisterone acetate;

1 tablet contains relugolix 40 mg, estradiol (as estradiol hemihydrate) 1 mg and norethisterone acetate 0.5 mg;

excipients: mannitol (E 421), sodium starch glycolate (type A), hydroxypropylcellulose, lactose monohydrate, magnesium stearate;

film coating: Opadry II yellow (hypromellose 2910, titanium dioxide (E 171), lactose monohydrate, triacetin, iron oxide yellow (E 172)).

Dosage form

Film-coated tablets.

Main physicochemical properties: round, film-coated tablets from light yellow to yellow, embossed with “415” on one side and with a smooth surface on the other.

Pharmacotherapeutic group

Pituitary, hypothalamic hormones and their analogues. Antigonadotropin-releasing hormones. ATC code H01C C54.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Relugolix is a non-peptide gonadotropin-releasing hormone (GnRH) antagonist that binds to and blocks GnRH receptors in the anterior pituitary. In humans, blockade of GnRH receptors results in a dose-dependent reduction in the release of luteinizing hormone (LH) and follicle-stimulating hormone (FH) from the anterior pituitary, resulting in decreased blood concentrations of LH and FH. The decreased FH concentration prevents follicular growth and maturation, thereby reducing estrogen production. Blocking LH release inhibits ovulation and the development of the corpus luteum, which prevents progesterone production. Thus, Rijeko provides adequate contraception when taken for at least 1 month (see section 4.2).

Estradiol is identical to the endogenous hormone and is a potent agonist of the nuclear estrogen receptor subtypes. Exogenously administered estradiol alleviates symptoms associated with decreased estrogen levels, such as vasomotor reactions and loss of bone mineral density.

Norethisterone acetate is a synthetic progestogen. Since estrogens promote endometrial growth, unopposed they increase the risk of endometrial hyperplasia and cancer. The use of a progestogen supplement reduces the estrogen-induced risk of endometrial hyperplasia in women with an intact uterus.

Effects on pituitary and ovarian hormones

Following administration of relugolix, there is a rapid dose-dependent decrease in blood LH, FG and estradiol concentrations. The near maximal decrease in estradiol concentrations is observed with a dose of 40 mg within the postmenopausal period. During clinical trials, mean estradiol concentrations were consistently maintained at a level at least 10 pg/mL higher with Rieko compared to relugolix monotherapy. During the phase 3 clinical trials of Rieko, mean pre-dose estradiol concentrations at 24 weeks were approximately 33 pg/mL, which is consistent with estradiol concentrations in the early follicular phase of the menstrual cycle. Progesterone levels remained at

Impact on ovulatory function

In a cohort study in healthy premenopausal women, once-daily administration of Rijeka for 84 days significantly suppressed follicular growth throughout the 84-day treatment period (mean dominant follicle size was approximately 6 mm), and ovulation was inhibited in 100% of women as assessed by the Hoagland-Scooby scale. After discontinuation of treatment, ovulation resumed in all women studied (66 of 67) within 43 days (mean 23.5 days).

Efficacy and safety over 24 weeks

The efficacy and safety of Rijeka once daily were evaluated in two replicate, 24-week, multinational, randomized, double-blind, placebo-controlled studies in patients aged 18 to 50 years with heavy menstrual bleeding associated with uterine fibroids. Patients had confirmed uterine fibroids by ultrasound and menstrual blood loss (MBL) ≥ 80 ml by alkaline hematin method.

In both studies, there were 3 treatment groups: women were randomized to receive relugolix 40 mg + estradiol 1 mg and norethisterone acetate 0.5 mg (Rieko) for 24 weeks or placebo for 24 weeks, or relugolix 40 mg for 12 weeks followed by relugolix 40 mg with estradiol and norethisterone acetate for 12 weeks. The mean age of the women was 42 years and the mean body mass index was 31.7 kg/m2. Approximately 49.4% of the women were of black race, 44.7% were Caucasian, and 5.9% were of other races.

Reducing heavy menstrual bleeding

In both studies, a statistically significantly higher percentage of respondents was observed, which was determined by indicators of MK volume.

Table 1

Results of primary and selected secondary efficacy assessments in Study 1 and Study 2

a A responder is a woman whose MC values have improved by at least 50% from baseline over the last 35 days of treatment.

b p-value 'by MK (

c Amenorrhea is defined as documented amenorrhea, spotting, or light bleeding (MC

d In patients with baseline hemoglobin ≤ 10.5 g/dL.

e In patients with moderate or severe pain at baseline.

Abbreviations: MC – menstrual blood loss; NBS – numerical rating scale.

Bone mineral density (BMD) measurement over 104 weeks

The effect of Rieko on BMD was assessed by dual X-ray absorptiometry (DXA) every 12 weeks. A total of 477 women who completed the 24-week main study (Studies 1 and 2) were enrolled in a 28-week, single-arm, open-label study (Study 3), in which all women received Rieko. A total of 228 women who completed the extension study were enrolled in an additional 52-week study (randomized withdrawal study), in which they were re-randomized to receive Rieko or placebo (see Table 2).

Table 2

Bone mineral density (BMD) measurement over 104 weeks

and % change from baseline.

b % change compared to week 52.

Abbreviation: mean of the least squares mean.

In the Rijeko group, the percentage change in mean NC BMD from baseline to weeks 36 and 52 in the lumbar spine was -0.73% and

-0.80%, respectively. Although the upper limit of the 95% CI at week 52 was below 0, the mean change from baseline was not considered clinically meaningful because the lower limit remained greater than -2.2%, a threshold considered clinically meaningful. The placebo group receiving Rieko after 24 weeks of treatment demonstrated a similar percent change from baseline in BMD at the lumbar spine. In the randomized withdrawal study, the percent change in mean BMD from week 52 in the Rieko group was 0.81%, while for those patients who completed week 104 of Rieko treatment, the mean percent change in mean BMD from baseline was 0.04% (n = 32).

BMD measurements over 12 weeks in women treated with relugolix monotherapy

To compare the effect of Rijeko on the percent change in BMD over 52 weeks of treatment, an observational study was conducted in age-matched, untreated women with uterine fibroids to assess longitudinal BMD in premenopausal women aged 18 to 50 years (historical study). The percent change in longitudinal BMD with Rijeko over 52 weeks of treatment is consistent with that observed in this cohort of age-matched, premenopausal women with uterine fibroids. The mean percent change in BMD over 52 weeks indicated a small decrease in BMD in the age group 35 years and older, which was only slightly lower in women treated with Rijeko compared to women of the same age group in the historical study.

Effect on the endometrium

A subset of women underwent endometrial biopsy at baseline, 24 weeks, and 52 weeks. No cases of endometrial hyperplasia were identified.

Pharmacokinetics

The pharmacokinetic parameters of relugolix, estradiol, total estrone, and norethisterone following oral administration of a single tablet of Rijeka to healthy postmenopausal women on an empty stomach are shown in Table 3.

Table 3

Pharmacokinetic parameters of relugolix, estradiol, total estrone and norethisterone after single administration in postmenopausal women

Abbreviations: AUC0-∞ – area under the pharmacokinetic concentration–time curve from extrapolated time 0 to infinity; Cmax – maximum observed concentration; Tmax – time to maximum observed concentration; t1/2 – half-life.

Note: The pharmacokinetic parameters of estradiol and unconjugated estrone, taking into account the baseline level, are presented in this table. Arithmetic means and standard deviations are given, except for Tmax, where the median and range (minimum, maximum) are shown. AUC0-∞ are presented in ng*h/mL for relugolix and norethisterone and in pg*h/mL for unconjugated estradiol and unconjugated estrone. Cmax is presented in ng/mL for relugolix and norethisterone and in pg/mL for unconjugated estradiol and unconjugated estrone.

The steady-state pharmacokinetic parameters of relugolix, estradiol, total estrone, and norethisterone after once-daily dosing of Rijeka for 6 weeks in healthy premenopausal women are presented in Table 4.

Table 4

Pharmacokinetic parameters of relugolix, estradiol, total estrone, and norethisterone after multiple doses in premenopausal women

Abbreviations: AUC0-24 – area under the pharmacokinetic concentration-time curve over the dosing interval (24); Cmax – maximum observed concentration; Tmax – time to maximum observed concentration.

Note: Means and standard deviations are given, except for Tmax where median and range (minimum, maximum) are shown. AUC0-24 is presented in ng*h/mL for relugolix and norethisterone and in pg*h/mL for unconjugated estradiol and unconjugated estrone. Cmax is presented in ng/mL for relugolix and norethisterone and in pg/mL for unconjugated estradiol and unconjugated estrone. The effective half-life for relugolix is estimated from accumulation ratios based on AUC values after multiple administration of relugolix at a dose of 40 mg.

Absorption

The absorption of relugolix after oral administration is primarily mediated by the P-gp transporter, for which relugolix is a substrate. After oral administration, relugolix is rapidly absorbed, reaching an initial peak at 0.25 hours post-dose, followed by one or more subsequent absorption peaks at 12 hours post-dose. The absolute bioavailability of relugolix is 11.6%. After administration of Rieko with a high-fat, high-calorie meal, the AUC0-∞ and Cmax of relugolix were reduced by 38% and 55%, respectively, compared to administration in the fasted state.

After oral administration, norethisterone acetate is rapidly biotransformed in the intestine and liver to norethisterone. After oral administration of a single dose of Rijeka in the fasted state, norethisterone was initially quantifiable 0.5 hours after dosing, after which the concentration increased rapidly, reaching peak values within 1 hour.

The impact of food intake

Food intake reduces relugolix AUC and Cmax by 38% and 55%, respectively, compared to fasting conditions; however, the reduction in relugolix exposure is not considered clinically relevant. There was no clinically relevant effect of food on the exposure of estradiol, estrogen metabolites, or norethisterone.

Distribution

Relugolix is 68–71% bound to human plasma proteins with a mean whole blood to plasma ratio of 0.78. The binding of circulating estradiol and norethisterone to sex hormone binding globulin (SHBG; 36–37%) and albumin (61%) is similar, with only approximately 1–2% remaining unbound. The relative volume of distribution (Vz) of 19 × 103 L obtained from an absolute bioavailability study after intravenous administration indicates that relugolix is widely distributed in 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 sex hormone target organs.

Biotransformation

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 ( and CYP2C8, respectively.

The metabolism of exogenous and endogenous estradiol is similar. The metabolism of estradiol occurs mainly in the liver and intestine, as well as in target organs, and includes the formation of less active or inactive metabolites, including estrone, catecholestrogens, and several estrogen sulfates and glucuronides. Estrogens are excreted in the bile, hydrolyzed, and reabsorbed (enterohepatic circulation), and are mainly excreted in the urine in a biologically inactive form. The oxidation of estrone and estradiol occurs with the help of cytochrome P450 enzymes, mainly CYP1A2, CYP1A2 (extrahepatic), CYP3A4, CYP3A5, as well as CYP1B1 and CYP2C9.

The most important metabolites of norethisterone are the isomers 5alpha-dihydronorethisterone and tetrahydronorethisterone, which are excreted mainly in the urine as sulfate or glucuronide conjugates.

Breeding

After absorption, approximately 20% of relugolix is excreted unchanged in the urine, and 80% is excreted after metabolism by several minor metabolic pathways and/or unchanged in the bile. Approximately 38% of the administered dose is excreted as metabolites (except metabolite-C) in the feces and urine. Metabolite-C, which is formed by intestinal microflora, is the major metabolite in the feces (51%) and further reflects unabsorbed active substance.

The mean terminal elimination half-lives (t1/2) of relugolix, estradiol and norethisterone following a single dose of Rijeko are 61.5 hours, 16.6 hours and 10.9 hours, respectively. Steady state of relugolix is achieved after 12–13 days of once daily dosing. The extent of accumulation of relugolix is approximately 2-fold higher with once daily dosing, indicating an effective half-life of approximately 25 hours, allowing relugolix to be administered once daily.

Accumulation of estradiol and norethisterone is known to range from 33% to 47% when administered once daily. When co-administered with relugolix, a weak inducer of intestinal (presystemic) metabolism mediated by CYP3A, accumulation of estradiol is expected to be similar or slightly lower.

Linearity/nonlinearity

Relugolix administration results in a greater than dose-proportional increase in exposure over the dose range of 1 to 80 mg, most pronounced at doses above 20 mg. This is thought to be due to saturation of intestinal P-gp, leading to increased oral bioavailability.

The pharmacokinetics of relugolix 40 mg once daily are not time-dependent.

Special patient groups

Single-dose pharmacokinetic parameters did not differ between Caucasian and Japanese healthy volunteers, indicating that the pharmacokinetics of relugolix are not affected by race. Population pharmacokinetic analysis indicated that there were no clinically relevant differences in relugolix exposure based on age, race or ethnicity, weight or BMI. Since both estradiol and norethisterone acetate are well-known components of combined hormonal medicinal products, no studies in special patient populations were conducted.

Following a single 40 mg dose of relugolix in patients with severe renal impairment, the AUC0-∞ and Cmax of relugolix were increased 1.5-fold and 1.1-fold, respectively, compared to healthy control subjects with normal renal function. Following a single 40 mg dose of relugolix in patients with moderate renal impairment, the AUC0-∞ and Cmax of relugolix were increased 1.5-fold compared to healthy control subjects with normal renal function. Mild renal impairment had no significant effect on any of the pharmacokinetic parameters of relugolix in a population pharmacokinetic study. Although Rijeko should be used with caution in patients with moderate or severe renal impairment (see section 4.4), no dose adjustment of Rijeko is required in patients with mild, moderate or severe renal impairment (see section 4.2).

The effect of end-stage renal disease with or without hemodialysis on the pharmacokinetics of estradiol, norethisterone, and relugolix, the components of Rieko, has not been evaluated in premenopausal women. The amount of relugolix, estradiol, or norethisterone removed by hemodialysis is unknown.

Liver dysfunction

Rieko should not be used in patients with severe hepatic impairment (see section 4.3). No dose adjustment of Rieko is required in patients with mild or moderate hepatic impairment (see section 4.2). Following a single 40 mg dose of relugolix in patients with mild hepatic impairment, the AUC0-∞ and Cmax of relugolix were decreased by 31% and 24%, respectively, compared to healthy control subjects with normal hepatic function. Following a single 40 mg dose of relugolix in patients with moderate hepatic impairment, the AUC0-∞ of relugolix was decreased by 5% and Cmax was increased by 1.2-fold compared to healthy control subjects with normal hepatic function.

Preclinical safety data

Preclinical studies of relugolix in combination with estradiol and norethisterone acetate have not been conducted. Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.

Reproductive toxicity and development

In pregnant rabbits treated orally with relugolix during the period of organogenesis, spontaneous abortions and total loss of litters were observed at exposure levels (AUC) comparable to those achieved at the recommended human dose of 40 mg/day. No effects on embryofetal development were observed in rats; however, relugolix does not interact significantly with GnRH receptors in this species.

In experimental animals, estradiol or estradiol valerate had a lethal effect on the embryo even at relatively low doses; malformations of the urogenital tract and feminization of male fetuses were observed.

Norethisterone, like other progestogens, has caused virilization of female fetuses in rats and monkeys. Embryo-lethal effects have been observed after high doses of norethisterone.

Lactation

In lactating rats given a single oral dose of 30 mg/kg radiolabeled relugolix on day 14 postpartum, relugolix and/or its metabolites were present in milk at concentrations 10-fold higher than plasma concentrations 2 hours post-dose. Levels declined 48 hours post-dose. The majority of the radioactivity detected in milk following administration of radiolabeled relugolix was due to unchanged relugolix.

Indication

Rijeko is indicated for the treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age.

Contraindication

- Hypersensitivity to the active substance(s) or to any of the excipients (see section "Composition").

- Venous thromboembolism, current or history (e.g. deep vein thrombosis, pulmonary embolism).

- Arterial thromboembolic cardiovascular disease, present or in history (e.g. myocardial infarction, cerebrovascular accident, angina pectoris).

- Known thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency or resistance to activated protein C, including factor V Leiden mutation (see section "Special warnings and precautions for use")).

- Diagnosed with osteoporosis.

- Headaches with focal neurological symptoms or migraine headaches with aura (see section "Special warnings and precautions for use").

- Existing or suspected malignant tumors dependent on the influence of sex hormones (for example, malignant tumors of the breast or genital organs).

- Benign or malignant liver tumors, present or in the past (see section "Special warnings and precautions for use").

- Severe liver disease, present or in history (until normalization of laboratory liver function tests).

- Pregnancy or suspected pregnancy and breastfeeding (see section "Use during pregnancy or breastfeeding").

- Vaginal bleeding of unknown etiology.

- Simultaneous use of hormonal contraceptives.

Interaction with other medicinal products and other types of interactions

Recommendations regarding interactions with the drug Rieko are based on an assessment of interactions with individual components of the drug.

The effect of other drugs on the components of the drug Rieko

Relugolix

Oral P-glycoprotein (P-gp) inhibitors

Concomitant use of Rijeko with oral P-gp inhibitors is not recommended. Relugolix is a P-gp substrate (see section 5.2); in an interaction study with erythromycin, P-gp, and a moderate inhibitor of cytochrome P450 (CYP) 3A4, the area under the pharmacokinetic curve (AUC) and maximum concentration (Cmax) of relugolix increased 6.2-fold. Relugolix exposure may be increased by concomitant use of P-gp inhibitors, including certain anti-infectives (such as erythromycin, clarithromycin, gentamicin, tetracycline), antifungals (ketoconazole, itraconazole), antihypertensives (e.g. carvedilol, verapamil), antiarrhythmics (e.g. amiodarone, dronedarone, propafenone, quinidine), antianginals (e.g. ranolazine), ciclosporin, human immunodeficiency virus (HIV) or hepatitis C virus (HCV) protease inhibitors (e.g. ritonavir, telaprevir). If co-administration with oral P-gp inhibitors once or twice daily is necessary (e.g. azithromycin), Rijeko should be taken first and the P-gp inhibitor should be delayed for at least 6 hours, with the patient monitored more frequently for adverse reactions.

Strong inducers of cytochrome P450 3A4 (CYP3A4) and/or P-gp

Concomitant use of Rieko with strong CYP3A4 and/or P-gp inducers is not recommended. In a clinical interaction study with rifampicin, a strong CYP3A4 and P-gp inducer, the Cmax and AUC of relugolix were decreased by 23% and 55%, respectively. Medicinal products that strongly induce CYP3A4 and/or P-gp, such as anticonvulsants (e.g. carbamazepine, topiramate, phenytoin, phenobarbital, primidone, oxcarbazepine, felbamate), anti-infectives (e.g. rifampicin, rifabutin, griseofulvin), St. John's wort (Hypericum perforatum), bosentan, and HIV or HCV protease inhibitors (e.g. ritonavir, boceprevir, telaprevir), as well as non-nucleoside reverse transcriptase inhibitors (e.g. efavirenz), may decrease relugolix plasma concentrations and reduce the therapeutic effect.

CYP3A4 inhibitors

Co-administration of relugolix with strong CYP3A4 inhibitors that do not inhibit P-gp (voriconazole) did not increase relugolix exposure. In addition, in a clinical interaction study, co-administration with atorvastatin, a weak CYP3A4 inhibitor, did not clinically meaningfully alter relugolix exposure.

Estradiol and norethisterone acetate

CYP3A4 inhibitors

Drugs that inhibit the activity of liver enzymes that metabolize drugs, such as ketoconazole, may increase the concentration of estrogen and norethisterone.

CYP enzyme inducers

The metabolism of estrogens and progestogens may be enhanced by concomitant use of substances known to induce drug-metabolizing enzymes, particularly cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir, telaprevir, and nelfinavir, although known as strong inhibitors, are also inducers and may reduce exposure to estrogens and progestogens.

Herbal preparations containing St. John's wort (Hypericum perforatum) may induce the metabolism of estrogens and progestogens. Clinically, increased estrogen metabolism may lead to reduced efficacy in protecting against bone loss. Therefore, long-term concomitant use of liver enzyme inducers with Rijeko is not recommended.

Possible effects of the components of the drug Rieko on other medicines

Relugolix

Relugolix is a weak inducer of CYP3A4. Following co-administration with 40 mg/day of relugolix, the AUC and Cmax of midazolam, a sensitive CYP3A4 substrate, were decreased by 18% and 26%, respectively. However, based on a clinical study with midazolam, no clinically relevant effect of relugolix on other CYP3A4 substrates is expected.

Relugolix has been shown to be an inhibitor of breast cancer resistance protein (BCRP) in vitro, and an interaction study with rosuvastatin, BCRP, and organic anion transporting polypeptide 1B1 (OATP1B1) was conducted. After co-administration with 40 mg daily of relugolix, rosuvastatin AUC and Cmax decreased by 13% and 23%, respectively. The effects are not considered clinically significant, and therefore no dose adjustment of rosuvastatin is recommended when co-administered with relugolix. The clinical effect of Rijeka on other BCRP substrates has not been evaluated, and the significance of other BCRP substrates is unknown.

Estradiol and norethisterone acetate

Medicinal products containing estrogen and progestogen may affect the metabolism of some other active substances. Accordingly, their plasma concentrations may either increase (e.g. cyclosporine) or decrease (e.g. lamotrigine) when Rijeko is used. Dose adjustment of these medicinal products may be necessary.

Application features

The drug Rieko should be used only after a thorough examination of the woman.

Medical examination and doctor's consultation

Before starting or resuming treatment with Rijeko, a complete medical history (including family history) should be taken, blood pressure should be measured, and the woman should undergo a complete medical examination, including a gynecological examination: contraindications (see section "Contraindications") and specific uses (see section "Special uses") of the drug should be taken into account. The examination should be repeated periodically during treatment with Rijeko, depending on the recommendations of the treatment protocols.

Hormonal contraceptives should be discontinued before starting Rijeko (see section "Contraindications"). Non-hormonal methods of contraception should be used for at least 1 month after starting treatment. Pregnancy should be excluded before starting or resuming treatment with Rijeko.

Risk of thromboembolic disorders

The use of medicines containing estrogen and progestogen increases the risk of arterial or venous thromboembolism (ATE or VTE) compared with no such use.

The risk of ATE/VTE with Rijeko has not been established. The doses of estrogen and progestogen included in Rijeko are lower than those used in combined hormonal contraceptives and are combined with relugolix, a gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits ovarian estrogen and progesterone secretion. The estradiol levels in Rijeko are within the range observed in the early follicular phase of the menstrual cycle (see section 5.1).

If ATE/VTE occurs, treatment should be discontinued immediately. Rijeko is contraindicated in women with a current or past history of arterial or venous thromboembolic disorders (see section 4.3).

Risk factors for venous thromboembolism (VTE)

The risk of venous thromboembolic complications in women using oestrogen-progestogen-only products may be significantly increased in women with additional risk factors, especially in the presence of multiple risk factors (see Table 5 below).

Table 5

Risk factors for developing VTE

The increased risk of thromboembolism during pregnancy should be considered, especially during