YSELTY Film-coated tablet Ref.[50145] Active ingredients: Linzagolix

Medical examination/consultation

Prior to the initiation or reinstitution of Yselty, a complete medical history (including family history) must be taken. Blood pressure must be measured, and a physical examination must be performed guided by the contraindications (see section 4.3) and warnings for use (see section 4.4). During treatment, periodic check-ups must be carried out according to standard clinical practice.

Any hormonal contraception needs to be stopped prior to initiation of Yselty. Pregnancy must be ruled out prior to administering or re-initiation of Yselty

Bone mineral density

In some women treated with Yselty, who had normal bone mineral density (BMD) at start of treatment, BMD loss varying from >3-8% was reported.

The benefits and risks of Yselty in patients with a history of a low trauma fracture or other risk factors for osteoporosis or bone loss (such as chronic alcohol and/or tobacco use, strong family history of osteoporosis, and low body weight), including those taking medications that may affect BMD (e.g., systemic corticosteroids, anticonvulsants), should be considered prior to initiating treatment. It is recommended to perform a DXA scan before commencing treatment with Yselty in these at-risk patients.

Further, a DXA scan is recommended after 1 year of treatment for all women to verify that the patient does not have an unwanted degree of BMD loss. Thereafter, depending on the prescribed dose of Yselty, BMD assessment is recommended annually (Yselty 100 mg) or at a frequency determined by the treating physician based on the woman’s individual risk and previous BMD assessment (Yselty 100 mg with concomitant ABT and Yselty 200 mg with concomitant ABT).

If the risks of BMD decrease exceed the potential benefit of treatment with Yselty, treatment should be discontinued.

Hepatic impairment

Yselty should be avoided in women with severe hepatic impairment (Child-Pugh C). No dose adjustment is necessary in women with mild or moderate hepatic impairment (Child-Pugh A or B), see section 4.2 and 5.2.

Renal impairment

Yselty should be avoided in women with moderate (eGFR = 30–59 mL/min), severe renal impairment (eGFR < 30 mL/min) or end-stage renal disease (see section 4.2). Prescribers are recommended to monitor for adverse reactions in women who have mild renal impairment (eGFR = 60-89 mL/min; see section 5.2) although no dose adjustment is required (see section 4.2).

Cardiovascular disorders/QT prolongation

Linzagolix marginally increases the QT interval but showed no evidence of clinically relevant risk of QT prolongation or Torsade de Pointes (see section 5.1). Caution should be exercised in patients who have known cardiovascular disease, family history of QT prolongation or hypokalaemia, and in concomitant use with medicinal products known to prolong the QT interval. Caution should also be exercised in patients with co-existing disorders leading to increased linzagolix plasma levels (see section 5.2).

Contraception

Linzagolix with or without concomitant ABT has not been demonstrated to provide contraception. Women of childbearing potential at risk of pregnancy have to use effective non-hormonal contraception while on treatment with Yselty (see section 4.6).

Change in menstrual bleeding pattern and reduced ability to recognise pregnancy

Women should be informed that treatment with Yselty usually leads to a significant reduction in menstrual blood loss and often leads to amenorrhoea, which may reduce the ability to recognise the occurrence of a pregnancy in a timely manner. Pregnancy testing should be performed if pregnancy is suspected, and treatment should be discontinued if pregnancy is confirmed (see section 4.3 and 4.6).

Liver enzymes

Asymptomatic transient liver enzyme elevations have been reported (see section 4.8). Patients should be instructed to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice. Treatment should be discontinued if jaundice develops. Acute liver test abnormalities may necessitate discontinuation of treatment with linzagolix until liver tests return to normal.

Women with abnormal hepatic function parameters (≥2 upper limit of normal, ULN) were excluded from studies with linzagolix. Therefore, in women with known abnormal hepatic history, a baseline level of hepatic function tests should be obtained, and further regular monitoring should be performed. These patients should be treated with caution.

Lipid levels

Increases in lipid levels were observed with linzagolix treatment (see section 5.1). These increases were generally of no clinical relevance. However, in women with pre-existing elevated lipid profiles monitoring of lipid levels is recommended.

Mood disorders

Mood disorders including depression, alterations in mood, and emotional lability have been observed with treatment with GnRH antagonists including linzagolix (see section 4.8). Caution is to be applied in women with a history of depression and/or suicidal ideation. Patients with known depression or history of depression should be carefully monitored during treatment. Treatment should be discontinued if depression recurs to a serious degree.

CYP2C8 substrates

Use of Yselty should be avoided in patients using CYP2C8 sensitive substrate medicinal products with a narrow therapeutic index (e.g., paclitaxel, sorafenib and repaglinide, see section 4.5). It is recommended to monitor for increases in adverse reactions associated with other CYP2C8 substrates when co-administered with Yselty.

Warnings and precautions relevant to ABT

If concomitant ABT is prescribed, all warnings and precautions relevant to ABT should be considered.

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

CYP2C8 substrate medicinal products

Linzagolix has been shown to increase mean repaglinide (a CYP2C8 sensitive substrate) exposure in healthy subjects by less than 2-fold. Due to the risk of increased plasma concentrations, concomitant administration of Yselty and medicinal products primarily cleared by CYP2C8 metabolism and with a narrow therapeutic index such as paclitaxel, sorafenib and repaglinide, should be avoided (see section 4.4). Prescribers are recommended to monitor for increases in adverse reactions associated with other CYP2C8 substrates when co-administered with Yselty.

Women of childbearing potential

Linzagolix with or without ABT has not been demonstrated to provide contraception. Women of childbearing potential at risk of pregnancy have to use effective non-hormonal contraception while on treatment with Yselty.

Pregnancy

There are no or limited amount of data from the use of linzagolix in pregnant women. Studies in animals have shown that exposure to linzagolix early in 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.

Yselty is contraindicated during pregnancy (see section 4.3). Treatment should be discontinued if pregnancy is confirmed.

Breast-feeding

Available pharmacodynamic/toxicological data in animals have shown excretion of linzagolix in milk (for details see 5.3).

It is unknown whether linzagolix/metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded.

Yselty is contraindicated during breast-feeding (see section 4.3).

Yselty has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions reported in the pivotal phase 3 clinical studies were hot flushes and headaches, which were reported with higher frequency at higher doses and less frequently when ABT was taken concomitantly (referred to as “with ABT”). Hot flushes were reported in 5.2%, 9.6%, 10.1% and 31% of women treated with 100 mg with ABT, 200 mg with ABT, 100 mg and 200 mg, respectively. Similarly, headaches were reported more frequently at higher doses and decreased with ABT (1.4%, 2.4%, 4% and 6.2% for 100 mg with ABT, 200 mg with ABT, 100 mg and 200 mg, respectively). All other adverse reactions listed below were reported in fewer than 3% of subjects.

Tabulated list of adverse reactions

Adverse reactions associated with linzagolix are reported based on pooled data from two pivotal phase 3 studies which included 828 patients with uterine fibroids who received linzagolix and 209 patients who received placebo up to 6 months. These are tabulated in Table 1 below.

Adverse reactions listed in Table 1 are classified by frequency category and MedDRA system organ class. Within each frequency grouping, adverse 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 the available data).

Table 1. Adverse drug reactions from pivotal clinical studies:

ABT: estradiol 1 mg and norethisterone acetate 0.5 mg tablet once daily
^* see sections 4.4 and/or 4.8, Description of selected adverse reactions, for further information
^a Mood disorders includes reports of mood swings, affect lability, emotional disorder, irritability, mood altered, anxiety, depression, depressed mood
^b Vaginal haemorrhage includes reports of vaginal haemorrhage, metrorrhagia, menorrhagia, menometrorrhagia and uterine haemorrhage
^c Change in menstrual bleeding pattern includes reports of menstruation delayed, irregular menstruation and amenorrhea

Description of selected adverse reactions

Mood disorders

The most common mood disorder adverse reactions were reports of mood swings, which were reported in up to 1.5% of subjects in all linzagolix dose groups. Affect lability and anxiety were reported in 0.6% of subjects on linzagolix. Anxiety was only reported in the 200 mg groups with or without ABT. Reports of depression and depressed mood were infrequent. No more than 1 subject in each of the linzagolix treatment groups reported depression or depressed mood in the phase 2 or phase 3 clinical studies. For specific recommendations, refer to section 4.4.

Elevated liver enzymes

Asymptomatic increases in hepatic enzyme levels, mainly alanine and aspartate transaminase (ALT and AST), were reported. Most increases were low grade and generally returned to normal during continued treatment. The incidence of ALT and/or AST increases in the linzagolix groups was below 3%. In approximately 1% of subjects, ALT/AST levels increased to at least 3 times ULN, with the highest increases reported with linzagolix 200 mg or 200 mg with ABT. No concurrent bilirubin elevation was observed. For specific recommendations, refer to section 4.4.

Bone mineral density changes

The effect of linzagolix on BMD was assessed by DXA scan. In the two phase 3 clinical studies, doseand time-dependent changes in BMD were observed. Concomitant ABT attenuated BMD loss (see Table 2).

Changes in BMD were most pronounced with the 200 mg dose; following 6 months of treatment, mean decreases from baseline of >3% and >8% in lumbar spine BMD were observed in 55% and 4% of patients, respectively.

Following 12 months of treatment with linzagolix 100 mg, 100 mg with ABT and 200 mg with ABT, mean decreases from baseline of >3% and >8% in lumbar spine BMD were observed in 38% and 7%, 16% and 0% and 27% and 1% of patients, respectively.

Table 2. Proportion of patients with lumbar spine BMD change from baseline >3% and >8% at 24 weeks and at 52 weeks of treatment in PRIMROSE 1 and 2:

ABT: estradiol 1 mg and norethisterone acetate 0.5 mg tablet once daily, CfB: change from baseline
^* Linzagolix 200 mg was studied up to 6 months

At 6 months after the end of treatment, increases of BMD were noted in all treatment groups, indicating partial recovery. For specific recommendations, refer to sections 4.2 and 4.4. For detailed information on BMD decrease refer to section 5.1.

Vaginal haemorrhage

Vaginal haemorrhage (including reports of vaginal haemorrhage, uterine haemorrhage, metrorrhagia, menorrhagia, and menometrorrhagia) was reported during treatment with linzagolix. The most frequent adverse reactions were vaginal haemorrhage, metrorrhagia and menorrhagia which were reported in 13 (1.6%), 11 (1.3%) and 5 (0.6%) of subjects treated with linzagolix, respectively.

Vaginal haemorrhage was reported more frequently in subjects in the 100 mg and 200 mg linzagolix with ABT group (up to 2.4%) compared to the groups without ABT (1%). Metrorrhagia was reported in 3 (1.5%), 3 (1.4%), 1 (0.5%) and 4 (1.9%) of subjects in the 100 mg, 100 mg with ABT, 200 mg, and 200 mg with ABT groups, respectively, and menorrhagia was reported for 1 (0.5%), 1 (0.5%), 2 (1.0%) and 1 (0.5%) of subjects in the linzagolix 100 mg, 100 mg with ABT, 200 mg and 200 mg with ABT groups, respectively.

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.

Not applicable.