4.1. Therapeutic indications

Yselty is indicated in adult women of reproductive age for:

- treatment of moderate to severe symptoms of uterine fibroids,

- symptomatic treatment of endometriosis in women with a history of previous medical or surgical treatment for their endometriosis (see section 5.1)..

4.2. Posology and method of administration

Posology

Yselty treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of uterine fibroids and/or endometriosis.

The recommended dose of Yselty is:

For Uterine Fibroids:

• 100 mg or, if needed, 200 mg once daily with concomitant hormonal add-back therapy (ABT, estradiol 1 mg and norethisterone acetate 0.5 mg tablet once daily), see section 5.1.

• 100 mg once daily for women in whom ABT is not recommended or who prefer to avoid hormonal therapy (see section 5.1)

• 200 mg once daily for short-term use (< 6 months) in clinical situations when reduction of uterine and fibroid volume is desired (see section 5.1). Fibroid size may increase when the treatment is stopped. Due to the risk of bone mineral density (BMD) decrease with prolonged use, the 200 mg dose without concomitant ABT should not be prescribed for longer than 6 months.

For Endometriosis:

• 200mg once daily with concomitant hormonal add-back therapy

Pregnancy must be ruled out prior to initiating treatment with Yselty.

Yselty should preferably be started in the first week of the menstrual cycle and should be taken continuously once daily.

In patients with risk factors for osteoporosis or bone loss, a dual X-ray absorptiometry (DXA) scan is recommended prior to starting Yselty treatment (see section 4.4).

Yselty can be taken without interruption. A DXA scan is recommended after 1 year of treatment for all women, and there is a need for continued BMD monitoring thereafter (see section 4.4).

Missed dose

If a dose is missed, treatment must be taken as soon as possible and then continued the next day at the usual time.

Special populations

Hepatic impairment

No dose adjustment is necessary in women with mild or moderate hepatic impairment (Child-Pugh A or B). Yselty should be avoided in women with severe hepatic impairment (Child-Pugh C) (see sections 4.4 and 5.2).

Renal impairment

Prescribers are recommended to monitor for adverse reactions in women who have mild renal impairment (eGFR = 60‑89 mL/min; see section 4.4 and 5.2) although no dose adjustment is required. 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 sections 4.4 and 5.2).

Paediatric population

There is no relevant use of Yselty in children aged under 18 years for the indication of treatment of moderate to severe symptoms of uterine fibroids.

The safety and efficacy of Yselty in children aged under 18 years for the indication of treatment of endometriosis has not been established.

Method of administration

Oral use.

Yselty can be taken with or without food (see section 5.2).

The 200 mg dose is to be taken as two times a 100 mg tablet.

4.3. Contraindications

• Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1

• Pregnancy or breast-feeding (see section 4.6)

• Known osteoporosis

• Genital bleeding of unknown aetiology

• Contraindications related to ABT should be respected if concomitant ABT is given

4.4. Special warnings and precautions for use

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'.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

Yselty was studied in 1605 patients in pivotal controlled trials for up to 6 months or more. These trials included uterine fibroid patients as well as endometriosis patients with short-term and long-term standing disease.

The safety data described in this section reflect the exposure to Yselty in four pivotal phase 3 trials. The most common adverse reactions reported in the pivotal phase 3 clinical studies in the uterine fibroid-treated population 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).

The most common adverse reactions reported in the endometriosis population treated with the recommended dose of 200 mg with ABT included hot flushes (6.3%) and headache (5.7%).

Tabulated list of adverse reactions

Adverse reactions associated with linzagolix are reported based on pooled data from two pivotal phase 3 studies in uterine fibroids (including 828 patients who received linzagolix and 209 patients who received placebo and two pivotal phase 3 studies in endometriosis (including 379 patients who received linzagolix and 189 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

Linzagolix

100 mg

Linzagolix

100 mg with ABT

Linzagolix

200 mg

Linzagolix

200 mg with ABT

Psychiatric disorders

Common

Mood disordersa/*

Mood disordersa/*

Libido decreased

Mood disordersa/*

Libido decreased

Mood disordersa/*

Uncommon

Libido decreased

Libido decreased

Nervous system disorders

Common

Headache

Headache

Headache

Headache

Vascular disorders

Very Common

Hot flush

Hot flush

Common

Hot flush

Hot flush

Uncommon

Hypertension

Hypertension

Hypertension

Hypertension

Gastrointestinal disorders

Common

Nausea/vomiting

Upper abdominal pain

Nausea/vomiting

Constipation

Nausea/vomiting

Uncommon

Upper abdominal pain

Upper abdominal pain

Constipation

Hepatobiliary disorder

Common

Elevated liver enzymes*

Elevated liver enzymes*

Elevated liver enzymes*

Elevated liver enzymes*

Skin and subcutaneous tissue disorders

Common

Hyperhidrosis

Hyperhidrosis

Night sweats

Uncommon

Night sweats

Night sweats

Musculoskeletal and connective tissue disorders

Common

Arthralgia

Bone mineral density decreased*

Arthralgia

Bone mineral density decreased*

Uncommon

Bone mineral density decreased*

Arthralgia

Bone mineral density decreased*

Reproductive system and breast disorders

Common

Vaginal haemorrhageb/*

Pelvic pain

Change in menstrual bleeding pattern c/*

Vaginal haemorrhageb/*

Pelvic pain

Vaginal haemorrhageb/*

Pelvic pain

Vulvovaginal dryness

Vaginal haemorrhageb/*

Pelvic pain

Change in menstrual bleeding pattern c/*

Uncommon

Vulvovaginal dryness

Vulvovaginal dryness

Change in menstrual bleeding patternc/*

Change in menstrual bleeding patternc/*

General disorders and administration site conditions

Common

Asthenia

Uncommon

Asthenia

Asthenia

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

aMood disorders includes reports of mood swings, affect lability, emotional disorder, irritability, mood altered, anxiety, panic attack, nervousness, depression, depressed mood

bVaginal haemorrhage includes reports of vaginal haemorrhage, metrorrhagia, menorrhagia, menometrorrhagia and uterine haemorrhage

cChange 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 2.5% 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 2 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

Uterine fibroid-treated population:

The effect of linzagolix on BMD was assessed by DXA scan. In the two phase 3 clinical studies, dose- and time-dependent changes in BMD were observed. Concomitant ABT attenuated BMD loss.

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.

Endometriosis treated population:

After 6 months of treatment with the recommended dose linzagolix 200 mg with ABT, mean decreases from baseline of > 3% and > 8% in lumbar spine BMD were observed in 14% and 0% of patients, respectively. Following 12 months of treatment with linzagolix 200 mg with ABT, mean decreases from baseline of > 3% and > 8% in lumbar spine BMD were observed in 27% and 2% of patients, respectively (see Table 2).

Table 2: Proportion of patients with lumbar spine BMD change from baseline >3% and >8% at 6 months and at 12 months of treatment in PRIMROSE 1 and 2 and EDELWEISS 3 and 6

PRIMROSE 1 and 2

EDELWEISS 3 and 6

Linzagolix

100 mg

Linzagolix

100 mg with ABT

Linzagolix

200 mg

Linzagolix

200mg with ABT

Linzagolix

200mg with ABT

6 months of treatment

Percentage of subjects (%) with BMD CfB > 3% / >8%

36 / 3

20 / 0

55 / 4

26 / 1

14 / 0

12 months of treatment

Percentage of subjects (%) with BMD CfB > 3% / >8%

38 / 7

16 / 0

*

27 / 1

27 / 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 uterine fibroids and endometriosis populations, 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. In the uterine fibroid studies, 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.

In the endometriosis studies the safety profile confirmed the findings described above.

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 Yellow Card Scheme at wwww.mhra.gov.uk/yellowcard or search for 'MHRA Yellow Card' in the Google Play or Apple App Store.

4.9. Overdose

No case of overdose has been reported.

In cases of overdose, patients should be monitored closely, and management should be symptomatic and supportive.

For women taking regimens with concomitant ABT, overdose of estrogen and progestin may cause hormone-related symptoms, including but not limited to nausea, vomiting, breast tenderness, abdominal pain, drowsiness, fatigue, and withdrawal bleeding.