This information is intended for use by health professionals

1. Name of the medicinal product

Luveris 75 IU powder and solvent for solution for injection.

2. Qualitative and quantitative composition

One vial contains 75 IU of lutropin alfa (recombinant human Luteinising Hormone {r-hLH}). Lutropin alfa is produced in genetically engineered Chinese Hamster Ovary (CHO) cells.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder and solvent for solution for injection.

Appearance of the powder: white lyophilised pellet

Appearance of the solvent: clear colourless solution

The pH of the reconstituted solution is 7.5-8.5.

Presentations other than ampoules should be considered for self administration by patients.

4. Clinical particulars
4.1 Therapeutic indications

Luveris in association with a Follicle Stimulating Hormone (FSH) preparation is recommended for the stimulation of follicular development in adult women with severe Luteinising Hormone (LH) and FSH deficiency. In clinical trials these patients were defined by an endogenous serum LH level <1.2 IU/l.

4.2 Posology and method of administration

Treatment with Luveris should be initiated under the supervision of a physician experienced in the treatment of fertility problems.

Posology

In LH and FSH deficient women, the objective of Luveris therapy in association with FSH is to develop a single mature Graafian follicle from which the oocyte will be liberated after the administration of human chorionic gonadotropin (hCG). Luveris should be given as a course of daily injections simultaneously with FSH. Since these patients are amenorrhoeic and have low endogenous oestrogen secretion, treatment can commence at any time.

Luveris should be administered concomitantly with follitropin alfa.

Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and oestrogen response. A recommended regimen commences at 75 IU of lutropin alfa (ie. one vial of Luveris) daily with 75-150 IU FSH.

In clinical trials, Luveris has been shown to increase the ovarian sensitivity to follitropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5 IU-75 IU increments. It may be acceptable to extend the duration of stimulation in any one cycle to up to 5 weeks.

When an optimal response is obtained, a single injection of 250 microgramsof r-hCG or 5,000 IU to 10,000 IU hCG should be administered 24-48 hours after the last Luveris and FSH injections. The patient is recommended to have coitus on the day of, and on the day following, hCG administration.

Alternatively, intrauterine insemination (IUI) may be performed.

Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum.

If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle.

Special populations

Older people

There is no relevant indication for the use of Luveris in the elderly population. Safety and effectiveness of Luveris in elderly patients have not been established.

Renal and hepatic impairment

Safety, efficacy, and pharmacokinetics of Luveris in patients with renal or hepatic impairment

have not been established.

Paediatric population

There is no relevant indication for the use of Luveris in the paediatric population.

Method of administration

Luveris is intended for subcutaneous use. The first injection of Luveris should be performed under direct medical supervision. The powder should be reconstituted immediately prior to use with the solvent provided. Self-administration of this medicinal product should only be performed by patients who are well-motivated, adequately trained and with access to expert advice.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Luveris is contraindicated in patients with:

• hypersensitivity to active substances or to any of the excipients listed in section 6.1.

• tumours of the hypothalamus and pituitary gland

• ovarian enlargement or ovarian cyst unrelated to polycystic ovarian disease and of unknown origin

• gynaecological haemorrhages of unknown origin

• ovarian, uterine, or mammary carcinoma

Luveris must not be used when a condition exists which would make a normal pregnancy impossible, such as:

• primary ovarian failure

• malformations of sexual organs incompatible with pregnancy

• fibroid tumours of the uterus incompatible with pregnancy

4.4 Special warnings and precautions for use

Before starting treatment, the couple's infertility should be assessed as appropriate and putative contraindications for pregnancy evaluated. In addition, patients should be evaluated for hypothyroidism, adrenocortical deficiency and hyperprolactinemia and appropriate specific treatment given.

Porphyria

In patients with porphyria or a family history of porphyria Luveris may increase the risk of an acute attack. Deterioration or a first appearance of this condition may require cessation of treatment.

Ovarian Hyperstimulation Syndrome (OHSS)

A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in women with polycystic ovarian syndrome and usually regresses without treatment.

In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities.

Mild manifestations of OHSS may include abdominal pain, abdominal discomfort and distension, or enlarged ovaries. Moderate OHSS may additionally present with nausea, vomiting, ultrasound evidence of ascites or marked ovarian enlargement.

Severe OHSS further includes symptoms such as severe ovarian enlargement, weight gain, dyspnoea or oliguria. Clinical evaluation may reveal signs such as hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, pleural effusions, or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events, such as pulmonary embolism, ischaemic stroke or myocardial infarction.

Independent risk factors for developing OHSS include young age, lean body mass, polycystic ovarian syndrome, higher doses of exogenous gonadotropins, high absolute or rapidly rising serum estradiol levels and previous episodes of OHSS, large number of developing ovarian follicles and large number of oocytes retrieved in ART cycles.

Adherence to recommended Luveris and FSH dosage and regimen of administration can minimise the risk of ovarian hyperstimulation. Monitoring of stimulation cycles by ultrasound scans as well as estradiol measurements are recommended to early identify risk factors.

There is evidence to suggest that hCG plays a key role in triggering OHSS and that the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur, it is recommended that hCG be withheld and the patient be advised to refrain from coitus or use barrier contraceptive methods for at least 4 days. As OHSS may progress rapidly (within 24 hours) or over several days to become a serious medical event, patients should be followed for at least two weeks after hCG administration.

Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing and that the patient be hospitalised and appropriate therapy be started.

Ovarian torsion

Ovarian torsion has been reported after treatment with other gonadotropins. This may be associated with other risk factors such as OHSS, pregnancy, previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst and polycystic ovarian syndrome. Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate detorsion.

Multiple pregnancy

In patients undergoing induction of ovulation, the incidence of multiple pregnancy and births is increased compared with natural conception. The majority of multiple conceptions are twins. Multiple pregnancy, especially high order, carry an increased risk of adverse maternal and perinatal outcomes.

To minimise the risk of higher order multiple pregnancy, careful monitoring of ovarian response is recommended.

In patients undergoing Assisted Reproductive Technology (ART) procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient age.

Pregnancy loss

The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction than following natural conception.

Ectopic pregnancy

Women with a history of tubal disease are at risk of ectopic pregnancy, whether the pregnancy is obtained by spontaneous conception or with fertility treatments. The prevalence of ectopic pregnancy after ART was reported to be higher than in the general population.

Congenital malformations

The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This could be due to parental factors (e.g. maternal age, genetics), ART procedures and multiple pregnancies.

Thromboembolic events

In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, thrombophilia or severe obesity (body mass index >30 kg/m2), treatment with gonadotropins may further increase the risk for aggravation or occurrence of such events. In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted however, that pregnancy itself, as well as OHSS, also carries an increased risk of thromboembolic events.

Reproductive system neoplasms

There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Luveris should not be administered as a mixture with other medicinal products, in the same injection, except follitropin alfa for which studies have shown that co-administration does not significantly alter the activity, stability, pharmacokinetic nor pharmacodynamic properties of the active substances.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is no indication for the use of Luveris during pregnancy.

Data on a limited number of exposed pregnancies indicate no adverse reactions of gonadotropins on pregnancy, embryonal or foetal development, parturition or postnatal development following controlled ovarian stimulation. No teratogenic effect of Luveris has been observed in animal studies. In case of exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of Luveris.

Breast-feeding

Luveris is not indicated during breast-feeding.

Fertility

Luveris is indicated for the stimulation of follicular development, in association with FSH (see section 4.1).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

Luveris is used for the stimulation of follicular development in association with follitropin alfa. In this context, it is difficult to attribute adverse reactions to any one of the substances used.

In a clinical trial, mild and moderate injection site reactions (bruising, pain, redness, itching or swelling) were reported in 7.4 % and 0.9 % of the injections, respectively. No severe injection site reactions were reported.

Ovarian Hyper-Stimulation Syndrome (OHSS) was observed in less than 6 % of patients treated with Luveris. No severe OHSS was reported (section 4.4).

In rare instances, adnexal torsion (a complication of ovarian enlargement), and haemoperitoneum have been associated with human menopausal gonadotropin therapy. Although these adverse reactions were not observed, there is the possibility that they may also occur with Luveris.

Ectopic pregnancy may also occur, especially in women with a history of prior tubal disease.

List of adverse reactions

The following definitions apply to the frequency terminology used hereafter: 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), frequency not known (cannot be estimated from the available data).

The following adverse reactions may be observed after administration of Luveris.

Immune system disorders

Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock.

Nervous system disorders

Common: Headache

Vascular disorders

Very rare: Thromboembolism, usually associated with severe OHSS

Gastrointestinal disorders

Common: Abdominal pain, abdominal discomfort, nausea, vomiting, diarrhoea.

Reproductive system and breast disorders

Common: Mild or moderate OHSS (including associated symptomatology), ovarian cyst, breast pain, pelvic pain

General disorders and administration site conditions:

Common: Injection site reaction (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection)

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 (see details below).

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

4.9 Overdose

The effects of an overdose of Luveris are unknown. Nevertheless there is a possibility that OHSS may occur, which is further described in section 4.4.

Single doses of up to 40,000 IU of lutropin alfa have been administered to healthy female volunteers without serious adverse reactions and were well tolerated.

Management

Treatment is directed to symptoms.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, gonadotropins. ATC code: G03GA07

Lutropin alfa is a recombinant human Luteinising Hormone (r-hLH), a glycoprotein composed of non-covalently bound α- and ß-subunits. Luteinising Hormone (LH) binds on the ovarian theca (and granulosa) cells and testicular Leydig cells, to a receptor shared with human chorionic gonadotropin hormone (hCG). This LH/CG transmembrane receptor is a member of the super-family of G protein-coupled receptors; specifically, it has a large extra-cellular domain. In vitro the affinity binding of recombinant hLH to the LH/CG receptor on Leydig tumour cells (MA-10) is between that for hCG and that of pituitary hLH, but within the same order of magnitude.

In the ovaries, during the follicular phase, LH stimulates theca cells to secrete androgens, which will be used as the substrate by granulosa cell aromatase enzyme to produce estradiol, supporting FSH-induced follicular development. At mid-cycle, high levels of LH trigger corpus luteum formation and ovulation. After ovulation, LH stimulates progesterone production in the corpus luteum by increasing the conversion of cholesterol to pregnenolone.

In the stimulation of follicular development in anovulatory women deficient in LH and FSH, the primary effect resulting from administration of lutropin alfa is an increase in estradiol secretion by the follicles, the growth of which is stimulated by FSH.

In clinical trials, patients were defined by an endogenous serum LH level < 1.2 IU/l as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories.

In these trials the ovulation rate per cycle was 70-75 %.

5.2 Pharmacokinetic properties

The pharmacokinetics of lutropin alfa have been studied in pituitary desensitised female volunteers from 75 IU up to 40,000 IU. The pharmacokinetic profile of lutropin alfa is similar to that of urinary-derived hLH.

Absorption

Following subcutaneous administration, the absolute bioavailability is approximately 60 %.

Distribution

Following intravenous administration, lutropin alfa is rapidly distributed with an initial half-life of approximately one hour. The steady state volume of distribution is around 10-14 l. The mean residence time is approximately 5 hours.

Lutropin alfa shows linear pharmacokinetics, as assessed by area under curve (AUC) which is directly proportional to the dose administered. The lutropin alfa pharmacokinetics following single and repeated administration of Luveris are comparable and the accumulation ratio of lutropin alfa is minimal. There is no pharmacokinetic interaction with follitropin alfa when administered simultaneously.

Elimination

Following subcutaneous administration of Luveris, lutropin alfa is eliminated from the body with a terminal half-life of about 10-12 hours. Following subcutaneous administration, the terminal half-life is slightly prolonged. Total body clearance is around 2 l/h with less than 5 % of the dose being excreted in the urine.

5.3 Preclinical safety data

Non clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential. As expected from the heterologous protein nature of the hormone, lutropin alfa raised an antibody response in experimental animals after a period that reduced the measurable serum LH levels but did not fully prevent its biological action. No signs of toxicity due to the development of antibodies to lutropin alfa were observed.

At doses of 10 IU/kg/day and greater, repeated administration of lutropin alfa to pregnant rats and rabbits caused impairment of reproductive function including resorption of foetuses and reduced body weight gain of the dams. However, drug-related teratogenesis was not observed in either animal model.

Other studies have shown that lutropin alfa is not mutagenic.

6. Pharmaceutical particulars
6.1 List of excipients

Powder:

Sucrose

Disodium phosphate dihydrate

Sodium dihydrogen phosphate monohydrate

Polysorbate 20

Phosphoric acid, concentrated (for pH adjustment)

Sodium hydroxide (for pH adjustment)

L-methionine

Nitrogen

Solvent:

Water for injection

6.2 Incompatibilities

This medicinal product must not be administered as a mixture in the same injection with other medicinal products except follitropin alfa.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25 °C.

Store in the original package in order to protect from light.

6.5 Nature and contents of container

The powder is packaged in 3 ml neutral colourless glass (type I) vials. The vials are sealed with bromobutyl stoppers protected by aluminium seal rings and flip-off caps. The solvent is packaged either in 2 or 3 ml neutral colourless glass (type I) vials with a Teflon-coated rubber stopper or in 2 ml neutral colourless glass (type I) ampoules.

Packs of 1, 3 or 10 vials with the corresponding number of solvent vials or ampoules. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

For immediate and single use following first opening and reconstitution.

The powder must be reconstituted with the solvent before use by gentle swirling.

The reconstituted solution should not be administered if it contains particles or is not clear.

Luveris may be mixed with follitropin alfa and co-administered as a single injection.

In this case Luveris should be reconstituted first and then used to reconstitute the follitropin alfa powder.

In order to avoid the injection of large volumes, one vial of Luveris can be reconstituted together with one or two ampoule(s)/vial(s) of follitropin alfa, 37.5 IU, 75 IU or 150 IU, in 1 ml of solvent.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Merck Europe B.V.

Gustav Mahlerplein 102

1082 MA Amsterdam

The Netherlands

8. Marketing authorisation number(s)

EU/1/00/155/001 (1 vial/ 1 ampoule)

EU/1/00/155/002 (3 vials/ 3 ampoules)

EU/1/00/155/003 (10 vials/ 10 ampoules)

EU/1/00/155/004 (1 vial/ 1 vial)

EU/1/00/155/005 (3 vial/ 3 vials)

EU/1/00/155/006 (10 vials/ 10 vials)

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 29th November 2000.

Date of latest renewal: 30th November 2005.

10. Date of revision of the text

08/2018

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.