Luveris 75 IU powder and solvent for solution for injection.

One vial contains 75 IU of lutropin alfa (recombinant human luteinising hormone {LH}). Lutropin alfa is produced in genetically engineered Chinese hamster ovary (CHO) cells.

For a full list of excipients, see section 6.1.

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.

Luveris in association with a follicle stimulating hormone (FSH) preparation is recommended for the stimulation of follicular development in 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.

Treatment with Luveris should be initiated under the supervision of a physician experienced in the treatment of fertility problems. Self-administration of this medicinal product should only be performed by patients who are well-motivated, adequately trained and with access to expert advice.

In LH and FSH deficient women, the objective of lutropin alfa 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 gonadotrophin (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 adminstered 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.

If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 714 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 microgram of r-hCG or 5,000 IU to 10,000 IU hCG should be administered 24-48 hours after the last lutropin alfa 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.

Luveris is intended for subcutaneous use. The powder should be reconstituted, immediately prior to use, with the solvent provided.

Luveris is contraindicated in patients with:

• hypersensitivity to gonadotrophins or to any of the excipients.

• ovarian, uterine, or mammary carcinoma;

• 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

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

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, hyperprolactinemia and pituitary or hypothalamic tumours, and appropriate specific treatment given.

Patients undergoing stimulation of follicular growth are at an increased risk of developing hyperstimulation in view of possible excessive oestrogen response and multiple follicular development.

Ovarian hyperstimulation syndrome (OHSS) can become a serious medical event characterised by large ovarian cysts which are prone to rupture. Excessive ovarian response seldom gives rise to significant hyperstimulation unless hCG is administered to induce ovulation. It is therefore prudent to withhold hCG in such cases and advise the patient to refrain from coitus or use barrier methods for at least 4 days.

Careful monitoring of ovarian response, based on ultrasound is recommended prior to and during stimulation therapy, especially in patients with polycystic ovaries.

In patients undergoing induction of ovulation, the incidence of multiple pregnancies and births is increased compared with natural conception.

When significant risk of OHSS or multiple pregnancies is assumed, treatment discontinuation is advised.

To minimise the risk of OHSS or of multiple pregnancy, ultrasound scans as well as oestradiol measurements are recommended. In anovulation the risk of OHSS is increased by a serum oestradiol level> 900 pg/ml (3300 pmol/l) and by the presence of more than 3 follicles of 14 mm or more in diameter.

Adherence to recommended lutropin alfa and FSH posology and regimen of administration and careful monitoring of therapy will minimise the incidence of ovarian hyperstimulation and multiple pregnancy.

In clinical trials, the medicinal product has been shown to increase the ovarian sensitivity to follitropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably with 37.5-75 IU increments.

In clinical trials, there have been no reports of hypersensitivity to lutropin alfa.

The incidence of pregnancy wastage by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction than in the normal population.

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 IVF was reported to be 2 to 5%, as compared to 1 to 1.5% in the general population.

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

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.

In women with generally recognised risk factors for thrombo-embolic events, such as personal or family history, treatment with gonadotrophins may further increase the risk. In these women, the benefits of gonadotrophin 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 thrombo-embolic events.

No interaction studies have been performed with lutropin alfa.

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.

Luveris should not be administered during pregnancy or lactation.

No studies on the effects on the ability to drive or use machines have been performed.

General description

Lutropin alfa is used for the stimulation of follicular development in association with follitropin alfa. In this context, it is difficult to attribute undesirable effects 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. To date no systemic allergic reactions have been reported following Luveris administration.

Ovarian hyperstimulation syndrome was observed in less than 6% of patients treated with Luveris. No severe ovarian hyperstimulation syndrome was reported (section 4.4).

In rare instances, adnexal torsion (a complication of ovarian enlargement), and haemoperitoneum have been associated with human menopausal gonadotrophin 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.

Adverse reactions

The following convention was used for the frequency (events/ no. of patients): 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), not known (cannot be estimated from the available data).

After best evidence assessment, the following undesirable effects may be observed after administration of Luveris. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The effects of an overdose of lutropin alfa are unknown, nevertheless there is a possibility that ovarian hyperstimulation syndrome 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.

Pharmacotherapeutic group: gonadotrophins. ATC code: G03G A07

Lutropin alfa is a recombinant human luteinising hormone, a glycoprotein composed of non-covalently bound α- and β-subunits. Luteinising hormone binds on the ovarian theca (and granulosa) cells and testicular Leydig cells, to a receptor shared with human chorionic gonadotrophin 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 oestradiol, supporting FSHinduced 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 oestradiol 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%.

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. Following intravenous administration, lutropin alfa is rapidly distributed with an initial half-life of approximately one hour and eliminated from the body with a terminal half-life of about 10-12 hours. The steady state volume of distribution is around 10-14 l. Lutropin alfa shows linear pharmacokinetics, as assessed by AUC which is directly proportional to the dose administered. Total clearance is around 2 l/h, and less than 5% of the dose is excreted in the urine. The mean residence time is approximately 5 hours.

Following subcutaneous administration, the absolute bioavailability is approximately 60%; the terminal half-life is slightly prolonged. 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.

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.

Sucrose

Disodium phosphate dihydrate

Sodium dihydrogen phosphate monohydrate

Polysorbate 20

Phosphoric acid, concentrated (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Methionine

Nitrogen

Solvent: Water for injection

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

3 years.

Do not store above 25°C. Store in the original package in order to protect from light.

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.

The product is supplied in packs of 1, 3 or 10 vials with the corresponding number of solvent vials or ampoules. Not all pack sizes may be marketed.

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

Merck Serono Europe Limited,

56 Marsh Wall,

London E14 9TP

United Kingdom

EU/1/00/155/001

EU/1/00/155/002

EU/1/00/155/003

EU/1/00/155/004

EU/1/00/155/005

EU/1/00/155/006

Date of first authorisation: 29^th November 2000.

Date of last renewal: 30^th November 2005.

July 2009