LUVERIS 75UI powder + solvent for injection medication leaflet

Luveris 75 IU powder and solvent for solution for injection

One vial contains 75 IU of lutropin alfa*.

* recombinant human luteinising hormone (r-hLH) produced in genetically engineered Chinesehamster ovary (CHO) cells by recombinant DNA technology

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection (powder 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 to 8.5.

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

Luveris in association with a follicle stimulating hormone (FSH) preparation is indicated for thestimulation of follicular development in adult women with severe luteinising hormone (LH) and FSHdeficiency.

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

In LH and FSH deficient women, the objective of Luveris therapy in association with FSH is topromote follicular development followed by final maturation after the administration of humanchorionic gonadotropin (hCG). Luveris should be given as a course of daily injections simultaneouslywith FSH. If the patient is amenorrhoeic and has low endogenous estrogen secretion, treatment cancommence at any time.

Luveris should be administered concomitantly with follitropin alfa.

A recommended regimen commences at 75 IU of lutropin alfa (i.e. one vial of Luveris) daily with 75to 150 IU FSH. Treatment should be tailored to the individual patient’s response as assessed bymeasuring follicle size by ultrasound and estrogen response.

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- to 14-dayintervals and preferably by 37.5 IU to 75 IU increments. It may be acceptable to extend the duration ofstimulation in any one cycle to up to 5 weeks.

When an optimal response is obtained, a single injection of 250 micrograms of r-hCG or 5 000 IU to10 000 IU hCG should be administered 24 to 48 hours after the last Luveris and FSH injections. Thepatient is recommended to have coitus on the day of, and on the day following, hCG administration.

Alternatively, intrauterine insemination or another medically assisted reproduction procedure may beperformed based on the physician’s judgment of the clinical case.

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 shouldrecommence in the next cycle at a dose of FSH lower than that of the previous cycle (see section 4.4.).

There is no relevant use of Luveris in the elderly population. Safety and efficacy of Luveris in elderlypatients have not been established.

Safety, efficacy and pharmacokinetics of Luveris in patients with renal or hepatic impairment have notbeen established.

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

Luveris is intended for subcutaneous use. The first injection of Luveris should be performed underdirect medical supervision. The powder should be reconstituted immediately prior to use with thesolvent provided. Self-administration of this medicinal product should only be performed by patientswho 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.

Luveris is contraindicated in patients with:

* hypersensitivity to the active substance 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 unknownorigin

* 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

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Before starting treatment, the couple's infertility should be assessed as appropriate and putativecontraindications for pregnancy evaluated. In addition, patients should be evaluated forhypothyroidism, adrenocortical deficiency and hyperprolactinemia and appropriate specific treatmentgiven.

Porphyria

In patients with porphyria or a family history of porphyria Luveris may increase the risk of an acuteattack. 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 ismore commonly seen in women with polycystic ovarian syndrome and usually regresses withouttreatment.

In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself withincreasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, andan 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, orenlarged ovaries. Moderate OHSS may additionally present with nausea, vomiting, ultrasoundevidence of ascites or marked ovarian enlargement.

Severe OHSS further includes symptoms such as severe ovarian enlargement, weight gain, dyspnoeaor 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 pulmonaryembolism, ischaemic stroke or myocardial infarction.

Independent risk factors for developing OHSS include young age, lean body mass, polycystic ovariansyndrome, higher doses of exogenous gonadotropins, high absolute or rapidly rising serum estradiollevels and previous episodes of OHSS, large number of developing ovarian follicles and large numberof oocytes retrieved in assisted reproductive technology (ART) cycles.

Adherence to recommended Luveris and FSH dosage and regimen of administration can minimise therisk of ovarian hyperstimulation. Monitoring of stimulation cycles by ultrasound scans as well asestradiol 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 maybe more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarianhyperstimulation occur, it is recommended that hCG be withheld and the patient be advised to refrainfrom 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 followedfor at least two weeks after hCG administration.

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

Ovarian torsion

Ovarian torsion has been reported after treatment with other gonadotropins. This may be associatedwith other risk factors such as OHSS, pregnancy, previous abdominal surgery, past history of ovariantorsion, previous or current ovarian cyst and polycystic ovarian syndrome. Damage to the ovary due toreduced 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 isincreased compared with natural conception. The majority of multiple conceptions are twins. Multiplepregnancy, 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 isrecommended. In patients undergoing ART procedures the risk of multiple pregnancy is relatedmainly 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 undergoingstimulation of follicular growth for ovulation induction or ART than following natural conception.

Ectopic pregnancy

Women with a history of tubal disease are at risk of ectopic pregnancy, whether the pregnancy isobtained by spontaneous conception or with fertility treatments. The prevalence of ectopic pregnancyafter 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 spontaneousconceptions. This could be due to parental factors (e.g. maternal age, genetics), ART procedures andmultiple pregnancies.

In women with recent or ongoing thromboembolic disease or women with generally recognised riskfactors 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 foraggravation or occurrence of such events. In these women, the benefits of gonadotropin administrationneed 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 andmalignant, in women who have undergone multiple treatment regimens for infertility. It is not yetestablished whether or not treatment with gonadotropins increases the risk of these tumours in infertilewomen.

Luveris contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially “sodium-free”.

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 alterthe activity, stability, pharmacokinetic nor pharmacodynamic properties of the active substances.

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 onpregnancy, embryonal or foetal development, parturition or postnatal development followingcontrolled 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.

Luveris is not indicated during breast-feeding.

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

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

Luveris is used for the stimulation of follicular development in association with follitropin alfa. In thiscontext, 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 orswelling) were reported in 7.4% and 0.9% of the injections, respectively. No severe injection sitereactions were reported.

Ovarian hyperstimulation syndrome (OHSS) was observed in less than 6% of patients treated with

Luveris. No severe OHSS was reported (see section 4.4).

In rare instances, adnexal torsion (a complication of ovarian enlargement), and haemoperitoneum havebeen associated with human menopausal gonadotropin therapy. Although these adverse reactions werenot 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), veryrare (< 1/10 000), frequency not known (cannot be estimated from the available data).

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

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

Common: Headache

Very rare: Thromboembolism, usually associated with severe OHSS

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

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

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The effects of an overdose of Luveris are unknown. Nevertheless, there is a possibility that OHSS mayoccur (see section 4.4).

Single doses of up to 40 000 IU of lutropin alfa have been administered to healthy female volunteerswithout serious adverse reactions and were well tolerated.

Treatment is directed to symptoms.

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, gonadotropins,

ATC code: G03GA07

Luteinising hormone (LH) and follicle stimulating hormone (FSH) are secreted from the anteriorpituitary gland in response to gonadotropin-releasing hormone (GnRH) and play a complementary rolein follicle development and ovulation. In theca cells, LH stimulates the secretion of androgens that aretransferred to granulosa cells to be converted to estradiol (E2) by aromatase. In granulosa cells, FSHstimulates the development of ovarian follicles, while LH action is involved in follicle development,steroidogenesis and maturation.

The primary effect resulting from administration of r-hLH is a dose-related increase of E2 secretion,enhancing the effect of FSH administration on follicular growth.

In clinical trials, patients were defined by an endogenous serum LH level < 1.2 IU/L as measured in acentral laboratory. In these trials the ovulation rate per cycle was 70 to 75%. However, it should betaken into account that there are variations between LH measurements performed in differentlaboratories.

In one clinical study of women with hypogonadotropic hypogonadism and an endogenous serum LHconcentration below 1.2 IU/L the appropriate dose of r-hLH was investigated. A dose of 75 IU r-hLHdaily (in combination with 150 IU r-hFSH) resulted in adequate follicular development and estrogenproduction. A dose of 25 IU r-hLH daily (in combination with 150 IU r-hFSH) resulted in insufficientfollicular development.

The pharmacokinetics of lutropin alfa have been studied in pituitary desensitised female volunteersfrom 75 IU up to 40 000 IU. The pharmacokinetic profile of lutropin alfa is similar to that ofendogenous LH.

There is no pharmacokinetic interaction with follitropin alfa when administered simultaneously.

Following intravenous administration, lutropin alfa is rapidly distributed with an initial half-life ofapproximately one hour and eliminated from the body with a terminal half-life of about 9 to 11 hours.

The steady state volume of distribution is in the range of 5 to 14 L. Lutropin alfa shows linearpharmacokinetics, as assessed by area under curve (AUC) which is directly proportional to the doseadministered.

Following subcutaneous administration, the absolute bioavailability is 56% and the apparent terminalhalf-life is in the range of 8 to 21 hours. Dose proportionality after subcutaneous administration wasdemonstrated up to 450 IU. The lutropin alfa pharmacokinetics following single and repeatedadministration of Luveris are comparable and the accumulation ratio of lutropin alfa is minimal.

Total body clearance is around 1.8 L/h and less than 5% of the dose is excreted in the urine.

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

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

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)

L-methionine

Nitrogen

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 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 withbromobutyl stoppers protected by aluminium seal rings and flip-off caps. The solvent is packagedeither in 2 or 3 mL neutral colourless glass (type I) vials with a Teflon-coated rubber stopper or in2 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 packsizes 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 alfapowder.

In order to avoid the injection of large volumes, one vial of Luveris can be reconstituted together withone or two vial(s) of follitropin alfa 75 IU in 1 mL of solvent.

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

Merck Europe B.V.

Gustav Mahlerplein 1021082 MA Amsterdam

The Netherlands

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 November 2000

Date of latest renewal: 24 January 2006

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Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.