PERGOVERIS 150UI / 75UI powder + solvent for injection medication leaflet

Pergoveris 150 IU/75 IU powder and solvent for solution for injection

One vial contains 150 IU (equivalent to 11 micrograms) of follitropin alfa* (r-hFSH) and 75 IU(equivalent to 3 micrograms) of lutropin alfa* (r-hLH).

After reconstitution, each mL of the solution contains 150 IU r-hFSH and 75 IU r-hLH per milliliter.

* produced in genetically engineered Chinese hamster ovary (CHO) cells.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

Powder: white to off-white lyophilised pellet.

Solvent: clear colourless solution.

Pergoveris is indicated for the stimulation of follicular development in adult women with severe LHand FSH deficiency.

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

In LH and FSH deficient women, the objective of Pergoveris therapy is to promote folliculardevelopment followed by final maturation after the administration of human chorionic gonadotropin(hCG). Pergoveris should be given as a course of daily injections. If the patient is amenorrhoeic andhas low endogenous oestrogen secretion, treatment can commence at any time.

A recommended regimen commences with one vial of Pergoveris daily. If less than one vial daily isused, the follicular response may be unsatisfactory because the amount of lutropin alfa may beinsufficient (see section 5.1).

Treatment should be tailored to the individual patient’s response as assessed by measuring follicle sizeby ultrasound and oestrogen response.

If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7 to 14 dayintervals and preferably by 37.5 to 75 IU increments using a licensed follitropin alfa preparation. Itmay 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 micrograms of r-hCG or 5 000 IU to10 000 IU hCG should be administered 24 to 48 hours after the last Pergoveris injection. The patient isrecommended 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 indication for the use of Pergoveris in the elderly population. Safety and efficacyof this medicinal product in elderly patients have not been established.

Safety, efficacy, and pharmacokinetics of this medicinal product in patients with renal or hepaticimpairment have not been established.

There is no relevant use of this medicinal product in the paediatric population.

Pergoveris is intended for subcutaneous administration. The first injection should be performed underdirect medical supervision. The powder should be reconstituted immediately prior to use with thesolvent provided. Self-administration should only be performed by patients who are well motivated,adequately trained and with access to expert advice.

For further instructions on reconstitution of the medicinal product before administration, seesection 6.6.

Pergoveris is contraindicated in patients with:

* hypersensitivity to the 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 unknownorigin

* gynaecological haemorrhages of unknown origin

* ovarian, uterine or mammary carcinoma

Pergoveris must not be used when an effective response cannot be obtained, 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.

Pergoveris contains potent gonadotropic substances capable of causing mild to severe adversereactions, and should only be used by physicians who are thoroughly familiar with infertility problemsand their management.

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

Gonadotropin therapy requires a certain time commitment by physicians and supportive health careprofessionals, as well as the availability of appropriate monitoring facilities. In women, safe andeffective use of Pergoveris calls for monitoring of ovarian response with ultrasound, alone orpreferably in combination with measurement of serum oestradiol levels, on a regular basis. There maybe a degree of interpatient variability in response to FSH/LH administration, with a poor response to

FSH/LH in some patients. The lowest effective dose in relation to the treatment objective should beused in women.

Porphyria

Patients with porphyria or a family history of porphyria should be closely monitored during treatmentwith Pergoveris. In these patients, Pergoveris may increase the risk of an acute attack. Deterioration ora 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.

The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominaldistension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptomsincluding nausea, vomiting and diarrhoea.

Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites,haemoperitoneum, pleural effusions, hydrothorax, or acute pulmonary distress, and thromboembolicevents.

Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events such aspulmonary embolism, 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 oestradiollevel (> 900 pg/mL or > 3 300 pmol/L in anovulation), previous episodes of OHSS and large numberof developing ovarian follicles (3 follicles of ≥ 14 mm in diameter in anovulation).

Adherence to recommended Pergoveris and FSH dosage and regimen of administration can minimisethe risk of ovarian hyperstimulation. Monitoring of stimulation cycles by ultrasound scans as well asoestradiol 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 OHSS occur such asserum oestradiol level > 5 500 pg/mL or > 20 200 pmol/L and/or ≥ 40 follicles in total, it isrecommended that hCG be withheld and the patient be advised to refrain from coitus or to use barriercontraceptive methods for at least 4 days. OHSS may progress rapidly (within 24 hours) or overseveral days to become a serious medical event. It most often occurs after hormonal treatment hasbeen discontinued and reaches its maximum at about seven to ten days following treatment. Usually,

OHSS resolves spontaneously with the onset of menses. Therefore patients should be followed for atleast two weeks after hCG administration.

If severe OHSS occurs, gonadotropin treatment should be stopped if still ongoing. The patient shouldbe hospitalised and specific therapy for OHSS started. This syndrome occurs with higher incidence inpatients with polycystic ovarian disease.

When a risk of OHSS is assumed, treatment discontinuation should be considered.

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 pregnancies 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 multiple pregnancy, careful monitoring of ovarian response is recommended.

The patients should be advised of the potential risk of multiple births before starting treatment. Whenrisk of multiple pregnancies is assumed, treatment discontinuation should be considered.

Pregnancy loss

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

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 assisted reproductive technologies (ART) was reported to be higher than in the generalpopulation.

Reproductive system neoplasms

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

Congenital malformation

The prevalence of congenital malformations after ART may be slightly higher than after spontaneousconceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age,sperm characteristics) and multiple 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. In thesewomen, the benefits of gonadotropin administration need to be weighed against the risks. It should benoted however, that pregnancy itself as well as OHSS also carries an increased risk of thromboembolicevents.

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

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

There is no indication for the use of Pergoveris during pregnancy. Data on a limited number ofexposed pregnancies indicate no adverse reactions of follitropin alfa and lutropin alfa on pregnancy,embryonal or foetal development, parturition or postnatal development following controlled ovarianstimulation. No teratogenic effect of such gonadotropins has been reported in animal studies. In caseof exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of

Pergoveris.

Pergoveris is not indicated during breast-feeding.

Pergoveris is indicated for use in infertility (see section 4.1).

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

The most commonly reported adverse reactions are headache, ovarian cysts and local injection sitereactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection). Mild ormoderate OHSS has been commonly reported and should be considered as an intrinsic risk of thestimulation procedure. Severe OHSS is uncommon (see section 4.4).

Thromboembolism may occur very rarely, usually associated with severe OHSS (see section 4.4).

Adverse reactions are listed below by MedDRA system organ class and by frequency. The frequencycategories used are: 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 fromthe available data).

Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions andshock

Very common: Headache

Very rare: Thromboembolism, usually associated with severe OHSS

Very rare: Exacerbation or aggravation of asthma

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

Very common: Ovarian cysts

Common: Breast pain, pelvic pain, mild or moderate OHSS (including associatedsymptomatology)

Uncommon: Severe OHSS (including associated symptomatology) (see section 4.4)

Rare: Complication of severe OHSS

Very common: Mild to severe injection site reactions (e.g. pain, erythema, haematoma, bruising,swelling and/or irritation at the site 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 Pergoveris are unknown. Nevertheless there is a possibility that OHSSmay occur, which is further described in section 4.4.

Treatment is directed to symptoms.

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, gonadotropins. ATCcode: G03GA30.

Pergoveris is a preparation of recombinant human follicle stimulating hormone (follitropin alfa,r-hFSH) and recombinant human luteinising hormone (lutropin alfa, r-hLH) produced in Chinesehamster ovary (CHO) cells by recombinant DNA technology.

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 oestradiol (E2) by aromatase. In granulosa cells, FSHstimulates the development of ovarian follicles, while LH action is involved in follicle development,steroidogenesis and maturation.

Inhibin and oestradiol levels are raised after administration of r-hFSH, with subsequent induction offollicular development. Inhibin serum level increase is rapid and can be observed as early as the thirdday of r-hFSH administration, while oestradiol levels take more time and an increase is observed onlyfrom the fourth day of treatment. Total follicular volume starts to increase after about 4 to 5 days ofr-hFSH daily dosing and, depending on patient response, the maximum effect is reached after about10 days from the start of gonadotropin administration. The primary effect resulting fromadministration of r-hLH is a dose-related increase of E2 secretion, enhancing the effect of r-hFSH onfollicular growth.

In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum

LH level < 1.2 IU/L as measured in a central laboratory. In these trials the ovulation rate per cycle was70 to 75%. However, it should be taken into account that there are variations between LHmeasurements performed in different laboratories.

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 oestrogenproduction. A dose of 25 IU r-hLH daily (in combination with 150 IU r-hFSH) resulted in insufficientfollicular development.

Therefore, administration of less than one vial of Pergoveris daily may provide too little LH-activity toensure adequate follicular development.

Clinical studies with Pergoveris were conducted with a freeze-dried formulation. A comparativeclinical study between the freeze-dried and the liquid formulation showed bioequivalence between thetwo formulations.

There is no pharmacokinetic interaction between follitropin alfa and lutropin alfa when administeredsimultaneously.

Follitropin alfa

Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space withan initial half-life of around 2 hours and eliminated from the body with a terminal half-life of 14 to17 hours. The steady state volume of distribution is in the range of 9 to 11 L.

Following subcutaneous administration, the absolute bioavailability is 66% and the apparent terminalhalf-life is in the range of 24 to 59 hours. Dose proportionality after subcutaneous administration wasdemonstrated up to 900 IU. Following repeated administration, follitropin alfa accumulates 3-foldachieving a steady-state within 3 to 4 days.

Total clearance is 0.6 L/h and about 12% of the follitropin alfa dose is excreted in the urine.

Lutropin alfa

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 AUC which is directly proportional to the dose administered.

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 lutropin alfa are comparable and the accumulation ratio of lutropin alfa is minimal.

Total clearance is in the range of 1.7 to 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.

Sucrose

Polysorbate 20

Methionine

Disodium phosphate dihydrate

Sodium dihydrogen phosphate monohydrate

Phosphoric acid, concentrated (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

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

Unopened vials3 years.

Pergoveris is for an immediate and single use following first opening and reconstitution. Therefore theproduct may not be stored once opened and reconstituted.

Do not store above 25°C.

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

Powder: 3 mL vials (Type I glass) with a stopper (bromobutyl rubber) and aluminium flip-off cap.

1 vial contains 11 micrograms r-hFSH and 3 micrograms r-hLH.

Solvent: 3 mL vials (Type I glass) with a Teflon coated rubber stopper and aluminium flip-off cap.

1 vial of solvent contains 1 mL of water for injections.

Pack sizes of 1, 3 and 10 vials with the corresponding number of solvent’s vial (1, 3 and 10 vials).

Not all pack sizes may be marketed.

For immediate and single use following first opening and reconstitution.

The pH of the reconstituted solution is 6.5 to 7.5.

Pergoveris must be reconstituted with the solvent before use by gentle swirling. The reconstitutedsolution should not be administered if it contains particles or is not clear.

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

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/1/07/396/001

EU/1/07/396/002

EU/1/07/396/003

Date of first authorisation: 25 June 2007

Date of latest renewal: 8 May 2017

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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.