GONAL-f 1050 IU/1.75 ml (77 micrograms/1.75 ml) powder and solvent for solution for injection.

One multidose vial contains 87 micrograms follitropin alfa, recombinant human follicle stimulating hormone (FSH) in order to deliver 77 micrograms, equivalent to 1050 IU. Follitropin alfa is produced in genetically engineered Chinese Hamster Ovary (CHO) cells.

Excipients : 30 mg sucrose, 1.11 mg disodium phosphate dihydrate, 0.45 mg sodium dihydrogen phosphate monohydrate

For full list of excipients, see section 6.1.

Powder and solvent for solution for injection in a pre-filled syringe.

Appearance of the powder: white lyophilised pellet.

Appearance of the solvent: clear colourless solution.

The pH of the reconstituted solution is 6.5 – 7.5.

• Anovulation (including polycystic ovarian disease, PCOD) in women who have been unresponsive to treatment with clomiphene citrate.

• Stimulation of multifollicular development in patients undergoing superovulation for assisted reproductive technologies (ART) such as in vitro fertilisation (IVF), gamete intra-fallopian transfer (GIFT) and zygote intra-fallopian transfer (ZIFT).

• GONAL-f in association with a luteinising hormone (LH) preparation is recommended for the stimulation of follicular development in women with severe LH and FSH deficiency. In clinical trials these patients were defined by an endogenous serum LH level <1.2 IU/l.

• GONAL-f is indicated for the stimulation of spermatogenesis in men who have congenital or acquired hypogonadotrophic hypogonadism with concomitant human Chorionic Gonadotrophin (hCG) therapy.

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

GONAL-f is intended for subcutaneous administration. The powder should be reconstituted prior to the first use with the solvent provided. GONAL-f 1050 IU/1.75 ml (77 micrograms/1.75 ml) preparation must not be reconstituted with any other GONAL-f container.

The dosage recommendations given for GONAL-f are those in use for urinary FSH. Clinical assessment of GONAL-f indicates that its daily doses, regimens of administration, and treatment monitoring procedures should not be different from those currently used for urinary FSH-containing preparations.

It is advised to adhere to the recommended starting doses indicated below.

Comparative clinical studies have shown that on average patients require a lower cumulative dosage and shorter treatment duration with GONAL-f compared with urinary FSH. Therefore, it is considered appropriate to give a lower total dosage of GONAL-f than generally used for urinary FSH, not only in order to optimise follicular development but also to minimise the risk of unwanted ovarian hyperstimulation. See section 5.1.

Bioequivalence has been demonstrated between equivalent doses of the monodose presentation and the multidose presentation of GONAL-f.

Women with anovulation (including PCOD):

The object of GONAL-f therapy is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG.

GONAL-f may be given as a course of daily injections. In menstruating patients treatment should commence within the first 7 days of the menstrual cycle.

Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and/or oestrogen secretion. A commonly used regimen commences at 75-150 IU FSH daily and is increased preferably by 37.5 or 75 IU at 7 or preferably 14 day intervals if necessary, to obtain an adequate, but not excessive, response. The maximal daily dose is usually not higher than 225 IU FSH. If a patient fails to respond adequately after 4 weeks of treatment, that cycle should be abandoned and the patient should recommence treatment at a higher starting dose than in the abandoned cycle.

When an optimal response is obtained, a single injection of 5 000 IU, up to 10 000 IU hCG should be administered 24-48 hours after the last GONAL-f injection. The patient is recommended to have coitus on the day of, and the day following, hCG administration. Alternatively intrauterine insemination (IUI) may be performed.

If an excessive response is obtained, treatment should be stopped and hCG withheld (see section 4.4). Treatment should recommence in the next cycle at a dosage lower than that of the previous cycle.

Women undergoing ovarian stimulation for multiple follicular development prior to in vitro fertilisation or other assisted reproductive technologies:

A commonly used regimen for superovulation involves the administration of 150-225 IU of GONALf daily, commencing on days 2 or 3 of the cycle. Treatment is continued until adequate follicular development has been achieved (as assessed by monitoring of serum oestrogen concentrations and/or ultrasound examination), with the dose adjusted according to the patient's response, to usually not higher than 450 IU daily. In general adequate follicular development is achieved on average by the tenth day of treatment (range 5 to 20 days).

A single injection of up to 10 000 IU hCG is administered 24-48 hours after the last GONAL-f injection to induce final follicular maturation.

Down-regulation with a gonadotrophin-releasing hormone (GnRH) agonist is now commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. In a commonly used protocol, GONAL-f is started approximately 2 weeks after the start of agonist treatment, both being continued until adequate follicular development is achieved. For example, following two weeks of treatment with an agonist, 150-225 IU GONAL-f are administered for the first 7 days. The dose is then adjusted according to the ovarian response.

Overall experience with IVF indicates that in general the treatment success rate remains stable during the first four attempts and gradually declines thereafter.

Women with anovulation resulting from severe LH and FSH deficiency:

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

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 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 37.5-75 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 5,000 IU to 10,000 IU hCG should be administered 24-48 hours after the last GONAL-f and lutropin alfa 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.

Men with hypogonadotrophic hypogonadism:

GONAL-f should be given at a dosage of 150 IU three times a week, concomitantly with hCG, for a minimum of 4 months. If after this period, the patient has not responded, the combination treatment may be continued; current clinical experience indicates that treatment for at least 18 months may be necessary to achieve spermatogenesis.

GONAL-f must not be used in:

• hypersensitivity to the active substance follitropin alfa, FSH or to any of the excipients

• case of tumours of the hypothalamus and pituitary gland

and in women:

• ovarian enlargement or cyst not due to polycystic ovarian disease

• gynaecological haemorrhages of unknown aetiology

• ovarian, uterine or mammary carcinoma

GONAL-f should not be used when an effective response cannot be obtained, such as:

In women:

• primary ovarian failure

• malformations of sexual organs incompatible with pregnancy

• fibroid tumours of the uterus incompatible with pregnancy

In men:

• primary testicular insufficiency

GONAL-f is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management.

Gonadotrophin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of GONAL-f calls for monitoring of ovarian response with ultrasound, alone or preferably in combination with measurement of serum oestradiol levels, on a regular basis. There may be a degree of interpatient variability in response to FSH administration, with a poor response to FSH in some patients. The lowest effective dose in relation to the treatment objective should be used in both men and women.

Self-administration of GONAL-f should only be performed by patients who are well motivated, adequately trained and with access to expert advice. During training of the patient for self-administration, special attention should be given to specific instructions for the use of the multidose presentation.

As GONAL-f multidose is intended for several injections, clear instructions should be provided to the patients to avoid misuse of the multidose presentation.

Due to a local reactivity to benzyl alcohol, the same site of injection should not be used on consecutive days.

The first injection of GONAL-f should be performed under direct medical supervision.

Patients with porphyria or a family history of porphyria should be closely monitored during treatment with GONAL-f. Deterioration or a first appearance of this condition may require cessation of treatment.

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

Treatment in women

Before starting treatment, the couple's infertility should be assessed as appropriate and putative contraindications for pregnancy evaluated. In particular, 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, whether in the frame of a treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to recommended GONAL-f dosage and regimen of administration, and careful monitoring of therapy will minimise the incidence of such events. Acute interpretation of the indices of follicle development and maturation require a physician whom is experienced in the interpretation of the relevant tests.

In clinical trials, an increase of the ovarian sensitivity to GONAL-f was shown when administered with lutropin 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.

No direct comparison of GONAL-f/LH versus human menopausal gonadotrophin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with GONALf/LH is similar to what can be obtained with hMG.

Ovarian Hyperstimulation Syndrome (OHSS)

OHSS is a medical event distinct from uncomplicated ovarian enlargement. OHSS is a syndrome 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.

The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events. Very rarely, severe OHSS may be complicated by pulmonary embolism, ischemic stroke and myocardial infarction.

Excessive ovarian response to gonadotrophin treatment seldom gives rise to OHSS unless hCG is administered to trigger ovulation. Therefore in cases of ovarian hyperstimulation it is prudent to withhold hCG and advise the patient to refrain from coitus or to use barrier methods for at least 4 days. OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event, therefore patients should be followed for at least two weeks after hCG administration.

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 and multiple pregnancy is increased by a serum oestradiol > 900 pg/ml (3300 pmol/l) and more than 3 follicles of 14 mm or more in diameter. In ART there is an increased risk of OHSS with a serum oestradiol > 3000 pg/ml (11000 pmol/l) and 20 or more follicles of 12 mm or more in diameter. When the oestradiol level is > 5500 pg/ml (20200 pmol/l) and where there are 40 or more follicles in total, it may be necessary to withhold hCG administration.

Adherence to recommended GONAL-f dosage, regimen of administration and careful monitoring of therapy will minimise the incidence of ovarian hyperstimulation and multiple pregnancy (see Sections 4.2 and 4.8). In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation.

OHSS may be more severe and more protracted if pregnancy occurs. Most often, OHSS occurs after hormonal treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses.

If severe OHSS occurs, gonadotrophin treatment should be stopped if still ongoing, the patient hospitalised and specific therapy for OHSS started.

This syndrome occurs with higher incidence in patients with polycystic ovarian disease.

Multiple pregnancy

Multiple pregnancy, specially high order, carries an increase risk in adverse maternal and perinatal outcomes.

In patients undergoing ovulation induction with GONAL-f, the incidence of multiple pregnancies is increased as compared with natural conception. The majority of multiple conceptions are twins. To minimise the risk of multiple pregnancy, careful monitoring of ovarian response is recommended.

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

The patients should be advised of the potential risk of multiple births before starting treatment.

Pregnancy wastage

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

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

Reproductive system neoplasms

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 tumors in infertile women.

Congenital malformation

The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and multiple pregnancies.

Thromboembolic events

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 also carries an increased risk of thrombo-embolic events.

Treatment in men

Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to GONAL-f/hCG therapy.

Semen analysis is recommended 4 to 6 months after the beginning of treatment in assessing the response.

Concomitant use of GONAL-f with other agents used to stimulate ovulation (e.g. hCG, clomiphene citrate) may potentiate the follicular response, whereas concurrent use of a GnRH agonist to induce pituitary desensitisation may increase the dosage of GONALf needed to elicit an adequate ovarian response. No other clinically significant drug interaction has been reported during GONAL-f therapy.

GONAL-f should not be administered as mixture with other medicinal products in the same injection.

Use during pregnancy

There is no indication for use of GONAL-f during pregnancy. No teratogenic risk has been reported, following controlled ovarian hyperstimulation, in clinical use with gonadotrophins. In case of exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of recombinant hFSH. However, to date, no particular malformative effect has been reported. No teratogenic effect has been observed in animal studies.

Use during lactation

GONAL-f is not indicated during lactation. During lactation, the secretion of prolactin can entail a poor prognosis to ovarian stimulation.

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

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The effects of an overdose of GONAL-f are unknown, nevertheless one could expect ovarian hyperstimulation syndrome to occur, which is further described in section 4.4.

Pharmacotherapeutic group: gonadotrophins, ATC code: G03GA05.

GONAL-f is a preparation of follicle stimulating hormone produced by genetically engineered Chinese Hamster Ovary (CHO) cells.

In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles.

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. However, it should be taken into account that there are variations between LH measurements performed in different laboratories.

In clinical studies comparing r-hFSH (follitropin alfa) and urinary FSH in assisted reproduction technologies (see table below) and in ovulation induction, GONAL-f was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation.

In assisted reproduction technologies, GONAL-f at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH.

Table: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of Gonal-f with u-FSH in assisted reproduction technologies)

Differences between the 2 groups were statistically significant (p<0.05) for all criteria listed.

In men deficient in FSH, GONAL-f administered concomitantly with hCG for at least 4 months induces spermatogenesis.

Following intravenous administration, GONAL-f is distributed to the extracellular fluid space with an initial half-life of around 2 hours and eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 l and 0.6 l/h, respectively. One-eighth of the GONAL-f dose is excreted in the urine.

Following subcutaneous administration, the absolute bioavailability is about 70%. Following repeated administration, GONAL-f accumulates 3-fold achieving a steadystate within 3-4 days. In women whose endogenous gonadotrophin secretion is suppressed, GONAL-f has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.

Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity additional to that already stated in other sections of this SPC.

In rabbits, the formulation reconstituted with 0.9% benzyl alcohol and 0.9% benzyl alcohol alone, both resulted in a slight haemorrhage and subacute inflammation after single subcutaneous injection or mild inflammatory and degenerative changes after single intramuscular injection respectively.

Impaired fertility has been reported in rats exposed to pharmacological doses of follitropin alfa ( 40 IU/kg/day) for extended periods, through reduced fecundity.

Given in high doses (> 5 IU/kg/day) follitropin alfa caused a decrease in the number of viable foetuses without being a teratogen, and dystocia similar to that observed with urinary hMG. However, since GONAL-f is not indicated in pregnancy, these data are of limited clinical relevance.

Powder:

Sucrose

Sodium dihydrogen phosphate monohydrate

Disodium phosphate dihydrate

Phosphoric acid, concentrated

Sodium hydroxide

Solvent:

Water for Injections

Benzyl alcohol

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

2 years.

The reconstituted solution is stable for 28 days.

Prior to reconstitution, do not store above 25°C. Store in the original package.

After reconstitution, do not store above 25ºC. Do not freeze. Store in the original container.

GONAL-f is presented as a powder and solvent for injection. The powder is presented in 3 ml vials (Type I glass), with rubber stopper (bromobutyl rubber) and aluminium flip-off cap. The solvent for reconstitution is presented in 2 ml pre-filled syringes (Type I glass) with a rubber stopper. The administration syringes made of polypropylene with a stainless steel pre-fixed needle are also provided.

The product is supplied as a pack of 1 vial of powder with 1 pre-filled syringe of solvent for reconstitution and 15 disposable syringes for administration graduated in FSH units.

GONAL-f 1050 IU/1.75 ml (77 micrograms/1.75 ml) must be reconstituted with the 2 ml solvent provided before use.

GONAL-f 1050 IU/1.75 ml (77 micrograms/1.75 ml) preparation must not be reconstituted with any other GONAL-f containers.

The solvent pre-filled syringe provided should be used for reconstitution only and then disposed of in accordance with local requirements. A set of administration syringes graduated in FSH units is supplied in the GONAL-f Multidose box. Alternatively, a 1 ml syringe, graduated in ml, with prefixed needle for subcutaneous administration could be used. Each ml of reconstituted solution contains 600 IU r-hFSH.

The following table states the volume to be administered to deliver the prescribed dose:

Individual reconstituted vials should be for single patient use only. The next injection should be done at the same time the next day.

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

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

Merck Serono Europe Ltd.

56 Marsh Wall

London E14 9TP

United Kingdom

EU/1/95/001/021

Date of first authorisation: 20 October 1995.

Date of last renewal: 19 October 2005.

11^th September 2009