Following EMA’s approval for the renewal of Bemfola solution for injection in pre-filled pen (follitropin alfa). Text shown in red indicates the main changes within the SmPCs. Text shown in green is additional instructions provided by the MAH to explain the changes but is not written or represented in the approved SmPCs.

The inverted black triangle symbol and following statement have been removed from all of the SmPCs:

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

3.         PHARMACEUTICAL form

Solution for injection in a pre-filled pen (injection).

4.4      Special warnings and precautions for use

Traceability

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

 4.8 Undesirable effects

List of adverse reactions

The adverse reactions are ranked under heading of frequency using the following convention The following definitions apply to the frequency terminology used hereafter

5.1      Pharmacodynamic properties

Bemfola is a biosimilar medicinal product, that has been demonstrated to be similar in quality, safety and efficacy to the reference medicinal product containing follitropin alfa GONAL-f.

6.1         List of excipients

Poloxamer 188

Sucrose

Methionine

Disodium phosphate dihydrate Disodium hydrogen phosphate dihydrate

Sodium dihydrogen phosphate dihydrate

Phosphoric acid

Water for injections

6.3      Shelf life

3 years

Once opened, the medicinal product should be injected immediately.

6.5         Nature and contents of container (please note different wording used within each SmPC for each of the Bemfola strengths)

In the Bemfola 300 IU/0.50 mL solution for injection in pre-filled pen SmPC:

1.5 mL cartridge (type I glass), with a plunger stopper (halobutyl rubber) and an aluminium crimp cap with a rubber inlay, assembled in a pre‑filled pen.

Each cartridge contains 0.5 mL solution for injection. 0.5 mL of solution for injection in 1.5 mL cartridge (type I glass), with a plunger stopper (halobutyl rubber) and an aluminium crimp cap with a rubber inlay.

Pack sizes of 1, 5 and 10 pre-filled pens including one disposable needle and alcohol swab per pen. Not all pack sizes may be marketed. One needle and one alcohol swab to be used with the pen for administration.

Not all pack sizes may be marketed.

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of latest renewal: 12/11/2018

10.       DATE OF REVISION OF THE TEXT

09/08/2017 12/11/2018

1.         NAME OF THE MEDICINAL PRODUCT

Bemfola 300 IU/0.50 mlmL solution for injection in a pre-filled pen

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mlmL of the solution contains 600 IU (equivalent to 44 micrograms) of follitropin alfa*. Each pre-filled pen delivers 300 IU (equivalent to 22 micrograms) in 0.5 mlmL.

* recombinant human follicle stimulating hormone (r-hFSH) produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.

For a full list of excipients, see section 6.1.

4.       Clinical particulars

4.1       Therapeutic indications

In adult women

·                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).

·                Follitropin alfa 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/lL.

In adult men

·                Follitropin alfa is indicated for the stimulation of spermatogenesis in men who have congenital or acquired hypogonadotrophic hypogonadism with concomitant human Chorionic Gonadotrophin (hCG) therapy.

4.2       Posology and method of administration

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

Patients must be provided with the correct number of pens for their treatment course and educated to use the proper injection techniques.

Posology

The dose recommendations given for follitropin alfa are those in use for urinary FSH. Clinical assessment of follitropin alfa indicates that its daily doses, regimens of administration and treatment monitoring procedures should not be different from those currently used for urinary FSH-containing medicinal products. 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 dose and shorter treatment duration with follitropin alfa compared with urinary FSH. Therefore, it is considered appropriate to give a lower total dose of follitropin alfa 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).

Women with anovulation (including polycystic ovarian syndrome)

Bemfola may be given as a course of daily injections. In menstruating women treatment should commence within the first 7 days of the menstrual cycle.

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. Treatment should be tailored to the individual patient’s response as assessed by measuring follicle size by ultrasound and/or oestrogen secretion. 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 undergo further evaluation after which she may recommence treatment at a higher starting dose than in the abandoned cycle.

When an optimal response is obtained, a single injection of 250 micrograms of recombinant human chorionic gonadotropin alfa (r-hCG) or 5,000 IU up to 10,000 IU hCG should be administered 24‑48 hours after the last follitropin alfa 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 dose 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 follitropin alfa 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 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG is administered 24‑48 hours after the last follitropin alfa injection to induce final follicular maturation.

Down-regulation with a gonadotropin-releasing hormone (GnRH) agonist or antagonist is now commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. In a commonly used protocol, follitropin alfa 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 follitropin alfa 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 Bemfola 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 gonadotropin (hCG). Follitropin alfa 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.

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

If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 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 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last follitropin alfa and lutropin alfa injections. The patient is recommended to have coitus on the day of, and on the day following hCG administration.

Alternatively, 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

Bemfola should be given at a dose 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.

Special populations

Elderly population

There is no relevant use of follitropin alfa in the elderly population. Safety and effectiveness of follitropin alfa in elderly patients have not been established.

Renal or hepatic impairment

Safety, efficacy and pharmacokinetics of follitropin alfa in patients with renal or hepatic impairment have not been established.

Paediatric population

There is no relevant use of follitropin alfa in the paediatric population.

Method of administration

Bemfola is intended for subcutaneous administration. The first injection of Bemfola should be performed under direct medical supervision. Self-administration of Bemfola should only be performed by patients who are well motivated, adequately trained and have access to expert advice.

As the Bemfola pre-filled pen with the single-dose cartridge is intended for only one injection, clear instructions should be provided to the patients to avoid misuse of the single dose presentation.

For instructions on the administration with the pre-filled pen, see section 6.6 and the package leaflet.

4.3     Contraindications

•        hypersensitivity to the active substance follitropin alfa, FSH or to any of the excipients listed in section 6.1;

•        tumours of the hypothalamus or pituitary gland;

•        ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome;

•        gynaecological haemorrhages of unknown aetiology;

•        ovarian, uterine or mammary carcinoma.

Follitropin alfa must not be used when an effective response cannot be obtained, such as in case of:

•        primary ovarian failure;

•        malformations of sexual organs incompatible with pregnancy;

•        fibroid tumours of the uterus incompatible with pregnancy;

•        primary testicular insufficiency.

4.4     Special warnings and precautions for use

Follitropin alfa 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 follitropin alfa calls for monitoring of the 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 and exaggerated response in others. The lowest effective dose in relation to the treatment objective should be used in both men and women.

Porphyria

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

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 appropriate specific treatment given.

Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to the recommended follitropin alfa dosage and regimen of administration, and careful monitoring of therapy will minimise the incidence of such events. For accurate interpretation of the indices of follicle development and maturation, the physician should be experienced in the interpretation of the relevant tests.

In clinical trials, an increase of the ovarian sensitivity to follitropin alfa 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 follitropin alfa/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with follitropin alfa/LH is similar to that obtained with hMG.

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.

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, 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 polycystic ovarian syndrome high absolute or rapidly rising serum oestradiol levels (e.g. > 900 pg/mlmL or > 3,300 pmol/lL in anovulation; > 3,000 pg/mlmL or > 11,000 pmol/lL in ART) and large number of developing ovarian follicles (e.g. > 3 follicles of ≥ 14 mm in diameter in anovulation; ≥ 20 follicles of ≥ 12 mm in diameter in ART).

Adherence to the recommended follitropin alfa dose and to the regimen of administration can minimise the risk of ovarian hyperstimulation (see sections 4.2 and 4.8). Monitoring of stimulation cycles by ultrasound scans as well as oestradiol 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 such as a serum oestradiol level > 5,500 pg/mlmL or > 20,200 pmol/lL and/or ≥ 40 follicles in total, it is recommended that hCG be withheld and the patient be advised to refrain from coitus or to use barrier contraceptive methods for at least 4 days. OHSS may progress rapidly (within 24 hours) or over several days to become a serious medical event. It most often occurs after hormonal treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Therefore patients should be followed for at least two weeks after hCG administration.

In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation.

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.

Multiple pregnancy

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

To minimise the risk of a 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 a multiple births before starting treatment.

Pregnancy loss

The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing stimulation 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, regardless of 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.

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 treatment. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours 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 recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, 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 carry an increased risk of thromboembolic events.

Treatment in men

Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to follitropin alfa/hCG therapy. Follitropin alfa should not be used when an effective response cannot be obtained.

Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response.

Sodium content

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

4.5     Interaction with other medicinal products and other forms of interaction

Concomitant use of follitropin alfa with other medicinal products used to stimulate ovulation (e.g. hCG, clomiphene citrate) may potentiate the follicular response, whereas concurrent use of a GnRH agonist or antagonist to induce pituitary desensitisation may increase the dose of follitropin alfa needed to elicit an adequate ovarian response. No other clinically significant drug interaction has been reported during follitropin alfa therapy so far.

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05.

Bemfola is a biosimilar medicinal product, i.e. a medicine that has been demonstrated to be similar in quality, safety and efficacy to the reference medicinal product GONAL-f. More detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Pharmacodynamic effects

In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the objective of therapy with follitropin alfa is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG.

Clinical efficacy and safety in women

In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/lL 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 ART (see table 1 below) and in ovulation induction, follitropin alfa was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation.

In ART, follitropin alfa 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 1: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of follitropin alfa with urinary FSH in assisted reproduction technologies)

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

Clinical efficacy and safety in men

In men deficient in FSH, follitropin alfa administered concomitantly with hCG for at least 4 months induces spermatogenesis.

5.2     Pharmacokinetic properties

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

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

5.3     Preclinical safety data

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 SmPC.

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 teratogenic, and dystocia similar to that observed with urinary mMenopausal gGonadotropin (hMG). However, since Bemfola is not indicated in pregnancy, these data are of limited clinical relevance.

6.4     Special precautions for storage

Store in a refrigerator (2°C - 8°C). Do not freeze.

Before opening and within its shelf life, the medicinal product may be removed from the refrigerator, and without being refrigerated again, may be stored for up to 3 months at or below 25°C. The product must be discarded if it has not been used after 3 months.

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

6.5       Nature and contents of container

0.5 mlmL of solution for injection in 1.5 mlmL cartridge (type I glass), with a plunger stopper (halobutyl rubber) and an aluminium crimp cap with a rubber inlay.

Pack sizes of 1, 5 and 10 pre-filled pens. Not all pack sizes may be marketed. One needle and one alcohol swab to be used with the pen for administration.

6.6     Special precautions for disposal and other handling

See the package leaflet.

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

Bemfola 300 IU/0.50 mlmL (22 micrograms/0.5 mlmL) is not designed to allow the cartridge to be removed.

Discard used pen and needle immediately after injection.

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

8.       MARKETING AUTHORISATION NUMBER(S)

EU/1/13/909/004

EU/1/13/909/012

EU/1/13/909/013

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 27/03/2014

10.     DATE OF REVISION OF THE TEXT

21/11/2016 23/06/2017