4.1 Therapeutic indications
In adult women
 Anovulation (including polycystic ovarian syndrome) in women who have been unresponsive to
treatment with clomiphene citrate.
 Stimulation of multifollicular development in women undergoing superovulation for assisted
reproductive technologies (ART) such as in vitro fertilisation (IVF), gamete intra-fallopian
transfer and zygote intra-fallopian transfer.
 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.
In adult men
 GONAL-f is indicated for the stimulation of spermatogenesis in men who have congenital or
acquired hypogonadotrophic hypogonadism with concomitant human Chorionic Gonadotropin
(hCG) therapy.

Treatment with GONAL-f 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 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 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 GONAL-f compared with urinary FSH. Therefore, it is considered
appropriate to give a lower total dose 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 polycystic ovarian syndrome)
GONAL-f 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 recombinant human
choriogonadotropin alfa (r-hCG) or 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 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 GONAL-f
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 GONAL-f 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, 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 GONAL-f
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). 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.
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 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, 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 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 population
Older people
There is no relevant use of GONAL-f in the elderly population. Safety and effectiveness of GONAL-f
in elderly patients have not been established.
Renal or hepatic impairment
Safety, efficacy and pharmacokinetics of GONAL-f in patients with renal or hepatic impairment have
not been established.
Paediatric population
There is no relevant use of GONAL-f in the paediatric population.
Method of administration
GONAL-f is intended for subcutaneous use. The first injection of GONAL--f should be performed
under direct medical supervision. Self-administration of GONAL-f should only be performed by
patients who are well motivated, adequately trained and have access to expert advice.

As GONAL-f pre-filled pen with multidose cartridge is intended for several injections, clear
instructions should be provided to the patients to avoid misuse of the multidose presentation.
For instructions on the administration with the pre-filled pen, see section 6.6 and the ”Instructions for
Use”.

 hypersensitivity to the active substance 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 GONAL-f 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  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.
Gonadotropin 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 inter-patient 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 GONAL-f. 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
recommended GONAL-f dose 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 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 gonadotropin (hMG) has been
performed. Comparison with historical data suggests that the ovulation rate obtained with
GONAL-f/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/mL or > 3,300 pmol/L in anovulation;
> 3,000 pg/mL or > 11,000 pmol/L 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 recommended GONAL-f dose and 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 serum oestradiol level > 5,500 pg/mL or > 20,200 pmol/L 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 multiple pregnancy is increased
compared with natural conception. The majority of multiple conceptions are twins. Multiple
pregnancy, especially of high order, carries an increased risk of adverse maternal and perinatal outcomes.

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

Concomitant use of GONAL-f 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 GONAL-f needed to elicit
an adequate ovarian response. No other clinically significant medicinal product interaction has been reported during GONAL-f therapy

 

Pregnancy
There is no indication for use of GONAL-f during pregnancy. Data on a limited number of exposed
pregnancies (less than 300 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of
follitropin alfa.
No teratogenic effect has been observed in animal studies (see section 5.3).
In case of exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of
GONAL-f.
Breast-feeding
GONAL-f is not indicated during breast-feeding.
Fertility
GONAL-f is indicated for use in infertility (see section 4.1).

GONAL-f is expected to have no or negligible influence on the ability to drive and use machines.

Summary of the safety profile
The most commonly reported adverse reactions are headache, ovarian cysts and local injection site
reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection).
Mild or moderate ovarian hyperstimulation syndrome (OHSS) has been commonly reported and
should be considered as an intrinsic risk of the stimulation procedure. Severe OHSS is uncommon
(see section 4.4).
Thromboembolism may occur very rarely, usually associated with severe OHSS (see section 4.4).
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), very
rare (< 1/10,000).
Treatment in women
Immune system disorders
Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock
Nervous system disorders
Very common: Headache
Vascular disorders
Very rare: Thromboembolism, usually associated with severe OHSS (see section 4.4)

Respiratory, thoracic and mediastinal disorders
Very rare: Exacerbation or aggravation of asthma
Gastrointestinal disorders
Common: Abdominal pain, abdominal distension, abdominal discomfort, nausea, vomiting,
diarrhoea
Reproductive system and breast disorders
Very common: Ovarian cysts
Common: Mild or moderate OHSS (including associated symptomatology)
Uncommon: Severe OHSS (including associated symptomatology) (see section 4.4)
Rare: Complication of severe OHSS
General disorders and administration site conditions
Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at
the site of injection)
Treatment in men
Immune system disorders
Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock
Respiratory, thoracic and mediastinal disorders
Very rare: Exacerbation or aggravation of asthma
Skin and subcutaneous tissue disorders
Common: Acne
Reproductive system and breast disorders
Common: Gynaecomastia, Varicocele
General disorders and administration site conditions
Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at
the site of injection)
Investigations
Common: Weight gain

The effects of an overdose of GONAL-f are unknown, nevertheless, there is a possibility that OHSS
may occur (see section 4.4).

 

ATC code: G03GA05.
In women, the most important effect resulting from parenteral administration of FSH is the
development of mature Graafian follicles. In women with anovulation, 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.
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/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 ART (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 ART, 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 urinary FSH in assisted reproduction technologies)

 

GONAL-f
(n = 130)
urinary FSH
(n = 116)
Number of oocytes retrieved 11.0 ± 5.9 8.8 ± 4.8
Days of FSH stimulation required 11.7 ± 1.9 14.5 ± 3.3
Total dose of FSH required (number
of FSH 75 IU ampoules)
27.6 ± 10.2 40.7 ± 13.6
Need to increase the dose (%) 56.2 85.3
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, GONAL-f administered concomitantly with hCG for at least 4 months
induces spermatogenesis.

Following intravenous administration, follitropin alfa 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 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 steady-state within 3-4 days.
In women whose endogenous gonadotropin secretion is suppressed, follitropin alfa 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
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 teratogen, and dystocia similar to that observed with urinary Menopausal
Gonadotropin (hMG). However, since GONAL-f is not indicated in pregnancy, these data are of
limited clinical relevance.

Poloxamer 188
Sucrose
Methionine
Sodium dihydrogen phosphate monohydrate
Disodium phosphate dihydrate
m-Cresol
Phosphoric acid, concentrated
Sodium hydroxide
Water for injections

Not applicable.

2 years. Once opened, the medicinal product may be stored for a maximum of 28 days at or below 25°C. The patient should write on the GONAL-f pre-filled pen the day of the first use.

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,
without being refrigerated again, 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.
For in-use storage conditions, see section 6.3.

0.75 mL of solution for injection in 3 mL cartridge (Type I glass), with a plunger stopper (halobutyl
rubber) and an aluminium crimp cap with a black rubber inlay.
Pack of one pre-filled pen and 12 needles to be used with the pen for administration.

See the “Instructions for Use”.
The solution should not be administered if it contains particles or is not clear.
Any unused solution must be discarded not later than 28 days after first opening.
GONAL-f 450 IU/0.75 mL (33 micrograms/0.75 mL) is not designed to allow the cartridge to be
removed.
Discard used needles immediately after injection.
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.