ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Fertavid 50 IU/0.5 ml solution for injection
2.
One vial contains 50 IU recombinant follicle-stimulating hormone (FSH) in 0.5 ml aqueous solution.
This corresponds to a strength of 100 IU/ml. One vial contains 5 microgram of protein (specific
in vivo
bioactivity equal to approximately 10 000 IU FSH / mg protein). The solution for injection contains
the active substance follitropin beta, produced by genetic engineering of a Chinese hamster ovary
(CHO) cell line.
For a full list of excipients, see section 6.1.
3.
Solution for injection (injection).
Clear and colourless solution.
4.
In the female:
Fertavid is indicated for the treatment of female infertility in the following clinical situations:
•
Anovulation (including polycystic ovarian syndrome, PCOS) in women who have been
unresponsive to treatment with clomifene citrate.
•
Controlled ovarian hyperstimulation to induce the development of multiple follicles in medically
assisted reproduction programs [e.g.
in vitro
fertilisation/embryo transfer (IVF/ET), gamete intra-
fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)].
In the male:
•
Deficient spermatogenesis due to hypogonadotrophic hypogonadism.
Treatment with Fertavid should be initiated under the supervision of a physician experienced in the
treatment of fertility problems.
The first injection with Fertavid should be performed under direct medical supervision.
Posology
Dosage in the female
There are great inter- and intra-individual variations in the response of the ovaries to exogenous
gonadotrophins. This makes it impossible to set a uniform dosage scheme. The dosage should,
therefore, be adjusted individually depending on the ovarian response. This requires ultrasonography
and monitoring of oestradiol levels.
Based on the results of comparative clinical studies, it is considered appropriate to give a lower total
dosage of Fertavid over a shorter treatment period
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).
2
Clinical experience with Fertavid is based on up to three treatment cycles in both indications.
Overall
experience with IVF indicates that in general the treatment success rate remains stable during the first
four attempts and gradually declines thereafter.
•
Anovulation
A sequential treatment scheme is recommended starting with daily administration of 50 IU
Fertavid. The starting dose is maintained for at least seven days. If there is no ovarian response,
the daily dose is then gradually increased until
follicle growth and/or plasma oestradiol levels
indicate an adequate pharmacodynamic response. A daily increase of
oestradiol levels of 40-
100% is considered to be optimal. The daily dose is then maintained until pre-ovulatory
conditions are reached. Pre-ovulatory conditions are reached when there is ultrasonographic
evidence of a dominant follicle of at least 18 mm in diameter and/or when plasma oestradiol
levels of 300-900 picograms/ml (1000-3000 pmol/l) are attained. Usually, 7 to 14 days of
treatment is sufficient to reach this state. The administration of Fertavid is then discontinued and
ovulation can be induced by administering human chorionic gonadotrophin (hCG).
If the number of responding follicles is too high or oestradiol levels increase too rapidly, i.e.
more than a daily doubling for oestradiol for two or three consecutive days, the daily dose
should be decreased.
Since follicles of over 14 mm may lead to pregnancies, multiple pre-ovulatory follicles
exceeding 14 mm carry the risk of multiple gestations. In that case hCG should be withheld and
pregnancy should be avoided in order to prevent multiple gestations.
•
Controlled ovarian hyperstimulation in medically assisted reproduction programs
Various stimulation protocols are applied. A starting dose of 100-225 IU is recommended for at
least the first four days. Thereafter, the dose may be adjusted individually, based upon ovarian
response. In clinical studies it was shown that maintenance dosages ranging from 75-375 IU for
six to twelve days are sufficient, although longer treatment may be necessary.
Fertavid can be given either alone, or, to prevent premature luteinisation, in combination with a
GnRH agonist or antagonist. When using a GnRH agonist, a higher total treatment dose of
Fertavid may be required to achieve an adequate follicular response.
Ovarian response is monitored by ultrasonography and measurement of plasma oestradiol
levels. When ultrasonographic evaluation indicates the presence of at least three follicles of 16-
20 mm, and there is evidence of a good oestradiol response (plasma levels of about 300-400
picograms/ml (1000-1300 pmol/l) for each follicle with a diameter greater than 18 mm), the
final phase of maturation of the follicles is induced by administration of hCG. Oocyte retrieval
is performed 34-35 hours later.
Dosage in the male
Fertavid should be given at a dosage of 450 IU/week, preferably divided in 3 dosages of 150 IU,
concomitantly with hCG. Treatment with Fertavid and hCG should be continued for at least 3 to 4
months before any improvement in spermatogenesis can be expected. To assess the response, semen
analysis is recommended 4 to 6 months after the beginning of treatment. If a patient has not responded
after this period, the combination therapy may be continued; current clinical experience indicates that
treatment for up to 18 months or longer may be necessary to achieve spermatogenesis.
There is no relevant indication for use of Fertavid in children.
Method of administration
To prevent painful injections and minimise leakage from the injection site Fertavid should be slowly
administered intramuscularly or subcutaneously. The subcutaneous injection site should be alternated
to prevent lipoatrophy. Any unused solution should be discarded.
Subcutaneous injection of Fertavid may be carried out by patient or partner, provided that proper
instructions are given by the physician.
Self administration of Fertavid should only be performed by
patients who are well-motivated, adequately trained and with access to expert advice.
3
For males and females
•
Hypersensitivity to the active substance or to any of the excipients.
•
Tumours of the ovary, breast, uterus, testis, pituitary or hypothalamus.
•
Primary gonadal failure
Additionally for females
•
Undiagnosed vaginal bleeding.
•
Ovarian cysts or enlarged ovaries, not related to polycystic ovarian syndrome (PCOS).
•
Malformations of the reproductive organs incompatible with pregnancy.
•
Fibroid tumours of the uterus incompatible with pregnancy.
•
Fertavid may contain traces of streptomycin and/or neomycin. These antibiotics may cause
hypersensitivity reactions in susceptible persons.
•
The presence of uncontrolled non-gonadal endocrinopathies (e.g. thyroid, adrenal or pituitary
disorders) should be excluded.
In females
•
In pregnancies occurring after induction of ovulation with gonadotropic preparations, there is an
increased risk of multiple gestations. Appropriate FSH dose adjustment(s) should prevent
multiple follicle development. Multiple gestation, especially high order, carries an increased risk
of adverse maternal and perinatal outcomes. The patients should be advised of the potential risks
of multiple births before starting treatment.
•
Since infertile women undergoing assisted reproduction, and particularly IVF, often have tubal
abnormalities the incidence of ectopic pregnancies might be increased. Early ultrasound
confirmation that a pregnancy is intrauterine is therefore important.
•
Rates of pregnancy loss in women undergoing assisted reproduction techniques are higher than in
the normal population.
•
The incidence of congenital malformations after Assisted Reproductive Technologies (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 gestations.
•
Unwanted ovarian hyperstimulation: in the treatment of female patients, ultrasonographic
assessment of follicular development, and determination of oestradiol levels should be performed
prior to treatment and at regular intervals during treatment. Apart from the development of a high
number of follicles, oestradiol levels may rise very rapidly, e.g. more than a daily doubling for
two or three consecutive days, and possibly reaching excessively high values. The diagnosis of
ovarian hyperstimulation may be confirmed by ultrasound examination. If this unwanted ovarian
hyperstimulation occurs (i.e. not as part of controlled ovarian hyperstimulation in medically
assisted reproduction programs), the administration of Fertavid should be discontinued. In that
case pregnancy should be avoided and hCG must be withheld, because it may induce, in addition
to multiple ovulation, the ovarian hyperstimulation syndrome (OHSS). Clinical symptoms and
signs of mild ovarian hyperstimulation syndrome are abdominal pain, nausea, diarrhoea, and mild
to moderate enlargement of ovaries and ovarian cysts. Transient liver function test abnormalities
suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver
biopsy, have been reported in association with ovarian hyperstimulation syndrome. In rare cases
severe ovarian hyperstimulation syndrome occurs, which may be life-threatening. This is
characterised by large ovarian cysts (prone to rupture), ascites, often hydrothorax and weight
gain.
In rare instances, venous or arterial thromboembolism may occur in association with OHSS.
•
Ovarian torsion has been reported after treatment with follitropin beta and after intervention with
other gonadotropins. This may be associated with other risk factors such as OHSS, pregnancy,
previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst and
polycystic ovaries. Damage to the ovary due to reduced blood supply can be limited by early
diagnosis and immediate detorsion.
•
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
4
not yet established whether or not treatment with gonadotrophins increases the baseline risk of
these tumours in infertile women.
•
Women with generally recognised risk factors for thrombosis, such as a personal or family
history, severe obesity (Body Mass Index > 30 kg/m2) or thrombophilia, may have an increased
risk of venous or arterial thrombo-embolic events, during or following treatment with
gonadotrophins. In these women the benefits of IVF treatment need to be weighed against the
risks. It should be noted, however, that pregnancy itself also carries an increased risk of
thrombosis.
In males
•
Elevated endogeneous FSH levels in men are indicative of primary testicular failure. Such
patients are unresponsive to Fertavid/hCG therapy.
Concomitant use of Fertavid and clomifene citrate may enhance the follicular response. After pituitary
desensitisation induced by a GnRH agonist, a higher dose of Fertavid may be necessary to achieve an
adequate follicular response.
Fertility
Fertavid is used in the treatment of women undergoing ovarian induction or controlled ovarian
hyperstimulation in assisted reproduction programmes. In males Fertavid is used in the treatment of
deficient spermatogenesis due to hypogonadotrophic hypogonadism. For posology and method of
administration, see section 4.2.
Pregnancy
There is no indication for use of Fertavid during pregnancy. No teratogenic risk has been reported,
following controlled ovarian hyperstimulation, in clinical use with gonadotropins. In case of exposure
during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of recombinant FSH.
However, to date, no particular malformative effect has been reported. No teratogenic effect has been
observed in animal studies.
Lactation
There is no information available from clinical or animal studies on the excretion of follitropin beta in
milk. It is unlikely that follitropin beta is excreted in human milk due to its high molecular weight. If
follitropin beta would be excreted in human milk, it would be degraded in the gastrointestinal tract of
the child. Follitropin beta may affect milk production.
Fertavid has no or negligible influence on the ability to drive and use machines.
Clinical use of Fertavid by the intramuscular or subcutaneous routes may lead to local reactions at the
site of injection (3% of all patients treated). The majority of these local reactions are mild and transient
in nature.
Generalised hypersensitivity reactions have been observed uncommonly (approximately
0.2% of all patients treated with Fertavid).
Treatment of females:
In approximately 4% of the women treated with Fertavid in clinical trials, signs and symptoms related
to ovarian hyperstimulation syndrome (OHSS) have been reported (see section 4.4). Undesirable
effects related to this syndrome include pelvic pain and/or congestion, abdominal pain and/or
distension, breast complaints and ovarian enlargement.
5
The table below lists the adverse reactions with Fertavid reported in clinical trials in females,
according to system organ class and frequency; common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to
< 1/100).
SOC
Frequency
Adverse reaction
Nervous system disorders
Common
Headache
Gastrointestinal disorders
Common
Abdominal distension
Abdominal pain
Uncommon
Abdominal discomfort
Constipation
Diarrhoea
Nausea
Reproductive system and breast
disorders
Common
OHSS
Pelvic pain
Uncommon
Breast Complaints
1
Metrorrhagia
Ovarian cyst
Ovarian enlargement
Ovarian torsion
Uterine enlargement
Vaginal hemorrhage
General disorders and
administration site conditions
Common
Injection site reaction
2
Uncommon
Generalised hypersensitivity
reactions
3
1.
Breast complaints include tenderness, pain and/or engorgement and nipple pain
2.
Local reactions at the site of injection include: bruising, pain, redness, swelling and itching
3.
Generalised hypersensitivity reactions include erythema, urticaria, rash and pruritus
In addition, ectopic pregnancy, miscarriage and multiple gestations have been reported. These are
considered to be related to the ART procedure or subsequent pregnancy.
In rare instances, thromboembolism has been associated with Fertavid/hCG therapy as with other
gonadotrophins.
Treatment of males:
The table below lists the adverse reactions with Fertavid reported in a clinical trial in males (30
p
atients dosed), according to system organ class and frequency; common (≥ 1/100 to < 1/10).
SOC
Frequency
1
Adverse reaction
Nervous system disorders
Common
Headache
Skin and subcutaneous tissue
disorders
Common
Acne
Rash
Reproductive system and breast
disorders
Common
Epididymal cyst
Gynaecomastia
General disorders and
administration site conditions
Common
Injection site reaction
2
1. Adverse reactions that are reported only once are listed as common because a single report raises the
frequency above 1%.
6
2. Local reactions at the site of injection include induration and pain.
No data on acute toxicity of Fertavid in humans is available, but the acute toxicity of Fertavid and of
urinary gonadotrophin preparations in animal studies has been shown to be very low. Too high a
dosage of FSH may lead to hyperstimulation of the ovaries (see section 4.4).
5
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: sex hormones and modulators of the genital system, gonadotrophins;
ATC code: G03G A06.
Fertavid contains a recombinant FSH. This is produced by recombinant DNA technology, using a
Chinese hamster ovary cell line transfected with the human FSH subunit genes. The primary amino
acid sequence is identical to that of natural human FSH. Small differences in the carbohydrate chain
structure are known to exist.
FSH is indispensable in normal follicular growth and maturation, and gonadal steroid production. In
the female the level of FSH is critical for the onset and duration of follicular development, and
consequently for the timing and number of follicles reaching maturity. Fertavid can thus be used to
stimulate follicular development and steroid production in selected cases of disturbed gonadal
function. Furthermore Fertavid can be used to promote multiple follicular development in medically
assisted reproduction programs [e.g.
in vitro
fertilisation/embryo transfer (IVF/ET), gamete intra-
fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)]. Treatment with Fertavid is
generally followed by administration of hCG to induce the final phase of follicle maturation,
resumption of meiosis and rupture of the follicle.
In clinical studies comparing recFSH (follitropin beta) and urinary FSH for controlled ovarian
stimulation in women participating in an assisted reproduction technology (ART) program and for
ovulation induction (see tables 1 and 2 below), follitropin beta was more potent than urinary FSH in
terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation.
For controlled ovarian stimulation, follitropin beta resulted in a higher number of oocytes retrieved at
a lower total dose and with a shorter treatment period, when compared to urinary FSH.
Table 1: Results of study 37608 (randomized, group comparative clinical study comparing safety and
efficacy of follitropin beta with urinary FSH in controlled ovarian stimulation).
follitropin beta
(n = 546)
u-FSH
(n = 361)
Mean no. of oocytes retrieved
10.84
*
8.95
Mean total dose (no. of 75 IU ampoules)
28.5
*
31.8
Mean duration of FSH stimulation (days)
10.7
*
11.3
* Differences between the 2 groups were statistically significant (p
<
0.05).
For ovulation induction, follitropin beta resulted in a lower median total dose and shorter median
duration of treatment when compared to urinary FSH.
Table 2: Results of study 37609 (randomized, group comparative clinical study comparing safety and
efficacy of follitropin beta with urinary FSH in ovulation induction).
7
follitropin beta
(n = 105)
u-FSH
(n = 66)
Mean no. of follicles
≥
12 mm
3.6
*
2.6
≥
15 mm
2.0
1.7
≥
18 mm
1.1
0.9
Median total dose (IU)
a
750
*
1035
Median duration of treatment (days)
a
10.0
*
13.0
0.05).
a
Restricted to women with ovulation induced (follitropin beta, n = 76; u-FSH, n = 42).
<
5.2 Pharmacokinetic properties
After intramuscular or subcutaneous administration of Fertavid, maximum concentrations of FSH are
reached within about 12 hours. After intramuscular administration of Fertavid, the maximum FSH
concentrations are higher and reached earlier in men as compared to women. Due to the sustained
release from the injection site and the elimination half-life of about 40 hours (ranging from 12 to 70
hours), FSH levels remain increased for 24-48 hours. Due to the relatively long elimination half-life,
repeated administration of the same dose will lead to plasma concentrations of FSH that are
approximately 1.5-2.5 times higher than after single dose administration. This increase enables
therapeutic FSH concentrations to be reached.
There are no significant pharmacokinetic differences between intramuscular and subcutaneous
administration of Fertavid. Both have an absolute bioavailability of approximately 77%. Recombinant
FSH is biochemically very similar to urinary human FSH and is distributed, metabolised, and excreted
in the same way.
5.3 Preclinical safety data
Single-dose administration of Fertavid to rats induced no toxicologically significant effects. In
repeated-dose studies in rats (two weeks) and dogs (13 weeks) up to 100-fold the maximal human
dose, Fertavid induced no toxicologically significant effects. Fertavid showed no mutagenic potential
in the Ames test and in the
in vitro
chromosome aberration test with human lymphocytes.
6.
6.1 List of excipients
Fertavid solution for injection contains:
sucrose
sodium citrate
L-methionine
polysorbate 20
water for injections.
The pH may have been adjusted with sodium hydroxide and/or hydrochloric acid.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf-life
8
* Differences between the 2 groups were statistically significant (p
3 years.
The contents of a vial should be used immediately after piercing of the rubber stopper.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Keep the vial(s) in the outer carton.
For patient convenience, Fertavid may be stored at or below 25ºC by the patient for a single period of
not more than 3 months.
6.5 Nature and contents of container
0.5 ml of solution in 3 ml vial (type I glass) with stopper (chlorobutyl rubber).
Pack of 1, 5 or 10.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Do not use if the solution contains particles or if the solution is not clear.
The contents of a vial should be used immediately after piercing of the rubber stopper.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
SP Europe
Rue de Stalle, 73
B-1180 Bruxelles
Belgium
8.
EU/1/09/510/001
EU/1/09/510/002
EU/1/09/510/003
9.
Date of first authorisation: 19 March 2009
Date of last renewal:
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
9
1.
Fertavid 75 IU/0.5 ml solution for injection
2.
One vial contains 75 IU recombinant follicle-stimulating hormone (FSH) in 0.5 ml aqueous solution.
This corresponds to a strength of 150 IU/ml. One vial contains 7,5 microgram of protein (specific
in
vivo
bioactivity equal to approximately 10 000 IU FSH / mg protein). The solution for injection
contains the active substance follitropin beta, produced by genetic engineering of a Chinese hamster
ovary (CHO) cell line.
For a full list of excipients, see section 6.1.
3.
Solution for injection (injection).
Clear and colourless solution.
4.
In the female:
Fertavid is indicated for the treatment of female infertility in the following clinical situations:
•
Anovulation (including polycystic ovarian syndrome, PCOS) in women who have been
unresponsive to treatment with clomifene citrate.
•
Controlled ovarian hyperstimulation to induce the development of multiple follicles in medically
assisted reproduction programs [e.g.
in vitro
fertilisation/embryo transfer (IVF/ET), gamete intra-
fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)].
In the male:
•
Deficient spermatogenesis due to hypogonadotrophic hypogonadism.
Treatment with Fertavid should be initiated under the supervision of a physician experienced in the
treatment of fertility problems.
The first injection with Fertavid should be performed under direct medical supervision.
Posology
Dosage in the female
There are great inter- and intra-individual variations in the response of the ovaries to exogenous
gonadotrophins. This makes it impossible to set a uniform dosage scheme. The dosage should,
therefore, be adjusted individually depending on the ovarian response. This requires ultrasonography
and monitoring of oestradiol levels.
Based on the results of comparative clinical studies, it is considered appropriate to give a lower total
dosage of Fertavid over a shorter treatment period
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).
10
Clinical experience with Fertavid is based on up to three treatment cycles in both indications.
Overall
experience with IVF indicates that in general the treatment success rate remains stable during the first
four attempts and gradually declines thereafter.
•
Anovulation
A sequential treatment scheme is recommended starting with daily administration of 50 IU
Fertavid. The starting dose is maintained for at least seven days. If there is no ovarian response,
the daily dose is then gradually increased until
follicle growth and/or plasma oestradiol levels
indicate an adequate pharmacodynamic response. A daily increase of
oestradiol levels of 40-
100% is considered to be optimal. The daily dose is then maintained until pre-ovulatory
conditions are reached. Pre-ovulatory conditions are reached when there is ultrasonographic
evidence of a dominant follicle of at least 18 mm in diameter and/or when plasma oestradiol
levels of 300-900 picograms/ml (1000-3000 pmol/l) are attained. Usually, 7 to 14 days of
treatment is sufficient to reach this state. The administration of Fertavid is then discontinued and
ovulation can be induced by administering human chorionic gonadotrophin (hCG).
If the number of responding follicles is too high or oestradiol levels increase too rapidly, i.e.
more than a daily doubling for oestradiol for two or three consecutive days, the daily dose
should be decreased.
Since follicles of over 14 mm may lead to pregnancies, multiple pre-ovulatory follicles
exceeding 14 mm carry the risk of multiple gestations. In that case hCG should be withheld and
pregnancy should be avoided in order to prevent multiple gestations.
•
Controlled ovarian hyperstimulation in medically assisted reproduction programs
Various stimulation protocols are applied. A starting dose of 100-225 IU is recommended for at
least the first four days. Thereafter, the dose may be adjusted individually, based upon ovarian
response. In clinical studies it was shown that maintenance dosages ranging from 75-375 IU for
six to twelve days are sufficient, although longer treatment may be necessary.
Fertavid can be given either alone, or, to prevent premature luteinisation, in combination with a
GnRH agonist or antagonist. When using a GnRH agonist, a higher total treatment dose of
Fertavid may be required to achieve an adequate follicular response.
Ovarian response is monitored by ultrasonography and measurement of plasma oestradiol
levels. When ultrasonographic evaluation indicates the presence of at least three follicles of 16-
20 mm, and there is evidence of a good oestradiol response (plasma levels of about 300-400
picograms/ml (1000-1300 pmol/l) for each follicle with a diameter greater than 18 mm), the
final phase of maturation of the follicles is induced by administration of hCG. Oocyte retrieval
is performed 34-35 hours later.
Dosage in the male
Fertavid should be given at a dosage of 450 IU/week, preferably divided in 3 dosages of 150 IU,
concomitantly with hCG. Treatment with Fertavid and hCG should be continued for at least 3 to 4
months before any improvement in spermatogenesis can be expected. To assess the response, semen
analysis is recommended 4 to 6 months after the beginning of treatment. If a patient has not responded
after this period, the combination therapy may be continued; current clinical experience indicates that
treatment for up to 18 months or longer may be necessary to achieve spermatogenesis.
There is no relevant indication for use of Fertavid in children.
Method of administration
To prevent painful injections and minimise leakage from the injection site Fertavid should be slowly
administered intramuscularly or subcutaneously. The subcutaneous injection site should be alternated
to prevent lipoatrophy. Any unused solution should be discarded.
Subcutaneous injection of Fertavid may be carried out by patient or partner, provided that proper
instructions are given by the physician.
Self administration of Fertavid should only be performed by
patients who are well-motivated, adequately trained and with access to expert advice.
11
For males and females
•
Hypersensitivity to the active substance or to any of the excipients.
•
Tumours of the ovary, breast, uterus, testis, pituitary or hypothalamus.
•
Primary gonadal failure
Additionally for females
•
Undiagnosed vaginal bleeding.
•
Ovarian cysts or enlarged ovaries, not related to polycystic ovarian syndrome (PCOS).
•
Malformations of the reproductive organs incompatible with pregnancy.
•
Fibroid tumours of the uterus incompatible with pregnancy.
•
Fertavid may contain traces of streptomycin and/or neomycin. These antibiotics may cause
hypersensitivity reactions in susceptible persons.
•
The presence of uncontrolled non-gonadal endocrinopathies (e.g. thyroid, adrenal or pituitary
disorders) should be excluded.
In females
•
In pregnancies occurring after induction of ovulation with gonadotropic preparations, there is an
increased risk of multiple gestations. Appropriate FSH dose adjustment(s) should prevent
multiple follicle development. Multiple gestation, especially high order, carries an increased risk
of adverse maternal and perinatal outcomes. The patients should be advised of the potential risks
of multiple births before starting treatment.
•
Since infertile women undergoing assisted reproduction, and particularly IVF, often have tubal
abnormalities the incidence of ectopic pregnancies might be increased. Early ultrasound
confirmation that a pregnancy is intrauterine is therefore important.
•
Rates of pregnancy loss in women undergoing assisted reproduction techniques are higher than in
the normal population.
•
The incidence of congenital malformations after Assisted Reproductive Technologies (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 gestations.
•
Unwanted ovarian hyperstimulation: in the treatment of female patients, ultrasonographic
assessment of follicular development, and determination of oestradiol levels should be performed
prior to treatment and at regular intervals during treatment. Apart from the development of a high
number of follicles, oestradiol levels may rise very rapidly, e.g. more than a daily doubling for
two or three consecutive days, and possibly reaching excessively high values. The diagnosis of
ovarian hyperstimulation may be confirmed by ultrasound examination. If this unwanted ovarian
hyperstimulation occurs (i.e. not as part of controlled ovarian hyperstimulation in medically
assisted reproduction programs), the administration of Fertavid should be discontinued. In that
case pregnancy should be avoided and hCG must be withheld, because it may induce, in addition
to multiple ovulation, the ovarian hyperstimulation syndrome (OHSS). Clinical symptoms and
signs of mild ovarian hyperstimulation syndrome are abdominal pain, nausea, diarrhoea, and mild
to moderate enlargement of ovaries and ovarian cysts. Transient liver function test abnormalities
suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver
biopsy, have been reported in association with ovarian hyperstimulation syndrome. In rare cases
severe ovarian hyperstimulation syndrome occurs, which may be life-threatening. This is
characterised by large ovarian cysts (prone to rupture), ascites, often hydrothorax and weight
gain.
In rare instances, venous or arterial thromboembolism may occur in association with OHSS.
•
Ovarian torsion has been reported after treatment with follitropin beta and after intervention with
other gonadotropins. This may be associated with other risk factors such as OHSS, pregnancy,
previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst and
polycystic ovaries. Damage to the ovary due to reduced blood supply can be limited by early
diagnosis and immediate detorsion.
•
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
12
not yet established whether or not treatment with gonadotrophins increases the baseline risk of
these tumours in infertile women.
•
Women with generally recognised risk factors for thrombosis, such as a personal or family
history, severe obesity (Body Mass Index > 30 kg/m2) or thrombophilia, may have an increased
risk of venous or arterial thrombo-embolic events, during or following treatment with
gonadotrophins. In these women the benefits of IVF treatment need to be weighed against the
risks. It should be noted, however, that pregnancy itself also carries an increased risk of
thrombosis.
In males
•
Elevated endogeneous FSH levels in men are indicative of primary testicular failure. Such
patients are unresponsive to Fertavid/hCG therapy.
Concomitant use of Fertavid and clomifene citrate may enhance the follicular response. After pituitary
desensitisation induced by a GnRH agonist, a higher dose of Fertavid may be necessary to achieve an
adequate follicular response.
Fertility
Fertavid is used in the treatment of women undergoing ovarian induction or controlled ovarian
hyperstimulation in assisted reproduction programmes. In males Fertavid is used in the treatment of
deficient spermatogenesis due to hypogonadotrophic hypogonadism. For posology and method of
administration, see section 4.2.
Pregnancy
There is no indication for use of Fertavid during pregnancy. No teratogenic risk has been reported,
following controlled ovarian hyperstimulation, in clinical use with gonadotropins. In case of exposure
during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of recombinant FSH.
However, to date, no particular malformative effect has been reported. No teratogenic effect has been
observed in animal studies.
Lactation
There is no information available from clinical or animal studies on the excretion of follitropin beta in
milk. It is unlikely that follitropin beta is excreted in human milk due to its high molecular weight. If
follitropin beta would be excreted in human milk, it would be degraded in the gastrointestinal tract of
the child. Follitropin beta may affect milk production.
Fertavid has no or negligible influence on the ability to drive and use machines.
Clinical use of Fertavid by the intramuscular or subcutaneous routes may lead to local reactions at the
site of injection (3% of all patients treated). The majority of these local reactions are mild and transient
in nature.
Generalised hypersensitivity reactions have been observed uncommonly (approximately
0.2% of all patients treated with Fertavid).
Treatment of females:
In approximately 4% of the women treated with Fertavid in clinical trials, signs and symptoms related
to ovarian hyperstimulation syndrome (OHSS) have been reported (see section 4.4). Undesirable
effects related to this syndrome include pelvic pain and/or congestion, abdominal pain and/or
distension, breast complaints and ovarian enlargement.
13
The table below lists the adverse reactions with Fertavid reported in clinical trials in females,
according to system organ class and frequency; common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to
< 1/100).
SOC
Frequency
Adverse reaction
Nervous system disorders
Common
Headache
Gastrointestinal disorders
Common
Abdominal distension
Abdominal pain
Uncommon
Abdominal discomfort
Constipation
Diarrhoea
Nausea
Reproductive system and breast
disorders
Common
OHSS
Pelvic pain
Uncommon
Breast Complaints
1
Metrorrhagia
Ovarian cyst
Ovarian enlargement
Ovarian torsion
Uterine enlargement
Vaginal hemorrhage
General disorders and
administration site conditions
Common
Injection site reaction
2
Uncommon
Generalised hypersensitivity
reactions
3
1.
Breast complaints include tenderness, pain and/or engorgement and nipple pain
2.
Local reactions at the site of injection include: bruising, pain, redness, swelling and itching
3.
Generalised hypersensitivity reactions include erythema, urticaria, rash and pruritus
In addition, ectopic pregnancy, miscarriage and multiple gestations have been reported. These are
considered to be related to the ART procedure or subsequent pregnancy.
In rare instances, thromboembolism has been associated with Fertavid/hCG therapy as with other
gonadotrophins.
Treatment of males:
The table below lists the adverse reactions with Fertavid reported in a clinical trial in males (30
p
atients dosed), according to system organ class and frequency; common (≥ 1/100 to < 1/10).
SOC
Frequency
1
Adverse reaction
Nervous system disorders
Common
Headache
Skin and subcutaneous tissue
disorders
Common
Acne
Rash
Reproductive system and breast
disorders
Common
Epididymal cyst
Gynaecomastia
General disorders and
administration site conditions
Common
Injection site reaction
2
1. Adverse reactions that are reported only once are listed as common because a single report raises the
frequency above 1%.
14
2. Local reactions at the site of injection include induration and pain.
No data on acute toxicity of Fertavid in humans is available, but the acute toxicity of Fertavid and of
urinary gonadotrophin preparations in animal studies has been shown to be very low. Too high a
dosage of FSH may lead to hyperstimulation of the ovaries (see section 4.4).
5
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: sex hormones and modulators of the genital system, gonadotrophins;
ATC code: G03G A06.
Fertavid contains a recombinant FSH. This is produced by recombinant DNA technology, using a
Chinese hamster ovary cell line transfected with the human FSH subunit genes. The primary amino
acid sequence is identical to that of natural human FSH. Small differences in the carbohydrate chain
structure are known to exist.
FSH is indispensable in normal follicular growth and maturation, and gonadal steroid production. In
the female the level of FSH is critical for the onset and duration of follicular development, and
consequently for the timing and number of follicles reaching maturity. Fertavid can thus be used to
stimulate follicular development and steroid production in selected cases of disturbed gonadal
function. Furthermore Fertavid can be used to promote multiple follicular development in medically
assisted reproduction programs [e.g.
in vitro
fertilisation/embryo transfer (IVF/ET), gamete intra-
fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)]. Treatment with Fertavid is
generally followed by administration of hCG to induce the final phase of follicle maturation,
resumption of meiosis and rupture of the follicle.
In clinical studies comparing recFSH (follitropin beta) and urinary FSH for controlled ovarian
stimulation in women participating in an assisted reproduction technology (ART) program and for
ovulation induction (see tables 1 and 2 below), follitropin beta was more potent than urinary FSH in
terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation.
For controlled ovarian stimulation, follitropin beta resulted in a higher number of oocytes retrieved at
a lower total dose and with a shorter treatment period, when compared to urinary FSH.
Table 1: Results of study 37608 (randomized, group comparative clinical study comparing safety and
efficacy of follitropin beta with urinary FSH in controlled ovarian stimulation).
follitropin beta
(n = 546)
u-FSH
(n = 361)
Mean no. of oocytes retrieved
10.84
*
8.95
Mean total dose (no. of 75 IU ampoules)
28.5
*
31.8
Mean duration of FSH stimulation (days)
10.7
*
11.3
* Differences between the 2 groups were statistically significant (p
<
0.05).
For ovulation induction, follitropin beta resulted in a lower median total dose and shorter median
duration of treatment when compared to urinary FSH.
Table 2: Results of study 37609 (randomized, group comparative clinical study comparing safety and
efficacy of follitropin beta with urinary FSH in ovulation induction).
15
follitropin beta
(n = 105)
u-FSH
(n = 66)
Mean no. of follicles
≥
12 mm
3.6
*
2.6
≥
15 mm
2.0
1.7
≥
18 mm
1.1
0.9
Median total dose (IU)
a
750
*
1035
Median duration of treatment (days)
a
10.0
*
13.0
0.05).
a
Restricted to women with ovulation induced (follitropin beta, n = 76; u-FSH, n = 42).
<
5.2 Pharmacokinetic properties
After intramuscular or subcutaneous administration of Fertavid, maximum concentrations of FSH are
reached within about 12 hours. After intramuscular administration of Fertavid, the maximum FSH
concentrations are higher and reached earlier in men as compared to women. Due to the sustained
release from the injection site and the elimination half-life of about 40 hours (ranging from 12 to 70
hours), FSH levels remain increased for 24-48 hours. Due to the relatively long elimination half-life,
repeated administration of the same dose will lead to plasma concentrations of FSH that are
approximately 1.5-2.5 times higher than after single dose administration. This increase enables
therapeutic FSH concentrations to be reached.
There are no significant pharmacokinetic differences between intramuscular and subcutaneous
administration of Fertavid. Both have an absolute bioavailability of approximately 77%. Recombinant
FSH is biochemically very similar to urinary human FSH and is distributed, metabolised, and excreted
in the same way.
5.3 Preclinical safety data
Single-dose administration of Fertavid to rats induced no toxicologically significant effects. In
repeated-dose studies in rats (two weeks) and dogs (13 weeks) up to 100-fold the maximal human
dose, Fertavid induced no toxicologically significant effects. Fertavid showed no mutagenic potential
in the Ames test and in the
in vitro
chromosome aberration test with human lymphocytes.
6.
6.1 List of excipients
Fertavid solution for injection contains:
sucrose
sodium citrate
L-methionine
polysorbate 20
water for injections.
The pH may have been adjusted with sodium hydroxide and/or hydrochloric acid.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf-life
16
* Differences between the 2 groups were statistically significant (p
3 years.
The contents of a vial should be used immediately after piercing of the rubber stopper.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Keep the vial(s) in the outer carton.
For patient convenience, Fertavid may be stored at or below 25ºC by the patient for a single period of
not more than 3 months.
6.5 Nature and contents of container
0.5 ml of solution in 3 ml vial (type I glass) with stopper (chlorobutyl rubber).
Pack of 1, 5 or 10.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Do not use if the solution contains particles or if the solution is not clear.
The contents of a vial should be used immediately after piercing of the rubber stopper.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
SP Europe
Rue de Stalle, 73
B-1180 Bruxelles
Belgium
8.
EU/1/09/510/004
EU/1/09/510/005
EU/1/09/510/006
9.
Date of first authorisation: 19 March 2009
Date of last renewal:
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
17
1.
Fertavid 100 IU/0.5 ml solution for injection
2.
One vial contains 100 IU recombinant follicle-stimulating hormone (FSH) in 0.5 ml aqueous solution.
This corresponds to a strength of 200 IU/ml. One vial contains 10 microgram of protein (specific
in
vivo
bioactivity equal to approximately 10 000 IU FSH / mg protein). The solution for injection
contains the active substance follitropin beta, produced by genetic engineering of a Chinese hamster
ovary (CHO) cell line.
For a full list of excipients, see section 6.1.
3.
Solution for injection (injection).
Clear and colourless solution.
4.
In the female:
Fertavid is indicated for the treatment of female infertility in the following clinical situations:
•
Anovulation (including polycystic ovarian syndrome, PCOS) in women who have been
unresponsive to treatment with clomifene citrate.
•
Controlled ovarian hyperstimulation to induce the development of multiple follicles in medically
assisted reproduction programs [e.g.
in vitro
fertilisation/embryo transfer (IVF/ET), gamete intra-
fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)].
In the male:
•
Deficient spermatogenesis due to hypogonadotrophic hypogonadism.
Treatment with Fertavid should be initiated under the supervision of a physician experienced in the
treatment of fertility problems.
The first injection with Fertavid should be performed under direct medical supervision.
Posology
Dosage in the female
There are great inter- and intra-individual variations in the response of the ovaries to exogenous
gonadotrophins. This makes it impossible to set a uniform dosage scheme. The dosage should,
therefore, be adjusted individually depending on the ovarian response. This requires ultrasonography
and monitoring of oestradiol levels.
Based on the results of comparative clinical studies, it is considered appropriate to give a lower total
dosage of Fertavid over a shorter treatment period
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).
18
Clinical experience with Fertavid is based on up to three treatment cycles in both indications.
Overall
experience with IVF indicates that in general the treatment success rate remains stable during the first
four attempts and gradually declines thereafter.
•
Anovulation
A sequential treatment scheme is recommended starting with daily administration of 50 IU
Fertavid. The starting dose is maintained for at least seven days. If there is no ovarian response,
the daily dose is then gradually increased until
follicle growth and/or plasma oestradiol levels
indicate an adequate pharmacodynamic response. A daily increase of
oestradiol levels of 40-
100% is considered to be optimal. The daily dose is then maintained until pre-ovulatory
conditions are reached. Pre-ovulatory conditions are reached when there is ultrasonographic
evidence of a dominant follicle of at least 18 mm in diameter and/or when plasma oestradiol
levels of 300-900 picograms/ml (1000-3000 pmol/l) are attained. Usually, 7 to 14 days of
treatment is sufficient to reach this state. The administration of Fertavid is then discontinued and
ovulation can be induced by administering human chorionic gonadotrophin (hCG).
If the number of responding follicles is too high or oestradiol levels increase too rapidly, i.e.
more than a daily doubling for oestradiol for two or three consecutive days, the daily dose
should be decreased.
Since follicles of over 14 mm may lead to pregnancies, multiple pre-ovulatory follicles
exceeding 14 mm carry the risk of multiple gestations. In that case hCG should be withheld and
pregnancy should be avoided in order to prevent multiple gestations.
•
Controlled ovarian hyperstimulation in medically assisted reproduction programs
Various stimulation protocols are applied. A starting dose of 100-225 IU is recommended for at
least the first four days. Thereafter, the dose may be adjusted individually, based upon ovarian
response. In clinical studies it was shown that maintenance dosages ranging from 75-375 IU for
six to twelve days are sufficient, although longer treatment may be necessary.
Fertavid can be given either alone, or, to prevent premature luteinisation, in combination with a
GnRH agonist or antagonist. When using a GnRH agonist, a higher total treatment dose of
Fertavid may be required to achieve an adequate follicular response.
Ovarian response is monitored by ultrasonography and measurement of plasma oestradiol
levels. When ultrasonographic evaluation indicates the presence of at least three follicles of 16-
20 mm, and there is evidence of a good oestradiol response (plasma levels of about 300-400
picograms/ml (1000-1300 pmol/l) for each follicle with a diameter greater than 18 mm), the
final phase of maturation of the follicles is induced by administration of hCG. Oocyte retrieval
is performed 34-35 hours later.
Dosage in the male
Fertavid should be given at a dosage of 450 IU/week, preferably divided in 3 dosages of 150 IU,
concomitantly with hCG. Treatment with Fertavid and hCG should be continued for at least 3 to 4
months before any improvement in spermatogenesis can be expected. To assess the response, semen
analysis is recommended 4 to 6 months after the beginning of treatment. If a patient has not responded
after this period, the combination therapy may be continued; current clinical experience indicates that
treatment for up to 18 months or longer may be necessary to achieve spermatogenesis.
There is no relevant indication for use of Fertavid in children.
Method of administration
To prevent painful injections and minimise leakage from the injection site Fertavid should be slowly
administered intramuscularly or subcutaneously. The subcutaneous injection site should be alternated
to prevent lipoatrophy. Any unused solution should be discarded.
Subcutaneous injection of Fertavid may be carried out by patient or partner, provided that proper
instructions are given by the physician.
Self administration of Fertavid should only be performed by
patients who are well-motivated, adequately trained and with access to expert advice.
19
For males and females
•
Hypersensitivity to the active substance or to any of the excipients.
•
Tumours of the ovary, breast, uterus, testis, pituitary or hypothalamus.
•
Primary gonadal failure
Additionally for females
•
Undiagnosed vaginal bleeding.
•
Ovarian cysts or enlarged ovaries, not related to polycystic ovarian syndrome (PCOS).
•
Malformations of the reproductive organs incompatible with pregnancy.
•
Fibroid tumours of the uterus incompatible with pregnancy.
•
Fertavid may contain traces of streptomycin and/or neomycin. These antibiotics may cause
hypersensitivity reactions in susceptible persons.
•
The presence of uncontrolled non-gonadal endocrinopathies (e.g. thyroid, adrenal or pituitary
disorders) should be excluded.
In females
•
In pregnancies occurring after induction of ovulation with gonadotropic preparations, there is an
increased risk of multiple gestations. Appropriate FSH dose adjustment(s) should prevent
multiple follicle development. Multiple gestation, especially high order, carries an increased risk
of adverse maternal and perinatal outcomes. The patients should be advised of the potential risks
of multiple births before starting treatment.
•
Since infertile women undergoing assisted reproduction, and particularly IVF, often have tubal
abnormalities the incidence of ectopic pregnancies might be increased. Early ultrasound
confirmation that a pregnancy is intrauterine is therefore important.
•
Rates of pregnancy loss in women undergoing assisted reproduction techniques are higher than in
the normal population.
•
The incidence of congenital malformations after Assisted Reproductive Technologies (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 gestations.
•
Unwanted ovarian hyperstimulation: in the treatment of female patients, ultrasonographic
assessment of follicular development, and determination of oestradiol levels should be performed
prior to treatment and at regular intervals during treatment. Apart from the development of a high
number of follicles, oestradiol levels may rise very rapidly, e.g. more than a daily doubling for
two or three consecutive days, and possibly reaching excessively high values. The diagnosis of
ovarian hyperstimulation may be confirmed by ultrasound examination. If this unwanted ovarian
hyperstimulation occurs (i.e. not as part of controlled ovarian hyperstimulation in medically
assisted reproduction programs), the administration of Fertavid should be discontinued. In that
case pregnancy should be avoided and hCG must be withheld, because it may induce, in addition
to multiple ovulation, the ovarian hyperstimulation syndrome (OHSS). Clinical symptoms and
signs of mild ovarian hyperstimulation syndrome are abdominal pain, nausea, diarrhoea, and mild
to moderate enlargement of ovaries and ovarian cysts. Transient liver function test abnormalities
suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver
biopsy, have been reported in association with ovarian hyperstimulation syndrome. In rare cases
severe ovarian hyperstimulation syndrome occurs, which may be life-threatening. This is
characterised by large ovarian cysts (prone to rupture), ascites, often hydrothorax and weight
gain. In rare instances, venous or arterial thromboembolism may occur in association with OHSS.
•
Ovarian torsion has been reported after treatment with follitropin beta and after intervention with
other gonadotropins. This may be associated with other risk factors such as OHSS, pregnancy,
previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst and
polycystic ovaries. Damage to the ovary due to reduced blood supply can be limited by early
diagnosis and immediate detorsion.
•
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
20
not yet established whether or not treatment with gonadotrophins increases the baseline risk of
these tumours in infertile women.
•
Women with generally recognised risk factors for thrombosis, such as a personal or family
history, severe obesity (Body Mass Index > 30 kg/m2) or thrombophilia, may have an increased
risk of venous or arterial thrombo-embolic events, during or following treatment with
gonadotrophins. In these women the benefits of IVF treatment need to be weighed against the
risks. It should be noted, however, that pregnancy itself also carries an increased risk of
thrombosis.
In males
•
Elevated endogeneous FSH levels in men are indicative of primary testicular failure. Such
patients are unresponsive to Fertavid/hCG therapy.
Concomitant use of Fertavid and clomifene citrate may enhance the follicular response. After pituitary
desensitisation induced by a GnRH agonist, a higher dose of Fertavid may be necessary to achieve an
adequate follicular response.
Fertility
Fertavid is used in the treatment of women undergoing ovarian induction or controlled ovarian
hyperstimulation in assisted reproduction programmes. In males Fertavid is used in the treatment of
deficient spermatogenesis due to hypogonadotrophic hypogonadism. For posology and method of
administration, see section 4.2.
Pregnancy
There is no indication for use of Fertavid during pregnancy. No teratogenic risk has been reported,
following controlled ovarian hyperstimulation, in clinical use with gonadotropins. In case of exposure
during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of recombinant FSH.
However, to date, no particular malformative effect has been reported. No teratogenic effect has been
observed in animal studies.
Lactation
There is no information available from clinical or animal studies on the excretion of follitropin beta in
milk. It is unlikely that follitropin beta is excreted in human milk due to its high molecular weight. If
follitropin beta would be excreted in human milk, it would be degraded in the gastrointestinal tract of
the child. Follitropin beta may affect milk production.
Fertavid has no or negligible influence on the ability to drive and use machines.
Clinical use of Fertavid by the intramuscular or subcutaneous routes may lead to local reactions at the
site of injection (3% of all patients treated). The majority of these local reactions are mild and transient
in nature.
Generalised hypersensitivity reactions have been observed uncommonly (approximately
0.2% of all patients treated with Fertavid).
Treatment of females:
In approximately 4% of the women treated with Fertavid in clinical trials, signs and symptoms related
to ovarian hyperstimulation syndrome (OHSS) have been reported (see section 4.4). Undesirable
effects related to this syndrome include pelvic pain and/or congestion, abdominal pain and/or
distension, breast complaints and ovarian enlargement.
21
The table below lists the adverse reactions with Fertavid reported in clinical trials in females,
according to system organ class and frequency; common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to
< 1/100).
SOC
Frequency
Adverse reaction
Nervous system disorders
Common
Headache
Gastrointestinal disorders
Common
Abdominal distension
Abdominal pain
Uncommon
Abdominal discomfort
Constipation
Diarrhoea
Nausea
Reproductive system and breast
disorders
Common
OHSS
Pelvic pain
Uncommon
Breast Complaints
1
Metrorrhagia
Ovarian cyst
Ovarian enlargement
Ovarian torsion
Uterine enlargement
Vaginal hemorrhage
General disorders and
administration site conditions
Common
Injection site reaction
2
Uncommon
Generalised hypersensitivity
reactions
3
1.
Breast complaints include tenderness, pain and/or engorgement and nipple pain
2.
Local reactions at the site of injection include: bruising, pain, redness, swelling and itching
3.
Generalised hypersensitivity reactions include erythema, urticaria, rash and pruritus
In addition, ectopic pregnancy, miscarriage and multiple gestations have been reported. These are
considered to be related to the ART procedure or subsequent pregnancy.
In rare instances, thromboembolism has been associated with Fertavid/hCG therapy as with other
gonadotrophins.
Treatment of males:
The table below lists the adverse reactions with Fertavid reported in a clinical trial in males (30
p
atients dosed), according to system organ class and frequency; common (≥ 1/100 to < 1/10).
SOC
Frequency
1
Adverse reaction
Nervous system disorders
Common
Headache
Skin and subcutaneous tissue
disorders
Common
Acne
Rash
Reproductive system and breast
disorders
Common
Epididymal cyst
Gynaecomastia
General disorders and
administration site conditions
Common
Injection site reaction
2
1. Adverse reactions that are reported only once are listed as common because a single report raises the
frequency above 1%.
22
2. Local reactions at the site of injection include induration and pain.
No data on acute toxicity of Fertavid in humans is available, but the acute toxicity of Fertavid and of
urinary gonadotrophin preparations in animal studies has been shown to be very low. Too high a
dosage of FSH may lead to hyperstimulation of the ovaries (see section 4.4).
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: sex hormones and modulators of the genital system, gonadotrophins;
ATC code: G03G A06.
Fertavid contains a recombinant FSH. This is produced by recombinant DNA technology, using a
Chinese hamster ovary cell line transfected with the human FSH subunit genes. The primary amino
acid sequence is identical to that of natural human FSH. Small differences in the carbohydrate chain
structure are known to exist.
FSH is indispensable in normal follicular growth and maturation, and gonadal steroid production. In
the female the level of FSH is critical for the onset and duration of follicular development, and
consequently for the timing and number of follicles reaching maturity. Fertavid can thus be used to
stimulate follicular development and steroid production in selected cases of disturbed gonadal
function. Furthermore Fertavid can be used to promote multiple follicular development in medically
assisted reproduction programs [e.g.
in vitro
fertilisation/embryo transfer (IVF/ET), gamete intra-
fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)]. Treatment with Fertavid is
generally followed by administration of hCG to induce the final phase of follicle maturation,
resumption of meiosis and rupture of the follicle.
In clinical studies comparing recFSH (follitropin beta) and urinary FSH for controlled ovarian
stimulation in women participating in an assisted reproduction technology (ART) program and for
ovulation induction (see tables 1 and 2 below), follitropin beta was more potent than urinary FSH in
terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation.
For controlled ovarian stimulation, follitropin beta resulted in a higher number of oocytes retrieved at
a lower total dose and with a shorter treatment period, when compared to urinary FSH.
Table 1: Results of study 37608 (randomized, group comparative clinical study comparing safety and
efficacy of follitropin beta with urinary FSH in controlled ovarian stimulation).
follitropin beta
(n = 546)
u-FSH
(n = 361)
Mean no. of oocytes retrieved
10.84
*
8.95
Mean total dose (no. of 75 IU ampoules)
28.5
*
31.8
Mean duration of FSH stimulation (days)
10.7
*
11.3
* Differences between the 2 groups were statistically significant (p
<
0.05).
For ovulation induction, follitropin beta resulted in a lower median total dose and shorter median
duration of treatment when compared to urinary FSH.
Table 2: Results of study 37609 (randomized, group comparative clinical study comparing safety and
efficacy of follitropin beta with urinary FSH in ovulation induction).
23
follitropin beta
(n = 105)
u-FSH
(n = 66)
Mean no. of follicles
≥
12 mm
3.6
*
2.6
≥
15 mm
2.0
1.7
≥
18 mm
1.1
0.9
Median total dose (IU)
a
750
*
1035
Median duration of treatment (days)
a
10.0
*
13.0
0.05).
a
Restricted to women with ovulation induced (follitropin beta, n = 76; u-FSH, n = 42).
<
5.2 Pharmacokinetic properties
After intramuscular or subcutaneous administration of Fertavid, maximum concentrations of FSH are
reached within about 12 hours. After intramuscular administration of Fertavid, the maximum FSH
concentrations are higher and reached earlier in men as compared to women. Due to the sustained
release from the injection site and the elimination half-life of about 40 hours (ranging from 12 to
70 hours), FSH levels remain increased for 24-48 hours. Due to the relatively long elimination half-
life, repeated administration of the same dose will lead to plasma concentrations of FSH that are
approximately 1.5-2.5 times higher than after single dose administration. This increase enables
therapeutic FSH concentrations to be reached.
There are no significant pharmacokinetic differences between intramuscular and subcutaneous
administration of Fertavid. Both have an absolute bioavailability of approximately 77%. Recombinant
FSH is biochemically very similar to urinary human FSH and is distributed, metabolised, and excreted
in the same way.
5.3 Preclinical safety data
Single-dose administration of Fertavid to rats induced no toxicologically significant effects. In
repeated-dose studies in rats (two weeks) and dogs (13 weeks) up to 100-fold the maximal human
dose, Fertavid induced no toxicologically significant effects. Fertavid showed no mutagenic potential
in the Ames test and in the
in vitro
chromosome aberration test with human lymphocytes.
6.
6.1 List of excipients
Fertavid solution for injection contains:
sucrose
sodium citrate
L-methionine
polysorbate 20
water for injections.
The pH may have been adjusted with sodium hydroxide and/or hydrochloric acid.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf-life
24
* Differences between the 2 groups were statistically significant (p
3 years.
The contents of a vial should be used immediately after piercing of the rubber stopper.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Keep the vial(s) in the outer carton.
For patient convenience, Fertavid may be stored at or below 25ºC by the patient for a single period of
not more than 3 months.
6.5 Nature and contents of container
0.5 ml of solution in 3 ml vial (type I glass) with stopper (chlorobutyl rubber).
Pack of 1, 5 or 10.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Do not use if the solution contains particles or if the solution is not clear.
The contents of a vial should be used immediately after piercing of the rubber stopper.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
SP Europe
Rue de Stalle, 73
B-1180 Bruxelles
Belgium
8.
EU/1/09/510/007
EU/1/09/510/008
EU/1/09/510/009
9.
Date of first authorisation: 19 March 2009
Date of last renewal:
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
25
1.
FURTHER INFORMATION
What Fertavid contains
•
Each cartridge contains the active substance follitropin beta, a hormone known as follicle-
stimulating hormone (FSH) in a strength of 833 IU/ml aqueous solution.
•
The other ingredients are sucrose, sodium citrate, L-methionine, polysorbate 20 and benzyl
alcohol in water for injections. The pH may have been adjusted with sodium hydroxide and/or
hydrochloric acid.
What Fertavid looks like and contents of the pack
Fertavid solution for injection (injection) is a clear, colourless liquid. It is supplied in a glass cartridge.
It is available in packs of 1 cartridge.
Marketing Authorisation Holder
SP Europe, Rue de Stalle 73, B-1180 Bruxelles, Belgium.
Manufacturer
•
N.V. Organon, Kloosterstraat 6, Postbus 20, 5340 BH Oss, The Netherlands
•
Organon (Ireland) Ltd., P.O. Box 2857, Drynam Road, Swords, Co. Dublin, Ireland
This leaflet was last approved in
188
In correspondence please quote the batch number.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
189
Source: European Medicines Agency
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