FERTAVID 50UI / 0.5ml injectible solution medication leaflet

Fertavid 50 IU/0.5 mL solution for injection

Fertavid 75 IU/0.5 mL solution for injection

Fertavid 100 IU/0.5 mL solution for injection

Fertavid 150 IU/0.5 mL solution for injection

Fertavid 200 IU/0.5 mL solution for injection

Fertavid 50 IU/0.5 mL solution for injection

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 (specificin vivo bioactivity equal to approximately 10,000 IU FSH/mg protein). The solution for injectioncontains the active substance follitropin beta, produced by genetic engineering of a Chinese hamsterovary (CHO) cell line.

Fertavid 75 IU/0.5 mL solution for injection

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 (specificin vivo bioactivity equal to approximately 10,000 IU FSH/mg protein). The solution for injectioncontains the active substance follitropin beta, produced by genetic engineering of a Chinese hamsterovary (CHO) cell line.

Fertavid 100 IU/0.5 mL solution for injection

One vial contains 100 IU recombinant follicle-stimulating hormone (FSH) in 0.5 mL aqueoussolution. 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 forinjection contains the active substance follitropin beta, produced by genetic engineering of a Chinesehamster ovary (CHO) cell line.

Fertavid 150 IU/0.5 mL solution for injection

One vial contains 150 IU recombinant follicle-stimulating hormone (FSH) in 0.5 mL aqueoussolution. This corresponds to a strength of 300 IU/mL. One vial contains 15 microgram of protein(specific in vivo bioactivity equal to approximately 10,000 IU FSH/mg protein). The solution forinjection contains the active substance follitropin beta, produced by genetic engineering of a Chinesehamster ovary (CHO) cell line.

Fertavid 200 IU/0.5 mL solution for injection

One vial contains 200 IU recombinant follicle-stimulating hormone (FSH) in 0.5 mL aqueoussolution. This corresponds to a strength of 400 IU/mL. One vial contains 20 microgram of protein(specific in vivo bioactivity equal to approximately 10,000 IU FSH/mg protein). The solution forinjection contains the active substance follitropin beta, produced by genetic engineering of a Chinesehamster ovary (CHO) cell line.

This medicinal product contains less than 1 mmol sodium (23 mg) per injection, i.e. essentially‘sodium-free’.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear and colourless solution.

In adult females:

Fertavid is indicated for the treatment of female infertility in the following clinical situations:

- Anovulation (including polycystic ovarian syndrome, PCOS) in women who have beenunresponsive to treatment with clomifene citrate.

- Controlled ovarian hyperstimulation to induce the development of multiple follicles inmedically assisted reproduction programs [e.g. in vitro fertilisation/embryo transfer (IVF/ET),gamete intra-fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)].

In adult males:

- Deficient spermatogenesis due to hypogonadotrophic hypogonadism.

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

The first injection with Fertavid should be performed under direct medical supervision.

Dosage in the female

There are great inter- and intra-individual variations in the response of the ovaries to exogenousgonadotrophins. This makes it impossible to set a uniform dosage scheme. The dosage should,therefore, be adjusted individually depending on the ovarian response. This requires ultrasoundassessment of follicular development. The concurrent determination of serum oestradiol levels mayalso be useful.

Based on the results of comparative clinical studies, it is considered appropriate to give a lower totaldosage of Fertavid over a shorter treatment period than generally used for urinary FSH, not only inorder to optimise follicular development but also to reduce the risk of unwanted ovarianhyperstimulation (see section 5.1).

Clinical experience with Fertavid is based on up to three treatment cycles in both indications. Overallexperience with IVF indicates that in general the treatment success rate remains stable during the firstfour 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 levelsindicate an adequate pharmacodynamic response. A daily increase of oestradiol levels of40-100% is considered to be optimal. The daily dose is then maintained until pre-ovulatoryconditions are reached. Pre-ovulatory conditions are reached when there is ultrasonographicevidence of a dominant follicle of at least 18 mm in diameter and/or when plasma oestradiollevels of 300-900 picograms/mL (1,000-3,000 pmol/L) are attained. Usually, 7 to 14 days oftreatment is sufficient to reach this state. The administration of Fertavid is then discontinuedand 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 doseshould be decreased.

Since follicles of over 14 mm may lead to pregnancies, multiple pre-ovulatory folliclesexceeding 14 mm carry the risk of multiple gestations. In that case hCG should be withheld andpregnancy 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 atleast the first four days. Thereafter, the dose may be adjusted individually, based upon ovarianresponse. In clinical studies it was shown that maintenance dosages ranging from 75-375 IU forsix 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 ultrasound assessment. The concurrent determination ofserum oestradiol levels may also be useful. When ultrasound assessment indicates the presenceof 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 (1,000-1,300 pmol/L) for each follicle with adiameter greater than 18 mm), the final phase of maturation of the follicles is induced byadministration 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 to4 months before any improvement in spermatogenesis can be expected. To assess the response, semenanalysis is recommended 4 to 6 months after the beginning of treatment. If a patient has not respondedafter this period, the combination therapy may be continued; current clinical experience indicates thattreatment for up to 18 months or longer may be necessary to achieve spermatogenesis.

There is no relevant use of Fertavid in the paediatric population for the approved indication.

To prevent painful injections and minimise leakage from the injection site Fertavid should be slowlyadministered intramuscularly or subcutaneously. The subcutaneous injection site should be alternatedto prevent lipoatrophy. Any unused solution should be discarded.

Subcutaneous injection of Fertavid may be carried out by patient or partner, provided that properinstructions are given by the physician. Self-administration of Fertavid should only be performed bypatients who are well-motivated, adequately trained and with access to expert advice.

For males and females

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- 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.

Antibiotic hypersensitivity reactions

- Fertavid may contain traces of streptomycin and/or neomycin. These antibiotics may causehypersensitivity reactions in susceptible persons.

Infertility evaluation before starting treatment

- Before starting treatment, the couple's infertility should be assessed as appropriate. Inparticular, patients should be evaluated for hypothyroidism, adrenocortical insufficiency,hyperprolactinemia and pituitary or hypothalamic tumours, and appropriate specific treatmentgiven.

In females

Ovarian Hyperstimulation Syndrome (OHSS)

OHSS is a medical event distinct from uncomplicated ovarian enlargement. Clinical signs andsymptoms of mild and moderate OHSS are abdominal pain, nausea, diarrhoea, mild to moderateenlargement of ovaries and ovarian cysts. Severe OHSS may be life-threatening. Clinical signs andsymptoms of severe OHSS are large ovarian cysts, acute abdominal pain, ascites, pleural effusion,hydrothorax, dyspnoea, oliguria, haematological abnormalities and weight gain. In rare instances,venous or arterial thromboembolism may occur in association with OHSS. Transient liver functiontest abnormalities suggestive of hepatic dysfunction with or without morphologic changes on liverbiopsy have also been reported in association with OHSS.

OHSS may be caused by administration of human Chorionic Gonadotropin (hCG) and by pregnancy(endogenous hCG). Early OHSS usually occurs within 10 days after hCG administration and may beassociated with an excessive ovarian response to gonadotropin stimulation. Late OHSS occurs morethan 10 days after hCG administration, as a consequence of the hormonal changes with pregnancy.

Because of the risk of developing OHSS, patients should be monitored for at least two weeks afterhCG administration.

Women with known risk factors for a high ovarian response may be especially prone to thedevelopment of OHSS during or following treatment with Fertavid. For women having their firstcycle of ovarian stimulation, for whom risk factors are only partially known, close observation forearly signs and symptoms of OHSS is recommended.

Follow current clinical practice for reducing the risk of OHSS during Assisted Reproductive

Technology (ART). Adherence to the recommended Fertavid dose and treatment regimen and carefulmonitoring of ovarian response is important to reduce the risk of OHSS. To monitor the risk of OHSS,ultrasonographic assessments of follicular development should be performed prior to treatment and atregular intervals during treatment; the concurrent determination of serum oestradiol levels may alsobe useful. In ART there is an increased risk of OHSS with 18 or more follicles of 11 mm or more indiameter.

If OHSS develops, standard and appropriate management of OHSS should be implemented andfollowed.

Mult iple Pregnancy

Multiple pregnancies and births have been reported for all gonadotropin treatments, includingfollitropin beta. Multiple gestation, especially high order, carries an increased risk of adverse maternal(pregnancy and delivery complications) and perinatal (low birth weight) outcomes. For anovulatorywomen undergoing ovulation induction, monitoring follicular development with transvaginalultrasonography may aid in determining whether or not to continue the cycle in order to reduce therisk of multiple pregnancies. The concurrent determination of serum oestradiol levels may also beuseful. The patients should be advised of the potential risks of multiple births before startingtreatment.

In women undergoing Assisted Reproduction Technologies (ART) procedures, the risk of a multiplepregnancy is mainly related to the number of embryos transferred. When used for an ovulationinduction cycle, appropriate FSH dose adjustment(s) should prevent multiple follicle development.

Ectopic Pregnancy

Infertile women undergoing ART have an increased incidence of ectopic pregnancies. Earlyultrasound confirmation that a pregnancy is intrauterine is therefore important.

Spontaneous Abortion

Rates of pregnancy loss in women undergoing assisted reproduction techniques are higher than in thenormal population.

Vascular Complications

Thromboembolic events, both in association with and separate from OHSS, have been reportedfollowing treatment with gonadotropins, including follitropin beta. Intravascular thrombosis, whichmay originate in venous or arterial vessels, can result in reduced blood flow to vital organs or theextremities. In women with generally recognised risk factors for thromboembolic events, such as apersonal or family history, severe obesity or thrombophilia, treatment with gonadotropins, including

Fertavid, may further increase this risk. In these women the benefits of gonadotropin administration,including Fertavid, need to be weighed against the risks. It should be noted, however, that pregnancyitself also carries an increased risk of thrombosis.

Congenital Malformations

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

Ovarian Torsion

Ovarian torsion has been reported after treatment with gonadotropins, including follitropin beta.

Ovarian torsion may be associated with other risk factors such as OHSS, pregnancy, previousabdominal surgery, past history of ovarian torsion, previous or current ovarian cyst and polycysticovaries. Damage to the ovary due to reduced blood supply can be limited by early diagnosis andimmediate detorsion.

Ovarian and Other Reproductive System Neoplasms

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

Other Medical Conditions

Medical conditions that contraindicate pregnancy should also be evaluated before starting treatmentwith Fertavid.

In males

Primary Testicular Failure

Elevated endogenous FSH levels in men are indicative of primary testicular failure. Such patients areunresponsive to Fertavid/hCG therapy.

Concomitant use of Fertavid and clomifene citrate may enhance the follicular response. After pituitarydesensitisation induced by a GnRH agonist, a higher dose of Fertavid may be necessary to achieve anadequate follicular response.

Fertavid is used in the treatment of women undergoing ovarian induction or controlled ovarianhyperstimulation in assisted reproduction programmes. In males Fertavid is used in the treatment ofdeficient spermatogenesis due to hypogonadotrophic hypogonadism. For posology and method ofadministration, see section 4.2.

The use of Fertavid during pregnancy is not indicated. In case of inadvertent exposure duringpregnancy, 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 beenobserved in animal studies.

There is no information available from clinical or animal studies on the excretion of follitropin beta inmilk. It is unlikely that follitropin beta is excreted in human milk due to its high molecular weight. Iffollitropin beta would be excreted in human milk, it would be degraded in the gastrointestinal tract ofthe 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 thesite of injection (3% of all patients treated). The majority of these local reactions are mild andtransient in nature. Generalised hypersensitivity reactions have been observed uncommonly(approximately 0.2% of all patients treated with follitropin beta).

Treatment of females:

In approximately 4% of the women treated with follitropin beta in clinical trials, signs and symptomsrelated to ovarian hyperstimulation syndrome (OHSS) have been reported (see section 4.4). Adversereactions related to this syndrome include pelvic pain and/or congestion, abdominal pain and/ordistension, breast complaints and ovarian enlargement.

The table below lists the adverse reactions with follitropin beta 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

Nausea

Reproductive system and Common OHSSbreast disorders Pelvic pain

Uncommon Breast complaints1

Metrorrhagia

Ovarian cyst

Ovarian enlargement

Ovarian torsion

Uterine enlargement

Vaginal haemorrhage

General disorders and Common Injection site reaction2administration site conditions

Uncommon Generalised hypersensitivityreaction31. Breast complaints include tenderness, pain and/or engorgement and nipple pain2. Local reactions at the site of injection include: bruising, pain, redness, swelling and itching3. Generalised hypersensitivity reaction include erythema, urticaria, rash and pruritus

In addition, ectopic pregnancy, miscarriage and multiple gestations have been reported. These areconsidered to be related to ART or subsequent pregnancy.

In rare instances, thromboembolism has been associated with follitropin beta/hCG therapy as withother gonadotrophins.

Treatment of males:

The table below lists the adverse reactions with follitropin beta reported in a clinical trial in males(30 patients dosed), according to system organ class and frequency; common (≥ 1/100 to < 1/10).

SOC Frequency1 Adverse reaction

Nervous system disorders Common Headache

Skin and subcutaneous tissue Common Acnedisorders Rash

Reproductive system and breast Common Epididymal cystdisorders Gynaecomastia

General disorders and Common Injection site reaction2administration site conditions1. Adverse reactions that are reported only once are listed as common because a single report raises thefrequency above 1%.2. Local reactions at the site of injection include induration and pain.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No data on acute toxicity of Fertavid in humans is available, but the acute toxicity of Fertavid and ofurinary gonadotrophin preparations in animal studies has been shown to be very low. Too high adosage of FSH may lead to hyperstimulation of the ovaries (see section 4.4).

5 PHARMACOLOGICAL 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 aminoacid sequence is identical to that of natural human FSH. Small differences in the carbohydrate chainstructure are known to exist.

Mechanism of Action

FSH is indispensable in normal follicular growth and maturation, and gonadal steroid production. Inthe female the level of FSH is critical for the onset and duration of follicular development, andconsequently for the timing and number of follicles reaching maturity. Fertavid can thus be used tostimulate follicular development and steroid production in selected cases of disturbed gonadalfunction. Furthermore Fertavid can be used to promote multiple follicular development in medicallyassisted reproduction programs [e.g. in vitro fertilisation/embryo transfer (IVF/ET), gamete intra-fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)]. Treatment with Fertavid isgenerally followed by administration of hCG to induce the final phase of follicle maturation,resumption of meiosis and rupture of the follicle.

Clinical Efficacy and Safety

In clinical studies comparing recFSH (follitropin beta) and urinary FSH for controlled ovarianstimulation in women participating in an assisted reproduction technology (ART) program and forovulation induction (see tables 1 and 2 below), follitropin beta was more potent than urinary FSH interms 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 ata lower total dose and with a shorter treatment period, when compared to urinary FSH.

Table 1: Results of study 37,608 (randomized, group comparative clinical study comparing safety andefficacy of follitropin beta with urinary FSH in controlled ovarian stimulation).

follitropin beta u-FSH(n = 546) (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 medianduration of treatment when compared to urinary FSH.

Table 2: Results of study 37,609 (randomized, group comparative clinical study comparing safety andeffic acy of follitropin beta with urinary FSH in ovulation induction).

follitropin beta u-FSH(n = 105) (n = 66)

Mean no. of follicles  12 mm 3.6* 2.6 15 mm 2.0 1.7 18 mm 1.1 0.9a

Median total dose (IU) 750* 1,035a

Median duration of treatment (days) 10.0* 13.0

* Differences between the 2 groups were statistically significant (p0.05).a

Restricted to women with ovulation induced (follitropin beta, n = 76; u-FSH, n = 42).

After intramuscular or subcutaneous administration of Fertavid, maximum concentrations of FSH arereached within about 12 hours. After intramuscular administration of Fertavid, the maximum FSHconcentrations are higher and reached earlier in men as compared to women. Due to the sustainedrelease from the injection site and the elimination half-life of about 40 hours (ranging from 12 to70 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 areapproximately 1.5-2.5 times higher than after single dose administration. This increase enablestherapeutic FSH concentrations to be reached.

There are no significant pharmacokinetic differences between intramuscular and subcutaneousadministration of Fertavid. Both have an absolute bioavailability of approximately 77%.

Distribution, biotransformation and elimination

Recombinant FSH is biochemically very similar to urinary human FSH and is distributed,metabolised, and excreted in the same way.

Single-dose administration of Fertavid to rats induced no toxicologically significant effects. Inrepeated-dose studies in rats (two weeks) and dogs (13 weeks) up to 100-fold the maximal humandose, Fertavid induced no toxicologically significant effects. Fertavid showed no mutagenic potentialin the Ames test and in the in vitro chromosome aberration test with human lymphocytes.

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.

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

3 years.

The contents of a vial should be used immediately after piercing of the rubber stopper.

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 ofnot more than 3 months.

For storage conditions after first opening of the medicinal product, see section 6.3.

0.5 mL of solution in 3 mL vial (type I glass) with stopper (chlorobutyl rubber).

Pack of 1, 5 or 10 vials.

Not all pack sizes may be marketed.

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 medicinal product or waste material should be disposed of in accordance with localrequirements.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

Fertavid 50 IU/0.5 mL solution for injection

EU/1/09/510/001

EU/1/09/510/002

EU/1/09/510/003

Fertavid 75 IU/0.5 mL solution for injection

EU/1/09/510/004

EU/1/09/510/005

EU/1/09/510/006

Fertavid 100 IU/0.5 mL solution for injection

EU/1 /09/510/007

EU/1/09/510/008

EU/1/09/510/009

Fertavid 150 IU/0.5 mL solution for injection

EU/1/09/510/010

EU/1/09/510/011

EU/1/09/510/012

Fertavid 200 IU/0.5 mL solution for injection

EU/1/09/510/013

EU/1/09/510/014

EU/1/09/510/015

Date of first authorisation: 19 March 2009

Date of latest renewal: 21 February 2014

DD month YYYY

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.