FERTAVID 900UI / 1.08ml injectible solution medication leaflet

Fertavid 150 IU/0.18 mL solution for injection

Fertavid 300 IU/0.36 mL solution for injection

Fertavid 600 IU/0.72 mL solution for injection

Fertavid 900 IU/1.08 mL solution for injection

Fertavid 150 IU/0.18 mL solution for injection

One cartridge contains a net total dose of 150 IU recombinant follicle-stimulating hormone (FSH) in0.18 mL aqueous solution. The solution for injection contains the active substance follitropin beta,produced by genetic engineering of a Chinese hamster ovary (CHO) cell line, in a concentration of833 IU/mL aqueous solution. This strength corresponds to 83.3 microgram of protein/mL (specificin vivo bioactivity equal to approximately 10,000 IU FSH/mg protein).

Fertavid 300 IU/0.36 mL solution for injection

One cartridge contains a net total dose of 300 IU recombinant follicle-stimulating hormone (FSH) in0.36 mL aqueous solution. The solution for injection contains the active substance follitropin beta,produced by genetic engineering of a Chinese hamster ovary (CHO) cell line, in a concentration of833 IU/mL aqueous solution. This strength corresponds to 83.3 microgram of protein/ml (specificin vivo bioactivity equal to approximately 10,000 IU FSH/mg protein).

Fertavid 600 IU/0.72 mL solution for injection

One cartridge contains a net total dose of 600 IU recombinant follicle-stimulating hormone (FSH) in0.72 mL aqueous solution. The solution for injection contains the active substance follitropin beta,produced by genetic engineering of a Chinese hamster ovary (CHO) cell line, in a concentration of833 IU/mL aqueous solution. This strength corresponds to 83.3 microgram of protein/mL (specificin vivo bioactivity equal to approximately 10,000 IU FSH/mg protein).

Fertavid 900 IU/1.08 mL solution for injection

One cartridge contains a net total dose of 900 IU recombinant follicle-stimulating hormone (FSH) in1.08 mL aqueous solution. The solution for injection contains the active substance follitropin beta,produced by genetic engineering of a Chinese hamster ovary (CHO) cell line, in a concentration of833 IU/mL aqueous solution. This strength corresponds to 83.3 microgram of protein/mL (specificin vivo bioactivity equal to approximately 10,000 IU FSH/mg protein).

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 cartridges, designed to be used in conjunction with a pen injector.

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.

When using the pen injector, it should be realised that the pen is a precision device which accuratelydelivers the dose to which it is set. It was shown that on average an 18% higher amount of FSH isgiven with the pen compared with a conventional syringe. This may be of particular relevance whenswitching between the pen injector and a conventional syringe within one treatment cycle. Especiallywhen switching from a syringe to the pen, small dose adjustments may be needed to prevent too higha dose being given.

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 of 40-100% 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 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.

Fertavid solution for injection in cartridges has been developed for use in a pen injector called

Puregon Pen and should be administered subcutaneously. The injection site should be alternated toprevent lipoatrophy.

Using the pen injector, injection of Fertavid can be carried out by the patient, provided that properinstructions are given by the physician.

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

SOC Frequency Adverse reaction

G astrointestinal 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).

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 subcutaneous administration of Fertavid, maximum concentration of FSH is reached withinabout 12 hours. Due to the sustained release from the injection site and the elimination half-life ofabout 40 hours (ranging from 12 to 70 hours), FSH levels remain increased for 24-48 hours. Due tothe relatively long elimination half-life, repeated administration of the same dose will lead to plasmaconcentrations of FSH that are approximately 1.5-2.5 times higher than after single doseadministration. This increase enables therapeutic FSH concentrations to be reached.

The absolute bioavailability of subcutaneously administered Fertavid is 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

Benzyl alcohol

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.

Once the rubber inlay of a cartridge is pierced by a needle, the product may be stored for a maximumof 28 days.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the cartridge 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.

Fertavid 150 IU/0.18 mL solution for injection0.18 mL of solution in 1.5 mL cartridge (type I glass) with a grey rubber piston and an aluminiumcrimp-cap with a rubber inlay.

Pack of 1 cartridge and 3 needles to be used with the Puregon Pen.

Cartridges contain a minimum of 225 IU FSH activity in 0.270 mL aqueous solution, which issufficient for a net total dose of 150 IU.

Fertavid 300 IU/0.36 mL solution for injection0.36 mL of solution in 1.5 mL cartridge (type I glass) with a grey rubber piston and an aluminiumcrimp-cap with a rubber inlay.

Pack of 1 cartridge and 6 needles to be used with the Puregon Pen.

Cartridges contain a minimum of 400 IU FSH activity in 0.480 mL aqueous solution, which issufficient for a net total dose of 300 IU.

Fertavid 600 IU/0.72 mL solution for injection0.72 mL of solution in 1.5 mL cartridge (type I glass) with a grey rubber piston and an aluminiumcrimp-cap with a rubber inlay.

Pack of 1 cartridge and 6 needles to be used with the Puregon Pen.

Cartridges contain a minimum of 700 IU FSH activity in 0.840 mL aqueous solution, which issufficient for a net total dose of 600 IU.

Fertavid 900 IU/1.08 mL solution for injection1.08 mL of solution in 1.5 mL cartridge (type I glass) with a grey rubber piston and an aluminiumcrimp-cap with a rubber inlay.

Pack of 1 cartridge and 9 needles to be used with the Puregon Pen.

Cartridges contain a minimum of 1,025 IU FSH activity in 1.230 mL aqueous solution, which issufficient for a net total dose of 900 IU.

Do not use if the solution contains particles or if the solution is not clear.

Fertavid solution for injection is designed for use in conjunction with a pen injector called Puregon

Pen. The instructions for using the pen must be followed carefully.

Air bubbles must be removed from the cartridge before injection (see instructions for using the pen).

Empty cartridges must not be refilled.

Fertavid cartridges are not designed to allow any other drug to be mixed in the cartridges.

Discard used needles immediately after injection.

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 150 IU/0.18 mL solution for injection

EU/1/09/510/016

Fertavid 300 IU/0.36 mL solution for injection

EU/1/09/510/017

Fertavid 600 IU/0.72 mL solution for injection

EU/1/09/510/018

Fertavid 900 IU/1.08 mL solution for injection

EU/1/09/510/019

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.