In adult females:

Puregon 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 adult males:

·            Deficient spermatogenesis due to hypogonadotrophic hypogonadism.

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

The first injection with Puregon 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 ultrasound assessment of follicular development. The concurrent determination of serum oestradiol levels may also be useful.

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

Based on the results of comparative clinical studies, it is considered appropriate to give a lower total dosage of Puregon over a shorter treatment period than generally used for urinary FSH, not only in order to optimise follicular development but also to reduce the risk of unwanted ovarian hyperstimulation (see section 5.1).

Clinical experience with Puregon 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 Puregon. 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 (1,000-3,000 pmol/L) are attained. Usually, 7 to 14 days of treatment is sufficient to reach this state. The administration of Puregon 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 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.

Puregon 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 Puregon may be required to achieve an adequate follicular response.

Ovarian response is monitored by ultrasound assessment. The concurrent determination of serum oestradiol levels may also be useful. When ultrasound assessment 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 (1,000-1,300 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

Puregon should be given at a dosage of 450 IU/week, preferably divided in 3 dosages of 150 IU, concomitantly with hCG. Treatment with Puregon and hCG should be continued for at least 3 to

3  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.

Paediatric population

There is no relevant use of Puregon in the paediatric population for the approved indication. Method of administration

Puregon solution for injection in cartridges has been developed for use in the Puregon Pen and should be administered subcutaneously. The injection site should be alternated to prevent lipoatrophy.

Using the pen, injection of Puregon can be carried out by the patient, provided that proper instructions are given by the physician.

Antibiotic hypersensitivity reactions

·            Puregon may contain traces of streptomycin and/or neomycin. These antibiotics may cause hypersensitivity reactions in susceptible persons.

Infertility evaluation before starting treatment

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

In females

Ovarian Hyperstimulation Syndrome (OHSS)

OHSS is a medical event distinct from uncomplicated ovarian enlargement. Clinical signs and symptoms of mild and moderate OHSS are abdominal pain, nausea, diarrhoea, mild to moderate enlargement of ovaries and ovarian cysts. Severe OHSS may be life-threatening. Clinical signs and symptoms 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 function test abnormalities suggestive of hepatic dysfunction with or without morphologic changes on liver biopsy 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 be associated with an excessive ovarian response to gonadotropin stimulation. Late OHSS occurs more than 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 after hCG administration.

Women with known risk factors for a high ovarian response may be especially prone to the development of OHSS during or following treatment with Puregeon. For women having their first cycle of ovarian stimulation, for whom risk factors are only partially known, close observation for early signs and symptoms of OHSS is recommended.

To reduce the risk of OHSS, ultrasonographic assessments of follicular development should be performed prior to treatment and at regular intervals during treatment. The concurrent determination of serum oestradiol levels may also be useful. In ART there is an increased risk of OHSS with 18 or more follicles of 11 mm or more in diameter. When there are 30 or more follicles in total it is advised to withhold hCG administration.

Depending on the ovarian response, the following measurements can be considered to reduce OHSS:

-        withhold further stimulation with a gonadotropin for a maximum of 3 days (coasting);

-        withhold hCG and cancel the treatment cycle;

-        administer a dose lower than 10,000 IU of urinary hCG for triggering final oocyte maturation, e.g. 5,000 IU urinary hCG or 250 micrograms rec-hCG (which is equivalent to approximately 6,500 IU of urinary hCG);

-        cancel the fresh embryo transfer and cryopreserve embryos;

-        avoid administration of hCG for luteal phase support.

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

Multiple Pregnancy

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

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

Ectopic Pregnancy

Infertile women undergoing ART have an increased incidence of ectopic pregnancies. Early ultrasound 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 the normal population.

Vascular Complications

Thromboembolic events, both in association with and separate from OHSS, have been reported following treatment with gonadotropins, including Puregon. Intravascular thrombosis, which may originate in venous or arterial vessels, can result in reduced blood flow to vital organs or the extremities. In women with generally recognised risk factors for thromboembolic events, such as a personal or family history, severe obesity or thrombophilia, treatment with gonadotropins, including Puregon, may further increase this risk. In these women the benefits of gonadotropin administration, including Puregon, need to be weighed against the risks. It should be noted, however, that pregnancy itself also carries an increased risk of thrombosis.

Congenital Malformations

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

Ovarian Torsion

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

Ovarian and Other Reproductive System Neoplasms

There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is

not established whether or not treatment with gonadotrophins increases the risk of these tumours in infertile women.

Other Medical Conditions

Medical conditions that contraindicate pregnancy should also be evaluated before starting treatment with Puregon.

In males

Primary Testicular Failure

Elevated endogeneous FSH levels in men are indicative of primary testicular failure. Such patients are unresponsive to Puregon/hCG therapy.

Concomitant use of Puregon and clomifene citrate may enhance the follicular response. After pituitary desensitisation induced by a GnRH agonist, a higher dose of Puregon may be necessary to achieve an adequate follicular response.

Fertility

Puregon is used in the treatment of women undergoing ovarian induction or controlled ovarian hyperstimulation in assisted reproduction programmes. In males Puregon is used in the treatment of deficient spermatogenesis due to hypogonadotrophic hypogonadism. For posology and method of administration, see section 4.2.

Pregnancy

The use of Puregon during pregnancy is not indicated. In case of inadvertent 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.

Breast-feeding

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.

Puregon has no or negligible influence on the ability to drive and use machines.

Clinical use of Puregon 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 follitropin beta).

Treatment of females:

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

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 reaction include erythema, urticaria, rash and pruritus

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

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

1.       Adverse reactions that are reported only once are listed as common because a single report raises the frequency above 1%.

2.       Local reactions at the site of injection include induration and pain.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via :

·       Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC). SFDA

o Fax: +966-11-205-7662

o Call NPC at +966-11-20382222, Exts: 2317-2356-2353-2354-2334-2340.

o Toll free phone: 8002490000

o E-mail: npc.drug@sfda.gov.sa

o Website: www.sfda.gov.sa/npc

·       Other GCC States:

Please contact the relevant competent authority.

No data on acute toxicity of Puregon in humans is available, but the acute toxicity of Puregon 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).

1.1       Pharmacodynamic properties

Pharmacotherapeutic group: sex hormones and modulators of the genital system, gonadotrophins; ATC code: G03G A06.

Puregon 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.

Mechanism of Action

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. Puregon can thus be used to stimulate follicular development and steroid production in selected cases of disturbed gonadal function. Furthermore Puregon 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 Puregon is generally 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 ovarian stimulation in women participating in an assisted reproduction technology (ART) program and for ovulation induction (see tables 1 and 2 below), Puregon 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, Puregon 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 37,608 (randomized, group comparative clinical study comparing safety and efficacy of Puregon with urinary FSH in controlled ovarian stimulation).

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

For ovulation induction, Puregon resulted in a lower median total dose and shorter median duration of treatment when compared to urinary FSH.

Table 2: Results of study 37,609 (randomized, group comparative clinical study comparing safety and efficacy of Puregon with urinary FSH in ovulation induction).

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

a

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

Absorption

After subcutaneous administration of Puregon, maximum concentration of FSH is reached within about 12 hours. 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.

The absolute bioavailability of subcutaneously administered Puregon 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 Puregon 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, Puregon induced no toxicologically significant effects. Puregon showed no mutagenic potential in the Ames test and in the in vitro chromosome aberration test with human lymphocytes.

Puregon solution for injection contains: Sucrose

Sodium citrate L-methionine Polysorbate 20 Benzyl alcohol

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 other medicinal products.

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

Keep the cartridge in the outer carton.

For patient convenience, Puregon may be stored at or below 30ºC by the patient for a single period of not more than 3 months.

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

Puregon 300 IU/0.36 ml solution for injection

0.36 mL of solution in 1.5 ml cartridge (type I glass) with a grey rubber piston and an aluminium crimp-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 is sufficient for a net total dose of 300 IU.

Puregon 600 IU/0.72 ml solution for injection

0.72 mL of solution in 1.5 mL cartridge (type I glass) with a grey rubber piston and an aluminium crimp-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 is sufficient for a net total dose of 600 IU.

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

Puregon solution for injection is designed for use in conjunction with the 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.

Puregon 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 local requirements.