Puregon 300 IU/0.36 ml solution for injection

Puregon 600 IU/0.72 ml solution for injection

Puregon 900 IU/1.08 ml solution for injection

One cartridge contains a net total dose of 300 IU recombinant follicle-stimulating hormone (FSH) in 0.36 ml aqueous solution, 600IU recombinant follicle-stimulating hormone (FSH) in 0.72ml aqueous solution or 900IU recombinant follicle-stimulating hormone (FSH) in 1.08ml 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 of 833 IU/ml aqueous solution. This strength corresponds to 83.3 microgram of protein / ml (specific in vivo bioactivity equal to approximately 10 000 IU FSH / mg protein).

For a 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 the female:

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 the male:

• 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 ultrasonography and monitoring of oestradiol levels.

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 minimise 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 (1000-3000 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 ultrasonography and measurement of plasma oestradiol levels. When ultrasonographic eva luation 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 retrieva l 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 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 Puregon in children.

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.

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.

• Puregon 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 Puregon 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 associated 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 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 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

There is no indication for use of Puregon 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.

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 Puregon).

Treatment of females:

In approximately 4% of the women treated with Puregon 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.

The table below lists the adverse reactions with Puregon 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 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 Puregon/hCG therapy as with other gonadotrophins.

Treatment of males:

The table below lists the adverse reactions with Puregon 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.

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).

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.

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.

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).

* 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).

* 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 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%. 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 300 IU/0.36 ml, Puregon 600IU/0.72ml and Puregon 900IU/1.08ml solution for injection contains:

sucrose

sodium citrate

Lmethionine

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.

3 years.

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

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 25 ºC by the patient for a single period of not more than 3 months.

Puregon 300IU/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 600IU/0.72 ml of solution in 1.5ml 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.

Puregon 900IU/1.08 ml of solution in 1.5ml cartridge (type I glass) with a grey rubber piston and an aluminium crimp-cap with a rubber inlay.

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

Cartridges contain a minimum of 1025 IU FSH activity in 1.230 ml aqueous solution, which is sufficient for a net total dose of 900 IU.

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

Puregon 300 IU/0.36 ml, 600 IU/0.72 ml and 900 IU/1.08ml 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 product or waste material should be disposed of in accordance with local requirements.

N.V. Organon

Kloosterstraat 6

Postbus 20

5340 BH Oss

The Netherlands

EU/1/96/008/038 (Puregon 300 IU/0.36 ml solution for injection)

EU/1/96/008/039 (Puregon 600 IU/0.72 ml solution for injection)

EU/1/96/008/041 (Puregon 900 IU/1.08ml solution for injection)

Date of first authorisation: 3 May 1996

Date of last renewal: 29 May 2006

29 November 2010

Prescription Only Medicine

Puregon PEN/01-11/3

RA 2535 EU S9 (Ref 4.0)