Puregon 50 IU / 0.5 ml Solution for injection, Puregon 100 IU / 0.5 ml Solution for injection

1. Name Of The Medicinal Product

Puregon 50 IU/0.5 ml solution for injection

Puregon 100 IU/0.5 ml solution for injection

2. Qualitative And Quantitative Composition

Puregon 50 IU/0.5ml 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 (specific in vivo bioactivity equal to approximately 10 000 IU FSH / mg protein). The solution for injection contains the active substance follitropin beta, produced by genetic engineering of a Chinese hamster ovary (CHO) cell line.

Puregon 100 IU/0.5ml solution for injection

One vial contains 100 IU recombinant follicle-stimulating hormone (FSH) in 0.5ml aqueous solution. This corresponds to a strength of 200 IU/ml. One vial contains 10 microgram of protein (specific in vivo bioactivity equal to approximately 10 000 IU FSH / mg protein). The solution for injection contains the active substance follitropin beta, produced by genetic engineering of a Chinese hamster ovary (CHO) cell line.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection (injection).

Clear and colourless solution.

4. Clinical Particulars

4.1 Therapeutic Indications

In the female:

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

• Anovulation (including polycystic ovarian disease, PCOD) 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.

4.2 Posology And Method Of Administration

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

Posology

Dosage in the female

There are great inter- and intra-individual variations in the response of the ovaries to exogenous gonadotrophins. This makes it impossible to set a uniform dosage scheme. The dosage should, therefore, be adjusted individually depending on the ovarian response. This requires ultrasonography and monitoring of oestradiol levels.

Based on the results of comparative clinical studies it is considered appropriate to give a lower dosage of Puregonthan generally used for urinary FSH, not only in order to optimise follicular development but also to minimise the risk of unwanted ovarian hyperstimulation.

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 in order to prevent multiple gestations.

• Controlled ovarian hyperstimulation in medically assisted reproduction programs

Various stimulation protocols are applied. A starting dose of 100-225 IU is recommended for at least the first four days. Thereafter, the dose may be adjusted individually, based upon ovarian response. In clinical studies it was shown that maintenance dosages ranging from 75-375 IU for six to twelve days are sufficient, although longer treatment may be necessary.

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 evaluation indicates the presence of at least three follicles of 16-20 mm, and there is evidence of a good oestradiol response (plasma levels of about 300-400 picograms/ml (1000-1300 pmol/l) for each follicle with a diameter greater than 18 mm), the final phase of maturation of the follicles is induced by administration of hCG. Oocyte retrieval is performed 34-35 hours later.

Dosage in the male

Puregon should be given at a dosage of 450 IU/week, preferably divided in 3 dosages of 150 IU, concomitantly with hCG. The treatment should be continued for at least 3 to 4 months before any improvement in spermatogenesis can be expected. 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

To prevent painful injections and minimise leakage from the injection site Puregon should be slowly administered intramuscularly or subcutaneously. The subcutaneous injection site should be alternated to prevent lipoatrophy. Any unused solution should be discarded.

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

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients.

• Tumours of the ovary, breast, uterus, testis, pituitary or hypothalamus.

• Undiagnosed vaginal bleeding.

• Primary ovarian failure.

• Ovarian cysts or enlarged ovaries, not related to polycystic ovarian disease (PCOD).

• Malformations of the sexual organs incompatible with pregnancy.

• Fibroid tumours of the uterus incompatible with pregnancy.

• Primary testicular failure.

4.4 Special Warnings And Precautions For Use

• The presence of uncontrolled non-gonadal endocrinopathies (e.g. thyroid, adrenal or pituitary disorders) should be excluded.

• 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.

• The first injection of Puregon should be performed under direct medical supervision.

• 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 association with ovarian hyperstimulation syndrome. In rare cases severe ovarian hyperstimulation syndrome occurs, which may be life-threatening. This is characterised by large ovarian cysts (prone to rupture), ascites, often hydrothorax and weight gain. In rare instances, venous or arterial thromboembolism may occur in association with OHSS.

• 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.

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

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

• In men, semen analysis is recommended 4 to 6 months after the beginning of treatment in assessing the response.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

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.

4.6 Pregnancy And Lactation

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.

Puregon should not be used during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

Clinical use of Puregon by the intramuscular or subcutaneous routes may lead to local reactions at the site of injection: bruising, pain, redness, swelling and itching are commonly reported (3% of all patients treated).The majority of these local reactions are mild and transient in nature. Generalised hypersensitivity reactions including erythema, urticaria, rash and pruritus have been observed uncommonly (approximately 0.1% of all patients treated with Puregon).

Treatment of women:

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). Other undesirable effects related to this syndrome were observed in clinical studies. These include pelvic pain and/or congestion, abdominal pain and/or distension, breast complaints (breast tenderness, pain and/or engorgement), ovarian enlargement, and spontaneous abortion. They were all reported at an incidence of approximately 1% (pelvic pain and abdominal distension) or less.

A slightly increased risk of ectopic pregnancy and multiple gestations has been seen.

Other more general symptoms that have been reported include headache and nausea (in up to 1% of the women treated with Puregon)

In rare instances, thromboembolism has been associated with Puregon/hCG therapy as with other gonadotrophins.

Treatment of men:

Gynaecomastia and acne may occur occasionally during Puregon/hCG therapy. These are known effects of hCG treatment.

4.9 Overdose

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).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: 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 men deficient in FSH, Puregon should be used concomitantly with hCG for at least four months to promote spermatogenesis.

5.2 Pharmacokinetic Properties

After intramuscular or subcutaneous administration of Puregon, maximum concentrations of FSH are reached within about 12 hours. After intramuscular administration of Puregon, the maximum FSH concentrations are higher and reached earlier in men as compared to women. Due to the sustained release from the injection site and the elimination half-life of about 40 hours (ranging from 12 to 70 hours), FSH levels remain increased for 24-48 hours. Due to the relatively long elimination half-life, repeated administration of the same dose will lead to plasma concentrations of FSH that are approximately 1.5-2.5 times higher than after single dose administration. This increase enables therapeutic FSH concentrations to be reached.

There are no significant pharmacokinetic differences between intramuscular and subcutaneous administration of Puregon. Both have an absolute bioavailability of approximately 77%. Recombinant FSH is biochemically very similar to urinary human FSH and is distributed, metabolised, and excreted in the same way.

5.3 Preclinical Safety Data

Single-dose administration of 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.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Puregon solution for injection contains:

sucrose

sodium citrate

L

polysorbate 20

water for injections.

The pH may have been adjusted with sodium hydroxide and/or hydrochloric acid.

6.2 Incompatibilities

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

6.3 Shelf Life

3 years.

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

6.4 Special Precautions For Storage

Store in a refrigerator (2 °C – 8 °C).

Do not freeze.

Keep the vial(s) in the outer carton.

For patient convenience, Puregon may be stored at or below 25 ºC by the patient for a single period of not more than 3 months.

6.5 Nature And Contents Of Container

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

Pack of 1, 5 or 10.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

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

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

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

N.V. Organon,

Kloosterstraat 6,

Postbus 20,

5340 BH Oss,

The Netherlands

8. Marketing Authorisation Number(S)

EU/1/96/008/17 (Puregon 50 IU/0.5 ml solution for injection)

EU/1/96/008/23 (Puregon 100 IU/0.5 ml solution for injection)

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 3 May 1996

Date of last renewal: 29 May 2006

10. Date Of Revision Of The Text

23 November 2009

11. LEGAL CATEGORY

Prescription Only Medicine

Puregon Solution/12-09/2

RA 2535 UK S8 (ref 3.1)