Merck Sharp & Dohme Limited

Please see below for a summary of the changes to the SmPC (all textual changes and additions in red):

·          Section 4.1

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

·          Section 4.2

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).

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

·          Section 4.3

Addition of the following sub-headings, "For males and females", "Additionally for females", and an extra bullet point for "Primary gonadal failure".

Update to two bullet points to include, "syndrome (PCOS)" and "reproductive"

·          Section 4.4

Addition of new bullet point, "Puregon may contain traces of streptomycin and/or neomycin. These antibiotics may cause hypersensitivity reactions in susceptible persons".

Two subheadings, "In females" and "In males".

New bullet point under "In females" subheading,

"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."

·          Section 4.6

Addition of three subheadings, "Fertility", "Pregnancy" and "Lactation"

Following statement under 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."

Following statement under 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."

·          Section 4.8

Update to include formatting of adverse reactions into two tables (female and male) listed in line with system organ class and frequency.

Following statement under the female table of adverse events, "In addition, ectopic pregnancy, miscarriage and multiple gestations have been reported. These are considered to be related to the ART procedure or subsequent pregnancy."

·          Section 5.1

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.

·          Section 10

Update to date of revision of text

In comparative clinical studies with Puregon and urinary FSH it was shown that Puregon is more effective than urinary FSH in terms of a lower total dose and a shorter treatment period needed to achieve pre-ovulatory conditions. Therefore, it is considered appropriate to give a lower dosage of Puregon than generally used for urinary FSH, not only in order to optimise follicular development but also to minimise the risk of unwanted ovarian hyperstimulation.

to:

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

Section 10 - updated date of revision of text

1.       NAME OF THE MEDICINAL PRODUCT

Reference to 150IU and 200IU have been removed as both strengths have been withdrawn

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

Reference to 150IU and 200IU have been removed as both strengths have been withdrawn

The word ‘activity’ has been removed after (FSH) on first line of each paragraph

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.

4.4          Special warnings and precautions for use

The text in bold has been added:

·                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.

4.8     Undesirable effects

The text in bold has been added – the text with strikethrough has been removed:

Clinical use of Puregon by the intramuscular or subcutaneous routes may lead to local reactions at the site of injection:such as bruising, pain, redness, swelling and itching are commonly reported (3% of all patients treated). The majority of these local reactions  which are mild and transient in nature. Very rarely 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 3% 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.

6.5     Nature and contents of container

Strikethrough text has been removed:

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

Pack of 1, or 5 or 10.

Not all pack sizes may be marketed.

8.       MARKETING AUTHORISATION NUMBERS

Reference to 150IU and 200IU have been removed as both strengths have been withdrawn

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)

10.     DATE OF REVISION OF THE TEXT

Date amended to January 2007