3.       PHARMACEUTICAL FORM

Solution for injection in pre-filled pen. ('a' has been removed - in a pre-filled pen).

4.2     Posology and method of administration
Method of Administration

For instructions on the administration with the pre-filled pen, see section 6.6 and the “Instructions for Use”.  (package leaflet has been replaced with Instructions).

4.4     Special warnings and precautions for use
          Thromboembolic Events

In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurrence of such events. In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted however that pregnancy itself as well as OHSS also carry an increased risk of thromboembolic events. (the - has been removed from the words 'thromboembolic').

4.8     Undesirable effects

Mild or moderate ovarian hyperstimulation syndrome (OHSS) has been commonly reported and should be considered as
 an intrinsic risk of the stimulation procedure. Severe OHSS is uncommon (see section 4.4). ('have' has been replaced with 'has' [has been commonly reported].

6.5     Nature and contents of container

Pack of one pre-filled pen and 12 needles to be used with the pen for administration. (7 needles changed to 12 needles).

6.6     Special precautions for disposal and other handling

See the “Instructions for Use”. (this sentence replaces "How to use the GONAL-f pre-filled pen" in the package leaflet.

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of last renewal: 20 October 2010. (2010 replaces 2005).

Serono Europe Ltd.

56 Marsh Wall

London E14 9TP

United Kingdom

Merck Serono Europe Ltd.

56 Marsh Wall

London E14 9TP

United Kingdom

4.2     Posology and method of administration

It is advised to adhere to the recommended starting doses indicated below.

Comparative clinical studies have shown that on average patients require a lower cumulative dosage and shorter treatment duration with GONAL-f compared with urinary FSH. Therefore, it is considered appropriate to give a lower total dosage of GONAL-f 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.

5.1     Pharmacodynamic properties

In clinical studies comparing r-hFSH (follitropin alfa) and urinary FSH in assisted reproduction technologies (see table below) and in ovulation induction, GONAL-f was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation.

In assisted reproduction technologies, GONAL-f at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved  when compared to urinary FSH.

Table: Results of study GF 8407 (randomised parallel group study comparing  efficacy and safety of Gonal-f with u-FSH in assisted reproduction technologies)

Differences between the 2 groups were statistically significant (p<0.05) for all criteria listed.

Changes to Section 6.4 Special precautions for storage (see highlighted):

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

Within its shelf life, the product may be stored at or below 25°C for up to  3 months without being refrigerated again and must be discarded if it has not been used after 3 months. Store in the original package in order to protect from light.

For in-use storage conditions, see section 6.3.

Section 2 Qualitative and Quantitative Composition: Text amended to include: ‘Excipients: 45 mg sucrose, 0.8325 mg disodium phosphate dihydrate, 0.3375 mg sodium dihydrogen phosphate monohydrate, 0.075 mg methionine, 2.25 mg m-cresol, 0.075 mg poloxamer 188.

‘For a full list of excipients, see section 6.1.’

Section 3 Pharmaceutical Form: pH added.

Section 4.4 Special warnings and precautions for use: The following warnings have been added:

‘Patients with porphyria or a family history of porphyria should be closely monitored during treatment with GONAL-f. Deterioration or a first appearance of this condition may require cessation of treatment.’

‘GONAL-f contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.’

‘Very rarely, severe OHSS may be complicated by pulmonary embolism, ischemic stroke and myocardial infarction.’

Section 4.8 Undesirable Effects: The listing of adverse events reported is updated presented by body systems. Adverse events added include:

Treatment in women

Very rare:

Immune system disorders: Urticaria, oedema, difficulty breathing. Serious cases of allergic reactions including anaphylactic reactions have also been reported.

Respiratory, thoracic and mediastinal disorders: exacerbation or worsening of asthma.

Treatment in men

Common:

Reproductive system and breast disorders: Varicocele

Very common:

General disorders and administration site conditions: Mild to severe injection site reaction (pain, redness, bruising, swelling and/or irritation at the site of injection)

The following paragraph has been added ‘Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.’

Section 5.3 Preclinical safety data: The first paragraph has been deleted and replaced with ‘Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity additional to that already stated in other sections of the SPC.’

Section 6.3 Shelf life: The last sentence ‘After first use: 28 days (within the 2 year shelf-life) has been amended to ‘After first use: 28 days (within the shelf-life)’.

Section 6.5 Nature and contents of container:  The first sentence has been amended as follows: 1.5 ml of solution for injection in 3 ml cartridge (Type I glass), with a plunger stopper (halobutyl rubber) and an aluminium crimp cap with a black rubber inlay.

Section 9 Date of First Authorisation / Renewal of Authorisation: Date of renewal has been added.

Section 10 Date of Revision of the Text: Amended to July 2006.