Merck Sharp & Dohme Limited

• Editorial changes replacing the words "trials" and "patients" with "studies" and "women", and the inclusion of the word "medicinal" in front of "product"
• The following updates to section 4.2 (Posology and method of administration), including two new sub headings, "Timing of last injection" and "Paediatric population". A statement confirming the use of Orgalutran is contraindicated in patients with moderate and severe renal or hepatic impairment
• Editorial change of text from "lactation" to "breast-feeding" in section 4.3 (Contraindications)
• The addition of a statement confirming that Orgalutran is "essentially sodium-free", in section 4.4 (Special warnings and precautions for use).
• An update to section 4.6 (Fertility, pregnancy and lactation), that includes formatting changes and the addition of three new sub headings, "Fertility", "Pregnancy" and "Breast-feeding". The following new paragraph under the sub heading, “Fertility" has been added, "Ganirelix is used in the treatment of women undergoing controlled ovarian hyperstimulation in assisted reproduction programmes.  Ganirelix is used to prevent premature LH surges that might otherwise occur in these women during ovarian stimulation"
• Section 4.8 (Undesirable effects) has been reformatted according to the MedDRA system organ class and frequency.  There is no change in the adverse effects.
• The following statement has been added to section 4.9 (Overdose), "In case of overdose, Orgalutran treatment should be (temporarily) discontinued"
• The pharmacotherapeutic group definition now includes "Pituitary and hypothalamic hormones and analogues" in section 5.1 (Pharmacodynamic properties).

Change details

Section 4.2 Posology and method of administration

Change of text under the Posology heading:

• Starting on day 6 of FSH administration  changed to starting on day 5 or day 6 of FSH administration depending on the ovarian response, i.e. the number and size of growing follicles and/or the amount of circulating oestradiol.
• The start of Orgalutran may be delayed in absence of follicular growth, although clinical experience is based on starting Orgalutran on day 6 of FSH changed to The start of Orgalutran may be delayed in absence of follicular growth, although clinical experience is based on starting Orgalutran on day 5 or day 6 of FSH

Section 4.8 Undesirable effects

Addition of following text:

“From clinical studies involving 1589 patients who started Orgalutran treatment on day 6, the following undesirable effects and their incidences became apparent.”

Section 5.1           Pharmacodynamic properties

Addition of text:

.         “In case of a high ovarian response, either as a result of a high FSH exposure in the early follicular phase or as a result of high ovarian responsiveness, premature LH rises may occur earlier than day 6 of stimulation. Initiation of Orgalutran treatment on day 5 can prevent these premature LH rises without compromising the clinical outcome.”

Removal of text:

“Early LH rises, prior to the start of Orgalutran at day 6 of stimulation, did occur especially in high responders, but did not affect the clinical outcome. In these patients LH production was rapidly suppressed after the first Orgalutran administration”

4.4 Special warnings and precautions for use

Addition of text:

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.

10. Date of revision of the text

January 2008

Text in bold has been added

Strikethrough text has been removed

2.          QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled syringe contains 0.25 mg of ganirelix in 0.5 ml aqueous solution. Orgalutran contains the The active substance ganirelix (INN) is a synthetic decapeptide ganirelix (INN) with high antagonistic activity to the naturally occurring gonadotrophin releasing hormone (GnRH). The amino acids at positions 1, 2, 3, 6, 8 and 10 of the natural GnRH decapeptide have been substituted resulting in N-Ac-D-Nal(2)¹, D-
-pClPhe², D-Pal(3)³, D-hArg(Et2)⁶, L-hArg(Et2)⁸, D-Ala¹⁰]-GnRH with a molecular weight of 1570.4.

Each pre filled syringe of Orgalutran contains the active substance ganirelix, 0.25 mg in a 0.5 ml aqueous solution.

For a full list of excipients, see section 6.1.

3.          PHARMACEUTICAL form

Solution for injection.

The aqueous solution contained within the syringe is clear and colourless Clear and colourless aqueous solution.

4.2        Posology and method of administration

Orgalutran should only be prescribed by a specialist experienced in the treatment of infertility.

Posology

Orgalutran is used to prevent premature LH surges in patients undergoing COH. Controlled ovarian hyperstimulation with FSH may start at day 2 or 3 of menses. Orgalutran (0.25 mg) should be injected subcutaneously once daily, starting on day 6 of FSH administration. The start of Orgalutran may be delayed in absence of follicular growth, although clinical experience is based on starting Orgalutran on day 6 of FSH. Orgalutran and FSH should be administered approximately at the same time. However, the preparations should not be mixed and different injection sites are to be used.
FSH dose adjustments should be based on the number and size of growing follicles, rather than on the amount of circulating oestradiol (see Ssection 5.1 Pharmacocynamic Properties). Daily treatment with Orgalutran should be continued up to the day that sufficient follicles of adequate size are present. Final maturation of follicles can be induced by administering human chorionic gonadotrophin (hCG). Because of the half-life of ganirelix, the time between two Orgalutran injections as well as the time between the last Orgalutran injection and the hCG injection should not exceed 30 hrs, as otherwise a premature LH surge may occur. Therefore, when injecting Orgalutran in the morning, treatment with Orgalutran should be continued throughout the gonadotrophin treatment period including the day of triggering ovulation. When injecting Orgalutran in the afternoon the last Orgalutran injection should be given in the afternoon prior to the day of triggering ovulation.

Orgalutran has shown to be safe and effective in patients undergoing multiple treatment cycles.

The need for luteal phase support in cycles using Orgalutran has not been studied. In clinical trials, luteal phase support was given according to study centres’ practice.

Subjects with renal or hepatic impairment: There is no experience of the use of Orgalutran in subjects with renal or hepatic impairement. Therefore, specific dose recommendations cannot be given (see section 4.3 Contraindications).

Method of administration

Orgalutran should be administered subcutaneously, preferably in the upper leg. The injection site should be varied to prevent lipoatrophy. The patient or her partner may perform the injections of Orgalutran themselves, provided that they are adequately instructed and have access to expert advice.

4.4        Special warnings and precautions for use

Special care should be taken in women with signs and symptoms of active allergic conditions. In the absence of clinical experience, Orgalutran treatment is not advised in women with severe allergic conditions.

Ovarian hyperstimulation syndrome (OHSS) may occur during or following ovarian stimulation. OHSS must be considered an intrinsic risk of gonadotrophin stimulation. OHSS should be treated symptomatically, e.g. with rest, intravenous infusion of electrolyte solutions or colloids and heparin.

The incidence of congenital malformations after Assisted Reproductive Technologies (ART) may be higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and an increased incidence of multiple gestations. In clinical trials investigating more than 1000 newborns it has been demonstrated that the incidence of congenital malformations in children born after COH treatment using Orgalutran is comparable with that reported after COH treatment using a GnRH agonist.

The safety and efficacy of Orgalutran have not been established in women weighing less than 50 kg or more than 90 kg (see also section 5.1 Pharmacodynamic properties and section 5.2 Pharmacokinetic properties).

4.5        Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Interactions of Orgalutran with other medicines have not been investigated.

The possibility of interactions with commonly used medicinal products, including histamine liberating products, cannot be excluded.

4.6        Pregnancy and lactation

There are no adequate data from the use of ganirelix in pregnant women.

No clinical data on exposed pregnancies are available.  See also section 4.4, Special earnings and special precautions for use.  In animals, exposure to ganirelix at the time of implantation resulted in litter resorption (see section 5.3 Preclinical safety data). The relevance of these data for humans is unknown.

It is not known whether ganirelix is excreted in breast milk.

The use of Orgalutran is contraindicated during pregnancy and lactation (see section 4.3).

4.8        Undesirable effects

General disorders and administration site conditions

Orgalutran may cause a local skin reaction at the site of injection (predominantly redness, with or without swelling). In clinical studies, one hour after injection, the incidence of at least once a moderate or severe local skin reaction per treatment cycle, as reported by patients, was 12% in Orgalutran treated patients and 25% in patients treated subcutaneously with a GnRH agonist. The local reactions generally disappear within 4 hours after administration. Adverse reactions for Orgalutran are all uncommon (<1%).  The incidences as reported in clinical trials are: nausea (0.5%), headache (0.4%) and malaise (0.3%).   Malaise was reported in 0.3% of patients.

Immune system disorders

Very rarely cases of hypersensitivity reactions including various symptoms such as rash, facial swelling and dyspnoea have been reported among patients administered Orgalutran with FSH. Worsening of a pre-existing eczema has been reported in one subject after the first Orgalutran dose.

Nervous system disorders

Headache (0.4%).

Gastrointestinal disorders

Nausea (0.5%).

Other reported undesirable effects are related to the controlled ovarian hyperstimulation treatment for ART, notably pelvic pain, abdominal distension, OHSS (Ssee also section 4.4 Special warnings and precautions for use of this SPC), ectopic pregnancy and spontaneous abortion.

6.1        List of excipients

Acetic acid,;

mMannitol and;

water Water for injections.

The pH may have been adjusted with sodium hydroxide and acetic acid.

6.2        Incompatibilities

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

6.5        Nature and contents of container

Orgalutran is presented as a sterile, ready to use, aqueous solution and supplied in dDisposable pre-filled syringes (siliconised Type I glass), containing 0.5 ml of sterile, ready for use, aqueous solution closed with a rubber piston. Each pre-filled syringe is affixed with a needle closed by a needle shield of natural rubber.

Supplied in cartons containing 1 or 5 pre-filled syringes.

Not all pack sizes may be marketed

10.        DATE OF REVISION OF THE TEXT

June 2007