Organon Laboratories Limited

Orgalutran 0.25 mg/0.5 ml solution for injection

Each pre-filled syringe contains 0.25 mg of ganirelix in 0.5 ml aqueous solution. The active substance ganirelix (INN) is a synthetic decapeptide 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.

For a full list of excipients, see section 6.1.

Solution for injection.

Clear and colourless aqueous solution.

The prevention of premature luteinising hormone (LH) surges in women undergoing controlled ovarian hyperstimulation (COH) for assisted reproduction techniques (ART).

In clinical studies Orgalutran was used with recombinant human follicle stimulating hormone (FSH) or corifollitropin alfa, the sustained follicle stimulant.

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

Posology

Orgalutran is used to prevent premature LH surges in women undergoing COH. Controlled ovarian hyperstimulation with FSH or corifollitropin alfa may start at day 2 or 3 of menses. Orgalutran (0.25 mg) should be injected subcutaneously once daily, starting on day 5 or day 6 of FSH administration or on day 5 or day 6 following the administration of or corifollitropin alfa. The starting day of Orgalutran is 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 5 or day 6 of stimulation.

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 section 5.1).

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).

Timing of last injection

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 hours, 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 women undergoing multiple treatment cycles.

The need for luteal phase support in cycles using Orgalutran has not been studied. In clinical studies, luteal phase support was given according to study centres' practice or according to the clinical protocol.

Paediatric population

There is no relevant use of Orgalutran in the paediatric population.

Renal and hepatic impairment

There is no experience on the use of Orgalutran in subjects with renal or hepatic impairment, as they were excluded from clinical studies. Therefore, the use of Orgalutran is contraindicated in patients with moderate or severe renal or hepatic impairment. (see section 4.3).

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.

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

− Hypersensitivity to gonadotrophin-releasing hormone (GnRH) or any other GnRH analogue.

− Moderate or severe impairment of renal or hepatic function.

− Pregnancy or breast-feeding.

− 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.

− Since infertile women undergoing assisted reproduction, and particularly in vitro fertilisation (IVF), often have tubal abnormalities the incidence of ectopic pregnancies might be increased. Early ultrasound confirmation that a pregnancy is intrauterine is therefore important.

− 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 studies 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 and 5.2).

− This medicinal product contains less than 1 mmol sodium (23 mg) per injection, i.e. essentially 'sodium-free'.

No interaction studies have been performed.

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

Fertility

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 the ovarian stimulation.

For posology and method of administration, see section 4.2.

Pregnancy

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

In animals, exposure to ganirelix at the time of implantation resulted in litter resorption (see section 5.3). The relevance of these data for humans is unknown.

Breast-feeding

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

The use of Orgalutran is contraindicated during pregnancy and breast-feeding (see section 4.3).

No studies on the effects on the ability to drive and use machines have been performed.

The listing below shows all adverse reactions in women treated with Orgalutran in clinical studies using recFSH for ovarian stimulation. The adverse reactions with Orgalutran using corifollitropin alfa for ovarian stimulation are expected to be similar. The adverse reactions are classified according to MedDRA system organ class and frequency; very common (1/10), common (1/100 to <1/10), uncommon (1/1000 to <1/100). The frequency of hypersensitivity (very rare, <1/10,000) has been deduced from post-marketing surveillance.

Immune system disorders

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

Nervous system disorders

Uncommon: Headache.

Gastrointestinal disorders

Uncommon: Nausea.

General disorders and administration site conditions

Very common: 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.

Uncommon: Malaise.

Other reported adverse reactions are related to the controlled ovarian hyperstimulation treatment for ART, notably pelvic pain, abdominal distension, OHSS (see also section 4.4), ectopic pregnancy and spontaneous abortion.

Overdose in humans may result in a prolonged duration of action.

No data on acute toxicity of Orgalutran in humans are available. Clinical studies with subcutaneous administration of Orgalutran at single doses up to 12 mg did not show systemic adverse reactions. In acute toxicity studies in rats and monkeys non-specific toxic symptoms such as hypotension and bradycardia were only observed after intravenous administration of ganirelix over 1 and 3 mg/kg, respectively.

In case of overdose, Orgalutran treatment should be (temporarily) discontinued.

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, anti-gonadotrophin-releasing hormones, ATC code: H01CC01.

Orgalutran is a GnRH antagonist, which modulates the hypothalamic-pituitary-gonadal axis by competitive binding to the GnRH receptors in the pituitary gland. As a result a rapid, profound, reversible suppression of endogenous gonadotrophins occurs, without initial stimulation as induced by GnRH agonists. Following administration of multiple doses of 0.25 mg Orgalutran to female volunteers serum LH, FSH and E₂ concentrations were maximally decreased by 74 %, 32 % and 25 % at 4, 16 and 16 hours after injection, respectively. Serum hormone levels returned to pre-treatment values within two days after the last injection.

In patients undergoing controlled ovarian stimulation the median duration of Orgalutran treatment was 5 days. During Orgalutran treatment the average incidence of LH rises (>10 IU/l) with concomitant progesterone rise (>1 ng/ml) was 0.3 - 1.2 % compared to 0.8 % during GnRH agonist treatment. There was a tendency towards an increased incidence of LH and progesterone rises in women with a higher body weight (>80 kg), but no effect on clinical outcome was observed. However, based on the small number of patients treated so far, an effect can not be excluded.

In case of a high ovarian response, either as a result of a high exposure to gonadotrophins 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.

In controlled studies of Orgalutran with FSH, using a long protocol of GnRH agonist as a reference, treatment with the Orgalutran regimen resulted in a faster follicular growth during the first days of stimulation but the final cohort of growing follicles was slightly smaller and produced on average less oestradiol. This different pattern of follicular growth requires that FSH dose adjustments are based on the number and size of growing follicles, rather than on the amount of circulating oestradiol. Similar comparative studies with corifollitropin alfa using either a GnRH antagonist or long agonist protocol have not been performed.

After a single subcutaneous administration of 0.25 mg, serum levels of ganirelix rise rapidly and reach peak levels (C_max) of approximately 15 ng/ml within 1 to 2 hours (t_max). The elimination half-life (t_½ ) is approximately 13 hours and clearance is approximately 2.4 l/h. Excretion occurs via faeces (approximately 75 %) and urine (approximately 22 %). The bioavailability of Orgalutran following subcutaneous administration is approximately 91 %.

Pharmacokinetic parameters after multiple subcutaneous dosing of Orgalutran (once daily injection) were similar to those after a single subcutaneous dose. After repeated dosing 0.25 mg/day steady-state levels of approximately 0.6 ng/ml were reached within 2 to 3 days.

Pharmacokinetic analysis indicates an inverse relationship between bodyweight and serum concentrations of Orgalutran.

Metabolite profile

The major circulating component in plasma is ganirelix. Ganirelix is also the main compound found in urine. Faeces only contain metabolites. The metabolites are small peptide fragments formed by enzymatic hydrolysis of ganirelix at restricted sites. The metabolite profile of Orgalutran in humans was similar to that found in animals.

Preclinical data reveal no special hazard for humans based on safety pharmacology, repeated dose toxicity and genotoxicity.

Reproduction studies carried out with ganirelix at doses of 0.1 to 10 µg/kg/day subcutaneously in the rat and 0.1 to 50 µg/kg/day subcutaneously in the rabbit showed increased litter resorption in the highest dose groups. No teratogenic effects were observed.

Acetic acid;

Mannitol;

Water for injections.

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

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

3 years.

Do not freeze.

Store in the original package in order to protect from light.

Disposable 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.

Inspect the syringe before use. Use only syringes with clear, particle-free solutions and from undamaged containers.

Any unused medicinal 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/1/00/130/001, 1 pre-filled syringe

EU/1/00/130/002, 5 pre-filled syringes

Date of first authorisation: 17 May 2000

Date of last renewal: 17 May 2010

27 January 2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Prescription Only Medicine

RA 2450 EU S7 (ref 4.0)

Orgalutran/UK-IRL/01-11/04