ORGALUTRAN 0.25mg / 0.5ml injectible solution medication leaflet

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 substanceganirelix (INN) is a synthetic decapeptide with high antagonistic activity to the naturally occurringgonadotrophin releasing hormone (GnRH). The amino acids at positions 1, 2, 3, 6, 8 and 10 of thenatural 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.

This medicinal product contains less than 1 mmol sodium (23 mg) per injection, that is to sayessentially ‘sodium-free’.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear and colourless aqueous solution.

Orgalutran is indicated for the prevention of premature luteinising hormone (LH) surges in womenundergoing 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.

Orgalutran is used to prevent premature LH surges in women undergoing COH. Controlled ovarianhyperstimulation 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 FSHadministration or on day 5 or day 6 following the administration of corifollitropin alfa. The startingday of Orgalutran is depending on the ovarian response, i.e. the number and size of growing folliclesand/or the amount of circulating oestradiol. The start of Orgalutran may be delayed in absence offollicular growth, although clinical experience is based on starting Orgalutran on day 5 or day 6 ofstimulation.

Orgalutran and FSH should be administered approximately at the same time. However, thepreparations 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 theamount of circulating oestradiol (see section 5.1).

Daily treatment with Orgalutran should be continued up to the day that sufficient follicles of adequatesize are present. Final maturation of follicles can be induced by administering human chorionicgonadotrophin (hCG).

Timing of last injection

Because of the half-life of ganirelix, the time between two Orgalutran injections as well as the timebetween the last Orgalutran injection and the hCG injection should not exceed 30 hours, as otherwise apremature 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 oftriggering ovulation. When injecting Orgalutran in the afternoon the last Orgalutran injection shouldbe 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 clinicalprotocol.

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

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

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

Orgalutran should be administered subcutaneously, preferably in the upper leg. The injection siteshould 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.

Air bubble(s) may be seen in the pre-filled syringe. This is expected, and removal of the air bubble(s)is not needed.

− Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

− Moderate or severe impairment of renal or hepatic function.

− Pregnancy or breast-feeding.

Hypersensitivity reaction

Special care should be taken in women with signs and symptoms of active allergic conditions. Casesof hypersensitivity reactions (both generalised and local), have been reported with Orgalutran, as earlyas with the first dose, during post-marketing surveillance. These events have included anaphylaxis(including anaphylactic shock), angioedema and urticaria (see section 4.8). If a hypersensitivityreaction is suspected, Orgalutran should be discontinued and appropriate treatment administered. Inthe absence of clinical experience, Orgalutran treatment is not advised in women with severe allergicconditions.

Latex allergy

The needle cover contains dry natural rubber/latex which comes into contact with the needle and maycause allergic reactions (see section 6.5).

Ovarian hyperstimulation syndrome (OHSS)

Ovarian hyperstimulation syndrome (OHSS) may occur during or following ovarian stimulation.

OHSS must be considered an intrinsic risk of gonadotrophin stimulation. OHSS should be treatedsymptomatically, e.g. with rest, intravenous infusion of electrolyte solutions or colloids and heparin.

Ectopic pregnancy

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

Congenital malformations

The incidence of congenital malformations after Assisted Reproductive Technologies (ART) may behigher than after spontaneous conceptions. This is thought to be due to differences in parentalcharacteristics (e.g. maternal age, sperm characteristics) and an increased incidence of multiplegestations. In clinical studies investigating more than 1,000 newborns it has been demonstrated thatthe incidence of congenital malformations in children born after COH treatment using Orgalutran iscomparable with that reported after COH treatment using a GnRH agonist.

Women weighing less than 50 kg or more than 90 kg

The safety and efficacy of Orgalutran have not been established in women weighing less than 50 kg ormore than 90 kg (see sections 5.1 and 5.2).

This medicinal product contains less than 1 mmol sodium (23 mg) per injection, that is to sayessentially ‘sodium-free’.

No interaction studies have been performed.

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

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 (seesection 5.3). 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 breast-feeding (see section 4.3).

Ganirelix is used in the treatment of women undergoing controlled ovarian hyperstimulation inassisted reproduction programmes. Ganirelix is used to prevent premature LH surges that mightotherwise occur in these women during the ovarian stimulation.

For posology and method of administration, see section 4.2.

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

The table below shows all adverse reactions in women treated with Orgalutran in clinical studies usingrecFSH for ovarian stimulation. The adverse reactions with Orgalutran using corifollitropin alfa forovarian stimulation are expected to be similar.

The adverse reactions are classified according to MedDRA system organ class and frequency; verycommon (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100). The frequency ofhypersensitivity reactions (very rare, < 1/10,000) has been deduced from post-marketing surveillance.

System organ class Frequency Adverse reaction

Immune system disorders Very rare Hypersensitivity reactions (including rash, facialswelling, dyspnoea, anaphylaxis (includinganaphylactic shock), angioedema and urticaria)1

Worsening of a pre-existing eczema2

Nervous system disorders Uncommon Headache

Gastrointestinal disorders Uncommon Nausea

General disorders and Very common Local skin reaction at the site of injectionadministration site (predominantly redness, with or withoutconditions swelling)3

Uncommon Malaise1 Cases have been reported, as early as with the first dose, among patients administered Orgalutran.2 Reported in one subject after the first Orgalutran dose.3 In clinical studies, one hour after injection, the incidence of at least once a moderate or severe localskin reaction per treatment cycle, as reported by patients, was 12 % in Orgalutran treated patients and25 % in patients treated subcutaneously with a GnRH agonist. The local reactions generally disappearwithin 4 hours after administration.

Other reported adverse reactions are related to the controlled ovarian hyperstimulation treatment for

ART, notably pelvic pain, abdominal distension, OHSS (see section 4.4), ectopic pregnancy andspontaneous abortion.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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 subcutaneousadministration of Orgalutran at single doses up to 12 mg did not show systemic adverse reactions. Inacute toxicity studies in rats and monkeys non-specific toxic symptoms such as hypotension andbradycardia 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 bycompetitive 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 femalevolunteers 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-treatmentvalues within two days after the last injection.

In patients undergoing controlled ovarian stimulation the median duration of Orgalutran treatment was5 days. During Orgalutran treatment the average incidence of LH rises (> 10 IU/L) with concomitantprogesterone 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 ahigher body weight (> 80 kg), but no effect on clinical outcome was observed. However, based on thesmall number of patients treated so far, an effect cannot be excluded.

In case of a high ovarian response, either as a result of a high exposure to gonadotrophins in the earlyfollicular phase or as a result of high ovarian responsiveness, premature LH rises may occur earlierthan day 6 of stimulation. Initiation of Orgalutran treatment on day 5 can prevent these premature LHrises 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 ofstimulation but the final cohort of growing follicles was slightly smaller and produced on average lessoestradiol. This different pattern of follicular growth requires that FSH dose adjustments are based onthe number and size of growing follicles, rather than on the amount of circulating oestradiol. Similarcomparative studies with corifollitropin alfa using either a GnRH antagonist or long agonist protocolhave not been performed.

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-statelevels of approximately 0.6 ng/mL were reached within 2 to 3 days.

Pharmacokinetic analysis indicates an inverse relationship between body weight and serumconcentrations of Orgalutran.

After a single subcutaneous administration of 0.25 mg, serum levels of ganirelix rise rapidly and reachpeak levels (Cmax) of approximately 15 ng/mL within 1 to 2 hours (tmax). The bioavailability of

Orgalutran following subcutaneous administration is approximately 91 %.

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

The elimination half-life (t½) is approximately 13 hours and clearance is approximately 2.4 L/h.

Excretion occurs via faeces (approximately 75 %) and urine (approximately 22 %).

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

Reproduction studies carried out with ganirelix at doses of 0.1 to 10 g/kg/day subcutaneously in therat and 0.1 to 50 g/kg/day subcutaneously in the rabbit showed increased litter resorption in thehighest 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 medicinalproducts.

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 that does not contain latex. Each pre-filled syringe isaffixed with a needle closed by a needle cover of dry natural rubber/latex which comes intocontact with the needle. (See section 4.4.)

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 fromundamaged containers.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

N.V. Organon

Kloosterstraat 65349 AB 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: 10 May 2010

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.