GANIRELIX GEDEON RICHTER 0.25mg / 0.5ml injection solution in pre-filled syringe medication leaflet

Ganirelix Gedeon Richter 0.25 mg/0.5 mL solution for injection in pre-filled syringe

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 thenaturally occurring gonadotropin releasing hormone (GnRH). The amino acids at positions 1, 2, 3, 6, 8and 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 the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear and colourless solution, with a pH of 4.8-5.2 and an osmolality of 260-300 mOsm/kg.

Ganirelix Gedeon Richter is indicated for the prevention of premature luteinising hormone (LH)surges in women undergoing controlled ovarian hyperstimulation (COH) for assisted reproductiontechniques (ART).

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

Ganirelix Gedeon Richter should only be prescribed by a specialist experienced in the treatment ofinfertility.

Ganirelix 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. Ganirelix Gedeon

Richter (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 ganirelix is depending on the ovarian response, i.e. the number and size of growing folliclesand/or the amount of circulating oestradiol. The start of ganirelix may be delayed in absence offollicular growth, although clinical experience is based on starting ganirelix on day 5 or day 6 ofstimulation.

Ganirelix and FSH should be administered approximately at the same time. However, these medicinalproducts 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 ganirelix should be continued up to the day that sufficient follicles of adequatesize are present. Final maturation of follicles can be induced by administering human chorionicgonadotropin (hCG).

Timing of last injection

Because of the half-life of ganirelix, the time between two injections of ganirelix as well as the timebetween the last injection of ganirelix and the hCG injection should not exceed 30 hours, as otherwisea premature LH surge may occur. Therefore, when injecting ganirelix in the morning, treatment withganirelix should be continued throughout the gonadotropin treatment period including the day oftriggering ovulation. When injecting ganirelix in the afternoon the last injection of ganirelix should begiven in the afternoon prior to the day of triggering ovulation.

Ganirelix has shown to be safe and effective in women undergoing multiple treatment cycles.

The need for luteal phase support in cycles using ganirelix 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 ganirelix in subjects with renal impairment, as they wereexcluded from clinical studies. Therefore, the use of ganirelix is contraindicated in patients withmoderate or severe renal impairment (see section 4.3).

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

There is no relevant use of Ganirelix Gedeon Richter in the paediatric population.

Ganirelix Gedeon Richter should be administered subcutaneously, preferably in the upper leg. Theinjection site should be varied to prevent lipoatrophy. The patient or her partner may perform theinjections of Ganirelix Gedeon Richter themselves, provided that they are adequately instructed andhave access to expert advice.

For instructions of the medicinal product before administration, see section 6.6 and the instructions foruse included at the end of the package leaflet.

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

- Hypersensitivity to gonadotropin-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 ganirelix, 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, ganirelix should be discontinued and appropriate treatment administered. In theabsence of clinical experience, ganirelix treatment is not advised in women with severe allergicconditions.

Ovarian hyperstimulation syndrome (OHSS)

OHSS may occur during or following ovarian stimulation. OHSS must be considered an intrinsic riskof gonadotropin stimulation. OHSS should be treated symptomatically, e.g. with rest, intravenousinfusion 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 new-borns it has been demonstrated thatthe incidence of congenital malformations in children born after COH treatment using ganirelix 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 ganirelix have not been established in women weighing less than 50 kg ormore than 90 kg (see also sections 5.1 and 5.2).

Excipient

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 (see section5.3). The relevance of these data for humans is unknown.

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

The use of Ganirelix Gedeon Richter is contraindicated during pregnancy and breast-feeding (seesection 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 ofadministration, 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 ganirelix in clinical studies usingrecFSH for ovarian stimulation. The adverse reactions with ganirelix 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 frequencyof hypersensitivity reactions (very rare, < 1/10,000) has been deduced from post-marketingsurveillance.

System organ class Frequency Adverse reaction

Immune system disorders Very rare Hypersensitivity reactions (including rash, facial swelling,dyspnoea, anaphylaxis [including anaphylactic shock],angioedema and urticaria)1

Worsening of a pre-existing eczema2

Nervous system disorders Uncommon Headache

Gastrointestinal disorders Uncommon Nausea

General disorders and Very Local skin reaction at the site of injection (predominantlyadministration site common redness, with or without swelling)3conditions Uncommon Malaise1 Cases have been reported, as early as with the first dose, among patients administered ganirelix.2 Reported in one subject after the first ganirelix 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 ganirelix-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 also 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 ganirelix in humans are available. Clinical studies with subcutaneousadministration of ganirelix 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, ganirelix treatment should be (temporarily) discontinued.

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

Ganirelix is a GnRH antagonist, which modulates the hypothalamic-pituitary-gonadal axis bycompetitive binding to the GnRH receptors in the pituitary gland. As result a rapid, profound,reversible suppression of endogenous gonadotropins occurs, without initial stimulation as induced by

GnRH agonists. Following administration of multiple doses of 0.25 mg ganirelix to female volunteersserum LH, FSH and E2 concentrations were maximally decreased by 74%, 32% and 25% at 4, 16 and16 hours after injection, respectively. Serum hormone levels returned to pre-treatment values withintwo days after the last injection.

In patients undergoing controlled ovarian stimulation the median duration of ganirelix treatment was5 days. During ganirelix 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 gonadotropins in the earlyfollicular phase or as a result of high ovarian responsiveness, premature LH rises may occur earlierthan day 6 of stimulation. Initiation of ganirelix treatment on day 5 can prevent these premature LHrises without compromising the clinical outcome.

In controlled studies of ganirelix with FSH, using a long protocol of GnRH agonist as a reference,treatment with the ganirelix 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 ganirelix (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 ganirelix.

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 ofganirelix 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 ganirelix in humans wassimilar 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%).

Non-clinical 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 μg/kg/day subcutaneously in therat and 0.1 to 50 μg/kg/day subcutaneously in the rabbit showed increased litter resorption in thehighest dose groups. No teratogenic effects were observed.

Glacial acetic acid

Mannitol (E 421)

Water for injections

Sodium hydroxide (for pH-adjustment)

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.

The medicinal product is filled in a glass syringe with staked stainless steel needle, closed with aplunger stopper and supplied with a plunger rod. The injection needle is provided with a rigid needleshield.

Pack sizes of 1 pre-filled syringe or 6 pre-filled syringes.

Not all pack sizes may be marketed.

Each pre-filled syringe is intended for only one injection.

Alcohol swabs, gauze pads and sharps container are needed for administration of this medicinalproduct but are not provided in the pack.

The syringe should be inspected before use. Use only syringes with clear, particle-free solutions andfrom undamaged containers.

Before using this medicinal product for the first time, the patient should carefully read the instructionsfor use at the end of the package leaflet where instructions are provided on how to administer

Ganirelix Gedeon Richter.

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

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements. The used syringes need to be disposed of in a sharp disposal container.

Gedeon Richter Plc.

Gyömrői út 19-21.1103 Budapest

Hungary

EU/1/22/1658/001

EU/1/22/1658/002

Date of first authorisation:

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

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