CETROTIDE 0.25mg powder + solvent for injection medication leaflet

Cetrotide 0.25 mg powder and solvent for solution for injection

Each vial contains 0.25 mg cetrorelix (as acetate).

After reconstitution with the solvent provided, each mL of the solution contains 0.25 mg cetrorelix.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

Appearance of the powder: white lyophilisate

Appearance of the solvent: clear and colourless solution

The pH of the reconstituted solution is 4.0-6.0.

Prevention of premature ovulation in patients undergoing a controlled ovarian stimulation, followedby oocyte pick-up and assisted reproductive techniques.

In clinical trials Cetrotide was used with human menopausal gonadotropin (HMG), however, limitedexperience with recombinant follicle-stimulating hormone (FSH) suggested similar efficacy.

Cetrotide should only be prescribed by a specialist experienced in this field.

The first administration of Cetrotide should be performed under the supervision of a physician andunder conditions where treatment of possible allergic/pseudo-allergic reactions (includinglife-threatening anaphylaxis) is immediately available. The following injections may beself-administered as long as the patient is made aware of the signs and symptoms that may indicatehypersensitivity, the consequences of such a reaction and the need for immediate medical intervention.

The contents of 1 vial are to be administered once daily, at 24 h intervals, either in the morning or inthe evening. Each vial contains 0.25 mg of cetrorelix; however, due to losses during reconstitution andadministration, only 0.21 mg can be administered (see section 6.6). Following the first administration,it is advised that the patient be kept under medical supervision for 30 minutes to ensure there is noallergic/pseudo-allergic reaction to the injection.

There is no relevant use of Cetrotide in the geriatric population.

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

Cetrotide is for subcutaneous injection into the lower abdominal wall.

The injection site reactions may be minimised by rotating the injection sites, delaying injection at thesame site and injecting the medicinal product in a slow rate to facilitate the progressive absorption ofthe medicinal product.

Administration in the morning

Treatment with Cetrotide should commence on day 5 or 6 of ovarian stimulation (approximately 96 to120 hours after start of ovarian stimulation) with urinary or recombinant gonadotropins and is to becontinued throughout the gonadotropin treatment period including the day of ovulation induction.

The starting day of Cetrotide is depending on the ovarian response, i.e. the number and size ofgrowing follicles and/or the amount of circulating oestradiol. The start of Cetrotide may be delayed inabsence of follicular growth, although clinical experience is based on starting Cetrotide on day 5 orday 6 of stimulation.

Administration in the evening

Treatment with Cetrotide should commence on day 5 of ovarian stimulation (approximately 96 to108 hours after start of ovarian stimulation) with urinary or recombinant gonadotropins and is to becontinued throughout the gonadotropin treatment period until the evening prior to the day of ovulationinduction.

The starting day of Cetrotide is depending on the ovarian response, i.e. the number and size ofgrowing follicles and/or the amount of circulating oestradiol. The start of Cetrotide may be delayed inabsence of follicular growth, although clinical experience is based on starting Cetrotide on day 5 orday 6 of stimulation.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Cetrorelix is not to be used in the presence of any of the conditions listed below:

* Hypersensitivity to the active substance or any structural analogues of gonadotropin-releasinghormone (GnRH), extrinsic peptide hormones or to any of the excipients listed in section 6.1.

* During pregnancy and lactation.

* Patients with severe renal impairment.

Allergic conditions

Cases of allergic/pseudoallergic reactions, including life-threatening anaphylaxis with the first dosehave been reported (see section 4.8).

Special care should be taken in women with signs and symptoms of active allergic conditions orknown history of allergic predisposition. Treatment with Cetrotide is not advised in women withsevere allergic conditions.

Ovarian Hyperstimulation Syndrome (OHSS)

During or following ovarian stimulation an ovarian hyperstimulation syndrome can occur. This eventmust be considered as an intrinsic risk of the stimulation procedure with gonadotropins

An OHSS should be treated symptomatically, e.g. with rest, intravenous electrolytes/colloids andheparin therapy.

Luteal phase support should be given according to the reproductive medical centre´s practice.

Repeated ovarian stimulation procedure

There is limited experience up to now with the administration of cetrorelix during a repeated ovarianstimulation procedure. Therefore, cetrorelix should be used in repeated cycles only after a carefulbenefit/risk evaluation.

Congenital anomalies

The prevalence of congenital anomalies after the use of assisted reproductive technologies (ART) withor without GnRH antagonists may be slightly higher than after spontaneous conceptions although it isunclear whether this is related to factors inherent to the couple's infertility or the ART procedures.

Limited data from clinical follow-up studies in 316 newborns of women administered cetrorelix forinfertility treatments suggest that cetrorelix does not increase the risk of congenital anomalies in theoffsprings.

Cetrorelix has not been studied in patients with hepatic impairment and caution is therefore warranted.

Cetrorelix has not been studied in patients with renal impairment and caution is therefore warranted.

Cetrorelix is contraindicated in patients with severe renal impairment (see section 4.3).

No formal drug-drug interaction studies have been performed with cetrorelix. In vitro investigationshave shown that interactions are unlikely with medicinal products that are metabolised by cytochrome

P450 or glucuronised or conjugated in some other way. However, the possibility of interactions withgonadotropins or medicinal products that may induce histamine release in susceptible individuals,cannot be totally excluded.

Cetrotide is not intended to be used during pregnancy and lactation (see section 4.3).

Studies in animals have indicated that cetrorelix exerts a dose related influence on fertility,reproductive performance and pregnancy. No teratogenic effects occurred when the medicinal productwas administered during the sensitive phase of gestation.

Cetrotide has no or negligible influence on the ability to drive and use machines.

The most commonly reported adverse reactions are local injection site reactions such as erythema,swelling and pruritus that are usually transient in nature and mild in intensity. In clinical trials, theseeffects were observed with a frequency of 9.4% following multiple injections of Cetrotide 0.25 mg.

Mild to moderate OHSS (WHO grade I or II) have been commonly reported and should be consideredas an intrinsic risk of the stimulation procedure. Inversely, severe OHSS remains uncommon.

Uncommonly, cases of hypersensitivity reactions including pseudo-allergic/anaphylactoid reactionshave been reported.

List of adverse reactions

The adverse reactions reported below are classified according to frequency of occurrence as follows:very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000to <1/1 000), very rare (<1/10 000).

Uncommon: Systemic allergic/pseudo-allergic reactions including life-threatening anaphylaxis.

Uncommon: Headache

Uncommon: Nausea

Common: Mild to moderate OHSS (WHO grade I or II) can occur which is an intrinsic risk ofthe stimulation procedure (see section 4.4).

Uncommon: Severe OHSS (WHO grade III)

Common: Local reactions at the injection site (e.g. erythema, swelling and pruritus).

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.

Overdosage in humans may result in a prolonged duration of action but is unlikely to be associatedwith acute toxic effects.

In acute toxicity studies in rodents non-specific toxic symptoms were observed after intraperitonealadministration of cetrorelix doses more than 200 times higher than the pharmacologically effectivedose after subcutaneous administration.

Pharmacotherapeutic group: anti-gonadotropin-releasing hormones, ATC code: H01CC02.

Cetrorelix is a luteinising hormone releasing hormone (LHRH) antagonist. LHRH binds to membranereceptors on pituitary cells. Cetrorelix competes with the binding of endogenous LHRH to thesereceptors. Due to this mode of action, cetrorelix controls the secretion of gonadotropins (LH and

FSH).

Cetrorelix dose-dependently inhibits the secretion of LH and FSH from the pituitary gland. The onsetof suppression is virtually immediate and is maintained by continuous treatment, without initialstimulatory effect.

In females, cetrorelix delays the LH surge and consequently ovulation. In women undergoing ovarianstimulation the duration of action of cetrorelix is dose dependent. Repeated injections of Cetrotide0.25 mg per vial (administered dose of 0.21 mg cetrorelix), every 24 hours will maintain the effect ofcetrorelix (see section 4.2).

In animals as well as in humans, the antagonistic hormonal effects of cetrorelix were fully reversibleafter termination of treatment.

The absolute bioavailability of cetrorelix after subcutaneous administration is about 85%.

The volume of distribution (V ) is 1.1 L x kg-1d .

The total plasma clearance and the renal clearance are 1.2 mL x min-1 x kg-1 and 0.1 mL x min-1 x kg-1,respectively.

The mean terminal half-lives following intravenous and subcutaneous administration are about 12 hand 30 h, respectively, demonstrating the effect of absorption processes at the injection site.

The subcutaneous administration of single doses (0.25 mg to 3 mg cetrorelix) and also daily dosingover 14 days show linear kinetics.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

No target organ toxicity could be observed from acute, subacute and chronic toxicity studies in ratsand dogs following subcutaneous administration of cetrorelix. No signs of medicinal product-relatedlocal irritation or incompatibility were noted in dogs after intravenous, intraarterial and paravenousinjection when cetrorelix was administered in doses clearly above the intended clinical use in man.

Cetrorelix showed no mutagenic or clastogenic potential in gene and chromosome mutation assays.

Mannitol

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial: 2 years

After reconstitution: use immediately

Store in a refrigerator (2°C - 8°C). Do not freeze or place next to the freezer compartment or a freezerpack.

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

The unopened medicinal product may be stored in the original package at room temperature (notabove 30°C) for up to three months.

This medicinal product must be allowed to reach room temperature prior to injection. It should beremoved from the refrigerator approximately 30 minutes before use.

Powder2 ml vials (Type I glass) with a stopper (bromobutyl rubber) and flip-off aluminium cap.

1 vial contains 0.25 mg cetrorelix.

Pre-filled syringe (Type I glass) with plunger stopper (siliconised bromobutyl rubber) and tip cap(polypropylene and styrene butadiene rubber).

1 pre-filled syringe contains 1 ml of water for injections.

Pack sizes1 vial and 1 pre-filled syringe or 7 vials and 7 pre-filled syringes.

Additionally, for each vial the pack contains:

1 injection needle (20 gauge)1 hypodermic injection needle (27 gauge)

Not all pack sizes may be marketed.

This medicinal product must be allowed to reach room temperature prior to injection. It should beremoved from the refrigerator approximately 30 minutes before use.

Cetrotide should only be reconstituted with the solvent provided, using a gentle, swirling motion.

Vigorous shaking with bubble formation should be avoided.

The reconstituted solution is without particles and clear. Do not use if the solution contains particles orif the solution is not clear.

The entire contents of the vial should be withdrawn to ensure a delivery to the patient of a dose of0.21 mg cetrorelix (see section 4.2).

The solution should be used immediately after reconstitution.

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

Merck Europe B.V.

Gustav Mahlerplein 1021082 MA Amsterdam

The Netherlands

EU/1/99/100/001

EU/1/99/100/002

Date of first authorisation: 13 April 1999

Date of latest renewal: 13 April 2009

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

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