Cetrotide 3 mg powder and solvent for solution for injection

Each vial contains 3 mg cetrorelix (as acetate).

After reconstitution with the solvent provided, each ml of the solution contains 1 mg cetrorelix.

For a 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, followed by oocyte pick-up and assisted reproductive techniques.

In clinical trials Cetrotide was used with human menopausal gonadotropin (HMG), however, limited experience with recombinant follicule-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 and under conditions where treatment of possible allergic/pseudo-allergic reactions (including life-threatening anaphylaxis) is immediately available. The following injections may be self-administered as long as the patient is made aware of the signs and symptoms that may indicate hypersensitivity, the consequences of such a reaction and the need for immediate medical intervention.

The contents of 1 vial (3 mg cetrorelix) are to be administered on day 7 of ovarian stimulation (approximately 132 to 144 hours after start of ovarian stimulation) with urinary or recombinant gonadotropins. Following the first administration, it is advised that the patient be kept under medical supervision for 30 minutes to ensure there is no allergic/pseudo-allergic reaction to the injection.

If the follicle growth does not allow ovulation induction on the fifth day after injection of Cetrotide 3 mg, additionally 0.25 mg cetrorelix (Cetrotide 0.25 mg) should be administered once daily beginning 96 hours after the injection of Cetrotide 3 mg until the day of ovulation induction.

Cetrotide is for subcutaneous injection into the lower abdominal wall.

The injection site reactions may be minimised by injecting the product in a slow rate to facilitate the progressive absorption of the product.

Additional information on special populations:

There is no relevant indication for the use of Cetrotide in children or geriatric populations.

For instructions for preparation, see section 6.6.

• Hypersensitivity to the active substance or any structural analogues of gonadotropin-releasing hormone (GnRH), extrinsic peptide hormones or to any of the excipients.

• Pregnancy and lactation.

• Postmenopausal women.

• Patients with moderate and severe renal and hepatic impairment.

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

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

An ovarian hyperstimulation syndrome should be treated symptomatically, e.g. with rest, intravenous electrolytes/colloids and heparin therapy.

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

There is limited experience up to now with the administration of Cetrotide during a repeated ovarian stimulation procedure. Therefore Cetrotide should be used in repeated cycles only after a careful risk/benefit eva luation.

In vitro investigations have shown that interactions are unlikely with medicinal products that are metabolised by cytochrome P450 or glucuronised or conjugated in some other way. However, though there has been no evidence of drug-interactions, especially with commonly used medicinal products, gonadotropins or products that may induce histamine release in susceptible individuals, the possibility of an interaction 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 product was administered during the sensitive phase of gestation.

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

The most commonly reported side effects are local injection site reactions such as erythema, swelling and pruritus that are usually transient in nature and mild in intensity.

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

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

The adverse reactions reported below are classified according to frequency of occurrence as follows:

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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

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

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

Cetrorelix is a luteinising hormone releasing hormone (LHRH) antagonist. LHRH binds to membrane receptors on pituitary cells. Cetrorelix competes with the binding of endogenous LHRH to these receptors. 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 onset of suppression is virtually immediate and is maintained by continuous treatment, without initial stimulatory effect.

In females, cetrorelix delays the LH surge and consequently ovulation. In women undergoing ovarian stimulation the duration of action of cetrorelix is dose dependent. Following a single dose of 3 mg of cetrorelix a duration of action of at least 4 days has been eva luated. On day 4 the suppression was approximately 70%. At a dose of 0.25 mg per injection repeated injections every 24 hours will maintain the effect of cetrorelix.

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

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

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 volume of distribution (V_d) is 1.1 l x kg^-1. The mean terminal half-lives following intravenous and subcutaneous administration are about 12 h and 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 dosing over 14 days show linear kinetics.

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

No target organ toxicity could be observed from acute, subacute and chronic toxicity studies in rats and dogs following subcutaneous administration of cetrorelix. No signs of medicinal product-related local irritation or incompatibility were noted in dogs after intravenous, intra-arterial and paravenous injection 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.

Powder:

Mannitol

Solvent:

Water for injections

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

2 years.

The solution should be used immediately after preparation.

Do not store above 25 °C. Keep the vial in the outer carton in order to protect from light.

Pack with 1 Type I glass vial sealed with a rubber stopper.

Additionally the pack contains:

1 pre-filled syringe (Type I glass cartridge closed with rubber stoppers) with 3 ml solvent for parenteral use

1 injection needle (20 gauge)

1 hypodermic injection needle (27 gauge)

2 alcohol swabs.

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 or if the solution is not clear.

Withdraw the entire contents of the vial. This ensures a delivery to the patient of a dose of at least 2.82 mg cetrorelix.

The solution should be used immediately after reconstitution.

Merck Serono Europe Limited

56 Marsh Wall

London E14 9TP

United Kingdom

EU/1/99/100/003

Date of first authorisation: 13 April 1999

Date of first renewal: 15 April 2004

Date of latest renewal: March 2009

03/2010