- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
1.NAME OF THE MEDICINAL PRODUCT
Cetrotide 0.25 mg powder and solvent for solution for injection
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
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
Prevention of premature ovulation in patients undergoing a controlled ovarian stimulation, followed by oocyte
In clinical trials Cetrotide was used with human menopausal gonadotropin (HMG), however, limited experience with recombinant
4.2Posology and method of administration
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
The contents of 1 vial (0.25 mg cetrorelix) are to be administered once daily, at 24 h intervals, either in the morning or in the evening. Following the first administration, it is advised that the patient be kept under medical supervision for 30 minutes to ensure there is no
There is no relevant indication for the use of Cetrotide in geriatric population.
There is no relevant use of Cetrotide in the paediatric population.
Method of administration
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 the same site and injecting the product in a slow rate to facilitate the progressive absorption of the product.
Administration in the morning: Treatment with Cetrotide should commence on day 5 or 6 of ovarian stimulation (approximately 96 to 120 hours after start of ovarian stimulation) with urinary or recombinant gonadotropins and is to be continued throughout the gonadotropin treatment period including the day of ovulation induction.
Administration in the evening: Treatment with Cetrotide should commence on day 5 of ovarian stimulation (approximately 96 to 108 hours after start of ovarian stimulation) with urinary or recombinant gonadotropins and is to be continued throughout the gonadotropin treatment period until the evening prior to the day of ovulation induction.
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
•During pregnancy and lactation.
•Patients with severe renal impairment.
4.4Special warnings and precautions for use
Cases of allergic/pseudoallergic reactions, including
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.
Ovarian Hyperstimulation Syndrome (OHSS)
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.
Repeated ovarian stimulation procedure
There is limited experience up to now with the administration of cetrorelix during a repeated ovarian stimulation procedure. Therefore cetrorelix should be used in repeated cycles only after a careful risk/benefit evaluation.
The prevalence of congenital anomalies after the use of assisted reproductive technologies (ART) with or without GnRH antagonists may be slightly higher than after spontaneous conceptions although it is unclear whether this is related to factors inherent to the couple's infertility or the ART procedures.
Limited data from clinical
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).
4.5Interaction with other medicinal products and other forms of interaction
4.6Fertility, pregnancy and lactation
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.
4.7Effects on ability to drive and use machines
Cetrotide has no or negligible influence on the ability to drive and use machines.
Summary of the safety profile
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. In clinical trials, these effects were observed with a frequency of 9.4% following multiple injections of Cetrotide 0.25 mg.
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
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 (≥1/10,000 to <1/1,000), very rare (<1/10,000).
Immune system disorders
Nervous system disorders
Reproductive system and breast disorders
Mild to moderate ovarian hyperstimulation syndrome (WHO grade I or II) can occur
which is an intrinsic risk of the stimulation procedure (see section 4.4).
Severe ovarian hyperstimulation syndrome (WHO grade III)
General disorders and administration site conditions
Common: Local reactions at the injection site (e.g. erythema, swelling and pruritus) have been reported.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
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
Mechanism of action
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).
Clinical efficacy and safety
In females, cetrorelix delays the LH surge and consequently ovulation. In women undergoing ovarian stimulation the duration of action of cetrorelix is dose dependent. 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 volume of distribution (Vd) is 1.1 l x
The total plasma clearance and the renal clearance are 1.2 ml x
The mean terminal
The subcutaneous administration of single doses (0.25 mg to 3 mg cetrorelix) and also daily dosing over 14 days show linear kinetics.
5.3Preclinical safety data
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
Cetrorelix showed no mutagenic or clastogenic potential in gene and chromosome mutation assays.
6.1List of excipients
Water for injections
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
The solution should be used immediately after preparation.
6.4Special precautions for storage
Do not store above 25°C.
Keep the vial(s) in the outer carton in order to protect from light.
6.5Nature and contents of container
Powder: 2 ml vials (Type I glass) with a stopper (bromobutyl rubber) and
1 vial contains 0.25 mg cetrorelix.
Additionally for each vial the pack contains:
1 injection needle (20 gauge)
1 hypodermic injection needle (27 gauge)
2 alcohol swabs
Pack sizes of 1 vial and 1
Not all pack sizes may be marketed.
6.6Special precautions for disposal and other handling
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 0.23 mg cetrorelix.
The solution should be used immediately after reconstitution.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.MARKETING AUTHORISATION HOLDER
Merck Serono Europe Limited
56 Marsh Wall
London E14 9TP
8.MARKETING AUTHORISATION NUMBER(S)
9.DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
Date of first authorisation: 13 April 1999
Date of first renewal: 15 April 2004
Date of latest renewal: 13 April 2009
10.DATE OF REVISION OF THE TEXT