One vial with 55.7 mg powder containing as active substance 0.26 - 0.27 mg cetrorelix acetate equivalent to 0.25 mg cetrorelix. Additionally, the powder contains mannitol as excipient.
One pre-filled syringe containing 1 ml water for injections.
Pharmacotherapeutic Group: LHRH-Antagonist. ATC Code: G03X.
Cetrotide 0.25 mg inhibits the effects of a natural hormone, called luteinising hormone releasing hormone (LHRH). LHRH regulates the secretion of another hormone, called luteinising hormone (LH), which induces ovulation during the menstrual cycle. Cetrotide 0.25 mg inhibits premature ovulation which is undesirable during hormone treatment for ovarian stimulation as only mature egg cells are suitable for fertilisation.
Pharmacology: Pharmacodynamics: 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 evaluated. 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.
Pharmacokinetics: 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 (Vd,area) 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.
Prevention of premature ovulation in patients undergoing a controlled ovarian stimulation, followed by oocyte pick-up and assisted reproductive techniques.
In clinical trials, Cetrotide 0.25 mg was used with human menopausal gonadotropin (HMG), however, limited experience with recombinant FSH suggested similar efficacy.
Cetrotide 0.25 mg 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 pseudo-allergic reactions 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.
Following the first administration of Cetrotide 0.25 mg, 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.
Cetrotide 0.25 mg is for subcutaneous injection into the lower abdominal wall.
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.
Administration in the Morning: Treatment with Cetrotide 0.25 mg 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 0.25 mg 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.
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.
Additional Information on Special Populations:
There is no relevant indication for the use of Cetrotide in children or geriatric populations.
Overdosage in humans may result in a prolonged duration of action but is unlikely to be associated with acute toxic effects. Therefore, in case of overdosage, no specific measures are required.
In acute toxicity studies in rodents, nonspecific toxic symptoms were observed after intraperitoneal administration of cetrorelix doses >200 times higher than the pharmacologically effective dose after SC administration.
Hypersensitivity to cetrorelix acetate, extrinsic peptide hormones or mannitol.
Pregnancy and lactation.
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 0.25 mg during a repeated ovarian stimulation procedure. Therefore Cetrotide 0.25 mg should be used in repeated cycles only after a careful risk/benefit evaluation.
Effects on the Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. Due to its pharmacological profile cetrorelix is unlikely to impair the patient’s ability to drive or to operate machinery.
Cetrotide 0.25 mg is not intended to be used during pregnancy and lactation (see Contraindications).
Studies in animals have indicated that cetrorelix exerts a dose related influence on fertility, reproductive performance and pregnancy. No teratogenic effects occurred when the drug was administered during the sensitive phase of gestation.
Mild and transient reactions at the injection site, e.g. erythema, itching and swelling.
A severe hypersensitivity reaction, associated with cough, rash and hypotension was observed in 1 patient after 7 months of treatment of ovarian cancer with cetrorelix (10 mg/day). The patient recovered completely within 20 minutes. A causal relationship could not be excluded. Uncommonly, cases of hypersensitivity reactions, including pseudoallergic/anaphylactoid reactions have been reported.
Mild to moderate ovarian hyperstimulation syndrome (OHSS) [World Health Organization (WHO) grade I or II] have been commonly reported which is an intrinsic risk of the stimulation procedure (see Precautions). Inversely, severe ovarian hyperstimulation syndrome (OHSS) remains uncommon.
Symptoms like abdominal pain, tension, nausea, vomiting, diarrhoea and breathing difficulties may indicate an OHSS. Inform the physician immediately if such symptoms are felt. Inform the physician or pharmacist of any unwanted effect not mentioned previously or if unsure about the effect of Cetrotide.
The adverse reactions reported as follows are classified according to frequency of occurrence: Very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1000 to <1/100; rare ≥1/10,000 to <1/1000; very rare: <1/10,000.
Within each frequency grouping, adverse effects are presented in order of decreasing seriousness: Immune System Disorders:
Uncommon: Systemic allergic/pseudoallergic reactions including life-threatening anaphylaxis.
Nervous System Disorders:
Reproductive System and Breast Disorders:
Common: Mild to moderate OHSS (WHO grade I or II) can occur which is an intrinsic risk of stimulation procedure (see Precautions). Uncommon: Severe OHSS (WHO grade III).
General Disorders and Administration Site Conditions:
Common: Local reactions at the injection site (eg, erythema, swelling and pruritus) have been reported. Usually, they were transient in nature and of mild intensity. The frequency as reported in clinical trials was 9.4% following multiple injections of cetrorelix 0.25 mg.
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, although there has been no evidence of drug interactions, especially with commonly used medications, gonadotropins or products that may induce histamine release in susceptible individuals, the possibility of interactions cannot be totally excluded.
Instructions for Use/Handling and Disposal: Before administering Cetrotide, read the following instructions carefully.
Use each needle, vial and syringe only once.
Instruction for Usage: Before Administering Cetrotide:
1. Wash hands. It is important that hands and all items being used are as clean as possible.
2. Lay-out on a clean surface everything that is needed [1 vial, 1 pre-filled syringe with water (solvent), 1 injection needle with a yellow mark - for injecting the sterile water into the vial, 1 injection needle with a grey mark - for injecting the Cetrotide into the belly, and 2 alcohol swabs].
Mixing the Powder and Water to make the Solution for Injection:
1. Remove the plastic cap from the vial. Keep the rubber stopper underneath the cap. Wipe the aluminum ring and the rubber stopper with an alcohol swab.
2. Adding the water from the pre-filled syringe to the powder in the vial: Unwrap the needle with the yellow mark on it. Remove the cap from the pre-filled syringe and screw the yellow needle onto it. Then remove the cap from the needle. Push the yellow needle through the centre of the rubber stopper of the vial. Slowly push the plunger of the syringe to inject the water into the vial. Do not use any other solvent. Leave the syringe in the rubber stopper.
3. Mixing the powder and water in the vial: While carefully holding the syringe and vial, swirl gently to mix the powder and water together. When it is mixed, it will look clear and have no particles in it. Do not shake to avoid forming bubbles during dissolution.
4. Refilling the syringe with the medicine from the vial: Turn the vial upside down. Pull the plunger out to draw the content from the vial into the syringe. If solution is left in the vial, pull out the yellow needle until the opening of the needle is just inside the stopper. If one will look from the side through the gap in the rubber stopper, one can control the movement of the needle and the liquid. It is important to withdraw the entire contents of the vial. Put the cap back on the yellow needle. Unscrew the yellow needle from the syringe and lay down the syringe.
Preparing the Injection Site and Injecting the Cetrotide:
1. Removing Air Bubbles: Unwrap the needle with grey mark on it. Screw the grey needle onto the syringe and remove the cap of the grey needle. Invert the syringe and check for air bubbles. To remove air bubbles, gently flick the syringe until all the air collects at the top, then slowly push the plunger in, until the air bubbles have been expelled. Do not touch the grey needle or allow the needle to touch any surface.
2. Clean The Injection Site: Choose an injection site on the belly, preferably around the belly button (navel). To reduce skin irritation, select a different part of the belly each day. Clean the skin at the injection site with the 2nd alcohol swab in a circular motion.
3. Piercing The Skin: Hold the syringe in 1 hand as one would hold a pencil. Gently pinch up the skin surrounding the site of injection and hold firmly with the other hand. Slowly push the grey needle completely into the skin at an angle of about 45-90°. Once the needle has been inserted completely, release the grasp of the skin.
4. Injecting Cetrotide: Gently pull back the plunger of the syringe. If blood appears, perform Step 5 as follows.
If no blood appears, slowly push the plunger to inject the solution. When all of the solution is injected, withdraw the grey needle slowly at the same angle. Use the 2nd alcohol swab to gently apply pressure where the needle was inserted.
5. If Blood Appears: Withdraw the grey needle slowly at the same angle. Use the 2nd alcohol swab to gently apply pressure to the injection site. Empty the syringe in a sink and do Step 6. Then wash hands and start again with a new vial and pre-filled syringe.
6. Disposal: Use each needle, vial and syringe only once. Put the cap back on the needles for safe disposal.
Incompatibilities: As cetrorelix is incompatible with several substances of common parenteral solutions, it should be dissolved only by using water for injections.
Store at 2-8°C. Protect from light.
Missed Dose: If patient missed to administer Cetrotide 0.25 mg on one day, contact the doctor immediately and ask for advise.
Ideally, Cetrotide 0.25 mg should be administered at 24 hours intervals. But if dose is missed to administer at the right time it is no problem to administer this dose at a different time of the same day.
H01CC02 - cetrorelix ; Belongs to the class of anti-gonadotropin-releasing hormones. Used in hypothalamic hormone preparations.
Inj (vial) 0.25 mg x 7's.