Cetrotide

Cetrorelix acetate.

One vial with 55.7 mg powder containing as active substance 0.26 - 0.27 mg cetrorelix acetate equivalent to 0.25 mg cetrorelix.
One pre-filled syringe containing 1 ml water for injections.
Excipients/Inactive Ingredients: Additionally, the powder contains mannitol as excipient.

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.
Posology: 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.
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 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.
Method of administration: Cetrotide 0.25 mg 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 medicinal product in a slow rate to facilitate the progressive absorption of the medicinal product.
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. The starting day of Cetrotide is depending on the ovarian response, i.e. the number and size of growing follicles and/or the amount of circulating oestradiol. The start of Cetrotide may be delayed in absence of follicular growth, although clinical experience is based on starting Cetrotide on day 5 or day 6 of stimulation.
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 starting day of Cetrotide is depending on the ovarian response, i.e. the number and size of growing follicles and/or the amount of circulating oestradiol. The start of Cetrotide may be delayed in absence of follicular growth, although clinical experience is based on starting Cetrotide on day 5 or day 6 of stimulation.
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 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.

Cetrotide is not to be used in the presence of any of the conditions listed as follows: Hypersensitivity to cetrorelix acetate, extrinsic peptide hormones or mannitol.
During pregnancy and lactation.
Patients with severe renal impairment.

Allergic conditions: Cases of allergic/pseudoallergic reactions, including life-threatening anaphylaxis with the first dose have been reported.
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 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.
Congenital anomalies: 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 follow-up studies in 316 newborns of women administered cetrorelix for infertility treatments suggest that cetrorelix does not increase the risk of congenital anomalies in the offsprings.
Hepatic impairment: Cetrorelix has not been studied in patients with hepatic impairment and caution is therefore warranted.
Renal impairment: Cetrorelix has not been studied in patients with renal impairment and caution is therefore warranted.
Cetrorelix is contraindicated in patients with severe renal impairment.
Effects on 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).
Fertility: 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 one 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 pseudo-allergic/anaphylactoid reactions have been reported.
Mild to moderate ovarian hyperstimulation syndrome (OHSS) (WHO grade I or II) have been commonly reported which is an intrinsic risk of the stimulation procedure (see Precautions). Inversely, severe OHSS remains uncommon.
Symptoms like abdominal pain, tension, nausea, vomiting, diarrhoea and breathing difficulties may indicate an OHSS. Inform the doctor immediately, if the patient feels such symptoms.
If the patient notices any unwanted effect not mentioned in this monograph or if the patient is unsure about the effect of this medicine, inform the doctor or pharmacist.
The adverse reactions reported are classified according to frequency of occurrence as follows: (See Table 1.)

Click on icon to see table/diagram/image

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Table 2.)

Click on icon to see table/diagram/image

No formal drug-drug interaction studies have been performed with Cetrotide.
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, the possibility of interactions with gonadotropins or medicinal products that may induce histamine release in susceptible individuals, cannot be totally excluded.

Instructions for use and handling, and disposal: HOW TO MIX AND INJECT CETROTIDE: Before starting to use this medicine, read these instructions the whole way through first.
This medicine is only for the patient - do not let anyone else use it.
Use each needle, vial and syringe only once.
Before starting Cetrotide: 1. This medicine must be at room temperature prior to injection. Remove from the refrigerator approximately 30 minutes before use.
2. Wash hands: It is important that the hands and the things used are as clean as possible.
Lay out everything needed on a clean surface: one vial of powder; one pre-filled syringe with sterile water (solvent); one needle with a yellow mark - for injecting the sterile water into the vial and drawing the made up medicine out from the vial; one needle with a grey mark - for injecting into the belly; two alcohol swabs.
Mixing the powder and water to make the medicine: 1. Remove the plastic cap from the vial: There will be a rubber stopper underneath - keep this in the vial.
Wipe the rubber stopper and metal ring with the first 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. Remove the cap from the needle.
Push the yellow needle through the centre of the rubber stopper of the vial.
Slowly push in the plunger of the syringe to inject the water into the vial. Do not use any other sort of water.
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 or it will create bubbles in the medicine.
4. Re-filling the syringe with the medicine from the vial: Turn the vial upside down.
Then, gently pull back the plunger, in order to draw the medicine from the vial into the syringe. Take care not to pull out completely the plunger with the attached plunger stopper. In case the plunger was pulled out with the plunger stopper by mistake, make sure to discard the dose as sterility will be lost, and prepare a new dose (and restart from step 1).
If any medicine is left in the vial, pull out the yellow needle until the end of the needle is just inside the rubber stopper. Looking from the side through the gap in the rubber stopper can control the movement of the needle and the liquid.
Make sure to collect all of the medicine from 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 medicine: 1. Removing air bubbles: Unwrap the needle with the grey mark on it. Screw the grey needle onto the syringe and remove the cap from the grey needle.
Hold the syringe with the grey needle pointing upwards and check for any 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 are gone.
Do not touch the grey needle and do not let the needle touch any surface.
2. Clean the injection site: Choose an injection site on the belly. It is best around the belly button (navel). To reduce skin irritation, select a different part of the belly each day.
Clean the skin at the chosen injection site with the second alcohol swab - use a circular motion.
3. Piercing the skin: Hold the syringe in one hand - like holding a pencil.
Gently pinch up the skin surrounding the site of injection and hold this firmly with the other hand.
Slowly push the grey needle completely into the skin at an angle of about 45 to 90 degrees - then let go of the skin.
4. Injecting the medicine: Gently pull back the plunger of the syringe. If blood appears, follow Step 5 as follows.
If no blood appears, slowly push the plunger in to inject the medicine.
When the syringe is empty, take out the grey needle slowly at the same angle.
Use the second alcohol swab to gently apply pressure where the needle was inserted.
5. If blood appears: take out the grey needle slowly at the same angle; use the second alcohol swab to gently apply pressure to the injection site; empty the medicine into a sink and follow Step 6 as follows; wash the 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 so that they are safe to be thrown away.
Ask the pharmacist how to safely dispose of used needles, vial and syringe.
Missing a dose: If the patient missed to administer Cetrotide 0.25 mg on one day, contact the doctor immediately and ask for advice.
Ideally Cetrotide 0.25 mg should be administered at 24 hours intervals. But if the patient missed to administer Cetrotide 0.25 mg at the right time it is no problem to administer this dose at a different time of the same day.
Incompatibilities: As cetrorelix is incompatible with several substances of common parenteral solutions it should be dissolved only by using water for injections.

The solution should be used immediately after preparation.
Store at 2- 8 °C. Keep the container in the outer carton in order to protect it from light.

Trophic Hormones & Related Synthetic Drugs

H01CC02 - cetrorelix ; Belongs to the class of anti-gonadotropin-releasing hormones. Used in hypothalamic hormone preparations.

POM