Zuellig Pharma
Full Prescribing Info
Cetrorelix acetate.
Each vial contains as active substance cetrorelix acetate 0.26 to 0.27 mg (equivalent to cetrorelix 0.25 mg).
Each pre-filled syringe contains water for injections 1 mL for cetrorelix 0.25 mg.
Excipients/Inactive Ingredients: Mannitol.
Pharmacotherapeutic Group: Anti-gonadotropin releasing hormone. ATC Code: H01CC02.
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 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/injection, repeated injections every 24 hrs will maintain the effect of cetrorelix.
In all 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 SC administration is about 85%. The total plasma clearance and the renal clearance are 1.2 mL/min/kg and 0.1 mL/min/kg, respectively. The volume of distribution (Vd) is 1.1 L/kg. The mean terminal half-lives following IV and SC administration are about 12 hrs and 30 hrs, respectively, demonstrating the effect of absorption processes at the injection site. The SC administration of single doses (0.25 to 3 mg cetrorelix) and also daily dosing over 14 days show linear kinetics.
Toxicology: Preclinical Safety Data: Nonclinical 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 SC administration of cetrorelix. No signs of medicinal product-related local irritation or incompatibility were noted in dogs after IV, 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.
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 folliculate-stimulating hormone (FSH) suggested similar efficacy.
Dosage/Direction for Use
Cetrotide should only be prescribed by a specialist experienced in this field.
For SC injection under the skin of the lower abdominal wall preferably around the navel.
To minimize local irritation, the injection site should be varied daily.
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 (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 allergic/pseudo-allergic reaction to the injection. Facilities for the treatment of such reactions should be immediately available.
Administration: In the Morning: Treatment with Cetrotide should commence on day 5 or 6 of ovarian stimulation (approximately 96-120 hrs 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.
In the Evening: Treatment with Cetrotide should commence on day 5 of ovarian stimulation (approximately 96-108 hrs 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.
Instructions for Use: Before self-administering Cetrotide, read the following instructions carefully: 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, 1 injection needle with a yellow mark, one injection needle with a grey mark and 2 alcohol swabs).
3. Flip-off the plastic cover of the vial. Wipe the aluminium ring and the rubber stopper with an alcohol swab.
4. Take the injection needle with the yellow mark and remove the wrapping. Take the pre-filled syringe and remove the cover. Put the needle on the syringe and remove the cover of the needle.
5. Push the needle through the centre of the rubber stopper of the vial. Inject the water into the vial by slowly pushing the plunger of the syringe.
6. Leave the syringe on the vial. Gently agitate the vial until the solution is clear and without residue. Avoid forming bubbles during dissolution.
7. Draw the whole contents of the vial into the syringe. If solution is left in the vial, invert the vial, pull back the needle until the opening of the needle is just inside the stopper. If one will look from the side through the gap in the stopper, one can control the movement of the needle and the liquid. It is important to withdraw the entire contents of the vial.
8. Detach the syringe from the needle and lay down the syringe. Take the injection needle with the grey mark and remove its wrapping. Put the needle on the syringe and remove the cover of the needle.
9. Invert the syringe and push the plunger until all air bubbles have been expelled. Do not touch the needle or allow the needle to touch any surface.
10. Choose an injection site at the lower abdominal wall, preferably around the navel. Take the 2nd alcohol swab and clean the skin at the injection site. Hold the syringe in one hand. Gently pinch up the skin surrounding the site of injection and hold firmly with the other hand.
11. Hold the syringe as one would hold a pencil, insert the needle completely into the skin at an angle of about 45°.
12. Once the needle has been inserted completely, release the grasp of the skin.
13. Pull back gently the plunger of the syringe. If blood appears, continue as described in Step 14. If no blood appears, inject the solution slowly by pushing the plunger gently forward. After all of the solution is injected, withdraw the needle slowly, applying gentle pressure with the alcohol swab on the skin where the needle was inserted. Withdraw the needle at the same angle as it was inserted.
14. If blood appears, withdraw the needle with the syringe and gently apply pressure to the injection site. Do not use this solution but empty the syringe in a sink. Start again with Step 1.
15. Use the syringe and needles only once. Dispose of the syringe and needles immediately after use (put the covers on the needles to avoid injury).
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, 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, or any structural analogues of gonadotropin-releasing hormone (GnRH), extrinsic peptide hormones or mannitol.
Postmenopausal women.
Patients with moderate to severe renal and hepatic impairment.
Use in pregnancy & lactation: Cetrotide is not intended to be used during pregnancy and lactation.
Studies in animals have indicated that cetrorelix exerts a dose-related influence on fertility, reproductive performance and pregnancy. No teratogenic effects occurred when Cetrotide was administered during the sensitive phase of gestation.
Special Precautions
Special care should be taken in women with signs and symptoms of 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 eg, with rest, IV 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 careful risk/benefit evaluation.
Effects on the Ability to Drive or Operate Machinery: Cetrotide has no or negligible influence on the ability to drive or use machines.
Use In Pregnancy & Lactation
Cetrotide is not intended to be used during pregnancy and lactation.
Studies in animals have indicated that cetrorelix exerts a dose-related influence on fertility, reproductive performance and pregnancy. No teratogenic effects occurred when Cetrotide was administered during the sensitive phase of gestation.
Adverse Reactions
The most commonly reported side effects are local injection site reactions eg, 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.
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.
Frequencies of occurrence are reported as: 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).
Immune System Disorders: Uncommon: Systemic allergic/pseudo-allergic reactions including life-threatening anaphylaxis.
Nervous System Disorders: Uncommon: Headache.
Gastrointestinal Disorders: Uncommon: Nausea.
Reproductive System and Breast Disorders: Common: Mild to moderate OHSS (WHO grade I or II) can occur which is an intrinsic risk of the stimulation procedure. 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 multiples injections of cetrorelix.
Drug Interactions
In vitro investigations have shown that interactions are unlikely with medicinal products that are metabolised by cytochrome P-450 or glucuronised or conjugated in some other way. However, although 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 interactions cannot be totally excluded.
Incompatibilities: Cetrotide must not be mixed with other medicinal products except the solvent provided.
Caution For Usage
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 cetrorelix 0.23 mg.
The solution should be used immediately after reconstitution.
Store in a refrigerator (2°C-8°C). Keep the container in the original carton in order to protect from light. The patient may remove the product from the refrigerator and store it not above 30°C for one single period of up to a maximum of 3 months. The solution must be used immediately after reconstitution. The product must not be used after expiry date.
ATC Classification
H01CC02 - cetrorelix ; Belongs to the class of anti-gonadotropin-releasing hormones. Used in hypothalamic hormone preparations.
Powd for inj (vial) 0.25 mg/mL x 7's.
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