Consumer medicine information

Cetrotide

Cetrorelix

BRAND INFORMATION

Brand name

Cetrotide

Active ingredient

Cetrorelix

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cetrotide.

What is in this leaflet

This leaflet answers some common questions about CETROTIDE.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using CETROTIDE against the benefits it is expected to have for you.

If you have any concerns about using this medicine, ask your doctor, nurse or pharmacist.

Keep this information with your medicine. You may need to read it again later.

What CETROTIDE is used for

CETROTIDE is used to prevent premature ovulation (the release of an egg from the ovary) in women undergoing an assisted reproduction cycle, such as in vitro fertilisation (IVF).

Ovulation that is too early, before the egg has fully matured, is undesirable during hormone treatment for ovarian stimulation, because only mature egg cells are suitable for fertilisation.

Ask your doctor if you have any questions about why CETROTIDE has been prescribed for you. Your doctor may have prescribed it for another reason.

CETROTIDE is available only with a doctor's prescription.

CETROTIDE is not habit-forming.

Before you are given CETROTIDE

When you must not use it

Do not use CETROTIDE if you have an allergy to:

  • Cetrorelix acetate
  • Mannitol
  • Exogenous peptide hormones (medicines similar to CETROTIDE).

Symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not use CETROTIDE if you have, or have had, any of the following medical conditions:

  • liver disease
  • kidney disease.

Do not use CETROTIDE if you have already reached menopause.

Do not use CETROTIDE if you are pregnant or suspect that you might be pregnant.

Do not breastfeed while you are using CETROTIDE. It is not known whether CETROTIDE passes into breast milk. The potential effects on breastfed infants are not known.

Do not use CETROTIDE after the expiry date printed on the packaging has passed, or if the packaging is torn or shows signs of tampering. If your medicine has expired or is damaged, return it to your pharmacist or clinic for disposal.

If you are not sure whether you should start using CETROTIDE, talk to your doctor.

Before you start to use it

Tell your doctor or pharmacist if:

  • you have allergies to any foods, dyes, preservatives or any other medicines
  • you are currently experiencing allergic symptoms.

A condition called Ovarian Hyperstimulation Syndrome (OHSS) may occur during or following a controlled ovarian stimulation. This is when the ovaries overreact to the hormone treatment and become too large. Your doctor will monitor your treatment and advise you what to do.

Compared to natural conceptions, the incidence of birth defects in women using assisted reproductive technologies (ART) may be slightly higher. It is unclear whether this is related to factors inherent to the couple's infertility or the ART procedures.

Talk to your doctor about any concerns you may have before undergoing treatment or before you start using CETROTIDE.

Taking other medicines

Tell your doctor or pharmacist if you are using any other medicines, including:

  • all prescription medicines
  • all medicines, vitamins, herbal supplements or natural therapies you buy without prescription from your pharmacy, supermarket, naturopath or health food shop.

There is a possibility that some medicines and CETROTIDE may interfere with each other.

Your doctor and pharmacist have more information on medicines to be careful with or to avoid while using CETROTIDE.

How CETROTIDE is given

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

Treatment with CETROTIDE should be started under the supervision of a specialist doctor experienced in fertility treatment.

CETROTIDE is given as a course of daily injections.

You should have your injection at the same time each day.

How much to inject

Your doctor will tell you how much CETROTIDE to use and when to inject it.

The contents of one vial of CETROTIDE 250 microgram are given once daily, at 24-hour intervals, either in the morning or in the evening. It is given over several days. Your doctor or nurse will advise you on which days you should use it.

How to inject

CETROTIDE is given as a subcutaneous (under the skin) injection in the lower abdomen.

Your first injection of CETROTIDE should be given by your doctor or nurse. You should remain under their supervision for 30 minutes after this injection in case of allergic reaction.

After the first injection you may be required to administer CETROTIDE yourself. Your doctor or nurse will provide you with appropriate instructions, including the signs, symptoms and treatment of allergic reactions.

Do not self-inject until you are sure of how to do it. Read carefully the Instruction for Use provided in the pack before commencing injections.

Where to inject

CETROTIDE is usually given in the lower abdomen. The injection site should be changed daily to minimise local irritation.

Do not inject into any areas in which you feel lumps, firm knots, depressions, pain or discolouration.

Talk to your doctor if you find anything unusual when injecting.

If you forget to inject it

If you forget an injection or are not sure what to do, contact your doctor or nurse immediately for advice.

Do not inject a double dose on any day.

Ask your doctor if you are not sure what to do or you are having trouble remembering to inject your medicine.

If you injected too much

Immediately contact your doctor or the Poisons Information Centre (In Australia telephone 131 126. In New Zealand telephone 0800 764 766) if you are concerned that you have given yourself too much or someone else has injected themselves with CETROTIDE.

While you are using CETROTIDE

Things you must do

See your doctor regularly and keep all your doctor's appointments so your progress can be checked. Your doctor will monitor you closely throughout your treatment.

Tell your doctor immediately if you become pregnant while using CETROTIDE.

If you are about to be started on any new medicine, tell your doctor or pharmacist that you are using CETROTIDE.

If you plan to have surgery, tell your doctor or dentist that you are using CETROTIDE.

Tell all doctors, dentists and pharmacists who are treating you that you are using CETROTIDE.

Things you must not do

Do not stop using CETROTIDE without telling your doctor.

Do not change the dose unless your doctor tells you to. Changing your dose without advising your doctor can increase your risk of unwanted side effects or prevent the medicine from working properly.

Do not give this medicine to anyone else, even if they have the same condition as you.

Things to be careful of

If you have any of the following symptoms, contact your doctor immediately:

  • nausea
  • vomiting
  • diarrhoea
  • stomach pain or discomfort.

These may be signs of overstimulation of the ovaries which requires urgent attention.

CETROTIDE is not expected to impair your ability to drive or to operate machinery.

Side effects

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are using CETROTIDE.

All medicines can have side effects. Sometimes they are serious, most of the time they are not.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor, nurse or pharmacist to answer any questions you may have.

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • signs of an allergic reaction, including swelling of the face, lips, tongue, or other parts of the body; shortness of breath, wheezing or difficulty breathing; severe skin rash, itching or hives
  • signs of severe OHSS such as lower abdominal pain, severe pelvic pain, nausea, vomiting, diarrhoea followed by rapid weight gain, reduced amounts of urine and shortness of breath.

Tell your doctor, nurse or pharmacist if you notice any of the following and they worry you:

  • redness, itching, swelling of the injection site (these are usually mild and short-lasting)
  • headache
  • feeling sick (nausea)
  • nausea, vomiting, diarrhoea, abdominal pain or discomfort.

Tell your doctor, nurse or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may occur in some patients.

After using CETROTIDE

Storage

Store at 2°C to 8°C (Refrigerate. Do not freeze).

For patients: Should refrigeration be unavailable, CETROTIDE can be stored below 30°C for a single period of up to 3 months after which it must be discarded.

Store in the original package in order to protect it from light.

Inject the reconstituted CETROTIDE as soon as it is prepared. The final solution does not contain a preservative.

Do not use the dissolved solution if it contains particles or is not clear.

Use each vial and syringe only once. Use a new vial and syringe for each dose.

Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it in the car.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If you are self-injecting, discard all sharps into a disposal unit.

If you have any CETROTIDE that has expired or is left over from your treatment, refer this to your clinic.

Product description

What it looks like

CETROTIDE is a sterile white powder in vial(s). CETROTIDE is available in one presentation: 250 microgram in packs of one or seven vials.

Each pack contains:

  • CETROTIDE 250 microgram powder in a glass vial
  • Pre-filled syringe(s) with solvent (water for injections) for dissolving the powder before injection
  • Injection needle(s), with a yellow mark, to be used for injecting the solvent into the vial and withdrawing the solution from the vial
  • Injection needle(s), with a grey mark, to be used for injecting the solution
  • Alcohol swabs for cleaning purposes.

Ingredients

Active ingredient:

  • Cetrorelix acetate

Inactive ingredient:

  • Mannitol

Supplier

CETROTIDE is supplied in Australia by:

Merck Healthcare Pty Ltd
Suite 1, Level 1, Building B
11 Talavera Road
Macquarie Park NSW 2113
E-mail: [email protected]
Phone: 1800 633 463

CETROTIDE is supplied in New Zealand by:

Healthcare Logistics
58 Richard Pearse Drive
Airport Oaks
Auckland
E-mail: [email protected]
Phone: 0800 426 252

Australian Registration Numbers:

CETROTIDE 250 microgram: AUST R 74888

This leaflet was prepared in April 2020.

A014-0420

Published by MIMS June 2020

BRAND INFORMATION

Brand name

Cetrotide

Active ingredient

Cetrorelix

Schedule

S4

 

1 Name of Medicine

Cetrorelix (as acetate).

6.7 Physicochemical Properties

Chemical structure.

Cetrorelix acetate is the acetate salt of a decapeptide with a sequence derived from luteinising hormone releasing hormone (LHRH) and subsequently modified. Five of the ten amino acids present are in the D configuration. The peptide is protected from degradation by means of C- and N-terminal protective groups (acetyl and amide protection). The peptide sequence and chemical structure are as follows:
The molecular formula is C70H92ClN17O14 and the molecular weight is 1431.06.

CAS number.

130143-01-0.

2 Qualitative and Quantitative Composition

Each vial contains 250 microgram of cetrorelix (as acetate). After reconstitution with the solvent provided, the concentration of cetrorelix is 250 microgram/mL.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Cetrorelix acetate is an amorphous white powder, moderately soluble in water and poorly soluble in organic solvents.
Cetrotide is a lyophilised powder for injection. The powder contains mannitol as excipient. The packs also contain solvent (water for injections) in pre-filled syringes.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: LHRH antagonist, ATC code: H01CC02.

Mechanism of action.

Cetrorelix is a 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 the gonadotrophins luteinising hormone (LH) and follicle stimulating hormone (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 250 microgram per injection, repeated injections every 24 hour 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.

Clinical trials.

The efficacy and safety of cetrorelix in controlled ovarian stimulation (COS) followed by assisted reproductive techniques was studied in 6 phase II and 3 phase III studies (total 884 patients). There were three pivotal phase III trials: the first trial was an open randomised controlled trial of cetrorelix 250 microgram per day and the LHRH agonist buserelin, both used with human menopausal gonadotrophin (HMG). One hundred and eighty eight patients were treated with cetrorelix and 86 with buserelin. The second trial was an open uncontrolled study also of cetrorelix 250 microgram per day, in 346 patients. The third study was an open randomised controlled study including cetrorelix 3 mg single dose and the LHRH agonist triptorelin; 115 patients were treated with cetrorelix and 39 with triptorelin.
All studies enrolled women aged 18-39 years with normal uterus and without abnormal ovarian or menstrual function. In the single dose study, the primary efficacy endpoint was defined as prevention of premature LH surge that might have led to termination of the COS cycle. In the multiple dose studies, the primary endpoint was whether or not triggering with human chorionic gonadotrophin (HCG) was performed. Other parameters evaluated included HMG dose, egg numbers, ovum pick-up (OPU), embryo transfer (ET) and pregnancy rates.
The studies concluded that both cetrorelix dosage regimens effectively prevented premature ovulation and luteinisation when used with gonadotrophins in controlled ovarian stimulation, and were comparable to the LHRH agonists tested in this and other ART treatment outcome parameters evaluated.

5.2 Pharmacokinetic Properties

The absolute bioavailability of cetrorelix after subcutaneous (s.c.) 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, area) is 1.1 L/kg. The mean terminal half-lives following intravenous (i.v.) and s.c. administration are about 12 hours and 30 hours, respectively, demonstrating the effect of absorption processes at the injection site. The s.c. administration of single doses (250 microgram to 3 mg cetrorelix) and also daily dosing over 14 days show linear kinetics.

5.3 Preclinical Safety Data

Genotoxicity.

Cetrorelix showed no evidence of genotoxicity in assays for gene mutation in bacterial or mammalian cells. Tests for chromosomal damage in human lymphocytes in vitro and for micronucleus formation in mice in vivo showed that cetrorelix was not clastogenic. Cetrorelix induced binucleated cells and polyploidy in a strain of Chinese hamster lung cells in vitro, but this effect was not seen in human lymphocytes in vitro or in mouse bone marrow cells in vivo.

Carcinogenicity.

Long term carcinogenicity studies with cetrorelix have not been carried out.

4 Clinical Particulars

4.1 Therapeutic Indications

Prevention of premature luteinisation and 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 gonadotrophin (HMG), however, limited experience with recombinant FSH suggested similar efficacy.

4.3 Contraindications

Hypersensitivity to cetrorelix acetate or any structural analogues of GnRH, extrinsic peptide hormones or mannitol.
Pregnancy and lactation.
Post-menopausal women.
Patients with moderate and severe renal and hepatic impairment.

4.4 Special Warnings and Precautions for Use

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

Ovarian hyperstimulation syndrome (OHSS).

During or following ovarian stimulation, ovarian hyperstimulation syndrome (OHSS) can occur. This event must be considered as an intrinsic risk of the stimulation procedure with gonadotrophins.
As OHSS can be life-threatening, the condition should be managed by a specialist experienced in the field.

Hypersensitivity.

Caution is advised in patients with hypersensitivity to GnRH. Special care should be taken in women with signs and symptoms of active allergic conditions or known history of allergic predisposition. The treatment with Cetrotide is not advised in women with severe allergic conditions.

Repeated ovarian stimulation cycles.

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 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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro investigations have shown that interactions are unlikely with medications that are metabolised by cytochrome P450 or glucuronised or conjugated in some other way. However, the possibility of interactions with commonly used medicinal products cannot entirely be excluded.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Cetrorelix treatment resulted in a reversible cessation of mating in female rats at a subcutaneous dose of 464 microgram/kg/day and a reversible decrease in fertility in males at a dose of 68 microgram/kg/day. These are expected pharmacological effects of this class of drug.
See Section 5.3 Preclinical Safety Data.
(Category D)
Cetrotide is not intended to be used during pregnancy (see Section 4.3 Contraindications). There is a theoretical risk of abortion if gonadotrophin releasing hormone antagonists are used during pregnancy. Studies in animals have indicated that cetrorelix increased the incidence of total foetal resorptions when administered to pregnant rats and rabbits during the period of organogenesis, at respective subcutaneous doses of 14.7 microgram/kg/day and 6.8 microgram/kg/day. Cetrorelix was not teratogenic in rats or rabbits at doses adversely affecting pregnancy.
Cetrotide is not intended for use during lactation (see Section 4.3 Contraindications). It is not known whether, or to what extent, cetrorelix is excreted into normal animal or human breast milk. Potential effects of cetrorelix on breastfed infants have not been determined and Cetrotide should, therefore, not be used in breastfeeding women.

4.8 Adverse Effects (Undesirable Effects)

The safety of Cetrotide in patients undergoing controlled ovarian stimulation was evaluated in 9 clinical studies. Cetrotide was given in doses ranging from 0.1 mg to 5 mg, as either a single or multiple dose(s).
Table 1 shows systemic adverse events from the beginning of Cetrotide treatment until the day of embryo transfer at an incidence of ≥ 1%.
Local reactions at the injection site (e.g. erythema, bruising, itching, swelling and pruritus) were reported. Usually, they were of transient nature and mild intensity. In very rare cases, general reactions have been reported.
A single case of hot flushes with a causality assessment of "likely" was also recorded during treatment with cetrorelix in clinical trials.
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.
The following definitions apply to the frequency terminology used hereafter (see Table 2):

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 ovarian hyperstimulation syndrome (WHO grade I or II) can occur which is an intrinsic risk of the stimulation procedure.
Uncommon: Severe ovarian hyperstimulation syndrome (WHO grade III).

General disorders and administration site conditions.

Common: Local reactions at the injection site (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection).

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems in Australia, or at https://nzphvc.otago.ac.nz/reporting/ in New Zealand.

4.2 Dose and Method of Administration

Cetrotide should only be prescribed by or under the supervision of a specialist experienced in this field.
Cetrotide is for subcutaneous injection into the lower abdominal wall.
The first administration of Cetrotide should be performed under the supervision of a physician. 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.
Subsequent injections with Cetrotide may be self-administered as long as the patient is made aware of the signs and symptoms that may include hypersensitivity, the consequences of such a reaction and the need for immediate intervention.
The contents of 1 vial of Cetrotide 250 microgram are to be administered once daily, at 24-hour intervals, either in the morning or in the evening.

Administration in the morning.

Treatment with Cetrotide 250 microgram should commence on day 5 or 6 of ovarian stimulation (approximately 96 to 120 hours after start of ovarian stimulation) with urinary or recombinant gonadotrophins and is to be continued throughout the gonadotrophin treatment period including the day of ovulation induction.

Administration in the evening.

Treatment with Cetrotide 250 microgram should commence on day 5 of ovarian stimulation (approximately 96 to 108 hours after start of ovarian stimulation) with urinary or recombinant gonadotrophins and is to be continued throughout the gonadotrophin treatment period until the evening prior to the day of ovulation induction.

Preparation for administration.

As cetrorelix is incompatible with several ingredients of common parenteral solutions, it should be dissolved only by using water for injections.
Cetrotide should only be reconstituted with the solvent provided, using a gentle, swirling motion. Vigorous shaking with bubble formation should be avoided.
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 230 microgram cetrorelix (250 microgram strength).
The solution should be used immediately after reconstitution.
Use in one patient on one occasion only. Cetrotide contains no antimicrobial preservative.
The injection site should be varied daily.

4.7 Effects on Ability to Drive and Use Machines

Due to its pharmacological profile cetrorelix is unlikely to impair the patient's ability to drive or to operate machinery.

4.9 Overdose

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.
Advise your patients to immediately contact their doctor or the Poisons Information Centre (in Australia telephone 131 126, in New Zealand 0800 764 766) if they are concerned that they have given themselves too much Cetrotide.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

6 Pharmaceutical Particulars

6.1 List of Excipients

Powder: Mannitol.
Solvent: Water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

Information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG) in Australia or on Medsafe Product Detail in New Zealand. The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2°C to 8°C (Refrigerate. Do not freeze).
For patients: Should refrigeration be unavailable, Cetrotide can be stored below 30°C for a single period of up to 3 months after which it must be discarded.
Store in the original package in order to protect from light.

6.5 Nature and Contents of Container

Packs with 1 or 7* Type 1 glass vials, each containing cetrorelix 250 microgram (as cetrorelix acetate) powder for injection, sealed with a rubber stopper.
In addition, for each vial the packs contain:
1 pre-filled syringe (Type 1 glass cartridge closed with rubber stoppers) with 1 mL solvent for parenteral use (water for injections);
1 injection needle (20 gauge);
1 hypodermic injection needle (27 gauge);
2 alcohol swabs.
*Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

Any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes