Cetrorelix Acetate for Injection 0.25mg

  1. Name of the medicinal product

Cetrorelix 0.25 mg powder and solvent for solution for injection Taj Pharma

  1. 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.

  1. Pharmaceutical form

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 4.0-6.0.

  1. Clinical particulars

4.1 Therapeutic indications

Prevention of premature ovulation in patients undergoing a controlled ovarian stimulation, followed by oocyte pick-up and assisted reproductive techniques.

In clinical trials Cetrorelix was used with human menopausal gonadotropin (HMG), however, limited experience with recombinant follicle-stimulating hormone (FSH) suggested similar efficacy.

4.2 Posology and method of administration

Cetrorelix should only be prescribed by a specialist experienced in this field.

Posology

The first administration of Cetrorelix 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.

Elderly

There is no relevant use of Cetrorelix in the geriatric population.

Paediatric population

There is no relevant use of Cetrorelix in the paediatric population.

Method of administration

Cetrorelix 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 Cetrorelix 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 Cetrorelix 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 Cetrorelix may be delayed in absence of follicular growth, although clinical experience is based on starting Cetrorelix on day 5 or day 6 of stimulation.

Administration in the evening

Treatment with Cetrorelix 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 Cetrorelix 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 Cetrorelix may be delayed in absence of follicular growth, although clinical experience is based on starting Cetrorelix on day 5 or day 6 of stimulation.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

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 gonadotropin-releasing hormone (GnRH), extrinsic peptide hormones or to any of the excipients listed in section 6.1.
  • During pregnancy and lactation.
  • Patients with severe renal impairment.

4.4 Special warnings and precautions for use

Allergic conditions

Cases of allergic/pseudoallergic reactions, including life-threatening anaphylaxis with the first dose have been reported (see section 4.8).

Special care should be taken in women with signs and symptoms of active allergic conditions or known history of allergic predisposition. Treatment with Cetrorelix 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 OHSS 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 benefit/risk 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 (see section 4.3).

4.5 Interaction with other medicinal products and other forms of interaction

No formal drug-drug interaction studies have been performed with cetrorelix. 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.

4.6 Fertility, pregnancy and lactation

Pregnancy and breast-feeding

Cetrorelix is not intended to be used during pregnancy and lactation (see section 4.3).

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 medicinal product was administered during the sensitive phase of gestation.

4.7 Effects on ability to drive and use machines

Cetrorelix has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions 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 Cetrorelix 0.25 mg.

Mild to moderate 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.

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
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 (see section 4.4).
Uncommon:Severe OHSS (WHO grade III)
General disorders and administration site conditions
Common:Local reactions at the injection site (e.g. erythema, swelling and pruritus).

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.

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.

  1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: anti-gonadotropin-releasing hormones.

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).

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.

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.

5.2 Pharmacokinetic properties

Absorption

The absolute bioavailability of cetrorelix after subcutaneous administration is about 85%.

Distribution

The volume of distribution (Vd) is 1.1 L x kg-1.

Elimination

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 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.

Linearity

The subcutaneous administration of single doses (0.25 mg to 3 mg cetrorelix) and also daily dosing over 14 days show linear kinetics.

5.3 Preclinical safety data

Non-clinical 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 subcutaneous administration of cetrorelix. No signs of medicinal product-related local irritation or incompatibility were noted in dogs after intravenous, intraarterial 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.

  1. Pharmaceutical particulars

6.1 List of excipients

Powder

Mannitol

Solvent

Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vial: 2 years

After reconstitution: use immediately

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C). Do not freeze or place next to the freezer compartment or a freezer pack.

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

The unopened medicinal product may be stored in the original package at room temperature (not above 30°C) for up to three months.

This medicinal product must be allowed to reach room temperature prior to injection. It should be removed from the refrigerator approximately 30 minutes before use.

6.5 Nature and contents of container

Powder

2 ml vials (Type I glass) with a stopper (bromobutyl rubber) and flip-off aluminium cap.

1 vial contains 0.25 mg cetrorelix.

Solvent

Pre-filled syringe (Type I glass) with plunger stopper (siliconised bromobutyl rubber) and tip cap (polypropylene and styrene butadiene rubber).

1 pre-filled syringe contains 1 ml of water for injections.

Pack sizes

1 vial and 1 pre-filled syringe or 7 vials and 7 pre-filled syringes.

Additionally, for each vial the pack contains:

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 and other handling

This medicinal product must be allowed to reach room temperature prior to injection. It should be removed from the refrigerator approximately 30 minutes before use.

Cetrorelix 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.

The entire contents of the vial should be withdrawn to ensure 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.

 

  1. Manufactured in India by:
    TAJ PHARMACEUTICALS LTD.
    Mumbai, India
    Unit No. 214.Old Bake House,
    Maharashtra chambers of Commerce Lane,
    Fort, Mumbai – 400001
    at:Gujarat, INDIA.
    Customer Service and Product Inquiries:
    1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
    Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
    E-mail: tajgroup@tajpharma.com

 

Cetrorelix Acetate for Injection 0.25mg

Package leaflet: Information for the user

Cetrorelix powder and solvent for solution for injection Taj Pharma

Cetrorelix

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

  • Keep this You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects, talk to your doctor or This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

  1. What Cetrorelix is and what it is used for
  2. What you need to know before you use Cetrorelix
  3. How to use Cetrorelix
  4. Possible side effects
  5. How to store Cetrorelix
  6. Contents of the pack and other information How to mix and inject Cetrorelix

 

1.   What Cetrorelix is and what it is  used for

What Cetrorelix is

This medicine stops your body from releasing an egg from your ovary (ovulation) during your menstrual cycle. Cetrorelix belongs to a group of medicines called ‘anti-gonadotropin-releasing hormones’.

What Cetrorelix is used for

Cetrorelix is one of the medicines used during ‘assisted reproductive techniques’ to help you get pregnant.    It stops eggs being released straight away. This is because if the eggs are released too early (premature ovulation) it may not be possible for your doctor to collect them.

How Cetrorelix works

Cetrorelix blocks a natural hormone in your body called LHRH (‘luteinising hormone releasing hormone’).

  • LHRH controls another hormone, called LH (‘luteinising hormone’).
  • LH stimulates ovulation during your menstrual

This means that Cetrorelix stops the chain of events that leads to an egg being released from your ovary. When your eggs are ready to be collected, another medicine will be given to you that will release them (ovulation induction).

2. What you need to know before you use Cetrorelix Do not use Cetrorelix

  • if you are allergic to cetrorelix or any of the other ingredients of this medicine (listed in section 6).
  • if you are allergic to medicines similar to Cetrorelix (any other peptide hormones)
  • if you are pregnant or breast-feeding
  • if you have severe kidney

Do not use Cetrorelix if any of the above applies to you. If you are not sure, talk to your doctor before using this medicine.

Warnings and precautions

Allergies

Tell your doctor before using Cetrorelix if you have an active allergy or have had allergies in the past.

Ovarian Hyper-stimulation Syndrome (OHSS)

Cetrorelix is used together with other medicines that stimulate your ovaries to develop more eggs ready to be released. During or after you receive these medicines, you may develop OHSS. This is when your follicles develop too much and become large cysts. For possible signs to look out for and what to do if this happens see section 4 ‘Possible side effects’.

Using Cetrorelix during more than one cycle

Experience of using Cetrorelix during more than one cycle is small. Your doctor will carefully look at the benefits and risks for you, if you need to have Cetrorelix during more than one cycle.

Liver disease

Tell your doctor before using Cetrorelix if you have a liver disease. Cetrorelix has not been investigated in patients with hepatic disease.

Kidney disease

Tell  your doctor before using Cetrorelix if you have     a kidney disease. Cetrorelix has not been investigated in patients with kidney disease.

Children and adolescents

Cetrorelix is not indicated for the use in children and adolescents.

Other medicines and Cetrorelix

Tell your doctor if you are using, have recently used or might use any other medicines.

Pregnancy and breast-feeding

Do not use Cetrorelix if you are pregnant, think you may be pregnant, or if you are breast-feeding.

Driving and using machines

Cetrorelix is not expected to affect your ability to drive and use machines.

3.  How to use Cetrorelix

Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

Using this medicine

This medicine is only for injection just under the skin of your belly (subcutaneous). To reduce skin irritation, select a different part of your belly each day.

  • Your doctor must supervise your first injection. Your doctor or nurse will show you how to prepare and inject the medicine.
  • You can carry out the following injections yourself as long as your doctor has made you aware of the symptoms that may indicate allergy and of the possibly serious or life-threatening consequences that would need immediate treatment (See Section 4 ‘Possible side effects’).
  • Please carefully read and follow the instructions at the end of this leaflet called ‘How to mix and inject Cetrorelix’.
  • You start by using another medicine on day 1 of your treatment You then start using Cetrorelix a few days later. (See next section ‘How much to use’).

How much to use

Inject the contents of one vial (0.25 mg Cetrorelix) once each day. It is best to use the medicine at the same time each day, leaving 24 hours between each dose.

You can choose to inject every morning or every evening.

  • If you are injecting every morning: Start your injections on day 5 or 6 of the treatment Based on your ovarian response, your doctor may decide to start on another day. Your doctor will tell you the exact date and time. You will keep using this medicine up until and including the morning that your eggs are collected (ovulation induction).

OR

  • If you are injecting every evening: Start your injections on day 5 of the treatment Based on your ovarian response, your doctor may decide to start on another day. Your doctor will tell you the exact date and time. You will keep using this medicine up until and including the evening before your eggs are collected (ovulation induction).

If you use more Cetrorelix than you should

Bad effects are not expected if you accidentally inject more of this medicine than you should. The effect of the medicine will last for longer. No specific measures are usually required.

If you forget to use Cetrorelix

  • If you forget a dose, inject it as soon as you remember and talk to your
  • Do not inject a double dose to make up for a forgotten dose.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.  Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Allergic reactions

  • Warm, red skin, itching (often in your groin or armpits), red, itchy, raised areas (hives), runny nose, fast or uneven pulse, swelling of your tongue and throat, sneezing, wheezing, or serious difficulty breathing, or dizziness . You may be having a possible serious, life-threatening allergic reaction to the medicine. This is uncommon (may affect up to 1 in 100 women).

If you notice any of the side effects above, stop using Cetrorelix and contact your doctor immediately.

Ovarian Hyper-stimulation Syndrome (OHSS)

This may occur due to the other medicines that you are using to stimulate your ovaries.

  • Lower abdominal pain together with feeling sick (nausea) or being sick (vomiting) may be the symptoms of OHSS. This may indicate that the ovaries

over-reacted to the treatment and that large ovarian cysts developed. This event is common (may affect up to 1 in 10 women).

  • The OHSS may become severe with clearly enlarged ovaries, decreased urine production, weight gain, difficulty breathing or fluid in your stomach or This event is uncommon (may affect up to 1 in 100 women).

If you notice any of the side effects above, contact your doctor immediately.

Other side effects

Common (may affect up to 1 in 10 women):

  • Mild and short-lasting skin irritation may occur at the injection site like redness, itching, or

Uncommon (may affect up to 1 in 100 women):

  • Feeling sick (nausea)

Reporting of side effects

If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet.

5.  How to store Cetrorelix

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton, vial and pre-filled syringe after EXP. The expiry date refers to the last day of that month.

Store in a refrigerator (2°C – 8°C). Do not freeze or place next to the freezer compartment or a freezer pack.

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

The unopened product may be stored in the original package at room temperature (not above 30°C) for up to three months.

The solution should be used immediately after preparation.

Do not use this medicine if you notice that the white powder in the vial has changed in appearance. Do not use the prepared solution in the vial if it is not clear and colourless or if it has particles in it.

Do not throw any medicine via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

6. Contents of the packs and other information

What Cetrorelix contains

  • The active substance is Each vial contains
    • mg cetrorelix (as acetate).
  • The other ingredients are:
    • In the powder:
    • In the solvent: water for

 

What Cetrorelix looks like and contents of the pack Cetrorelix is a powder and solvent for solution for injection. The white powder comes in a glass vial with a rubber stopper. The solvent is a clear and colourless solution in a pre-filled syringe.

The powder vial contains 0.25 mg cetrorelix and the pre-filled syringe contains 1 ml solvent.

It is available in packs of 1 vial and 1 pre-filled syringe or 7 vials and 7 pre-filled syringes (not all pack sizes may be marketed).

For each vial, the pack also contains:

  • 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 the medicine into your belly
  • two alcohol swabs for cleaning

 

  1. Manufactured in India by:
    TAJ PHARMACEUTICALS LTD.
    Mumbai, India
    Unit No. 214.Old Bake House,
    Maharashtra chambers of Commerce Lane,
    Fort, Mumbai – 400001
    at:Gujarat, INDIA.
    Customer Service and Product Inquiries:
    1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
    Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
    E-mail: tajgroup@tajpharma.com