CETNOSURGE Injection (Cetrorelix Acetate)

Table of Content

Cetrorelix is a luteinising hormone releasing hormone (LHRH) antagonist. LHRH binds to membrane receptors on pituitary cells. It competes with the binding of endogenous LHRH to these receptors. Due to this mode of action, Cetrorelix controls the secretion of gonadotropins.

Cetrorelix is used for 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 HMG, however, limited experience with recombinant FSH suggested similar efficacy.

Ovarian stimulation therapy with gonadotropins is started on cycle Day 2 or 3.  The dose of gonadotropin should be adjusted according to individual response. In the multiple dose regimen, 0.25 mg CETNOSURGE (Cetrorelix )is administered subcutaneously on either day 5 mornings or evening or day 6 morning and continued daily until the day of HCG administration. 

For the use of a Registered Medical Practitioner or a Hospital or a laboratory only

Qualitative and Quantitative Composition

Each combipack contains:

(A) Cetrorelix Acetate for injection 0.25 mg

Each vial contains:

Cetrorelix Acetate eq. to Cetrorelix.................0.25 mg

Excipients................................q.s.

(B) Sterile water for injection IP 1 ml ampoule

Each Ampoule contains:

Sterile Water for Injection I.P.

Dosage Form and Strength

Lyophilized powder for injection 0.25 mg

Subcutaneous use only.

Clinical Particulars

Therapeutic Indications

CETNOSURGE is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian stimulation.

Posology and Method of Administration

CETNOSURGE should only be prescribed by a specialist experienced in this field. CETNOSURGE is for subcutaneous injection into the lower abdominal wall.

Ovarian stimulation therapy with gonadotropins (FSH, hMG) is started on cycle day 2 or 3. The dose of gonadotropins should be adjusted according to individual response. CETNOSURGE should be administered subcutaneously once daily during the early-to-mid-follicular phase.

CETNOSURGE is administered on either stimulation day 5 (morning or evening) or day 6 (morning) and continued daily until the day of hCG administration.

When assessment by ultrasound shows a sufficient number of follicles of adequate size, hCG is administered to induce ovulation and final maturation of the oocytes. No hCG should be administered if the ovaries show an excessive response to the treatment with gonadotropins to reduce the chance of developing ovarian hyperstimulation syndrome (OHSS).

Instructions for Administration

Cetrorelix acetate for injection is a sterile lyophilized powder intended for subcutaneous injection alter reconstitution with Sterile Water for Injection.

  1. CETNOSURGE should only be reconstituted with the solvent provided (Sterile Water for Injection).
  2. Aseptically withdraw the entire contents of the diluent ampoule into a syringe. Push the needle through the centre of the rubber stopper of the appropriate CETNOSURGE vial and slowly inject the solvent into the vial.
  3. Leaving the syringe in the vial, gently swirl the vial until the solution is clear and without residues. Vigorous shaking with bubble formation should be avoided.
  4. Draw the total contents of the vial into the syringe. If necessary, invert the vial and pull back the needle as far as needed to withdraw the entire contents at the vial. This ensures a delivery in the patient of a dose of at least 0.23 mg cetrorelix.
  5. Do not use if the solution contains particles or if the solution is not clear.
  6. The solution should be used immediately after reconstitution.
  7. The injection site should be varied daily when being used in the multiple dose regimen.

Contraindications

  • Hypersensitivity to cetrorelix acetate, extrinsic peptide hormones or mannitol
  • Known hypersensitivity to GnRH or any other GnRH analogues
  • Known or suspected pregnancy and lactation
  • Patients with severe renal impairment

Special Warnings and Precautions for Use

Cetrorelix acetate for injection should be prescribed by specialists who are experienced in fertility treatment. Before starting treatment with cetrorelix, pregnancy must be excluded. Cetrorelix should not be prescribed if a patient is pregnant.

A severe anaphylactic reaction associated with cough, rash and hypotension was observed in one patient after seven months of treatment with cetrorelix (10 mg/day) in a study for an indication unrelated to infertility.

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

During or following ovarian stimulation an OHSS 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 centres practice.

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 risk / benefit evaluation.

Information for Patients

Prior to therapy with cetrorelix acetate for injection, patients should be informed of the duration of treatment and monitoring procedures that will be required. The risk of possible adverse reactions should be discussed.

Laboratory Tests

After the exclusion of pre-existing conditions, enzyme elevations (ALT, AST, GGT, alkaline phosphatase) were found in 1-2% of patients receiving cetrorelix during controlled ovarian stimulation. The elevations ranged up to three times the upper limit of normal. The clinical significance of these findings was not determined.

During stimulation with human menopausal gonadotropin, cetrorelix had no notable effects on hormone levels aside from inhibition of LH surges.

Drug 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, interactions with commonly used medicinal products, including drugs that may induce histamine release in susceptible individuals, may occur.

Use in Special Populations

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.

Pregnant Women

The use of Cetrorelix Injection is contraindicated in pregnant women.

The foetal resorption observed in animal studies is a logical consequence of the alteration in hormonal levels resulting from the antigonadotrophic properties of cetrorelix, which could result in foetal loss in humans as well. Therefore, this drug should not be administered to pregnant women.

Lactating Women

It is not known whether cetrorelix is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of cetrorelix on lactation and/or the breastfed child have not been determined, the use of Cetrorelix Injection is not recommended in nursing mothers.

Undesirable Effects

Local reactions at the injection site (e.g., erythema, redness, itching, bruising, swelling and pruritus) have been reported. Usually, they were transient in nature and mild intensity. Rare cases of hypersensitivity reactions including pseudo-allergic / anaphylactoid reactions have also been reported. Nausea and headache have also been reported.

Mild to moderate OHSS (WHO grade 1 or II) can occur which is an intrinsic risk of the stimulation procedure. Uncommonly severe OHSS (WHO grade III) can occur.

Two still births were reported in phase 3 studies with cetrorelix acetate for Injection.

Clinical follow up studies of 316 newborns of women administered cetrorelix were reviewed. One infant of a set of twin neonates was found to have anencephaly at birth and died after 4 days. The other twin was normal. Developmental findings from ongoing baby follow-up included a child with a ventricular septal detect and another child with bilateral congenital glaucoma.

Four pregnancies that resulted in therapeutic abortion in Phase 2 and Phase 3 controlled ovarian stimulation studies had major anomalies (diaphragmatic hernia, trisomy 21, Klinefelter syndrome, polymalformation, and trisomy 18). In three of these four cases, intracytoplasmic sperm injection (ICSI) was the fertilization method employed; in the fourth case, in vitro fertilization (IVF) was the method employed.

The minor congenital anomalies reported include supernumerary nipple, bilateral strabismus, imperforate hymen, congenital nevi, hemangiomata, and QT syndrome.

The causal relationship between the reported anomalies and cetrorelix is unknown. Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, and progesterone) make causal attribution difficult to study.

Reporting of Side Effects

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@guficbio.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024. By reporting side-effects, you can help provide more information on the safety of this product.

Overdose

Overdosage in humans may result in a prolonged duration of action but is unlikely to be associated with acute toxic effects. There have been no reports of overdosage with cetrorelix injection in humans. Single doses up to 120 mg cetrorelix has been well tolerated in patients treated for other indications without signs of overdosage.

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.

Pharmacological Properties

Mechanism of Action

GnRH induces the production and release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the gonadotrophic cells of the anterior pituitary. Due to a positive estradiol (E2) feedback at midcycle, GnRH liberation is enhanced resulting in an LH surge. This LH surge induces the ovulation of the dominant follicle, resumption of oocyte meiosis and subsequently luteinization as indicated by rising progesterone levels.

Pharmacodynamic Properties

Cetrorelix competes with natural GnRH for binding to membrane receptors on pituitary cells and thus controls the release of LH and FSH in a dose dependent manner. The onset of LH suppression is approximately one hour with the 3 mg dose and two hours with the 0.25 mg dose. This suppression is maintained by continuous treatment and there is a more pronounced effect on LH than on FSH. An initial release of endogenous gonadotropins has not been detected with cetrorelix, which is consistent with an antagonist effect.

The effects of cetrorelix on LH and FSH are reversible after discontinuation of treatment. In women, cetrorelix delays the LH surge, and consequently ovulation, in a dose dependent fashion. FSH levels are not affected at the doses used during controlled ovarian stimulation, following a single 3 mg dose of cetrorelix duration of action of at least 4 days has been established. A dose of cetrorelix 0.25 mg every 24 hours has been shown to maintain the effect.

Pharmacokinetic Properties

The pharmacokinetic parameters of single and multiple doses of cetrorelix acetate injection in adult healthy female subjects are summarized in the following table:

Pharmacokinetic parameters of Cetrorelix for injection following 3 mg single or 0.25 mg single and multiple (daily for 14 days) subcutaneous administration

 

Single dose 3 mg

Single dose 0.25

Multiple dose 0.25 mg

No. of subjects

12

12

12

tmax* (h)

T1/2* (h)

Cmax (ng/ml)

AUC (ng.h/ml)

CL** (ml/min.kg)

Vz** (l/kg)

1.5 (0.5-2)

62.8 (38.2-108)

28.5 (22.5-36.2)

536 (451-636)

1.28a

1.16a

1.0 (0.5-1.5)

5.0 (2.4-48.8)

4.97 (4.17-5.92)

31.4 (23.4-42.0)

1.0 (0.5-2)

20.6 (4.1-179.3)

6.42 (5.18-7.96)

44.5 (36.7-54.2)

* median (min-max)

**arithmetic mean

Tmax -Time to reach observed maximum plasma concentration.

T1/2- Elimination half-life

Cmax - Maximum plasma concentration; multiple dose Css, max

AUC - Area under the Curve; single dose AUCo-inf, multiple dose AUCt

CL - Total plasma clearance

Vz - Volume of distribution

a - Based on IV administration

Absorption

Cetrorelix is rapidly absorbed following subcutaneous injection with maximal plasma concentrations being achieved approximately 1-2 hours after administration. The mean absolute bioavailability of cetrorelix following subcutaneous administration to healthy female subjects is 85%.

Distribution

The volume of distribution of cetrorelix following a single intravenous dose of 3 mg is about 1 l/kg. In vitro protein binding to human plasma is 86%. Cetrorelix concentrations in follicular fluid and plasma were similar on the day of oocyte pick-up in patients undergoing controlled ovarian stimulation. Following subcutaneous administration of cetrorelix 0.25 mg plasma concentrations of cetrorelix were below or in the range of the lower limit of quantitation on the day of oocyte pick-up and embryo transfer.

Metabolism

After subcutaneous administration of 10 mg cetrorelix to females and males, cetrorelix and small amounts of (1-9), (1-7), (1-6), and (1-4) peptides were found in bile samples over 24 hours. In in vitro studies, cetrorelix was stable against phase I- and phase II-metabolism. Cetrorelix was transformed by peptidases, and the (1-4) peptide was the predominant metabolite.

Excretion

Following subcutaneous administration of 10 mg cetrorelix males and females, only unchanged cetrorelix was detected in urine. In 24 hours, cetrorelix and small amounts of the (1-9), (1-7), (1-6), and (1-4) peptides were found in bile samples. 2-4% of the dose was eliminated in the urine as unchanged cetrorelix, while 5-10% was eliminated as cetrorelix and the four metabolites in bile. Therefore, only 7-14% of the total dose was recovered as unchanged cetrorelix and metabolites in urine and bile up to 24 hours. The remaining portion of the dose may not have been recovered since bile and urine were not collected for a longer period of time.

Special Populations

Pharmacokinetic investigations have not been performed either in subjects with impaired renal or liver function, or in the elderly, or in children. There is no evidence of differences in pharmacokinetic parameters for cetrorelix between healthy subjects and patients undergoing controlled ovarian stimulation.

Nonclinical Properties

Animal Toxicology or Pharmacology

Long-term carcinogenicity studies in animals have not been performed with cetrorelix acetate. Cetrorelix acetate was not genotoxic in vitro (Ames test, HPRT test, chromosome aberration test) or in vivo (chromosome aberration test, mouse micronucleus test). Cetrorelix acetate induced polyploidy in CHL-Chinese hamster lung fibroblasts, but not in V79-Chinese hamster lung fibroblasts, cultured peripheral human lymphocytes or in an in vitro micronucleus test in the CHL-cell line. Treatment with 0.46 mg/kg cetrorelix acetate for 4 weeks resulted in complete infertility in female rats which was reversed 8 weeks after cessation of treatment.

Description

Cetrorelix acetate for injection is a synthetic decapeptide with gonadotropin releasing hormone (GnRH) antagonistic activity.

Pharmaceutical Particulars

Incompatibilities

As cetrorelix is incompatible with several substances of common parenteral solutions it should be dissolved only by using the supplied Sterile Water for injection.

Shelf-life

Refer product label for expiry date. Do not use after expiry date.

Packaging Information

CETNOSURGE is available as a vial containing 0.25 mg lyophilized powder for Injection of cetrorelix acetate, along with ampoule containing 1 ml of Sterile Water for injection I.P. as diluent.

Storage and Handling Instructions

Store at 2oC to 8oC. Protect from light. Do not freeze.

Patient Counselling Information

Do not use cetrorelix acetate if you have kidney disease, are allergic to cetrorelix acetate or exogenous peptide hormones (medicines similar to Cetrorelix acetate), are pregnant or think that you might be pregnant, or if you are breastfeeding. Consult your doctor before taking Cetrorelix acetate if you have had severe allergic reactions.

Details of Manufacturer

Gufic Bioscience Ltd.

N.H.No.8, Near Grid, Kabilpor – 396424, Navsari, Gujarat, India.

Marketed by

CIPLA LTD.

Registered Office:

Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg,

Lower Parel, Mumbai - 400013, INDIA

Details of Permission or Licence Number with Date

G/64 dated 22.01.2022

Date of Revision

June 2022