CETROTIDE POWDER AND SOLVENT FOR SOLUTION FOR INJECTION 0.25MG

Indications

• Adjunct in the treatment of female infertility
• Prevention of premature ovulation during assisted reproductive techniques

Dosage

Adults: 250 micrograms once daily, administered in the morning or each afternoon starting on day 5 or 6 of ovarian stimulation with gonadotrophins and continued throughout administration of gonadotrophins including the day of ovulation induction.

Mechanism of action

Cetrorelix binds to the gonadotropin-releasing hormone receptor, acting as a potent inhibitor of gonadotropin secretion. It competes with natural GnRH for binding to membrane receptors on pituitary cells, thus controlling the release of LH and FSH in a dose-dependent manner. The onset of LH suppression occurs approximately one hour after administration, with continuous treatment maintaining this suppression, predominantly affecting LH more than FSH.

Pharmacodynamics

Cetrorelix exhibits gonadotropin-releasing hormone antagonistic activity, effectively suppressing the production and release of LH and FSH from the anterior pituitary. This suppression prevents the LH surge that triggers ovulation, hence its use in fertility treatments. The drug does not induce an initial release of endogenous gonadotropins, consistent with its antagonistic mechanism.

Pharmacokinetics

Cetrorelix is administered via subcutaneous injection, with its pharmacokinetics characterized by rapid absorption and peak serum concentrations occurring shortly after administration. The elimination half-life and detailed distribution characteristics are not extensively documented, but the suppression of LH levels is maintained with continued dosing. The manufacturer's recommendations advise caution in hepatic and renal impairment, although specific pharmacokinetic data in these populations are lacking.

Contra-indications

• Confirmed pregnancy
• Severe renal impairment
• Moderate to severe hepatic impairment

Adverse effects

• Ovarian hyperstimulation syndrome
• Headache
• Nausea
• Skin reactions
• Malaise
• Dyspnoea
• Facial swelling
• Hypersensitivity
• Abdominal distension

Precautions

• Use with caution in mild to moderate renal impairment
• Use with caution in hepatic impairment

Pregnancy

Avoid in confirmed pregnancy.

Breast-feeding

Avoid.

Storage

Store in a cool, dry place, protected from light. Follow specific manufacturer guidelines.

Formulations

• Powder and solvent for solution for injection (Cetrorelix acetate 250 micrograms)

Mechanism of action

Cetrorelix binds to the gonadotropin releasing hormone receptor and acts as a potent inhibitor of gonadotropin secretion. It 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. Cetrotide 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 Cetrotide, which is consistent with an antagonist effect. 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. The mechanisms through which luteinizing hormone (LH)-releasing hormone (LHRH) antagonists suppress pituitary gonadotroph functions and LHRH-receptor (LHRH-R) expression are incompletely understood. Consequently, we investigated the direct effect of LHRH antagonist cetrorelix in vitro on the expression of the pituitary LHRH-R gene and its ability to counteract the exogenous LHRH and the agonist triptorelin in the regulation of this gene. We also compared the effects of chronic administration of cetrorelix and triptorelin on the LHRH-R mRNA level and gonadotropin secretion in ovariectomized (OVX) and normal female rats. The exposure of pituitary cells in vitro to 3-min pulses of 1 nM LHRH or 0.1 nM triptorelin for 5 hr increased the LHRH-R mRNA level by 77-88%. Continuous perfusion of the cells with 50 nM cetrorelix did not cause any significant changes, but prevented the stimulatory effect of LHRH pulses on the receptor mRNA expression. In OVX rats, 10 days after administration of a depot formulation of cetrorelix, releasing 100 microg of peptide daily, the elevated LHRH-R mRNA level was decreased by 73%, whereas daily injection of 100 microg of triptorelin caused a 41% suppression. In normal female rats, cetrorelix treatment suppressed the LHRH-R mRNA level by 33%, but triptorelin increased it by 150%. The highly elevated serum LH levels in OVX rats and the normal LH concentration of cycling rats were rapidly and completely suppressed by cetrorelix. Triptorelin decreased the serum LH in OVX rats to the precastration level, but had no effect on basal LH in normal rats. Our results confirm that LHRH antagonists, such as cetrorelix, inhibit the gene expression of pituitary LHRH-R indirectly, by counteracting the stimulatory effect of LHRH. A rapid suppression of serum LH by LHRH antagonists would be advantageous in the treatment of sex hormone-dependent tumors and other conditions. Cetrorelix binds with high affinity to luteinising hormone releasing hormone (LHRH) receptors, and labelled LHRH was shown to be displaced from the two classes of LHRH receptors by the compound. In vitro, cetrorelix dose-dependently inhibited the LHRH-mediated LH release in perfused rat pituitary cell systems. Further, in a recently established in vitro assay, cetrorelix proved to be a high affinity antagonist at the LHRH-receptor and dose-dependently blocked the signal transduction induced by LHRH.

Pharmacodynamics

Cetrorelix is a synthetic decapeptide with gonadotropin-releasing hormone (GnRH) antagonistic activity. 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. 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.