There have been no reports of overdosage with Цетротидe® 0.25 mg or 3 mg in humans. Single doses up to 120 mg Цетротидe® have been well tolerated in patients treated for other indications without signs of overdosage.
Цетротидe® (cetrorelix acetate for injection) is contraindicated under the following conditions:
The safety of Цетротидe® (cetrorelix acetate for injection) in 949 patients undergoing controlled ovarian stimulation in clinical studies was evaluated. Women were between 19 and 40 years of age (mean: 32). 94.0% of them were Caucasian. Цетротидe® was given in doses ranging from 0.1 mg to 5 mg as either a single or multiple dose.
Table 3 shows systemic adverse events, reported in clinical studies without regard to causality, from the beginning of Цетротидe® treatment until confirmation of pregnancy by ultrasound at an incidence ≥ 1% in Цетротидe® treated subjects undergoing COS.
Table 3: Adverse Events in ≥ 1%
| (WHO preferred term) | Цетротидe® N=949 % (n) |
| Ovarian Hyperstimulation Syndrome* | 3.5 (33) |
| Nausea | 1.3 (12) |
| Headache | 1.1 (10) |
| * Intensity moderate or severe, or WHO Grade II or III, respectively |
Local site reactions (e.g. redness, erythema, bruising, itching, swelling, and pruritus) were reported. Usually, they were of a transient nature, mild intensity and short duration. During post-marketing surveillance, rare cases of hypersensitivity reactions including anaphylactoid reactions have been reported.
Two stillbirths were reported in Phase 3 studies of Цетротидe®.
Congenital AnomaliesClinical follow-up studies of 316 newborns of women administered Цетротидe® were reviewed. One infant of a set of twin neonates was found to have anencephaly at birth and died after four days. The other twin was normal. Developmental findings from ongoing baby follow-up included a child with a ventricular septal defect 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 Цетротидe® is unknown. Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, and progesterone) make causal attribution difficult to study.
Цетротидe® (cetrorelix acetate for injection) is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian stimulation.
The pharmacokinetic parameters of single and multiple doses of Цетротидe® (cetrorelix acetate for injection) in adult healthy female subjects are summarized in Table 1.
Table 1: Pharmacokinetic parameters of Цетротидe® following 3 mg single or 0.25 mg single and multiple (daily for 14 days) subcutaneous (sc) administration.
| Single dose 3 mg | Single dose 0.25 mg | Multiple dose 0.25 mg | |
| No. of subjects | 12 | 12 | 12 |
| tmax† [h] | 1.5 (0.5-2) | 1.0 (0.5-1.5) | 1.0 (0.5-2) |
| t½† [h] | 62.8 (38.2-108) | 5.0 (2.4-48.8) | 20.6 (4.1-179.3) |
| Cmax [ng/ml] | 28.5 (22.5-36.2) | 4.97 (4.17-5.92) | 6.42 (5.18-7.96) |
| AUC [ngh/ml] | 536 (451-636) | 31.4 (23.4-42.0) | 44.5 (36.7-54.2) |
| * CL [ml/minkg] | 1.28‡ | ||
| Vz [l/kg] | 1.16‡ | ||
| tmax Time to reach observed maximum plasma concentration t½ Elimination half-life Cmax Maximum plasma concentration; multiple dose Css, max AUC Area under the curve; single dose AUC0-inf, multiple dose AUCt CL Total plasma clearance Vz Volume of distribution Geometric mean (95% CIln), *arithmetic mean, † median (min-max) ‡ Based on iv administration (n=6, separate study 0013) |
Цетротидe® is rapidly absorbed following subcutaneous injection, maximal plasma concentrations being achieved approximately one to two hours after administration. The mean absolute bioavailability of Цетротидe® following subcutaneous administration to healthy female subjects is 85%.
DistributionThe volume of distribution of Цетротидe® following a single intravenous dose of 3 mg is about 1 l/kg. In vitro protein binding to human plasma is 86%.
Цетротидe® 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 Цетротидe® 0.25 mg and 3 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.
MetabolismAfter subcutaneous administration of 10 mg Цетротидe® to females and males, Цетротидe® 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, Цетротидe® was stable against phase I- and phase II-metabolism. Цетротидe® was transformed by peptidases, and the (1-4) peptide was the predominant metabolite.
ExcretionFollowing subcutaneous administration of 10 mg cetrorelix to 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.
Цетротидe® (cetrorelix acetate for injection) should be prescribed by physicians who are experienced in fertility treatment. Before starting treatment with Цетротидe®, pregnancy must be excluded (see CONTRAINDICATIONS and PRECAUTIONS).
PRECAUTIONS GeneralCases of hypersensitivity reactions, including anaphylactoid reactions with the first dose, have been reported during post-marketing surveillance (see ADVERSE REACTIONS). A severe anaphylactic reaction associated with cough, rash, and hypotension, was observed in one patient after seven months of treatment with Цетротидe® (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 Цетротидe® is not advised in women with severe allergic conditions.
Information for PatientsPrior to therapy with Цетротидe® (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 (see ADVERSE REACTIONS). Цетротидe® should not be prescribed if a patient is pregnant.
If Цетротидe® is prescribed to patients for self-administration, information for proper use is given in the Patient Leaflet (see below).
Laboratory TestsAfter the exclusion of preexisting conditions, enzyme elevations (ALT, AST, GGT, alkaline phosphatase) were found in 1-2% of patients receiving Цетротидe® 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, Цетротидe® had no notable effects on hormone levels aside from inhibition of LH surges.
Carcinogenesis, Mutagenesis, Impairment Of FertilityLong-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.
Pregnancy Category X(see CONTRAINDICATIONS)
Цетротидe® is contraindicated in pregnant women.
When administered to rats for the first seven days of pregnancy, cetrorelix acetate did not affect the development of the implanted conceptus at doses up to 38 μg/kg (approximately 1 times the recommended human therapeutic dose based on body surface area). However, a dose of 139 μg/kg (approximately 4 times the human dose) resulted in a resorption rate and a postimplantation loss of 100%. When administered from day 6 to near term to pregnant rats and rabbits, very early resorptions and total implantation losses were seen in rats at doses from 4.6 μg/kg (0.2 times the human dose) and in rabbits at doses from 6.8 μg/kg (0.4 times the human dose). In animals that maintained their pregnancy, there was no increase in the incidence of fetal abnormalities.
The fetal resorption observed in animals is a logical consequence of the alteration in hormonal levels effected by the antigonadotrophic properties of Цетротидe®, which could result in fetal loss in humans as well. Therefore, this drug should not be used in pregnant women.
Nursing MothersIt is not known whether Цетротидe® is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of Цетротидe® on lactation and/or the breast-fed child have not been determined, Цетротидe® should not be used by nursing mothers.
Geriatric UseЦетротидe® is not intended to be used in subjects aged 65 and over.
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. Цетротидe® (cetrorelix acetate for injection) 0.25 mg may be administered subcutaneously once daily during the early- to mid-follicular phase.
Цетротидe® 0.25 mg 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).
AdministrationЦетротидe® 0.25 mg can be administered by the patient herself after appropriate instructions by her doctor.
Directions for using Цетротидe® 0.25 mg with the enclosed needles and pre-filled syringe:
