Cetrorelix Acetate For

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

Cetrorelix Acetate for Injection is contraindicated under the following conditions: Hypersensitivity to cetrorelix acetate, extrinsic peptide hormones or mannitol. Known hypersensitivity to GnRH or any other GnRH analogs. Known or suspected pregnancy, and lactation (see PRECAUTIONS ). Severe renal impairment

Cetrorelix Acetate for Injection should be prescribed by physicians who are experienced in fertility treatment. Before starting treatment with cetrorelix acetate for injection, pregnancy must be excluded (see CONTRAINDICATIONS and PRECAUTIONS ).

General Cases 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 cetrorelix acetate for injection (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 acetate for injection is not advised in women with severe allergic conditions. 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 (see ADVERSE REACTIONS ). Cetrorelix Acetate for Injection should not be prescribed if a patient is pregnant. If cetrorelix acetate for injection is prescribed to patients for self-administration, information for proper use is given in the Patient Leaflet (see below). Laboratory Tests After the exclusion of preexisting conditions, enzyme elevations (ALT, AST, GGT, alkaline phosphatase) were found in 1-2% of patients receiving cetrorelix acetate for injection 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 acetate for injection had no notable effects on hormone levels aside from inhibition of LH surges. Drug Interactions No formal drug interaction studies have been performed with cetrorelix acetate for injection. Carcinogenesis, Mutagenesis, Impairment of Fertility 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. Pregnancy (see CONTRAINDICATIONS ) Cetrorelix Acetate for Injection 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 time 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 post implantation 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 cetrorelix acetate for injection, which could result in fetal loss in humans as well. Therefore, this drug should not be used in pregnant women. Nursing Mothers It is not known whether cetrorelix acetate for injection is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of cetrorelix acetate for injection on lactation and/or the breast-fed child have not been determined, cetrorelix acetate for injection should not be used by nursing mothers. Geriatric Use Cetrorelix Acetate for Injection is not intended to be used in subjects aged 65 and over.

The safety of 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. Cetrorelix Acetate for Injection 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 cetrorelix acetate for injection treatment until confirmation of pregnancy by ultrasound at an incidence ≥ 1% in cetrorelix acetate for injection treated subjects undergoing COS. Table 3: Adverse Events in ≥1% (WHO preferred term) Cetrorelix Acetate for Injection N=949 % (n) Ovarian Hyperstimulation Syndrome Intensity moderate or severe, or WHO Grade II or III, respectively 3.5 (33) Nausea 1.3 (12) Headache 1.1 (10) 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, cases of mild to moderate Ovarian Hyperstimulation syndrome and cases of hypersensitivity reactions including anaphylactoid reactions have been reported. Two stillbirths were reported in Phase 3 studies of cetrorelix acetate for injection. Congenital Anomalies Clinical follow-up studies of 316 newborns of women administered cetrorelix acetate for injection 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 cetrorelix acetate for injection is unknown. Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, and progesterone) make causal attribution difficult to study.

No formal drug interaction studies have been performed with cetrorelix acetate for injection.

(see CONTRAINDICATIONS ) Cetrorelix Acetate for Injection 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 time 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 post implantation 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 cetrorelix acetate for injection, which could result in fetal loss in humans as well. Therefore, this drug should not be used in pregnant women.

It is not known whether cetrorelix acetate for injection is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of cetrorelix acetate for injection on lactation and/or the breast-fed child have not been determined, cetrorelix acetate for injection should not be used by nursing mothers.

Cetrorelix Acetate for Injection is not intended to be used in subjects aged 65 and over.