Cetrotide

INDICATIONS AND USAGE Cetrotide ® (cetrorelix acetate for injection) is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian stimulation.

HOW SUPPLIED Cetrotide ® (cetrorelix acetate for injection) 0.25 mg is available in a carton of one packaged tray (NDC 44087-1225-1). Each packaged tray contains: one glass vial containing 0.26 - 0.27 mg cetrorelix acetate (corresponding to 0.25 mg cetrorelix), one pre-filled glass syringe with 1 mL of Sterile Water for Injection, one 20 gauge needle (yellow) and one 27 gauge needle (grey). Storage Store Cetrotide ® 0.25 mg refrigerated, 2ºC - 8ºC (36ºF - 46ºF). Store the packaged tray in the outer carton in order to protect from light.

DOSAGE AND ADMINISTRATION 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. Cetrotide ® (cetrorelix acetate for injection) 0.25 mg may be administered subcutaneously once daily during the early- to mid-follicular phase. Cetrotide ® 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). Administration Cetrotide ® 0.25 mg can be administered by the patient herself after appropriate instructions by her doctor. Directions for using Cetrotide ® 0.25 mg with the enclosed needles and pre-filled syringe: Wash hands thoroughly with soap and water. Flip off the plastic cover of the vial and wipe the aluminum ring and the rubber stopper with an alcohol swab. Twist the injection needle with the yellow mark (20 gauge) on the pre-filled syringe. Push the needle through the center of the rubber stopper of the vial and slowly inject the solvent into the vial. Leaving the syringe in the vial, gently swirl the vial until the solution is clear and without residues. Avoid forming bubbles. 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 of the vial. Replace the needle with the yellow mark by the injection needle with the grey mark (27 gauge). Invert the syringe and push the plunger until all air bubbles have been expelled. Choose an injection site in the lower abdominal area, preferably around, but staying at least one inch away from the navel. Choose a different injection site each day to minimize local irritation. Use a second alcohol swab to clean the skin at the injection site and allow alcohol to dry. Gently pinch up the skin surrounding the site of injection. Inject the prescribed dose as directed by your doctor, nurse or pharmacist. Use the syringe and needles only once. Dispose of the syringe and needles properly after use. If available, use a medical waste container for disposal.

CONTRAINDICATIONS Cetrotide ® (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

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

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 Cetrotide ® (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 Cetrotide ® is not advised in women with severe allergic conditions. Information for Patients Prior to therapy with Cetrotide ® (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 ). Cetrotide ® should not be prescribed if a patient is pregnant. If Cetrotide ® 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 Cetrotide ® 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, Cetrotide ® had no notable effects on hormone levels aside from inhibition of LH surges. Drug Interactions No formal drug interaction studies have been performed with Cetrotide ® . 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 ) Cetrotide ® 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 Cetrotide ® , 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 Cetrotide ® is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of Cetrotide ® on lactation and/or the breast-fed child have not been determined, Cetrotide ® should not be used by nursing mothers. Geriatric Use Cetrotide ® is not intended to be used in subjects aged 65 and over.

Information for Patients Prior to therapy with Cetrotide ® (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 ). Cetrotide ® should not be prescribed if a patient is pregnant. If Cetrotide ® 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 Cetrotide ® 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, Cetrotide ® had no notable effects on hormone levels aside from inhibition of LH surges.

Drug Interactions No formal drug interaction studies have been performed with Cetrotide ® .

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 ) Cetrotide ® 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 Cetrotide ® , which could result in fetal loss in humans as well. Therefore, this drug should not be used in pregnant women.

Geriatric Use Cetrotide ® is not intended to be used in subjects aged 65 and over.

ADVERSE REACTIONS The safety of Cetrotide ® (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. Cetrotide ® 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 Cetrotide ® treatment until confirmation of pregnancy by ultrasound at an incidence ≥ 1% in Cetrotide ® treated subjects undergoing COS. Table 3: Adverse Events in ≥1% (WHO preferred term) Cetrotide ® 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 Cetrotide ® . Congenital Anomalies Clinical follow-up studies of 316 newborns of women administered Cetrotide ® 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 Cetrotide ® is unknown. Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, and progesterone) make causal attribution difficult to study.

OVERDOSAGE There have been no reports of overdosage with Cetrotide ® 0.25 mg or 3 mg in humans. Single doses up to 120 mg Cetrotide ® have been well tolerated in patients treated for other indications without signs of overdosage.