Cetrotide

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

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.

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 .

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 . Severe renal impairment

Pregnancy 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.

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

3.5Nausea

1.3Headache

1.1Local

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.