Cetrorelix

INDICATIONS AND USAGE Cetrorelix acetate for injection is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian stimulation.

CLINICAL PHARMACOLOGY 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 acetate for injection 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 cetrorelix acetate for injection, which is consistent with an antagonist effect. The effects of cetrorelix acetate for injection on LH and FSH are reversible after discontinuation of treatment. In women, cetrorelix acetate for injection delays the LH-surge, and consequently ovulation, in a dose-dependent fashion. FSH levels are not affected at the doses used during controlled ovarian stimulation. Following a single 3 mg dose of cetrorelix acetate for injection, duration of action of at least 4 days has been established. A dose of cetrorelix acetate for injection 0.25 mg every 24 hours has been shown to maintain the effect. Pharmacokinetics The pharmacokinetic parameters of single and multiple doses of cetrorelix acetate for injection in adult healthy female subjects are summarized in Table 1. Table 1: Pharmacokinetic parameters of Cetrorelix Acetate for Injection 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 t max *[h] 1.5 (0.5-2) 1.0 (0.5-1.5) 1.0 (0.5-2) t 1/2 *[h] 62.8 (38.2-108) 5.0 (2.4-48.8) 20.6 (4.1-179.3) C max [ng/ml] 28.5 (22.5-36.2) 4.97 (4.17-5.92) 6.42 (5.18-7.96) AUC [ng∙h/ml] 536 (451-636) 31.4 (23.4-42.0) 44.5 (36.7-54.2) CL † [ml/min∙kg] 1.28 ‡ Vz † [l/kg] 1.16 ‡ t max Time to reach observed maximum plasma concentration t 1/2 Elimination half-life C max Maximum plasma concentration; multiple dose C ss, max AUC Area under the curve; single dose AUC 0-inf , multiple dose AUC t CL Total plasma clearance Vz Volume of distribution Geometric mean (95% Cl In ), * median (min-max) † arithmetic mean, ‡ Based on iv administration (n=6, separate study 0013) Absorption Cetrorelix acetate for injection is rapidly absorbed following subcutaneous injection, maximal plasma concentrations being achieved approximately one to two hours after administration. The mean absolute bioavailability of cetrorelix acetate for injection following subcutaneous administration to healthy female s

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. Cetrorelix acetate for injection 0.25 mg may be administered subcutaneously once daily during the early- to mid-follicular phase. Cetrorelix acetate for Injection 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 Cetrorelix acetate for Injection 0.25 mg can be administered by the patient herself after appropriate instructions by her doctor. Directions for using Cetrorelix Acetate for Injection 0.25 mg with the enclosed needles and pre-filled syringe: 1. Wash hands thoroughly with soap and water. 2. Flip off the plastic cover of the vial and wipe the aluminum ring and the rubber stopper with an alcohol swab. 3. Twist the injection needle with the yellow mark (20 gauge) on the pre-filled syringe. 4. Push the needle through the center of the rubber stopper of the vial and slowly inject the solvent into the vial. 5. Leaving the syringe in the vial, gently swirl the vial until the solution is clear and without residues. Avoid forming bubbles. 6. 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. Discard unused portion. 7. Replace the needle with the yellow mark by the injection needle with the grey mark (27 gauge). 8. Invert the syringe and push the plunger until all air bubbles have been expelled. 9. 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. 10. Inject the prescribed dose as directed by your doctor, nurse or pharmacist. 11. 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.

ADVERSE REACTIONS 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* 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, 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. To report SUSPECTED ADVERSE REACTIONS contact Gland Pharma Limited at (609)-250‐7990 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

WARNINGS 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).

CONTRAINDICATIONS Cetrorelix acetate for injection is contraindicated under the following conditions: 1. Hypersensitivity to cetrorelix acetate, extrinsic peptide hormones or mannitol. 2. Known hypersensitivity to GnRH or any other GnRH analogs. 3. Known or suspected pregnancy, and lactation (see PRECAUTIONS). 4. Severe renal impairment.

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