0.5 ML ganirelix acetate 0.5 MG/ML Prefilled Syringe

INDICATIONS AND USAGE Ganirelix Acetate Injection is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian hyperstimulation.

DOSAGE AND ADMINISTRATION After initiating FSH therapy on Day 2 or 3 of the cycle, Ganirelix Acetate Injection 250 mcg may be administered subcutaneously once daily during the mid to late portion of the follicular phase. By taking advantage of endogenous pituitary FSH secretion, the requirement for exogenously administered FSH may be reduced. Treatment with Ganirelix Acetate should be continued daily until the day of hCG administration. When a sufficient number of follicles of adequate size are present, as assessed by ultrasound, final maturation of follicles is induced by administering hCG. The administration of hCG should be withheld in cases where the ovaries are abnormally enlarged on the last day of FSH therapy to reduce the chance of developing OHSS (Ovarian Hyperstimulation Syndrome). Directions for Using Ganirelix Acetate Injection Ganirelix Acetate Injection is supplied in a single dose, sterile, prefilled syringe and is intended for SUBCUTANEOUS administration only. Air bubble(s) may be seen in the pre-filled syringe. This is expected, and removal of the air bubble(s) is not needed. Wash hands thoroughly with soap and water. The most convenient sites for SUBCUTANEOUS injection are in the abdomen around the navel or upper thigh. The injection site should be swabbed with a disinfectant to remove any surface bacteria. Clean about two inches around the point where the needle will be inserted and let the disinfectant dry for at least one minute before proceeding. With syringe held upward, remove needle cover. Pinch up a large area of skin between the finger and thumb. Vary the injection site a little with each injection. The needle should be inserted at the base of the pinched-up skin at an angle of 45–90° to the skin surface. When the needle is correctly positioned, it will be difficult to draw back on the plunger. If any blood is drawn into the syringe, the needle tip has penetrated a vein or artery. If this happens, withdraw the needle slightly and reposition the needle without removing it from the skin. Alternatively, remove the needle and use a new, sterile, prefilled syringe. Cover the injection site with a swab containing disinfectant and apply pressure; the site should stop bleeding within one or two minutes. 10. Once the needle is correctly placed, depress the plunger slowly and steadily, so the solution is correctly injected and the skin is not damaged. 11. Pull the syringe out quickly and apply pressure to the site with a swab containing disinfectant. 12. Use the sterile, prefilled syringe only once. Discard the unused portion and dispose of it properly.

WARNINGS Ganirelix acetate injection should be prescribed by physicians who are experienced in infertility treatment. Before starting treatment with ganirelix acetate, pregnancy must be excluded. Safe use of ganirelix acetate during pregnancy has not been established (see CONTRAINDICATIONS and PRECAUTIONS ).

CONTRAINDICATIONS Ganirelix Acetate Injection is contraindicated under the following conditions: Known hypersensitivity to Ganirelix Acetate or to any of its components including dry natural rubber/latex which may be contained in the rigid needle shield (see HOW SUPPLIED ). Known hypersensitivity to GnRH or any other GnRH analog. Known or suspected pregnancy (see PRECAUTIONS ).

CLINICAL PHARMACOLOGY The pulsatile release of GnRH stimulates the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The frequency of LH pulses in the mid and late follicular phase is approximately 1 pulse per hour. These pulses can be detected as transient rises in serum LH. At midcycle, a large increase in GnRH release results in an LH surge. The midcycle LH surge initiates several physiologic actions including: ovulation, resumption of meiosis in the oocyte, and luteinization. Luteinization results in a rise in serum progesterone with an accompanying decrease in estradiol levels. Ganirelix acetate acts by competitively blocking the GnRH receptors on the pituitary gonadotroph and subsequent transduction pathway. It induces a rapid, reversible suppression of gonadotropin secretion. The suppression of pituitary LH secretion by ganirelix acetate is more pronounced than that of FSH. An initial release of endogenous gonadotropins has not been detected with ganirelix acetate, which is consistent with an antagonist effect. Upon discontinuation of ganirelix acetate, pituitary LH and FSH levels are fully recovered within 48 hours. Pharmacokinetics The pharmacokinetic parameters of single and multiple injections of ganirelix acetate in healthy adult females are summarized in Table I . Steady-state serum concentrations are reached after 3 days of treatment. The pharmacokinetics of ganirelix acetate are dose-proportional in the dose range of 125 to 500 mcg. TABLE I: Mean (SD) pharmacokinetic parameters of 250 mcg of ganirelix acetate following a single subcutaneous (SC) injection (n=15) and daily SC injections (n=15) for seven days. t max Time to maximum concentration t ½ Elimination half-life C max Maximum serum concentration AUC Area under the curve; Single dose: AUC 0–∞ ; multiple dose: AUC 0–24 V d Volume of distribution † Based on intravenous administration CL Clearance = Dose/AUC 0–∞ F Absolute bioavailability t max h t 1/2 h C max ng/mL AUC ng•h/mL CL/F L/h V d /F L Ganirelix Acetate single dose 1.1 (0.3) 12.8 (4.3) 14.8 (3.2) 96 (12) 2.4 (0.2) † 43.7 (11.4) † Ganirelix Acetate multiple dose 1.1 (0.2) 16.2 (1.6) 11.2 (2.4) 77.1 (9.8) 3.3 (0.4) 76.5 (10.3) Absorption Ganirelix acetate is rapidly absorbed following subcutaneous injection with maximum serum concentrations reached approximately one hour after dosing. The mean absolute bioavailability of ganirelix acetate following a single 250-mcg subcutaneous injection to healthy female volunteers is 91.1%. Distribution The mean (SD) volume of distribution of ganirelix acetate in healthy females following intravenous administration of a single 250 mcg dose is 43.7 (11.4) liters (L). In vitro protein binding to human plasma is 81.9%. Metabolism Following single-dose intravenous administration of radiolabeled ganirelix acetate to healthy female volunteers, ganirelix acetate is the major compound present in the plasma (50–70% of total radioactivity in the plasma) up to 4 hours and urine (17.1–18.4% of administered dose) up to 24 hours. Ganirelix acetate is not found in the feces. The 1–4 peptide and 1–6 peptide of ganirelix acetate are the primary metabolites observed in the feces. Excretion On average, 97.2% of the total radiolabeled ganirelix acetate dose is recovered in the feces and urine (75.1% and 22.1%, respectively) over 288 h following intravenous single dose administration of 1 mg [ 14 C]-ganirelix acetate. Urinary excretion is virtually complete in 24 h, whereas fecal excretion starts to plateau 192 h after dosing. Special Populations The pharmacokinetics of ganirelix acetate have not been determined in special populations such as geriatric, pediatric, renally impaired and hepatically impaired patients (see PRECAUTIONS ). Drug-Drug Interactions Formal in vivo or in vitro drug-drug interaction studies have not been conducted (see PRECAUTIONS ). Since ganirelix acetate can suppress the secretion of pituitary gonadotropins, dose adjustments of exogenous gonadotropins may be necessary when used during controlled ovarian hyperstimulation (COH). Clinical Studies The efficacy of ganirelix acetate was established in two adequate and well-controlled clinical studies which included women with normal endocrine and pelvic ultrasound parameters. The studies intended to exclude subjects with polycystic ovary syndrome (PCOS) and subjects with low or no ovarian reserve. One cycle of study medication was administered to each randomized subject. For both studies, the administration of exogenous recombinant FSH [Follistim ® (follitropin beta for injection)] 150 IU daily was initiated on the morning of Day 2 or 3 of a natural menstrual cycle. Ganirelix acetate injection was administered on the morning of Day 7 or 8 (Day 6 of recombinant FSH administration). The dose of recombinant FSH administered was adjusted according to individual responses starting on the day of initiation of ganirelix acetate. Both recombinant FSH and ganirelix acetate were continued daily until at least three follicles were 17 mm or greater in diameter at which time hCG [Pregnyl ® (chorionic gonadotropin for injection, USP)] was administered. Following hCG administration, ganirelix acetate and recombinant FSH administration were discontinued. Oocyte retrieval, followed by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), was subsequently performed. In a multicenter, double-blind, randomized, dose-finding study, the safety and efficacy of ganirelix acetate were evaluated for the prevention of LH surges in women undergoing COH with recombinant FSH. Ganirelix acetate injection doses ranging from 62.5 mcg to 2,000 mcg and recombinant FSH were administered to 332 patients undergoing COH for IVF (see TABLE II ). Median serum LH on the day of hCG administration decreased with increasing doses of ganirelix acetate. Median serum E 2 (17β-estradiol) on the day of hCG administration was 1475, 1110, and 1160 pg/mL for the 62.5, 125, and 250 mcg doses, respectively. Lower peak serum E 2 levels of 823, 703, and 441 pg/mL were seen at higher doses of ganirelix acetate 500, 1,000, and 2,000 mcg, respectively. The highest pregnancy and implantation rates were achieved with the 250 mcg dose of ganirelix acetate as summarized in Table II . TABLE II: Results from the multicenter, double-blind, randomized, dose-finding study to assess the efficacy of ganirelix acetate to prevent premature LH surges in women undergoing COH with recombinant FSH. (Protocol 38602) * Following initiation of ganirelix acetate therapy. Includes subjects who have complied with daily injections ‡ Median values ϒ Mean (standard deviation) † ET: Embryo Transfer Ω As evidenced by ultrasound at 5–6 weeks following ET Daily Dose (mcg) of Ganirelix Acetate 62.5 mcg 125 mcg 250 mcg 500 mcg 1,000 mcg 2,000 mcg No. subjects receiving Ganirelix Acetate 31 66 70 69 66 30 No. subjects with ET † 27 61 62 54 61 27 No. of subjects with LH rise ≥ 10 mIU/mL* 4 6 1 0 0 0 Serum LH (mIU/mL) on day of hCG ‡ 5 th –95 th percentiles 3.6 0.6–19.9 2.5 0.6–11.4 1.7 < 0.25–6.4 1.0 0.4–4.7 0.6 < 0.25–2.2 0.3 < 0.25–0.8 Serum E 2 (pg/mL) on day of hCG ‡ 5 th –95 th percentiles 1475 645–3720 1110 424–3780 1160 384–3910 823 279–2720 703 284–2360 441 166–1940 Vital pregnancy rate Ω per attempt, n (%) 7 (22.6) 17 (25.8) 25 (35.7) 8 (11.6) 9 (13.6) 2 (6.7) per transfer, n (%) 7 (25.9) 17 (27.9) 25 (40.3) 8 (14.8) 9 (14.8) 2 (7.4) Implantation rate (%) ϒ 14.2 (26.8) 16.3 (30.5) 21.9 (30.6) 9.0 (23.7) 8.5 (21.7) 4.9 (20.1) Transient LH rises alone were not deleterious to achieving pregnancy with ganirelix acetate at doses of 125 mcg (3/6 subjects) and 250 mcg (1/1 subjects). In addition, none of the subjects with LH rises ≥ 10 mIU/mL had premature luteinization indicated by a serum progesterone above 2 ng/mL. A multicenter, open-label, randomized study was conducted to assess the efficacy and safety of ganirelix acetate in women undergoing COH. Follicular phase