Antagona (ganirelix acetate) Injection is a synthetic decapeptide with high antagonistic activity against naturally occurring gonadotropin-releasing hormone (GnRH). Ganirelix acetate is derived from native GnRH with substitutions of amino acids at positions 1, 2, 3, 6, 8, and 10 to form the following molecular formula of the peptide: N-acetyl-3-(2- naphthyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridyl)-D-alanyl-L-seryl-L-tyrosyl- N9,N10-diethyl-D-homoarginyl-L-leucyl-N9,N10-diethyl-L-homoarginyl-L-prolyl-D- alanylamide acetate. The molecular weight for ganirelix acetate is 1570.4 as an anhydrous free base. The structural formula is as follows: Ganirelix acetate
19 + x C2H4O2 + y H2O Antagona is supplied as a colorless, sterile, ready-to-use, aqueous solution intended for SUBCUTANEOUS administration only. Each sterile, pre-filled syringe contains 250
m
g/0.5 mL of ganirelix acetate, 0.1 mg glacial acetic acid, 23.5 mg mannitol, and water for
injection adjusted to pH 5.0 with acetic acid, NF and/or sodium hydroxide, NF.
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. Antagona (ganirelix acetate) Injection 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 Antagona is more pronounced than that of FSH. An initial release of endogenous gonadotropins has not been detected with Antagona, which is consistent with an antagonist effect. Upon discontinuation of Antagona, pituitary LH and FSH levels are fully recovered within 48 hours.
The pharmacokinetic parameters of single and multiple injections of AntagonTM (ganirelix acetate) Injection 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 mg.
TABLE I: Mean (SD) pharmacokinetic parameters of 250 mg of AntagonTM following a
single subcutaneous (SC) injection (n=15) and daily SC injections (n=15) for seven days.
| t max h | t 1/2 h | C max ng/mL | AUC ng A h/mL | CL/F L/hr | V d /F L | |
| Antagon single dose | 1.1(0.3) | 12.8(4.3) | 14.8(3.2) | 96(12) | 2.4 (0.2)+ | 43.7(11.4)+ |
| Antagon 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) |
tmax Time to maximum concentration
t1/2 Elimination half-life
Cmax Maximum serum concentration
AUC Area under the curve; Single dose: AUC 0-Y=; multiple dose AUC 0-24
Vd Volume of distribution
+ Based on intravenous administration
CL Clearance = Dose/AUC0-Y=
F Absolute bioavailability
Absorption
Ganirelix acetate is rapidly absorbed following subcutaneous injection with maximum serum concentrations reached approximately one hour after dosing. The mean absolute bioavailability of Antagona following a single 250 mg subcutaneous injection to healthy female volunteers is 91.1%.
Distribution
The mean (SD) volume of distribution of Antagona in healthy females following intravenous administration of a single 250 mg 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 Antagona to healthy female volunteers, Antagona 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. Antagona is not found in the feces. The 1-4 peptide and 1-6 peptide of Antagona are the primary metabolites observed in the feces.
Excretion
On average, 97.2% of the total radiolabeled Antagona 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 [14C]-ganirelix acetate. Urinary excretion is virtually complete in 24 h, whereas fecal excretion starts to plateau 192 h after dosing.
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 Antagona can suppress the secretion of pituitary gonadotropins, dose adjustments of exogenous gonadotropins may be necessary when used during controlled ovarian hyperstimulation (COH).
The efficacy of Antagona (ganirelix acetate) Injection 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 [FollistimO (follitropin beta for injection)] 150 IU daily was initiated on the morning of Day 2 or 3 of a natural menstrual cycle. Antagona 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 Antagona. Both recombinant FSH and Antagona were continued daily until at least three follicles were 17 mm or greater in diameter at which time hCG [Pregnyla (chorionic gonadotropin for injection, USP)] was administered. Following hCG administration, Antagona and recombinant FSH administration were discontinued. Oocyte retrieval, followed by in vitro fertilization (IVF) or intracytoplasmatic sperm injection (ICSI), was subsequently performed. In a multicenter, double-blind, randomized, dose-finding study, the safety and efficacy of Antagona were evaluated for the prevention of LH surges in women undergoing COH with recombinant FSH. Antagona doses ranging from 62.5 mg to 2000 mg 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 Antagona. Median serum E2 (17b-estradiol) on the day of hCG administration was 1475, 1110, and 1160 pg/mL for the 62.5, 125, and 250 mg doses, respectively. Lower peak serum E2 levels of 823, 703, and 441 pg/mL were seen at higher doses of Antagona 500, 1000, and 2000 mg, respectively. The highest pregnancy and implantation rates were achieved with the 250 mg dose of Antagona as summarized in Table II.
: Results from the multicenter, double-blind, randomized, dose-finding study
to assess the efficacy of Antagona to prevent premature LH surges in women undergoing COH with recombinant FSH.
Daily dose (mg) of Antagona
| 62.5 m g | 125 m g | 250 m g | 500 m g | 1000 m g | 2000 m g | |
| No. subjects receiving Antagon | 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 ++ | 3.6 | 2.5 | 1.7 | 1.0 | 0.6 | 0.3 |
| 5 th -95 t h percentiles | 0.6-19.9 | 0.6-11.4 | <0.25-6.4 | 0.4-4.7 | <0.25-2.2 | <0.25-0.8 |
| Serum E 2 (pg/mL) on day of hCG ++ | 1475 | 1110 | 1160 | 823 | 703 | 441 |
| 5 th -95 t h percentiles | 645-3720 | 424-3780 | 384-3910 | 279-2720 | 284-2360 | 166-1940 |
| Vital pregnancy rate | ||||||
| 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 (%) U | 14.2(26.8) | 16.3(30.5) | 21.9(30.6) | 9.0(23.7) | 8.5(21.7) | 4.9(20.1) |
(Protocol 38602)
Following initiation of Antagona therapy. Includes subjects who have complied with daily injections.
++ Median values
SS Restricted to subjects with hCG injection
!
Mean (standard deviation)
+ ET: Embryo Transfer
W
As evidenced by ultrasound at 5-6 weeks following ET.
Transient LH rises alone were not deleterious to achieving pregnancy with Antagona at doses of 125 mg (3/6 subjects) and 250 mg (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 AntagonTM in women undergoing COH. Follicular phase treatment with AntagonTM 250 mg was studied using a luteal phase GnRH agonist as a reference treatment. A total of 463 subjects were treated with AntagonTM by subcutaneous injection once daily starting on Day 6 of recombinant FSH treatment. Recombinant FSH was maintained at 150 IU for the first 5 days of ovarian stimulation and was then adjusted by the investigator on the sixth day of gonadotropin use according to individual responses. The results for the AntagonTM arm are summarized in Table III.
: Results from the multicenter, open-label, randomized study to assess the
efficacy and safety of AntagonTM in women undergoing COH.
| Antagon 250 m g | |
| No. subjects treated | 463 |
| Duration of GnRH analog (days) SSY= | 5.4(2.0) |
| Duration of recombinant FSH (days) SSY= | 9.6(2.0) |
| Serum E 2 (pg/mL) on day of hCG ++ 5 th -95 t h percentiles | 1190 373-3105 |
| Serum LH (mIU/mL) on day of hCG ++ 5 th -95 t h percentiles | 1.6 0.6-6.9 |
| No. of subjects with LH rise > 10 mIU/mL * | 13 |
| No. of follicles >11mm Y=SS | 10.7(5.3) |
| No. of subjects with oocyte retrieval | 440 |
| No. of oocytes Y= | 8.7(5.6) |
| Fertilization rate | 62.1% |
| No. subjects with ET + | 399 |
| No. of embryos transferred Y= | 2.2(0.6) |
| No. of embryos Y= | 6.0(4.5) |
| Ongoing pregnancy rate SS | |
| per attempt, n (%) l | 94(20.3) |
| per transfer, n (%) | 93(23.3) |
| Implantation rate (%) Y= | 15.7(29) |
(Protocol 38607)
Following initiation of Antagona therapy
++ Median values
SS Restricted to subjects with hCG injection
Y= Mean (standard deviation)
+ ET: Embryo Transfer
W
As evidenced by ultrasound at 12-16 weeks following ET
l
Includes one patient who achieved pregnancy with intrauterine induction.
Some centers were limited to the transfer of < 2 embryos based on local practice standards
The mean number of days of Antagona treatment was 5.4(2-14). There was no incidence of drug related allergic reactions within the adequate and well-controlled clinical studies.
LH Surges
The midcycle LH surge initiates several physiologic actions including: ovulation, resumption of meiosis in the oocyte, and luteinization. In 463 subjects administered Antagona 250 mg, a premature LH surge prior to hCG administration, (LH rise > 10 mIU/mL with a significant rise in serum progesterone > 2 ng/mL, or a significant decline in serum estradiol) occurred in less than 1% of subjects.
Antagona (ganirelix acetate) Injection is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian hyperstimulation.
Antagona (ganirelix acetate) Injection is contraindicated under the following conditions:
Known hypersensitivity to Antagona or to any of its components.
Known hypersensitivity to GnRH or any other GnRH analog. Known or suspected pregnancy (see PRECAUTIONS).
Antagona (ganirelix acetate) Injection should be prescribed by physicians who are experienced in infertility treatment. Before starting treatment with Antagona, pregnancy must be excluded. Safe use of Antagona during pregnancy has not been established (see CONTRAINDICATIONS and PRECAUTIONS).
Caution is advised in patients with hypersensitivity to GnRH. These patients should be carefully monitored after the first injection. Anaphylactic reactions or ganirelix antibody formation have not been reported in the clinical trials for Antagona (ganirelix acetate) Injection. The packaging of this product contains natural rubber latex which may cause allergic reactions.
Prior to therapy with Antagona (ganirelix acetate) 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). Antagona should not be prescribed if the patient is pregnant.
A neutrophil count 3 8.3 ( x 109/L) was noted in 11.9% (up to 16.8 x 109/L) of all subjects treated within the adequate and well-controlled clinical trials. In addition, downward shifts within the Antagona (ganirelix acetate) Injection group were observed for hematocrit and total bilirubin. The clinical significance of these findings was not determined.
No formal drug/drug interaction studies have been performed.
Long-term toxicity studies in animals have not been performed with Antagona (ganirelix acetate) Injection to evaluate the carcinogenic potential of the drug. Antagona did not induce a mutagenic response in the Ames test (S. typhimurium and E. coli) or produce chromosomal aberrations in in vitro assay using Chinese Hamster Ovary cells.
Pregnancy Category X
Antagona ( ganirelix acetate) is contraindicated in pregnant women. When administered from day 7 to near term to pregnant rats and rabbits at doses up to 10 and 30 mg/day (approximately 0.4 to 3.2 times the human dose based on body surface area), Antagona increased the incidence of litter resorption. There was no increase in fetal abnormalities. No treatment related changes in fertility, physical, or behavioral characteristics were observed in the offspring of female rats treated with Antagona during pregnancy and lactation. The effects on fetal resorption are logical consequences of the alteration in hormonal levels brought about by the antigonadotrophic properties of this drug and could result in fetal loss in humans. Therefore, this drug should not be used in pregnant women (see CONTRAINDICATIONS).
Antagona (ganirelix acetate) Injection should not be used by lactating women. It is not known whether this drug is excreted in human milk.
Clinical studies with Antagona (ganirelix acetate) Injection did not include a sufficient number of subjects aged 65 and over.
The safety of Antagona (ganirelix acetate) Injection was evaluated in two randomized, parallel-group, multicenter controlled clinical studies. Treatment duration for Org 37462 ranged from 1 to 14 days. Table IV represents adverse events (AEs) from first day of Antagona administration until confirmation of pregnancy by ultrasound at an incidence of
31% in Antagona treated subjects without regard to causality. TABLE IV: Incidence of common adverse events (Incidence 31% in Antagona-treated subjects) Completed controlled clinical studies (All-subjects-treated group).
Adverse Events Occurring in > 1% Antagona N=794
%(n)
Abdominal Pain (gynecological) 4.8 (38)
Death Fetal 3.7 (29)
Headache 3.0 (24)
Ovarian Hyperstimulation Syndrome 2.4 (19)
Vaginal Bleeding 1.8 (14)
Injection Site Reaction 1.1 (9)
Nausea 1.1 (9)
Abdominal Pain (gastrointestinal) 1.0 (8)
Congenital Anomalies
Ongoing clinical follow-up studies of 283 newborns of women administered AntagonO (ganirelix acetate) Injection were reviewed. There were three neonates with major congenital anomalies and 18 neonates with minor congenital anomalies. The major congenital anomalies were: hydrocephalus/meningocele, omphalocele, and Beckwith- Wiedemann Syndrome. The minor congenital anomalies were: nevus, skin tags, sacral sinus, hemangioma, torticollis/ asymmetric skull, talipes, supernumerary digit finger, hip subluxation, torticollis/high palate, occiput/abnormal hand crease, hernia umbilicalis, hernia inguinalis, hydrocele, undescended testis, and hydronephrosis. The causal relationship between these congenital anomalies and Antagona is unknown. Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, progesterone) may confound ART (Assisted Reproductive Technology) procedures.
There have been no reports of overdosage with Antagona (ganirelix acetate) Injection in humans.
After initiating FSH therapy on Day 2 or 3 of the cycle, Antagona (ganirelix acetate) Injection 250 mg may be administered subcutaneously once daily during the early to mid follicular phase. By taking advantage of endogenous pituitary FSH secretion, the requirement for exogenously administered FSH may be reduced. Treatment with Antagona 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.
Antagona is supplied in a sterile, pre-filled syringe and is intended for
SUBCUTANEOUS administration only. 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. 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 - 90deg 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. Once the needle is correctly placed, depress the plunger slowly and steadily, so the solution is correctly injected and the skin is not damaged. Pull the syringe out quickly and apply pressure to the site with a swab containing disinfectant. Use the sterile, pre-filled syringe only once and dispose of it properly.
Antagona (ganirelix acetate) Injection is supplied in: Disposable, sterile, pre-filled 1 mL glass syringes containing 250 mg/0.5 mL of ganirelix acetate. Each Antagona sterile, pre-filled syringe is affixed with a 27 gauge x 2 inch needle and is blister-packed. Single syringe NDC 0052-0301-51 Box of 5 NDC 0052-0301-61 Box of 50 NDC 0052-0301-71
Store at 25degC (77degF); excursions permitted to 15-30degC (59-86degF) [see USP Controlled Room Temperature]. Protect from light.
L
only
| 292 | ||
| 293 | Manufactured for Organon Inc. | |
| 294 | West Orange, NJ 07052 | |
| 295 | by Vetter Pharma-Fertigung GmbH & Co. KG | |
| 296 | Ravensburg, Germany | |
| 297 | and packaged by Organon (Ireland) Ltd, Swords Co. | |
| 298 | Dublin, Ireland | |
| 299 | ||
| 300 | 5310194 | |
| 301 | ||
| 302 | ||
| 303 | ||
| 304 | ||