Antagon

Antagon Medicine

Overdose

Injection; SolutionInjectable

There have been no reports of overdosage with Antagon Acetate Injection (Antagon) in humans.

There have been no reports of overdosage with Antagon Injection (ganirelix) in humans.

Contraindications

Injection; SolutionInjectable

Antagon Acetate Injection (Antagon) is contraindicated under the following conditions:

  • Known hypersensitivity to Antagon Acetate or to any of its components.
  • Known hypersensitivity to GnRH or any other GnRH analog.
  • Known or suspected pregnancy (see PRECAUTIONS).

Antagon Injection (ganirelix) is contraindicated under the following conditions:

  • Known hypersensitivity to Antagon or to any of its components.
  • Known hypersensitivity to GnRH or any other GnRH analog.
  • Known or suspected pregnancy (see PRECAUTIONS).

Undesirable effects

Injection; SolutionInjectable

The safety of Antagon Acetate Injection (Antagon) was evaluated in two randomized, parallel-group, multicenter controlled clinical studies. Treatment duration for Antagon Acetate ranged from 1 to 14 days. Table IV represents adverse events (AEs) from first day of Antagon Acetate administration until confirmation of pregnancy by ultrasound at an incidence of ≥ 1% in Antagon Acetate-treated subjects without regard to causality.

TABLE IV: Incidence of common adverse events (Incidence ≥ 1% in Antagon Acetate-treated subjects). Completed controlled clinical studies (All-subjects-treated group).

Adverse Events Occurring in ≥ 1% Antagon Acetate 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)

During post-marketing surveillance, rare cases of hypersensitivity reactions, including anaphylactoid reactions with the first dose, have been reported (see PRECAUTIONS).

Congenital Anomalies

Ongoing clinical follow-up studies of 283 newborns of women administered Antagon Acetate Injection (Antagon) 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 Antagon Acetate is unknown. Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, progesterone) may confound ART (Assisted Reproductive Technology) procedures.

The safety of Antagon Injection (ganirelix) was evaluated in two randomized, parallel-group, multicenter controlled clinical studies. Treatment duration for Antagon ranged from 1 to 14 days. Table IV represents adverse events (AEs) from first day of Antagon administration until confirmation of pregnancy by ultrasound at an incidence of ≥ 1% in Antagon-treated subjects without regard to causality.

TABLE IV: Incidence of common adverse events (Incidence ≥ 1% in Antagon-treated subjects). Completed controlled clinical studies (All-subjects-treated group).

Adverse Events Occurring in ≥ 1% Antagon 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)

During post-marketing surveillance, rare cases of hypersensitivity reactions, including anaphylactoid reactions with the first dose, have been reported (see PRECAUTIONS).

Congenital Anomalies

Ongoing clinical follow-up studies of 283 newborns of women administered Antagon Injection (ganirelix) 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 Antagon is unknown. Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, progesterone) may confound ART (Assisted Reproductive Technology) procedures.

Therapeutic indications

Injection; SolutionInjectable

Antagon Acetate Injection (Antagon) is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian hyperstimulation.

Antagon Injection (ganirelix) is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian hyperstimulation.

Pharmacokinetic properties

Injection; SolutionInjectable

The pharmacokinetic parameters of single and multiple injections of Antagon 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 Antagon Acetate are dose-proportional in the dose range of 125 to 500 µg.

TABLE I: Mean (SD) pharmacokinetic parameters of 250 µg of Antagon Acetate following a single subcutaneous (SC) injection (n=15) and daily SC injections (n=15) for seven days.

  tmax h t1/2 h Cmax
ng/mL
AUC
ng•h/mL
CL/F L/h Vd/F L
Antagon 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)†
Antagon 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)
tmax Time to maximum concentration
t1/2 Elimination half-life
Cmax Maximum serum concentration
AUC Area under the curve; Single dose: AUC0-&inifn;; multiple dose: AUC0-24
Vd Volume of distribution
† Based on intravenous administration CL Clearance = Dose/AUC0-&inifn;
F Absolute bioavailability
Absorption

Antagon Acetate is rapidly absorbed following subcutaneous injection with maximum serum concentrations reached approximately one hour after dosing. The mean absolute bioavailability of Antagon Acetate following a single 250 µg subcutaneous injection to healthy female volunteers is 91.1%

Distribution

The mean (SD) volume of distribution of Antagon Acetate in healthy females following intravenous administration of a single 250 µg 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 Antagon Acetate to healthy female volunteers, Antagon 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. Antagon Acetate is not found in the feces. The 1-4 peptide and 1-6 peptide of Antagon Acetate are the primary metabolites observed in the feces.

Excretion

On average, 97.2% of the total radiolabeled Antagon 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 [14C]-Antagon Acetate. Urinary excretion is virtually complete in 24 h, whereas fecal excretion starts to plateau 192 h after dosing.

The pharmacokinetic parameters of single and multiple injections of 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 Antagon are dose-proportional in the dose range of 125 to 500 µg.

TABLE I: Mean (SD) pharmacokinetic parameters of 250 µg of Antagon following a single subcutaneous (SC) injection (n=15) and daily SC injections (n=15) for seven days.

  tmax h t1/2 h Cmax
ng/mL
AUC
ng•h/mL
CL/F L/h Vd/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: AUC0-&inifn;; multiple dose: AUC0-24
Vd Volume of distribution
† Based on intravenous administration CL Clearance = Dose/AUC0-&inifn;
F Absolute bioavailability
Absorption

Antagon is rapidly absorbed following subcutaneous injection with maximum serum concentrations reached approximately one hour after dosing. The mean absolute bioavailability of Antagon following a single 250 µg subcutaneous injection to healthy female volunteers is 91.1%

Distribution

The mean (SD) volume of distribution of Antagon in healthy females following intravenous administration of a single 250 µg 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 Antagon to healthy female volunteers, Antagon 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. Antagon is not found in the feces. The 1-4 peptide and 1-6 peptide of Antagon are the primary metabolites observed in the feces.

Excretion

On average, 97.2% of the total radiolabeled Antagon 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]-Antagon. Urinary excretion is virtually complete in 24 h, whereas fecal excretion starts to plateau 192 h after dosing.

Name of the medicinal product

Antagon

Qualitative and quantitative composition

Ganirelix

Special warnings and precautions for use

Injection; SolutionInjectableWARNINGS

Antagon Acetate Injection (Antagon) should be prescribed by physicians who are experienced in infertility treatment. Before starting treatment with Antagon Acetate, pregnancy must be excluded. Safe use of Antagon Acetate during pregnancy has not been established (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).

The packaging of this product contains natural rubber latex which may cause allergic reactions.

Laboratory Tests

A neutrophil count ≥ 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 Antagon Acetate Injection (Antagon) group were observed for hematocrit and total bilirubin. The clinical significance of these findings was not determined.

Carcinogenesis and Mutagenesis, Impairment of Fertility

Long-term toxicity studies in animals have not been performed with Antagon Acetate Injection to evaluate the carcinogenic potential of the drug. Antagon Acetate 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 Pregnancy Category X

Antagon Acetate Injection (Antagon) 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 µg/day (approximately 0.4 to 3.2 times the human dose based on body surface area), Antagon Acetate 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 Antagon Acetate 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).

Nursing Mothers

Antagon Acetate Injection (Antagon) should not be used by lactating women. It is not known whether this drug is excreted in human milk.

Geriatric Use

Clinical studies with Antagon Acetate Injection (Antagon) did not include a sufficient number of subjects aged 65 and over.

WARNINGS

Antagon Injection (ganirelix) should be prescribed by physicians who are experienced in infertility treatment. Before starting treatment with Antagon, pregnancy must be excluded. Safe use of Antagon during pregnancy has not been established (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).

The packaging of this product contains natural rubber latex which may cause allergic reactions.

Laboratory Tests

A neutrophil count ≥ 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 Antagon Injection (ganirelix) group were observed for hematocrit and total bilirubin. The clinical significance of these findings was not determined.

Carcinogenesis and Mutagenesis, Impairment of Fertility

Long-term toxicity studies in animals have not been performed with Ganirelix Acetate Injection to evaluate the carcinogenic potential of the drug. Ganirelix Acetate 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 Pregnancy Category X

Antagon Injection (ganirelix) 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 µg/day (approximately 0.4 to 3.2 times the human dose based on body surface area), Antagon 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 Antagon 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).

Nursing Mothers

Antagon Injection (ganirelix) should not be used by lactating women. It is not known whether this drug is excreted in human milk.

Geriatric Use

Clinical studies with Antagon Injection (ganirelix) did not include a sufficient number of subjects aged 65 and over.

Dosage (Posology) and method of administration

Injection; SolutionInjectable

After initiating FSH therapy on Day 2 or 3 of the cycle, Antagon Acetate Injection (Antagon) 250 µg 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 Antagon 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 Antagon Acetate Injection

  1. Antagon Acetate Injection (Antagon) is supplied in a sterile, prefilled syringe and is intended for SUBCUTANEOUS administration only.
  2. Wash hands thoroughly with soap and water.
  3. The most convenient sites for SUBCUTANEOUS injection are in the abdomen around the navel or upper thigh.
  4. 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.
  5. With syringe held upward, remove needle cover.
  6. Pinch up a large area of skin between the finger and thumb. Vary the injection site a little with each injection.
  7. The needle should be inserted at the base of the pinched-up skin at an angle of 45-the skin surface.
  8. 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.
  9. Once the needle is correctly placed, depress the plunger slowly and steadily, so the solution is correctly injected and the skin is not damaged.
  10. Pull the syringe out quickly and apply pressure to the site with a swab containing disinfectant. 11. Use the sterile, prefilled syringe only once and dispose of it properly.

After initiating FSH therapy on Day 2 or 3 of the cycle, Antagon Injection (ganirelix) 250 µg 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 Antagon 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 Antagon Injection

  1. Antagon Injection (ganirelix) is supplied in a sterile, prefilled syringe and is intended for SUBCUTANEOUS administration only.
  2. Wash hands thoroughly with soap and water.
  3. The most convenient sites for SUBCUTANEOUS injection are in the abdomen around the navel or upper thigh.
  4. 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.
  5. With syringe held upward, remove needle cover.
  6. Pinch up a large area of skin between the finger and thumb. Vary the injection site a little with each injection.
  7. The needle should be inserted at the base of the pinched-up skin at an angle of 45-the skin surface.
  8. 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.
  9. Once the needle is correctly placed, depress the plunger slowly and steadily, so the solution is correctly injected and the skin is not damaged.
  10. Pull the syringe out quickly and apply pressure to the site with a swab containing disinfectant. 11. Use the sterile, prefilled syringe only once and dispose of it properly.