There have been no reports of overdosage with Orgalutran Acetate Injection (Orgalutran) in humans.
There have been no reports of overdosage with Orgalutran Injection (ganirelix) in humans.
Orgalutran Acetate Injection (Orgalutran) is contraindicated under the following conditions:
Orgalutran Injection (ganirelix) is contraindicated under the following conditions:
The safety of Orgalutran Acetate Injection (Orgalutran) was evaluated in two randomized, parallel-group, multicenter controlled clinical studies. Treatment duration for Orgalutran Acetate ranged from 1 to 14 days. Table IV represents adverse events (AEs) from first day of Orgalutran Acetate administration until confirmation of pregnancy by ultrasound at an incidence of ≥ 1% in Orgalutran Acetate-treated subjects without regard to causality.
TABLE IV: Incidence of common adverse events (Incidence ≥ 1% in Orgalutran Acetate-treated subjects). Completed controlled clinical studies (All-subjects-treated group).
| Adverse Events Occurring in ≥ 1% | Orgalutran 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 AnomaliesOngoing clinical follow-up studies of 283 newborns of women administered Orgalutran Acetate Injection (Orgalutran) 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 Orgalutran 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 Orgalutran Injection (ganirelix) was evaluated in two randomized, parallel-group, multicenter controlled clinical studies. Treatment duration for Orgalutran ranged from 1 to 14 days. Table IV represents adverse events (AEs) from first day of Orgalutran administration until confirmation of pregnancy by ultrasound at an incidence of ≥ 1% in Orgalutran-treated subjects without regard to causality.
TABLE IV: Incidence of common adverse events (Incidence ≥ 1% in Orgalutran-treated subjects). Completed controlled clinical studies (All-subjects-treated group).
| Adverse Events Occurring in ≥ 1% | Orgalutran 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 AnomaliesOngoing clinical follow-up studies of 283 newborns of women administered Orgalutran 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 Orgalutran is unknown. Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, progesterone) may confound ART (Assisted Reproductive Technology) procedures.
Orgalutran Acetate Injection (Orgalutran) is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian hyperstimulation.
Orgalutran Injection (ganirelix) is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian hyperstimulation.
The pharmacokinetic parameters of single and multiple injections of Orgalutran 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 Orgalutran Acetate are dose-proportional in the dose range of 125 to 500 µg.
TABLE I: Mean (SD) pharmacokinetic parameters of 250 µg of Orgalutran 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 | |
| Orgalutran 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)† |
| Orgalutran 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 |
Orgalutran Acetate is rapidly absorbed following subcutaneous injection with maximum serum concentrations reached approximately one hour after dosing. The mean absolute bioavailability of Orgalutran Acetate following a single 250 µg subcutaneous injection to healthy female volunteers is 91.1%
DistributionThe mean (SD) volume of distribution of Orgalutran 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%.
MetabolismFollowing single dose intravenous administration of radiolabeled Orgalutran Acetate to healthy female volunteers, Orgalutran 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. Orgalutran Acetate is not found in the feces. The 1-4 peptide and 1-6 peptide of Orgalutran Acetate are the primary metabolites observed in the feces.
ExcretionOn average, 97.2% of the total radiolabeled Orgalutran 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]-Orgalutran 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 Orgalutran are dose-proportional in the dose range of 125 to 500 µg.
TABLE I: Mean (SD) pharmacokinetic parameters of 250 µg of Orgalutran 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 | |
| Orgalutran single dose | 1.1 (0.3) | 12.8 (4.3) | 14.8 (3.2) | 96 (12) | 2.4 (0.2)† | 43.7 (11.4)† |
| Orgalutran 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 |
Orgalutran is rapidly absorbed following subcutaneous injection with maximum serum concentrations reached approximately one hour after dosing. The mean absolute bioavailability of Orgalutran following a single 250 µg subcutaneous injection to healthy female volunteers is 91.1%
DistributionThe mean (SD) volume of distribution of Orgalutran 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%.
MetabolismFollowing single dose intravenous administration of radiolabeled Orgalutran to healthy female volunteers, Orgalutran 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. Orgalutran is not found in the feces. The 1-4 peptide and 1-6 peptide of Orgalutran are the primary metabolites observed in the feces.
ExcretionOn average, 97.2% of the total radiolabeled Orgalutran 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]-Orgalutran. Urinary excretion is virtually complete in 24 h, whereas fecal excretion starts to plateau 192 h after dosing.
Orgalutran Acetate Injection (Orgalutran) should be prescribed by physicians who are experienced in infertility treatment. Before starting treatment with Orgalutran Acetate, pregnancy must be excluded. Safe use of Orgalutran Acetate during pregnancy has not been established (see CONTRAINDICATIONS and PRECAUTIONS).
PRECAUTIONS GeneralCases 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 TestsA 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 Orgalutran Acetate Injection (Orgalutran) group were observed for hematocrit and total bilirubin. The clinical significance of these findings was not determined.
Carcinogenesis and Mutagenesis, Impairment of FertilityLong-term toxicity studies in animals have not been performed with Orgalutran Acetate Injection to evaluate the carcinogenic potential of the drug. Orgalutran 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 XOrgalutran Acetate Injection (Orgalutran) 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), Orgalutran 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 Orgalutran 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 MothersOrgalutran Acetate Injection (Orgalutran) should not be used by lactating women. It is not known whether this drug is excreted in human milk.
Geriatric UseClinical studies with Orgalutran Acetate Injection (Orgalutran) did not include a sufficient number of subjects aged 65 and over.
WARNINGSOrgalutran Injection (ganirelix) should be prescribed by physicians who are experienced in infertility treatment. Before starting treatment with Orgalutran, pregnancy must be excluded. Safe use of Orgalutran during pregnancy has not been established (see CONTRAINDICATIONS and PRECAUTIONS).
PRECAUTIONS GeneralCases 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 TestsA 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 Orgalutran Injection (ganirelix) group were observed for hematocrit and total bilirubin. The clinical significance of these findings was not determined.
Carcinogenesis and Mutagenesis, Impairment of FertilityLong-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 XOrgalutran 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), Orgalutran 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 Orgalutran 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 MothersOrgalutran Injection (ganirelix) should not be used by lactating women. It is not known whether this drug is excreted in human milk.
Geriatric UseClinical studies with Orgalutran Injection (ganirelix) did not include a sufficient number of subjects aged 65 and over.
After initiating FSH therapy on Day 2 or 3 of the cycle, Orgalutran Acetate Injection (Orgalutran) 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 Orgalutran 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 Orgalutran Acetate Injection
After initiating FSH therapy on Day 2 or 3 of the cycle, Orgalutran 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 Orgalutran 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 Orgalutran Injection
