Orgalutran

Overdose

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.

Contraindications

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

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

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

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

Pharmaceutical form

Undesirable effects

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).

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

Ongoing 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).

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

Ongoing 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.

Therapeutic indications

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.

Pharmacokinetic properties

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.

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%

The 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%.

Following 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.

On 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.

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%

The 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%.

Following 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.

On 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.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

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).

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.

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 Orgalutran Acetate Injection (Orgalutran) group were observed for hematocrit and total bilirubin. The clinical significance of these findings was not determined.

Long-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.

Orgalutran 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).

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

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

Orgalutran 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).

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.

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 Orgalutran Injection (ganirelix) group were observed for hematocrit and total bilirubin. The clinical significance of these findings was not determined.

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.

Orgalutran 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).

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

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

Dosage (Posology) and method of administration

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

1. Orgalutran Acetate Injection (Orgalutran) 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, 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

1. Orgalutran 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.