Aerogel Coating vs Traditional Coating Comparison

Warnings for Fyremadel

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).

Precautions for Fyremadel

General

Special care should be taken in women with signs and symptoms of active allergic conditions.

Cases of hypersensitivity reactions (both generalized and local), including anaphylaxis (including anaphylactic shock), angioedema and urticaria have been reported with ganirelix acetate, as early as with the first dose, during postmarketing surveillance (see ADVERSE REACTIONS). If a hypersensitivity reaction is suspected, ganirelix acetate should be discontinued and appropriate treatment administered. In the absence of clinical experience, ganirelix acetate treatment is not advised in women with severe allergic conditions.

The needle shield of this product contains dry natural rubber/latex which comes into contact with this product and may cause allergic reactions (see CONTRAINDICATIONS and HOW SUPPLIED).

Laboratory Tests

A neutrophil count ≥ 8.3 ( × 109/L) was noted in 11.9% (up to 16.8 × 109/L) of all subjects treated within the adequate and well-controlled clinical trials. In addition, downward shifts within the ganirelix acetate injection group were observed for hematocrit and total bilirubin. The clinical significance of these findings was not determined.

Nonclinical Toxicology

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

Ganirelix acetate injection 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 mcg/day (approximately 0.4 to 3.2 times the human dose based on body surface area), ganirelix 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 ganirelix acetate during pregnancy and lactation.

The effects on fetal resorption are logical consequences of the alteration in hormonal levels brought about by the antigonadotropic 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

Ganirelix acetate injection should not be used by lactating women. It is not known whether this drug is excreted in human milk.

Geriatric Use

Clinical studies with ganirelix acetate injection did not include a sufficient number of subjects aged 65 and over.

Clinical Pharmacology for Fyremadel

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 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 mcg 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.

tmax h t½ h Cmax ng/mL AUC ng•h/mL CL/F L/h Vd/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) tmax Time to maximum concentration
t½ Elimination half-life
Cmax Maximum serum concentration
AUC Area under the curve; Single dose: AUC0-∞ ; multiple dose: AUC
Vd Volume of distribution
CL Clearance = Dose/AUC0-∞
F Absolute bioavailability
*Based on intravenous administration

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 to 70% of total radioactivity in the plasma) up to 4 hours and urine (17.1 to 18.4% of administered dose) up to 24 hours. Ganirelix acetate is not found in the feces. The 1 to 4 peptide and 1 to 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 [14C]-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 injection 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 injection was established in two adequate and wellcontrolled 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®1 (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®1 (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 injection 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 (17β-estradiol) on the day of hCG administration was 1,475; 1,110; and 1,160 pg/mL for the 62.5 mcg, 125 mcg, and 250 mcg doses, respectively. Lower peak serum E levels of 823, 703, and 441 pg/mL were seen at higher doses of ganirelix acetate 500 mcg, 1,000 mcg, and 2,000 mcg, respectively. The highest pregnancy and implantation rates were achieved with the 250 mcg dose of ganirelix acetate injection as summarized in Table II.

TABLE II: Results from the multicenter, double-blind, randomized, dose-finding study to assess the efficacy of ganirelix acetate injection to prevent premature LH surges in women undergoing COH with recombinant FSH.

Daily Dose (mcg) of Ganirelix Acetate Injection 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‡ 5th to 95th percentiles 3.6 0.6 to 19.9 2.5 0.6 to 11.4 1.7 < 0.25 to 6.4 1 0.4 to 4.7 0.6 < 0.25 to 2.2 0.3 < 0.25 to 0.8 Serum E2 (pg/mL) on day of hCG‡ 5th to 95th percentiles 1,475 645 to 3,720 1,110 424 to 3,780 1,160 384 to 3,910 823 279 to 2,720 703 284 to 2,360 441 166 to 1,940 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 (%)¶ 14.2 (26.8) 16.3 (30.5) 21.9 (30.6) 9 (23.7) 8.5 (21.7) 4.9 (20.1) (Protocol )
*ET: Embryo Transfer
†Following initiation of ganirelix acetate therapy. Includes subjects who have complied with daily injections
‡Median values
§As evidenced by ultrasound at 5 to 6 weeks following ET
¶Mean (standard deviation)

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 injection in women undergoing COH. Follicular phase treatment with ganirelix acetate 250 mcg was studied using a luteal phase GnRH agonist as a reference treatment. A total of 463 subjects were treated with ganirelix acetate 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 ganirelix acetate arm are summarized in Table III.

TABLE III: Results from the multicenter, open-label, randomized study to assess the efficacy and safety of ganirelix acetate injection in women undergoing COH.

Ganirelix Acetate 250 mcg No. subjects treated 463 Duration of GnRH analog (days)*† 5.4 (2) Duration of recombinant FSH (days)*† 9.6 (2) Serum E2 (pg/mL) on day of hCG‡ 5th to 95th percentiles 1,190 373 to 3,105 Serum LH (mIU/mL) on day of hCG‡ 5th to 95th percentiles 1.6 0.6 to 6.9 No. of subjects with LH rise ≥ 10 mIU/mL§ 13 No. of follicles ≥ 11 mm*† 10.7 (5.3) No. of subjects with oocyte retrieval 440 No. of oocytes† 8.7 (5.6) Fertilization rate 62.1% No. subjects with ET¶ 399 No. of embryos transferred† 2.2 (0.6) No. of embryos† 6 (4.5) Ongoing pregnancy rate#* per attempt, n (%)Þ 94 (20.3) per transfer, n (%) 93 (23.3) Implantation rate (%)† 15.7 (29) (Protocol )
*Restricted to subjects with hCG injection
†Mean (standard deviation)
‡Median values
§Following initiation of ganirelix acetate therapy
¶ET: Embryo Transfer
#As evidenced by ultrasound at 12 to 16 weeks following ET
Þ 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 ganirelix acetate treatment was 5.4 (2 to 14).

LH Surges

The midcycle LH surge initiates several physiologic actions including: ovulation, resumption of meiosis in the oocyte, and luteinization. In 463 subjects administered ganirelix acetate injection 250 mcg, 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.

REFERENCES

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