Gonal-f® RFF (follitropin alfa for injection) - America[美国药品]

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Gonal-f® RFF (follitropin alfa for injection)

2015-05-13 18:58:00 来源: 作者: 【大中小】浏览:443次评论:0条

SPL UNCLASSIFIED SECTION

*revised formulation female

For subcutaneous injection

DESCRIPTION

Gonal-f® RFF (follitropin alfa for injection) is a human follicle stimulating hormone (FSH) preparation of recombinant DNA origin, which consists of two non-covalently linked, non-identical glycoproteins designated as the α- and β-subunits. The α- and β-subunits have 92 and 111 amino acids, respectively, and their primary and tertiary structure are indistinguishable from those of human follicle stimulating hormone. Recombinant FSH production occurs in genetically modified Chinese Hamster Ovary (CHO) cells cultured in bioreactors. Purification by immunochromatography using an antibody specifically binding FSH results in a highly purified preparation with a consistent FSH isoform profile, and a high specific activity. The biological activity of follitropin alfa is determined by measuring the increase in ovary weight in female rats. The in vivo biological activity of follitropin alfa has been calibrated against the first International Standard for recombinant human follicle stimulating hormone established in 1995 by the Expert Committee on Biological Standards of the World Health Organization. Gonal-f® RFF contains no luteinizing hormone (LH) activity. Based on available data derived from physico-chemical tests and bioassays, follitropin alfa and follitropin beta, another recombinant follicle stimulating hormone product, are indistinguishable.

Gonal-f® RFF is a sterile, lyophilized powder intended for subcutaneous injection after reconstitution.

Each Gonal-f® RFF single-dose vial is filled with 82 IU (6 μg) follitropin alfa to deliver 75 IU (5.5 μg) and contains 30 mg sucrose, 1.11 mg dibasic sodium phosphate dihydrate, 0.45 mg monobasic sodium phosphate monohydrate, 0.1 mg methionine, and 0.05 mg polysorbate 20. Phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for pH adjustment. Vials are reconstituted with Sterile Water for Injection, USP.

Under current storage conditions, Gonal-f® RFF may contain up to 10% of oxidized follitropin alfa.

Therapeutic Class: Infertility

CLINICAL PHARMACOLOGY

Gonal-f® RFF (follitropin alfa for injection) stimulates ovarian follicular growth in women who do not have primary ovarian failure. FSH, the active component of Gonal-f® RFF is the primary hormone responsible for follicular recruitment and development. In order to effect final maturation of the follicle and ovulation in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given following the administration of Gonal-f® RFF when monitoring of the patient indicates that sufficient follicular development has occurred. There is interpatient variability in response to FSH administration.

Pharmacokinetics

Single-dose pharmacokinetics of follitropin alfa were determined following subcutaneous administration of 300 IU Gonal-f® RFF to 21 pre-menopausal healthy female volunteers who were pituitary down-regulated with a GnRH agonist.

The descriptive statistics for the pharmacokinetic parameters are presented in Table 1.

Table 1: Pharmacokinetic parameters of FSH following administration of Gonal-f® RFF
Population Dose (IU)	Healthy Volunteers (n=21) 300 IU SC in a single dose
	Mean	%CV
Abbreviations are: Cmax: peak concentration (above baseline); tmax : time of Cmax; t1/2: elimination half life
AUClast (IU∙hr/L)	884	20%
Cmax (IU/L)	9.83	23%
tmax (hr)	15.5	43%
t1/2 (hr)	53	52%

Absorption

The absorption rate of Gonal-f® RFF following subcutaneous administration is slower than the elimination rate. Hence, the pharmacokinetics of Gonal-f® RFF are absorption rate-limited.

Distribution

Human tissue or organ distribution of FSH has not been determined for Gonal-f® RFF.

Metabolism/Excretion

FSH metabolism and excretion following administration of Gonal-f® RFF have not been studied in humans.

Special populations

Safety, efficacy, and pharmacokinetics of Gonal-f® RFF in patients with renal or hepatic insufficiency have not been established.

Drug-Drug Interactions

No drug-drug interaction studies have been conducted (see PRECAUTIONS).

Clinical Studies

The safety and efficacy of Gonal-f® RFF have been examined in two clinical studies: one study (Study 22240) for ovulation induction and one study (Study 21884) for assisted reproductive technologies (ART).

1. Ovulation Induction (OI)

Study 22240 was a phase III, assessor-blind, randomized, comparative, multinational, multicenter study in oligo-anovulatory infertile women undergoing ovulation induction. Patients were randomized to either Gonal-f® RFF (n=83), administered subcutaneously, or a comparator recombinant human FSH. The use of insulin-sensitizing agents was allowed during the study. Efficacy was assessed using the mean ovulation rate in the first cycle of treatment. The cycle 1 ovulation rate (primary outcome) for Gonal-f® RFF is presented in Table 2. Additionally, this table includes cumulative secondary outcome results from cycle 1 through 3. Study 22240 was not powered to demonstrate differences in these secondary outcomes.

Table 2: Cumulative Ovulation and Clinical Pregnancy Rates in Ovulation Induction
Study 22240	Gonal-f® RFF (n=83)
* Cumulative rates were determined per patient over cycles 1, 2, and 3. † Non-inferior to comparator recombinant human FSH based on a two-sided 95% confidence interval, intent-to-treat analysis. ‡ Secondary efficacy parameter. Study 22240 was not powered to demonstrate differences in this parameter. § A clinical pregnancy was defined as a pregnancy during which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34-36 after hCG administration.
Cumulative* Ovulation Rate
Cycle 1	72%†
Cycle 2	89%‡
Cycle 3	92%‡
Cumulative* Clinical Pregnancy§ Rate
Cycle 1	28%‡
Cycle 2	41%‡
Cycle 3	45%‡

2. Assisted Reproductive Technologies (ART)

Study 21884 was a phase III, assessor-blind, randomized, comparative, multinational, multicenter study in ovulatory, infertile women undergoing stimulation of multiple follicles for Assisted Reproductive Technologies (ART) after pituitary down-regulation with a GnRH agonist. Patients were randomized to either Gonal-f® RFF (n=237), administered subcutaneously, or a comparator recombinant human FSH. Randomization was stratified by insemination technique [conventional in vitro fertilization (IVF) vs. intra-cytoplasmic sperm injection (ICSI)]. Efficacy was assessed using the mean number of fertilized oocytes the day after insemination. The initial doses of Gonal-f® RFF were 150 IU a day for patients < 35 years old and 225 IU for patients ≥ 35 years old. The maximal dose allowed for both age groups was 450 IU per day. Treatment outcomes for Gonal-f® RFF are summarized in Table 3.

Table 3: Treatment Outcomes in ART
Study 21884	Gonal-f® RFF value (n)
* Non-inferior to comparator recombinant human FSH based on a two-sided 95% confidence interval, intent-to-treat analysis † Study 21884 was not powered to demonstrate differences in subgroups ‡ A clinical pregnancy was defined as a pregnancy during which a fetal sac (with or without heart activity) was visualized by ultrasound on day 35-42 after hCG administration. § Secondary efficacy parameter. Study 21884 was not powered to demonstrate differences in this parameter
Mean number of 2PN oocytes per patient	6.3 (237)*
Mean number of 2PN oocytes per patient receiving IVF	6.1 (88)†
Mean number of 2PN oocytes per patient receiving ICSI	6.5 (132)†
Clinical pregnancy‡ rate per attempt	33.5% (218)§
Clinical pregnancy‡ rate per embryo transfer	35.8% (204)§
Mean treatment duration in days (range)	9.7 [3-21] (230)§

INDICATIONS AND USAGE

Gonal-f® RFF (follitropin alfa for injection) is indicated for the induction of ovulation and pregnancy in the oligo-anovulatory infertile patient in whom the cause of infertility is functional and not due to primary ovarian failure. Gonal-f® RFF is also indicated for the development of multiple follicles in the ovulatory patient participating in an Assisted Reproductive Technology (ART) program.

Selection of Patients

Before treatment with Gonal-f® RFF is instituted, a thorough gynecologic and endocrinologic eva luation must be performed. This should include an assessment of pelvic anatomy. Patients with tubal obstruction should receive Gonal-f® RFF only if enrolled in an in vitro fertilization program.
Primary ovarian failure should be excluded by the determination of gonadotropin levels.
Appropriate eva luation should be performed to exclude pregnancy.
Patients in later reproductive life have a greater predisposition to endometrial carcinoma as well as a higher incidence of anovulatory disorders. A thorough diagnostic eva luation should always be performed in patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities before starting Gonal-f® RFF therapy.
eva luation of the partner's fertility potential should be included in the initial eva luation.