Gonal-f RFF Redi-ject - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Gonal-f RFF Redi-ject - Scientific Information

Manufacture: EMD Serono, Inc
Country: United States
Condition: Follicle Stimulation
Class: Gonadotropins
Form: Liquid solution, Subcutaneous (SC)
Ingredients: follitropin alfa (r-hFSH), sucrose, meta-cresol, di-sodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate monohydrate, methionine, Poloxamer 188, O-phosphoric acid, sodium hydroxide.

Description

Gonal-f RFF Redi-ject contains human follicle stimulating hormone (hFSH), a glycoprotein hormone manufactured by recombinant DNA technology. The active drug substance, follitropin alfa, has a dimeric structure consisting 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 structures are indistinguishable from those of human follicle stimulating hormone.

Recombinant human 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 protein content is assessed by size exclusion high pressure liquid chromatography. 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 Redi-ject 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 Redi-ject is a disposable, prefilled drug delivery system intended for the subcutaneous injection of multiple and variable doses of a liquid formulation of follitropin alfa.

Each Gonal-f RFF Redi- ject is filled with 415 International Units (30 mcg), 568 International Units (41 mcg), or 1026 International Units (75 mcg) follitropin alfa to deliver at least 300 International Units (22 mcg) in 0.5 mL, 450 International Units (33 mcg) in 0.75 mL, or 900 International Units (66 mcg) in 1.5 mL, respectively. Each Redi-ject also contains 60 mg/mL sucrose, 3.0 mg/mL m-cresol, 1.1 mg/mL di-sodium hydrogen phosphate dihydrate, 0.45 mg/mL sodium dihydrogen phosphate monohydrate, 0.1 mg/mL methionine, 0.1 mg/mL Poloxamer 188. O-phosphoric acid and/or sodium hydroxide may be used for pH adjustment.

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

Therapeutic Class: Infertility

Clinical Pharmacology

Mechanism of Action

Follicle stimulating hormone (FSH), the active component in Gonal-f RFF Redi-ject, is required for normal follicular growth, follicular maturation, and gonadal steroid production. The level of FSH is critical for the onset and duration of follicular development, and consequently for the timing and number of follicles reaching maturity.

Gonal-f RFF Redi-ject stimulates ovarian follicular growth in women who do not have primary ovarian failure. In order to effect the final phase of follicle maturation, resumption of meiosis, and rupture of the follicle in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given following treatment with Gonal-f RFF Redi-ject when monitoring of the woman indicates that appropriate follicular development parameters have been achieved. There is inter-woman variability in response to FSH administration.

Pharmacokinetics

Single-dose pharmacokinetics of follitropin alfa were determined following subcutaneous administration of 300 International Units of Gonal-f RFF Redi-ject 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 Redi-ject (300 International Units subcutaneously in a single dose)
ParameterHealthy Volunteers
(N=21)
Mean% CV
AUClast (IU hr/L)88420%
Cmax (IU/L)9.8323%
tmax (hr)15.543%
t½ (hr)5352%

Abbreviations are:
Cmax: peak concentration (above baseline)
tmax: time of Cmax
t½: elimination half life

Absorption

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

Distribution

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

Metabolism/Excretion

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

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Gonal-f RFF Redi-ject. However, follitropin alfa showed no mutagenic activity in a series of tests performed to evaluate its potential genetic toxicity including, bacterial and mammalian cell mutation tests, a chromosomal aberration test and a micronucleus test.

Impaired fertility has been reported in rats, exposed to pharmacological doses of follitropin alfa (greater than or equal to 40 International Units per kg per day, greater than or equal to 5 times the lowest clinical dose of 75 International Units) for extended periods, through reduced fecundity.

Clinical Studies

The safety and efficacy of Gonal-f RFF were examined in two clinical studies (one ovulation induction study and one ART study).

Ovulation Induction (OI)

Ovulation induction was evaluated in a randomized, assessor-blind, multinational, multicenter, active-controlled, study in oligo-anovulatory infertile women. Women 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. The study was designed to evaluate and compare mean ovulation rates in the first cycle of treatment. Results for Gonal-f RFF are presented in Table 2. Also presented in this table are secondary outcome results from cycle 1 through cycle 3. The study was not powered to demonstrate differences in any of the secondary outcomes.

Table 2: Cumulative Ovulation and Clinical Pregnancy Rates in Ovulation Induction
CycleGonal-f RFF (n=83)
Cumulativea Percent
Ovulation
Cumulativea Clinical Pregnancyd
Rate
Cycle 172%b28%c
Cycle 289%c41%c
Cycle 392%c45%c

a Cumulative rates were determined per woman over cycles 1, 2, and 3.
b Non-inferior to comparator recombinant human FSH based on a two-sided 95% confidence interval, intent-to-treat analysis.
c Secondary efficacy outcomes. The study was not powered to demonstrate differences in these outcomes.
d Clinical pregnancy was defined as a pregnancy for which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34-36 after hCG administration.

Assisted Reproductive Technology (ART)

The efficacy of Gonal-f RFF was evaluated in a randomized, assessor -blind, multinational, multicenter, active controlled study in healthy normal ovulatory, infertile women treated for one cycle with controlled ovarian stimulation, as part of an ART [in vitro fertilization (IVF), or intracytoplasmic sperm injection (ICSI)] cycle. Women were randomized to either Gonal-f RFF (n=237), administered subcutaneously, or a comparator recombinant human FSH. Randomization was stratified by insemination technique, (IVF vs. ICSI). All women received pituitary down-regulation with a GnRH agonist before stimulation with recombinant FSH. Efficacy was assessed using the mean number of fertilized oocytes the day after insemination. The initial doses of Gonal-f RFF were 150 International Units per day for women less than 35 years of age and 225 International Units per day for women 35 years of age and older. The maximum dose given for both age groups was 450 International Units per day. Treatment outcomes for Gonal-f RFF are summarized in Table 3.

Table 3: Treatment Outcomes in ART
Study Outcomevalue (n)
Mean number of 2PN oocytes per woman6.3 (237)a
Mean number of 2PN oocytes per subject receiving IVF6.1 (88)b
Mean number of 2PN oocytes per subject receiving ICSI6.5 (132)b
Clinical pregnancyc rate per attempt33.5% (218)d
Clinical pregnancyc rate per embryo transfer35.8% (204)d
Mean treatment duration in days (range)9.7 [3-21] (230)d

a Non-inferior to comparator recombinant human FSH based on a two-sided 95% confidence interval, intent-to-treat analysis.
b Subgroup analyses. The study was not powered to demonstrate differences in subgroups.
c 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.
d Secondary efficacy outcomes. The study was not powered to demonstrate differences in these outcomes.