Gonadotrophin f.s.h.
The properties are similar to Follitrophin alpha, whose details are given below.
Follitropin Alfa
Indications: Infertility
DESCRIPTION:
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 alpha- and beta-subunits. The alpha- and beta-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 second International Reference Preparation for Human Menopausal Gonadotrophins established in September 1964 by the Expert Committee on Biological Standards of the World Health Organization. Follitropin alfa 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: A sterile, lyophilized powder intended for subcutaneous injection after reconstitution with sterile water for injection. Each ampule of Gonal-F contains either 75 IU or 150 IU recombinant FSH, 30 mg sucrose, 1.11 mg dibasic sodium phosphate and 0.45 mg monobasic sodium phosphate monohydrate. O-phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for pH adjustment. Under current storage conditions, Gonal-F may contain up to 15% of oxidized follitropin alfa.
Therapeutic Class: Infertility.
CLINICAL PHARMACOLOGY:
Follitropin alfa stimulates ovarian follicular growth in women who do not have primary ovarian failure. FSH, the active component of follitropin alfa 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 follitropin alf when monitoring of the patient indicates that sufficient follicular development has occurred. There is interpatient variability in response to FSH administration. The physicochemical, immunological, and biological activities of recombinant FSH are comparable to those of pituitary and human menopausal urine-derived FSH.
Pharmacokinetics
Single dose pharmacokinetics of r-hFSH were determined following intravenous subcutaneous and intramuscular administration of 150 IU follitropin alfa to 12 healthy, down-regulated female volunteers. Steady-state pharmacokinetics were also determined in 12 healthy down-regulated female volunteers who were administered a single daily dose of 150 IU for seven days. These pharmacokinetics were confirmed in pituitary down-regulated women undergoing in vitro fertilization and embryo transfer (IVF/ET), treated with FSH doses of up to 450 IU per day.
Absorption: The absorption rate of follitropin alfa following subcutaneous or intramuscular administration was found to be slower than the elimination rate. Hence the pharmacokinetics of follitropin alfa are absorption rate-limited.
Distribution: Human tissue or organ distribution of FSH has not been determined for follitropin alfa.
After intravenous administration, the serum profile of FSH appears to be described by a two compartment open model with a distribution half-life of about 2-2.5 hours. Steady-state serum levels were reached after 4 to 5 days of daily administration.
Metabolism/Elimination: FSH metabolism following administration of follitropin alfa has not been studied in humans. Total clearance after IV administration was 0.6 L/hr; mean residence time was 17-20 hours. FSH renal clearance was 0.07 L/hr after intravenous administration representing approximately 1/8 of total clearance.
Pharmacodynamics: Following daily subcutaneous administration of 150 IU of follitropin alfa for 7 days, serum inhibin and estradiol, and total follicular volume responded as a function of time, with pronounced inter-individual variability. Pharmacodynamic effect lagged behind FSH serum concentration. Of the three pharmacodynamic parameters, serum inhibin levels responded with the least delay and declined rapidly after discontinuation of follitropin alfa. Follicular growth was most delayed and continued even after discontinuation of follitropin alfa administration, and after serum FSH levels had declined. Maximum follicular volume was better correlated with either inhibin or estradiol peak levels than with FSH concentration. Inhibin rise was an early index of follicular development.
Population Pharmacokinetics and Pharmacodynamics: To establish the pharmacokinetics and pharmacodynamics of FSH in a target population, measurements performed during a clinical study of in vitro fertilization/embryo transfer were used in conjunction with pharmacokinetic data from studies in healthy volunteers. The apparent clearance was comparable to that in healthy volunteers. The absorption rate was found to be influenced by the body mass index (BMI), suggesting that the higher the BMI, the lower the rate of absorption. However, FSH serum levels following fixed (during the first five days) and then adjusted doses of follitropin alfa were found to be poor predictors of follicular growth rate. High pre-treatment serum FSH levels may predict lower follicular growth rates.
Special Populations
Safety, efficacy, and pharmacokinetics of follitropin alfa in patients with renal or hepatic insufficiency have not been established.
CLINICAL STUDIES:
The safety and efficacy of follitropin alfa have been examined in four clinical studies, two studies for ovulation induction and two studies for assisted reproductive technologies (ART). In these comparative studies, there were no clinically significant differences between treatment groups in study outcomes.
Ovulation Induction
The safety and efficacy of follitropin alfa administered subcutaneously vs. urofollitropin administered intramuscularly were assessed in a phase III, open-label, randomized, comparative, multinational, multicenter study in oligo-anovulatory infertile women who failed to ovulate or conceive following adequate clomiphene citrate therapy (Study 5642).
The primary efficacy parameter was the ovulation rate. Two hundred and twenty-two patients entered into the first cycle of treatment, of whom 110 received follitropin alfa and 112 received urofollitropin. Ovulation rates were similar between follitropin alfa and urofollitropin treatment groups.
A second randomized, comparative, open-label, multicenter study was conducted in 23 U.S. centers (Study 5727). The primary efficacy parameter was ovulation rate. Ovulation rates were similar between follitropin alfa and urofollitropin treatment groups. Two hundred and thirty-two patients with oligo-anovulatory infertility received treatment with up to three cycles of follitropin alfa administered subcutaneously (118 patients) or urofollitropin administered intramuscularly (114 patients).
The cumulative patient ovulation rate and clinical pregnancy rates by cycle are presented for the 232 patients who received treatment in at least one cycle.
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.
For the 85 patients who had a clinical pregnancy (44 in follitropin alfa group; 41 in urofollitropin group
Assisted Reproductive Technologies (ART)
The safety and efficacy of follitropin alfa administered subcutaneous vs. urofollitropin administered intramuscularly were assessed in a phase III, open-label, randomized, comparative, multinational, multicenter study in ovulatory, infertile women undergoing stimulation of multiple follicles for In Vitro Fertilization and Embryo Transfer (IVF/ET) after pituitary down-regulation with a GnRH agonist (Study 5503). The purpose of the study was to demonstrate that follitropin alfa, administered subcutaneously, was clinically not different in terms of safety and efficacy from urofollitropin, administered intramuscularly. The initial and maximal doses of follitropin alfa were 225 and 450 IU, respectively. The primary efficacy-parameter was the number of mature pre-ovulatory follicles on the day of hCG administration. One hundred and twenty-three patients were randomized and received either follitropin alfa (60 patients) or urofollitropin (63 patients).
The results summarized in TABLE 6are mean data with follitropin alfa and urofollitropin administered to ovulatory infertile women undergoing multiple follicular development for IVF/ET.
For the 22 patients who had a clinical pregnancy (12 in follitropin alfa group; 10 in urofollitropin group), the outcome of the pregnancy is shown in TABLE 7.
A second randomized, comparative, open-label, multicenter study was conducted in 7 U.S. centers (Study 5533). One hundred and fourteen patients with ovulatory infertility undergoing IVF/ET were randomized and received either follitropin alfa by subcutaneous administration (56 patients) or urofollitropin by intramuscular administration (58 patients) following pituitary down-regulation with a GnRH agonist. The primary efficacy parameter was the number of mature pre-ovulatory follicles on the day of hCG administration.
INDICATIONS AND USAGE:
Follitropin alfa is indicated for the induction of ovulation and pregnancy in the anovulatory infertile patient in whom the cause of infertility is functional and not due to primary ovarian failure. Follitropin alfa is also indicated for the development of multiple follicles in the ovulatory patient participating in an Assisted Reproductive Technology (ART) program.
Selection of Patients
1. Before treatment with follitropin alfa is instituted, a thorough gynecologic and endocrinologic evaluation must be performed. This should include an assessment of pelvic anatomy. Patients with tubal obstruction should receive follitropin alfa only if enrolled in an in vitro fertilization program.
2. Primary ovarian failure should be excluded by the determination of gonadotropin levels.
3. Appropriate evaluation should be performed to exclude pregnancy.
4. Patients in later reproductive life have a greater predisposition to endometrial carcinoma as well as a higher incidence of anovulatory disorders. A thorough diagnostic evaluation should always be performed in patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities before starting follitropin alfa therapy.
5. Evaluation of the partner's fertility potential should be included in the initial evaluation.
CONTRAINDICATIONS:
Follitropin Alfa is Contraindicated in Women Who Exhibit
1. Prior hypersensitivity to recombinant FSH preparations or one of their excipients.
2. High levels of FSH indicating primary ovarian failure.
3. Uncontrolled thyroid or adrenal dysfunction.
4. An organic intracranial lesion such as a pituitary tumor.
5. Abnormal uterine bleeding of undetermined origin (see INDICATIONS AND USAGE, Selection of Patients).
6. Ovarian cysts or enlargement of undetermined origin (see INDICATIONS AND USAGE, Selection of Patients).
7. Sex hormone dependent tumors of the reproductive tract and accessory organs.
8. Pregnancy.