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| |  Fertinex Cleared by FDA to Reduce the Stress of Infertility Treatment NORWELL, MA, Aug. 28, 1996 -- The U.S. Food and Drug Administration (FDA) has granted Serono Laboratories, Inc., authorization to market Fertinex(TM) (urofollitropin for injection, purified), the first highly purified follicle stimulating hormone (FSH) that can be administered via subcutaneous injection. Fertinex will be marketed for patients undergoing infertility treatments with Assisted Reproductive Technologies (ART), such as In Vitro Fertilization (IVF), as well as for infertile patients with polycystic ovary disease (PCO)1. First introduced outside the U.S. in 1993, this highly purified formulation of FSH quickly became the most popular hormone treatment for infertility in many countries, including Germany, the United Kingdom, France, Italy, Spain and Sweden. The manufacturing process for Fertinex, developed by The Ares-Serono Group, results in an FSH product of very high purity and consistency. FSH is the primary natural hormone that stimulates development and maturation of follicles, found in the ovaries, which contain oocytes (eggs); during ovulation, egg(s) are released from the follicles. Because of its high purity, Fertinex can be administered with a very small needle just under the skin (subcutaneous injection), an additional improvement compared to older products which must be injected deep into muscle tissue (intramuscular administration), usually with the aid of the patient's physician, nurse or partner. A recent study by Louis Harris pollsters2 found that patients using older FSH preparations experienced both discomfort and stress because the injection was intramuscular and because they needed a partner or healthcare provider to administer the injection for them. Fertinex reduces discomfort and affords greater independence for patients because it can be self-administered. 1- Development of multiple cysts in the ovaries due to arrested follicular growth caused by an imbalance of fertility hormones released during the ovulatory cycle. Serono has been a pioneer in infertility therapies for decades and supports all aspects of infertility treatment, including clinical trials, professional education and patient support. "The approval of Fertinex(TM) marks the beginning of a series of new products to treat infertility which are being developed by Ares-Serono and which will continue to improve patients' quality of care," said Ernesto Bertarelli, chief executive officer of The Ares-Serono Group. Since the early 1960s, Ares-Serono has been a leader in developing the most effective and convenient drug therapies to treat infertility and offers a full range of pharmaceutical products in this therapeutic area. Committed to improving the quality of care in reproductive health, Ares-Serono is also developing a complete portfolio of recombinant fertility hormones. "Fertinex represents another major advance in the development of ethical pharmaceuticals to treat couples with infertility. This new therapy offers a high level of purity and, therefore, can be administered subcutaneously, a tremendous advantage for patients," said Hisham Samra, M.D., president of Serono Laboratories. "In addition, the high specific activity and purity of Fertinex offers the reproductive specialist a new benchmark for drug therapies." Infertility affects about 10 percent of the reproductive-age population in the U.S., or about 5.3 million people, according to the American Society for Reproductive Medicine (ASRM). Infertility is commonly defined as the inability to conceive or carry a pregnancy to term, and may be the result of various medical conditions. Infertility affects both the male and female partners equally. Serono Laboratories, Inc., headquartered in Norwell, MA, is a member company of The Ares-Serono Group, the world's foremost developer and manufacturer of pharmaceuticals for the treatment of infertility. Ares-Serono, with headquarters in Geneva, Switzerland, also specializes in the development, production and marketing of biopharmaceutical products in the areas of growth, metabolism and immunology/oncology. Fertinex(TM) FOR SUBCUTANEOUS INJECTION DESCRIPTION Fertinex (urofollitropin for injection, purified) is a preparation of highly purified Follicle Stimulating Hormone (FSH) extracted from the urine of post-menopausal women. Purification is by immunoaffinity chromatography using murine monoclonal antibody to human FSH. The purification process results in a consistent FSH isoform profile, significantly enhanced specific activity (8,500-13,500 IU FSH/mg protein), and 95% purity. Each ampule of Fertinex contains either 75 IU or 150 IU of highly purified FSH and 10 mg lactose in a sterile, lyophilized form. If required, pH is adjusted with 0.1 M hydrochloric acid and/or 0.1 M sodium hydroxide. Fertinex is administered by subcutaneous injection. Fertinex contains an acidic, water soluble glycoprotein biologically standardized for FSH gonadotropin activity in terms of the Second International Reference Preparation for Human Menopausal Gonadotropins established in September, 1964 by the Expert Committee on Biological Standards of the World Health Organization. Negligible amounts (0.1 IU LH/1000 IU FSH) of luteinizing hormone (LH) activity are contained in Fertinex. Therapeutic Class: Infertility. CLINICAL PHARMACOLOGY Fertinex (urofollitropin for injection, purified) stimulates ovarian follicular growth in women who do not have primary ovarian failure. FSH, the active component of Fertinex, 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 Fertinex when monitoring of the patient indicates that sufficient follicular development has occurred. There may be a degree of interpatient variability in response to FSH administration. Pharmacokinetics: In a comparative, single-dose, double-blind, double-dummy, randomized, cross-over study, Fertinex administered subcutaneously demonstrated a similar pharmacokinetic profile to urofollitropin and Fertinex administered intramuscularly. No significant differences were found between the treatment groups in AUC/dose and CMAX/dose parameters. A variability in TMAX was observed. Subcutaneous administration of Fertinex led to a slower absorption rate resulting in a later TMAX (15 + or - 7 h) than following IM administration of either Fertinex (10 + or - 4 h) or urofollitropin (9 + or - 4 h). Plasma inhibin levels were measured as a pharmacodynamic marker of FSH activity. The inhibin concentration-time profile of inhibin following Fertinex administered subcutaneously was found to be similar to that following urofollitropin and Fertinex administered intramuscularly. Special Populations: Safety and efficacy of Fertinex in renal or hepatic insufficiency have not been established. Drug-Drug Interactions: No clinically significant drug-drug interactions have been reported (see PRECAUTIONS). Clinical Studies: 1. Ovulation Induction: The safety and efficacy of Fertinex administered subcutaneously vs. urofollitropin administered intramuscularly for ovulation induction was assessed in a phase III, open-label, randomized, comparative, multicenter study in oligo-ovulatory infertile women who failed to ovulate or conceive following adequate clomiphene citrate therapy. The purpose of the study was to demonstrate that Fertinex, a highly purified follicle stimulating hormone (FSH) administered subcutaneously, is clinically not different in terms of safety and efficacy from urofollitropin administered intramuscularly. The principal efficacy parameters recorded were serum estradiol levels, follicular growth, ovulation rate and pregnancy rate. Two hundred eleven patients entered treatment, of whom 108 received Fertinex and 103 received urofollitropin. Overall, two-hundred and four patients (491 cycles) were considered evaluable. There were no differences between the Fertinex administered subcutaneously and the urofollitropin intramuscular treatment groups in serum estradiol levels and follicular growth (follicle number and size) on the day of human chorionic gonadotropin (hCG) administration, nor were there any differences between the treatment groups in ovulation rates or pregnancy rates per patient. The results of safety and efficacy with Fertinex administered subcutaneously for ovulation induction in oligo-ovulatory infertile women are summarized below: Cumulative Patient Ovulation Rates: The cumulative patient ovulation rate by cycle is presented for the 102 evaluable patients with documentation of ovulatory status in at least one cycle: Cycle 1 83% Cycle 2 97% Cycle 3 100%
Cumulative Patient Pregnancy Rates: The cumulative patient pregnancy rate by cycle is presented for 86 evaluable patients who received hCG: Cycle 1 14% Cycle 2 21% Cycle 3 29%
Patients Aborting* 8% Multiple Births* 21% Severe Hyperstimulation Syndrome** 0%
*Based upon 25 evaluable clinical pregnancies **Based upon 108 patients and 266 cycles evaluable for safety
2. Assisted Reproductive Technologies (ART): The safety and efficacy of Fertinex administered subcutaneously for Assisted Reproductive Technologies (ART) were assessed in a phase III, multicenter, non-comparative, clinical trial in ovulatory infertile women undergoing stimulation of multiple follicular development for In Vitro Fertilization and Embryo Transfer (IVF/ET) after pituitary down-regulation with a GnRH agonist. The initial and maximal doses of Fertinex were 225 and 450 IU, respectively. The principal parameters recorded were serum estradiol on day of hCG administration, the number and maturity of retrieved oocytes, drug therapy and duration, and clinical pregnancy rate per initiated cycle and per retrieval. One hundred and thirty-nine patients were enrolled in the study; 135 patients were treated with Fertinex and 122 patients were considered evaluable for efficacy. The results listed below represent mean data of 118 evaluable patients who received hCG in the 10 study centers: Total number of oocytes recovered 8.4
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