Follitropin beta (DB00066) Approved Drug Chemical Formula: C975H1513N267O304S26 Molecular Weight: 22672.9 Follitropin beta 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. The alpha subunit is glycosylated at Asn 51 and Asn 78 while the beta subunit is glycosylated at Asn 7 and Asn 24. Follitropin beta is produced in genetically engineered Chinese hamster cell lines (CHO). The nomenclature alpha and beta differentiates it from another recombinant human FSH product that was marketed earlier as follitropin alpha. Follitropin is important in the development of follicles produced by the ovaries. Given by subcutaneous injection, it is used in combination with human chorionic gonadotropin (hCG) to assist in ovulation and fertility. Follitropin may also be used to cause the ovary to produce several follicles, which can then be harvested for use in gamete intrafallopian transfer (GIFT) or in vitro fertilization (IVF). Numerous physio-chemical tests and bioassays indicate that follitropin beta and follitropin alpha are indistinguishable. However, a more recent study showed there is may be a slight clinical difference, with the alpha form tending towards a higher pregnancy rate and the beta form tending towards a lower pregnancy rate, but with significantly higher estradiol (E2) levels.

Structural analysis shows that the amino acid sequence of follitropin beta is identical to that of natural human follicle stimulating hormone (FSH). Further, the ogliosaccharide side chains are very similar, but not completely identical to that of natural FSH. However, these small differences do not affect the bioactivity compared to natural FSH. Indication/Usage For treatment of female infertility Pharmacodynamics Used for the treatment of female infertility, Follitropin beta or follicle stimulating hormone (FSH) stimulates ovarian follicular growth in women who do not have primary ovarian failure. FSH, the active component of Follitropin beta is the primary hormone responsible for follicular recruitment and development. Mechanism Of Action Follitropin alpha is a recombinant form of endogenous follicle stimulating hormone (FSH). FSH binds to the follicle stimulating hormone receptor which is a G-coupled transmembrane receptor. Binding of the FSH to its receptor seems to induce phosphorylation and activation of the PI3K (Phosphatidylinositol-3-kinase) and Akt signaling pathway, which is known to regulate many other metabolic and related survival/maturation functions in cells.. Half-life Circulation half life of 3-4 hours, elimination half life of 35-40 hours Route of Elimination Via liver and Kidneys

Volume of Distribution * 8 L [female subjects following intravenous administration of a 300 IU dose] Clearence * 0.01 1*h-1kg-1 [European women with a single intramuscular dose of 300 IU]* 0.01 1*h-1kg-1 [Japanese women with a single intramuscular dose of 300 IU] Category Fertility agents Affected Organisms Humans and other mammals Patents Patent no. 7741268, USA, approved: 2004-04-02 expired: 2024-04-02 Patent no. 5270057, USA, approved: 1994-03-20 expired: 2011-03-20 Patent no. 2037884, Canada, approved: 2003-10-21 expired: 2011-03-08 Sequence Alpha chain:APDVQDCPECTLQENPFFSQPGAPILQCMGCCFSRAYPTPLRSKKTMLVQKNVTSESTCCVAKSYNRVTVMGGFKVENHTACHCSTCYYHKS Beta chain:NSCELTNITIAIEKEECRFCISINTTWCAGYCYTRDLVYKDPARPKIQKTCTFKELVYETVRVPGCAHHADSLYTYPVATQCHCGKCDSDSTDCTVRGLGPSYCSFGEMKE

Experimental Properties Melting Point- 55 °C Hydrophobicity: 0.330 Isoelectric Point: 7.50 Targets Follicle-stimulating hormone receptor General References Goa KL, Wagstaff AJ: Follitropin alpha in infertility: a review. BioDrugs. 1998 Mar;9(3):235-60. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/18020563 Brands Follistim AQ - Merck

Follistim AQ Formulation Used/Prescribed for Dosage Follistim® AQ (follitropin beta injection) contains human follicle-stimulating hormone (hFSH), a glycoprotein hormone which is manufactured by recombinant DNA (rDNA) technology. The active drug substance, follitropin beta, has a dimeric structure containing two glycoprotein subunits (alpha and beta). Both the 92 amino acid alpha-chain and the 111 amino acid beta-chain have complex heterogeneous structures arising from two N-linked oligosaccharide chains. Follitropin beta is synthesized in a Chinese hamster ovary (CHO) cell line that has been transfected with a plasmid containing the two subunit DNA sequences encoding for hFSH. Follistim AQ (follitropin beta) is presented as a sterile aqueous solution for SUBCUTANEOUS or INTRAMUSCULAR administration Formulation Each single-use vial of Follistim® AQ (follitropin beta) contains the following per 0.5 mL: 75 IU or 150 IU of FSH activity; 25 mg sucrose, NF; 7.35 mg sodium citrate (dihydrate), USP; 0.25 mg L-methionine, USP; 0.1 mg polysorbate 20, NF; and water for injection, USP. Hydrochloric acid, NF and/or sodium hydroxide, NF are used to adjust the pH to 7. Used/Prescribed for Follistim® AQ (follitropin beta injection) is indicated for the development of multiple follicles in ovulatory patients participating in an Assisted Reproductive Technology (ART) program. Follistim® AQ (follitropin beta) is also indicated for the induction of ovulation and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not due to primary ovarian failure. Dosage starting dose of 150 to 225 IU of Follistim® AQ (follitropin beta injection) is recommended for at least the first four days of treatment. After this, the dose may be adjusted for the individual patient based upon their ovarian response.

Contraindications Side-effects Drug Interactions References Tumor of the ovary, breast, uterus, hypothalamus or pituitary gland; Pregnancy; Uncontrolled thyroid or adrenal dysfunction; High levels of FSH indicating primary ovarian failure Side-effects The following adverse events have been reported in women treated with gonado tropins: pulmonary and vascular complications, hemoperitoneum, adnexal torsion (as a complication of ovarian enlargement), dizziness, tachycardia, dyspnea, tachypnea, febrile reactions, flu-like symptoms including fever, chills, mus culoskeletal aches, joint pains, nausea, headache and malaise, breast tenderness, and dermatological symptoms Drug Interactions No drug-drug interaction studies have been performed. References http://www.merck.com/product/usa/pi_circulars/f/follistim_aq_cartridge/follistim_cartridge_pi.pdf