Follistim Beta

Follistim® (follitropin beta for injection) contains human follicle-stimulating hormone (hFSH), a glycoprotein hormone which is manufactured by recombinant DNA (rDNA) technology. 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. The purification process results in a highly purified preparation with a consistent hFSH isoform profile and high specific activity1. The biological activity is determined by measuring the increase in ovary weight in female rats. The intrinsic luteinizing hormone (LH) activity in follitropin beta is less than 1 IU per 40,000 IU FSH. The compound is considered to contain no LH activity.

The amino acid sequence and tertiary structure of the product are indistinguishable from that of human follicle-stimulating hormone (hFSH) of urinary source. Also, based on available data derived from physio-chemical tests and bioassay, follitropin beta and follitropin alfa, another recombinant follicle-stimulating hormone product, are indistinguishable.

Follistim® is presented as a sterile, freeze-dried cake, intended for SUBCUTANEOUS or INTRAMUSCULAR administration after reconstitution with Sterile Water for Injection, USP. Each vial of Follistim® contains 75 IU of FSH activity plus 25.0 mg sucrose, NF; 7.35 mg sodium citrate dihydrate, USP; 0.10 mg polysorbate 20, NF, and hydrochloric acid, NF and/or sodium hydroxide, NF to adjust the pH in a sterile, lyophilized form. The pH of the reconstituted preparation is approximately 7.0. The recombinant protein in Follistim® has been standardized for FSH in vivo bioactivity in terms of the First International Reference Preparation for human menopausal gonadotropins (code 70/45), issued by the World Health Organization Expert Committee on Biological Standardization (1982). Under current storage conditions, Follistim® may contain up to 20% of oxidized follitropin beta.

In clinical trials with Follistim®, serum antibodies to FSH or anti-CHO cell derived proteins were not detected in any of the treated patients after exposure to Follistim® for up to three cycles.

Therapeutic Class: Infertility.

General

Careful attention should be given to the diagnosis of infertility and in the selection of candidates for Follistim® (follitropin beta for injection) therapy (see INDICATIONS AND USAGE - Selection of Patients).

Information for Patients

Prior to therapy with Follistim®, patients should be informed of the duration of treatment and monitoring procedures that will be required. The risks of Ovarian Hyperstimulation Syndrome and multiple births (see WARNINGS), and other possible adverse reactions (see ADVERSE REACTIONS) should be discussed.

Laboratory Tests

In most instances, treatment with Follistim® will result only in follicular growth and maturation. In order to complete the final phase of follicular maturation and to induce ovulation, hCG must be given following the administration of Follistim® or when clinical assessment of the patient indicates that sufficient follicular maturation has occurred. This may be directly estimated by sonographic visualization of the ovaries and endometrial lining and/or measuring serum estradiol levels. The combination of both ultrasonography and measurement of estradiol levels is useful for monitoring the growth and development of follicles, timing hCG administration, as well as minimizing the risk of OHSS and multiple gestations.

The clinical evaluation of estrogenic activity (changes in vaginal cytology, changes in appearance and volume of cervical mucus, spinnbarkeit, and ferning of the cervical mucus) provides an indirect estimate of the estrogenic effect upon the target organs, and therefore it should only be used adjunctively with more direct estimates of follicular development (e.g., ultrasonography and serum estradiol determinations).

The clinical confirmation of ovulation is obtained by direct and indirect indices of progesterone production. The indices most generally used are as follows:

a) A rise in basal body temperature,

b) Increase in serum progesterone, and

c) Menstruation following the shift in basal body temperature.

When used in conjunction with indices of progesterone production, sonographic visualization of the ovaries will assist in determining if ovulation has occurred. Sonographic evidence of ovulation may include the following:

a) Fluid in the cul-de-sac,

b) Follicle showing marked decrease in size, and

c) Collapsed follicle.

Drug Interactions

No drug/drug interaction studies have been performed.

Carcinogenesis and Mutagenesis and Impairment of Fertility

Long-term toxicity studies in animals have not been performed with Follistim® to evaluate the carcinogenic potential of the drug. Follistim® was not mutagenic in the Ames test using S. typhimurium and E. coli tester strains and did not produce chromosomal aberrations in an in vitro assay using human lymphocytes.

Pregnancy

Pregnancy Category X: (See CONTRAINDICATIONS).

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the nursing infant from Follistim®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Follistim® did not include subjects aged 65 and over.

Assisted Reproductive Technologies (ART)

Rates of adverse events from a randomized, assessor-blind, group comparative, multicenter safety and efficacy study of Follistim® (Protocol 37608) in 989 infertile women treated with in vitro fertilization with Follistim® or Metrodin® after pituitary suppression with a GnRH agonist are summarized in Table VIII.

Ovulation Induction

Rates of adverse events from a randomized, assessor-blind, group comparative, multicenter safety and efficacy study of Follistim® (Protocol 37609) in 172 chronic anovulatory women who failed to ovulate and/or conceive during clomiphene citrate treatment are summarized in Table IX.

The following adverse events have been reported in women treated with gonadotropins: pulmonary and vascular complications (see WARNINGS), hemoperitoneum, adnexal torsion (as a complication of ovarian enlargement), dizziness, tachycardia, dyspnea, tachypnea, febrile reactions, flu-like symptoms including fever, chills, musculoskeletal aches, joint pains, nausea, headache and malaise, breast tenderness, and dermatological symptoms (dry skin, body rash, hair loss and hives).

There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for ovulation induction; however, a causal relationship has not been established.

Aside from the possibility of Ovarian Hyperstimulation Syndrome (see WARNINGS-Overstimulation of the Ovary During Follistim® Therapy) and multiple gestations (see WARNINGS-Multiple Births), there is no additional information concerning the consequences of acute overdosage with Follistim® (follitropin beta for injection).

Follistim® (follitropin beta for injection) is supplied in a sterile, freeze-dried form, as a white to off-white cake or powder in vials containing 75 IU of FSH activity. The following package combinations are available:

• 5 vials 75 IU Follistim® and 5 vials 5 mL Sterile Water for Injection, USP.
  NDC 0052-0306-31

Storage

Lyophilized powder may be stored refrigerated or at room temperature (2o-25oC/36o-77oF). Protect from light. Use immediately after reconstitution. Discard unused material.

Rx Only

Manufactured by
Organon Inc.
West Orange, NJ 07052
Diluent manufactured by
Luitpold Pharmaceuticals, Inc.
Shirley, NY 11967