Gonadotropin; Ovulation Stimulator

Urofollitropin (Fertinex™):

Polycystic ovary syndrome: Administered sequentially with hCG for the stimulation of follicular recruitment and development and the induction of ovulation in patients with polycystic ovary syndrome and infertility, who have failed to respond or conceive following adequate clomiphene citrate therapy

Follicle stimulation: Stimulation of the development of multiple follicles in ovulatory patients undergoing assisted reproductive technologies such as in vitro fertilization

Follitropin alpha (Gonal-F™) / follitropin beta (Follistim™):

Ovulation induction: Induction of ovulation and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not caused by primary ovarian failure

Follicle stimulation: Stimulation of the development of multiple follicles in ovulatory patients undergoing assisted reproductive technologies such as in vitro fertilization

Spermatogenesis induction: Induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism in whom the cause of infertility is not due to primary testicular failure

X

High levels of FSH indicating primary ovarian failure; uncontrolled thyroid or adrenal dysfunction; the presence of any cause of infertility other than anovulation; tumor of the ovary, breast, uterus, hypothalamus, or pituitary gland; abnormal vaginal bleeding of undetermined origin; ovarian cysts or enlargement not due to polycystic ovary syndrome; hypersensitivity to the product or any of its components; pregnancy

These medications should only be used by physicians who are thoroughly familiar with infertility problems and their management. To minimize risks, use only at the lowest effective dose. Monitor ovarian response with serum estradiol and vaginal ultrasound on a regular basis.

Serious pulmonary conditions (atelectasis, acute respiratory distress syndrome and exacerbation of asthma) have been reported. Thromboembolic events, both in association with and separate from ovarian hyperstimulation syndrome, have been reported.

Multiple pregnancies have been associated with these medications, including triplet and quintuplet gestations. Advise patient of the potential risk of multiple births before starting the treatment.

1% to 10%:

Endocrine & metabolic: Ovarian hyperstimulation syndrome, adnexal torsion, mild to moderate ovarian enlargement, abdominal pain, ovarian cysts, breast tenderness

Gastrointestinal: Nausea, vomiting, diarrhea, abdominal cramps, bloating

Local: Pain, rash, swelling, or irritation at the site of injection

Respiratory: Atelectasis, acute respiratory distress syndrome, exacerbation of asthma

Miscellaneous: Febrile reactions accompanied by chills, musculoskeletal, joint pains, malaise, headache, and fatigue

Symptoms of overdose: Aside from possible ovarian hyperstimulation and multiple gestations, little is known concerning the consequences of an acute overdose

Treatment is symptomatic

Urofollitropin (Fertinex™): Lyophilized powder may be stored in the refrigerator or at room temperature (3°C to 25°C/37°F to 77°F). Protect from light; use immediately after reconstitution.

Urofollitropin (Fertinex™): Dissolve the contents of one or more ampuls of urofollitropin in 0.5-1 mL of sterile saline (concentration should not exceed 225 international units/0.5 mL)

Follitropin alpha (Gonal-F®)/follitropin beta (Follistim™): Store powder refrigerated or at room temperature (2°C to 25°C/36°F to 77°F). Protect from light; use immediately after reconstitution.

Follitropin alpha (Gonal-F®): Dissolve the contents of one or more ampuls in 0.5-1 mL of sterile water for injection (concentration should not exceed 225 international units/0.5 mL)

Follitropin beta (Follistim™): Inject 1 mL of 0.45% sodium chloride injection into vial of follitropin beta. Do not shake, but gently swirl until solution is clear; generally the follitropin beta dissolves immediately

Urofollitropin is a preparation of highly purified follicle-stimulating hormone (FSH) extracted from the urine of postmenopausal women. Follitropin alpha and follitropin beta are human FSH preparations of recombinant DNA origin. Follitropins stimulate ovarian follicular growth in women who do not have primary ovarian failure. FSH is required for normal follicular growth, maturation, and gonadal steroid production.

Absorption: Absorption-rate limited pharmacokinetics; absorption rate following I.M. or S.C. administration is slower than the elimination rate

Mean T_max:

Follitropin alpha: 16 hours after subcutaneous administration; 25 hours after intramuscular administration

Follitropin beta: 27 hours after intramuscular administration

Urofollitropin: 15 hours after subcutaneous administration; 10 hours after intramuscular administration

Distribution: Mean V_d: Follitropin alpha: 10 L; Follitropin beta: 8 L

Bioavailability: Ranges from ~66% to 78% depending on the agent

Metabolism: Total clearance of follitropin alpha was 0.6 Liters/hour following IV administration

Half-life:

Mean elimination:

Follitropin alpha: 24-32 hours after subcutaneous administration

Follitropin beta: ~30 hours after intramuscular administration

Mean terminal: Follitropin alpha (intramuscular) & follitropin beta (subcutaneous): ~30 hours with multiple dosing

Urofollitropin (Fertinex™): Adults: S.C.:

Polycystic ovary syndrome: Initial recommended dose of the first cycle: 75 international units/day; consider dose adjustment after 5-7 days; additional dose adjustments may be considered based on individual patient response. The dose should not be increased more than twice in any cycle or by more than 75 international units per adjustment. To complete follicular development and affect ovulation in the absence of an endogenous LH surge, give 5000 to 10,000 units hCG, 1 day after the last dose of urofollitropin. Withhold hCG if serum estradiol is >2000 pg/mL.

Individualize the initial dose administered in subsequent cycles for each patient based on her response in the preceding cycle. Doses of >300 international units of FSH/day are not routinely recommended. As in the initial cycle, 5000 to 10,000 units of hCG must be given 1 day after the last dose of urofollitropin to complete follicular development and induce ovulation.

Give the lowest dose consistent with the expectation of good results. Over the course of treatment, doses may range between 75 to 300 international units/day depending on individual patient response. Administer urofollitropin until adequate follicular development as indicated by serum estradiol and vaginal ultrasonography. A response is generally evident after 5-7 days.

Encourage the couple to have intercourse daily, beginning on the day prior to the administration of hCG until ovulation becomes apparent from the indices employed for determination of progestational activity. Take care to ensure insemination.

Follicle stimulation: For Assisted Reproductive Technologies, initiate therapy with urofollitropin in the early follicular phase (cycle day 2 or 3) at a dose of 150 international units/day, until sufficient follicular development is attained. In most cases, therapy should not exceed 10 days.

Follitropin alpha (Gonal-F®): Adults: S.C.:

Ovulation induction: Initial recommended dose of the first cycle: 75 international units/day. Consider dose adjustment after 5-7 days; additional dose adjustments of up to 37.5 international units may be considered after 14 days. Further dose increases of the same magnitude can be made, if necessary, every 7 days. To complete follicular development and affect ovulation in the absence of an endogenous LH surge, give 5000 to 10,000 units hCG, 1 day after the last dose of follitropin alpha. Withhold hCG if serum estradiol is >2000 pg/mL.

Individualize the initial dose administered in subsequent cycles for each patient based on her response in the preceding cycle. Doses of >300 international units of FSH/day are not routinely recommended. As in the initial cycle, 5000 to 10,000 units of hCG must be given 1 day after the last dose of urofollitropin to complete follicular development and induce ovulation.

Give the lowest dose consistent with the expectation of good results. Over the course of treatment, doses may range between 75 to 300 international units/day depending on individual patient response. Administer urofollitropin until adequate follicular development as indicated by serum estradiol and vaginal ultrasonography. A response is generally evident after 5-7 days.

Encourage the couple to have intercourse daily, beginning on the day prior to the administration of hCG until ovulation becomes apparent from the indices employed for determination of progestational activity. Take care to ensure insemination.

Follicle stimulation: Initiate therapy with follitropin alpha in the early follicular phase (cycle day 2 or 3) at a dose of 150 international units/day, until sufficient follicular development is attained. In most cases, therapy should not exceed 10 days.

In patients undergoing Assisted Reproductive Technologies, whose endogenous gonadotropin levels are suppressed, initiate follitropin alpha at a dose of 225 international units/day. Continue treatment until adequate follicular development is indicated as determined by ultrasound in combination with measurement of serum estradiol levels. Consider adjustments to dose after 5 days based on the patient's response; adjust subsequent dosage every 3-5 days by less than or equal to 75-150 international units additionally at each adjustment. Doses >450 international units/day are not recommended. Once adequate follicular development is evident, administer hCG (5000-10,000 units) to induce final follicular maturation in preparation for oocyte.

Follitropin beta (Follistim™): Adults: S.C. or I.M.:

Ovulation induction: Stepwise approach: Initiate therapy with 75 international units/day for up to 14 days. Increase by 37.5 international units at weekly intervals until follicular growth or serum estradiol levels indicate an adequate response. The maximum, individualized, daily dose that has been safely used for ovulation induction in patients during clinical trials is 300 international units. Treat the patient until ultrasonic visualizations or serum estradiol determinations indicate preovulatory conditions greater than or equal to normal values followed by 5000 to 10,000 units hCG.

During treatment and during a 2-week post-treatment period, examine patients at least every other day for signs of excessive ovarian stimulation. Discontinue follitropin beta administration if the ovaries become abnormally enlarged or abdominal pain occurs.

Encourage the couple to have intercourse daily, beginning on the day prior to the administration of hCG until ovulation becomes apparent from the indices employed for determination of progestational activity. Take care to ensure insemination.

Follicle stimulation: A starting dose of 150-225 international units of follitropin beta is recommended for at least the first 4 days of treatment. The dose may be adjusted for the individual patient based upon their ovarian response. Daily maintenance doses ranging from 75-300 international units for 6-12 days are usually sufficient, although longer treatment may be necessary. However, maintenance doses of up to 375-600 international units may be necessary according to individual response. The maximum daily dose used in clinical studies is 600 international units. When a sufficient number of follicles of adequate size are present, the final maturation of the follicles is induced by administering hCG at a dose of 5000-10,000 international units. Oocyte retrieval is performed 34-36 hours later. Withhold hCG in cases where the ovaries are abnormally enlarged on the last day of follitropin beta therapy.

Monitor sufficient follicular maturation. This may be directly estimated by sonographic visualization of the ovaries and endometrial lining or measuring serum estradiol levels. The combination of both ultrasonography and measurement of estradiol levels is useful for monitoring for the growth and development of follicles and timing hCG administration.

The clinical confirmation of ovulation is obtained by direct and indirect indices of progesterone production. The indices most generally used are: rise in basal body temperature, increase in serum progesterone, and menstruation following the shift in basal body temperature.

Discontinue immediately if possibility of pregnancy. Prior to therapy, inform patients of the following: Duration of treatment and monitoring required; possible adverse reactions; risk of multiple births.

Urofollitropin (Fertinex®): Powder for injection: 75 international units (1, 10, 100 mL ampuls with diluent), 150 international units (1 mL ampuls with diluent)

Follitropin alpha (Gonal-F®): Powder for injection: 75 international units (1, 10, 100 mL ampuls with diluent), 150 international units (1 mL ampuls with diluent)

Follitropin beta (Follistim®): Powder for injection:: 75 international units (1, 5 mL vials with diluent)