Follitropin Beta

Follicle-stimulating hormone (FSH), the active component in Follistim® AQ (follitropin beta injection), is required for normal follicular growth, maturation, and gonadal steroid production. In women, the level of FSH is critical for the onset and duration of follic-ular development, and consequently for the timing and number of follicles reaching maturity. Follistim® AQ (follitropin beta) stimulates ovarian follicular growth in women who do not have primary ovarian failure. In order to effect the final phase of follicle maturation, resumption of meiosis and rupture of the follicle in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given following treatment with Follistim® AQ (follitropin beta) when patient monitoring indicates appropriate follicular development parameters have been reached.

Pharmacokinetics

Exposures of follitropin beta from Follistim® AQ (follitropin beta) and Follistim®are expected to be equivalent.

The bioavailability of Follistim®following subcutaneous and intramuscular administration was investigated in healthy, pituitary-suppressed, female subjects given a single 300 IU dose. After subcutaneous or intramuscular injection the apparent dose absorbed was 77.8% and 76.4%, respectively.

The subcutaneous (455.6 ± 141.4 IU*h/L) and intramuscular (445.7 ± 135.7 IU*h/L) routes of administration were equivalent with respect to area under the curve (AUC) in healthy, pituitary-suppressed, female subjects given a single 300 IU dose. However, equivalence could not be established for peak serum FSH levels (Cmax) between the subcutaneous (5.41 ± 0.72 IU/L) and intramuscular (6.86 ± 2.90 IU/L) routes of administration.

The pharmacokinetics and pharmacodynamics of a single, intramuscular dose (300 IU) of Follistim®were also investigated in a group (n=8) of gonadotropin-deficient, butotherwise healthy women. In these women, FSH (mean ±SD) AUC was 339 ± 105 IU*h/L, Cmax was 4.3 ± 1.7 IU/L. Cmax occurred at approximately 27 ± 5.4hours after intramuscular administration.

A multiple, dose proportionality, pharmacokinetic study of Follistim®was completed in healthy, pituitary-suppressed, female subjects given intramuscular doses of 75, 150, or 225 IU for 7 days. Steady-state blood concentrations of FSH were reached with all doses after 4 days of treatment based on the minimum concentrations of FSH just prior to dosing (Cmin). Peak blood concentrations with the 75, 150, and 225 IU dose were 4.65 ±1.49 IU/L, 9.46±2.57 IU/L and 11.30 ±1.77 IU/L, respectively.

A multiple, dose proportionality, pharmacokinetic study of Follistim®was completed in healthy, pituitary-suppressed, female subjects given subcutaneous doses of 75, 150, or 225 IU for 7 days. Steady-state blood concentrations of FSH were reached with all doses after 5 days of treatment based on the minimum concentrations of FSH just prior to dosing (Cmin). Peak blood concentrations with the 75, 150, and 225 IU dose were 4.30 ±0.60 IU/L, 8.51±1.16 IU/L and 13.92 ±1.81 IU/L, respectively.

The volume of distribution of Follistim®in healthy, pituitary-suppressed, female subjects following intravenous administration of a 300 IU dose was approximately8 L.

The recombinant FSH in Follistim® AQ (follitropin beta) is biochemically very similar to urinary FSH and it is therefore anticipated that it is metabolized in the same manner.

The elimination half-life (t½) following a single intramuscular dose (300 IU) of Follistim®in female subjects was 43.9 ± 14.1 hours (mean ± SD). The elimination half-life following a 7-day intramuscular treatment with 75, 150, or 225 IU was 26.9 ± 7.8 hours (mean ±SD), 30.1 ±6.2 and 28.9 ±6.5, respectively.

Special Populations

The effect of body weight on the pharmacokinetics of Follistim®was evaluated in a group of European and Japanese women who were significantly different in terms of body weight. The European subjects had a body weight of (mean ± SD) 67.4 ± 13.5 kg and the Japanese subjects were 46.8 ±11.6kg. Following a single intramuscular dose of 300 IU of Follistim®, the AUC (IU*h/L) was significantly smaller in European subjects (339 ±105) than in Japanese subjects (544 ±201). However, clearance per kg of bodyweight was essentially the same for the respective groups (0.014 and 0.013 1*h-1kg-1).

The pharmacokinetics of Follistim®have not been determined in special populations such as geriatric, pediatric, renally impaired, and hepatically impaired patients.

Clinical Studies

The efficacy of Follistim®was established in four controlled, clinical studies [three studies for Assisted Reproductive Technologies (ART) and one study for Ovulation Induction], three of which are described below. In these comparative studies, there were no clinically significant differences between treatment groups in study outcomes.

Follistim®was studied in a randomized, assessor-blind, group comparative, multi-center safety and efficacy study of 981 infertile women treated for one cycle with in vitro fertilization with Follistim®or urofollitropin after pituitary suppression with a GnRH agonist. The results with Follistim®are summarized in Table 1.

Table 1. Results From a Randomized, Assessor-blind, Group Comparative, Multicenter Safety and Efficacy Study of Follistim® in Infertile Women Treated With In Vitro Fertilization After Pituitary Suppression With a GnRH Agonist1

Follistim®was also evaluated in a randomized, assessor-blind, group comparative, single center safety and efficacy study in 89 infertile women treated with in vitro fertilization with Follistim®or menotropins without pituitary suppression with a GnRH agonist. The results with Follistim®are summarized in Table 2.

Table 2. Results From a Randomized, Assessor-blind, Group Comparative, Single Center Safety and Efficacy Study of Follistim® in Infertile Women Treated With In Vitro Fertilization Without Pituitary Suppression1

Results from a randomized, assessor-blind, group comparative, multicenter safety and efficacy study of Follistim®in 172 chronic anovulatory women who failed to ovulate and/or conceive during clomiphene citrate treatment are summarized in Tables 3 and 4.

Table 3. Cumulative Ovulation Rates

Table 4. Cumulative Ongoing1,2 Pregnancy Rates

Follitropin Beta is part of the drug class:

• Gonadotropins

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of follitropin beta, there are no specific foods that you must exclude from your diet when receiving this medication.

Before you take follitropin beta, tell your healthcare provider if you:

• have an increased risk of blood clots (thrombosis)
• have ever had a blood clot (thrombosis), or anyone in your immediate family has ever had a blood clot (thrombosis)
• had stomach (abdominal) surgery
• had twisting of your ovary (ovarian torsion)
• had or have a cyst in your ovary
• have polycystic ovary disease
• have any other medical conditions
• are breastfeeding or plan to breastfeed

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

This medication is not effective in women with primary ovarian failure (when the ovaries are unable to produce an egg).

This medication is not effective in men with primary testicular failure (when the testicles are unable to produce sperm).

You should not use follicle stimulating hormone if you are allergic to it, if you are already pregnant, or if you have:

• an untreated or uncontrolled disorder of the thyroid, pituitary gland, or adrenal glands;
• heavy or abnormal vaginal bleeding that has not been checked by a doctor;
• an ovarian cyst;
• cancer of the breast, ovary, uterus, testicle, hypothalamus, or pituitary gland; or
• if you are allergic to neomycin (Mycifradin, Neo-Fradin) or streptomycin.

To make sure you can safely use follicle stimulating hormone, tell your doctor if you have:

• polycystic ovary disease;
• asthma; or
• a history of stroke or blood clot.

FDA pregnancy category X. Follicle stimulating hormone can harm an unborn baby or cause birth defects. Do not use this medication if you are already pregnant. Your doctor may give you a pregnancy test to make sure you are not pregnant before you receive follicle stimulating hormone. Tell your doctor right away if you become pregnant during treatment.

Fertility treatment may increase your chance of having twins, triplets, etc (multiple births). These are high-risk pregnancies both for the mother and the babies. Talk to your doctor if you have concerns about this risk.

It is not known whether follicle stimulating hormone passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using follicle stimulating hormone.

• If you have an allergy to follitropin beta or any other part of follitropin beta.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Adrenal gland disease, brain tumor, cancer where hormones make it grow, pituitary gland disease, or thyroid gland disease.
• If you have any of these health problems: A tumor in your female organs, enlarged ovaries or ovarian cysts, or vaginal bleeding where the cause is not known.
• If you are pregnant or may be pregnant. Do not take this medicine if you are pregnant.

This is not a list of all drugs or health problems that interact with follitropin beta.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Follitropin beta is a human FSH preparation of recombinant DNA origin. Follitropins stimulate ovarian follicular growth in women who do not have primary ovarian failure and stimulate spermatogenesis in men with hypogonadotrophic hypogonadism. FSH is required for normal follicular growth, maturation, gonadal steroid production, and spermatogenesis.

Absorption

Females: IM: 76%; SubQ: 78%

Distribution

Females: 8 L

Follistim AQ: Administered by IM or SubQ injection

Follistim AQ Cartridge: Follistim AQ cartridge may be administered only by SubQ injection using the Follistim Pen which can be set to deliver the appropriate dose.

There are no known significant interactions.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, acne, headache, or loss of strength and energy. Have patient report immediately to prescriber signs of ovarian hyperstimulation syndrome (severe abdominal pain or bloating; severe nausea, vomiting, or diarrhea; excessive weight gain; shortness of breath; or change in amount of urine passed), signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; angina; shortness of breath; tachycardia; or coughing up blood), breast pain or soreness, enlarged breasts, vaginal bleeding, severe injection site irritation, pale skin, or skin discoloration (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.