Pharmacokinetics

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 ± 11.6 kg. 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 body weight was essentially the same for the respective groups (0.014 and 0.013 1*h-1kg-1).

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.

Selection of Patients

Before treatment with Follistim® is instituted:

1. A thorough gynecologic and endocrinologic evaluation of the patient must be performed. The evaluation should include a hysterosalpingogram (to rule out uterine and tubal pathology) and documentation of anovulation by means of reviewing a patient's history, performing a physical examination, determining serum hormonal levels as indicated, and optionally performing an endometrial biopsy. Patients with tubal pathology should receive Follistim® only if enrolled in an ART program.
2. Primary ovarian failure should be excluded by the determination of circulating gonadotropin levels.
3. Careful examination should be made to rule out early pregnancy.
4. Evaluation of the partner's fertility potential should be included in the workup procedure.

Overstimulation of the Ovary During Follistim® Therapy

In order to minimize the hazards associated with the occasional abnormal ovarian enlargement that may occur with Follistim® therapy, the lowest effective dose should be used (see DOSAGE AND ADMINISTRATION). Use of ultrasound monitoring of ovarian response and/or measurement of serum estradiol levels can further minimize the risk of overstimulation.

If the ovaries are abnormally enlarged on the last day of Follistim® therapy, hCG should not be administered in this course of treatment; this will reduce the chances of developing Ovarian Hyperstimulation Syndrome (OHSS).

The Ovarian Hyperstimulation Syndrome (OHSS): OHSS is a medical entity distinct from uncomplicated ovarian enlargement and may progress rapidly to become a serious medical event. OHSS is characterized by a dramatic increase in vascular permeability, which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium. The early warning signs of OHSS developing are severe pelvic pain, nausea, vomiting and weight gain. The following symptoms have been reported in cases of OHSS: abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events (see WARNINGS-Pulmonary and Vascular Complications).

During clinical trials with Follistim® therapy, OHSS occurred in 53 (5.2%) of the 1,029 women treated and of these 29 (2.8%) were hospitalized. Cases of OHSS are more common, more severe, and more protracted if pregnancy occurs; therefore, patients should be followed for at least two weeks after hCG administration. Most often, OHSS occurs after treatment has been discontinued and it can develop rapidly, reaching its maximum about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be developing prior to hCG administration (see PRECAUTIONS-Laboratory Tests), the hCG must be withheld.

If serious OHSS occurs, treatment should be stopped and the patient should be hospitalized. Treatment is primarily symptomatic and should consist of bed rest, fluid and electrolyte management, and analgesics (if needed). Hemoconcentration associated with fluid loss into the peritoneal cavity, pleural cavity, and the pericardial cavity may occur and should be thoroughly assessed in the following manner: 1) fluid intake and output; 2) weight; 3) hematocrit; 4) serum and urinary electrolytes; 5) urine specific gravity; 6) BUN and creatinine; 7) total proteins with albumin: globulin ratio; 8) coagulation studies; 9) electrocardiogram to monitor for hyperkalemia and 10) abdominal girth. These determinations should be performed daily or more often based on clinical need.

OHSS increases the risk of injury to the ovary. The ascitic, pleural, and pericardial fluid should not be removed unless there is the necessity to relieve symptoms such as pulmonary distress or cardiac tamponade. Pelvic examination may cause rupture of an ovarian cyst, which may result in hemoperitoneum, and should therefore be avoided. If bleeding occurs and requires surgical intervention, the clinical objective should be to control the bleeding and retain as much ovarian tissue as possible. Intercourse should be prohibited in patients with significant ovarian enlargement after ovulation because of the danger of hemoperitoneum resulting from ruptured ovarian cysts.

The management of OHSS may be divided into three phases: an acute, a chronic, and a resolution phase. Because the use of diuretics can accentuate the diminished intravascular volume, diuretics should be avoided except in the late phase of resolution as described below.

Acute Phase: Management during the acute phase should be directed at preventing hemoconcentration due to loss of intravascular volume to the third space and minimizing the risk of thromboembolic phenomena and kidney damage. Treatment is intended to normalize electrolytes while maintaining an acceptable but somewhat reduced intravascular volume. Full correction of the intravascular volume deficit may lead to an unacceptable increase in the amount of third space fluid accumulation.

Management includes administration of limited intravenous fluids, electrolytes, human serum albumin and strict monitoring of fluid intake and output. Monitoring for the development of hyperkalemia is recommended.

Chronic Phase: After stabilizing the patient during the acute phase, excessive fluid accumulation in the third space should be limited by instituting severe potassium, sodium, and fluid restriction.

Resolution Phase: A fall in hematocrit and an increasing urinary output without an increased intake are observed due to the return of the third space fluid to the intravascular compartment. Peripheral and/or pulmonary edema may result if the kidneys are unable to excrete third space fluid as rapidly as it is mobilized. Diuretics may be indicated during the resolution phase, if necessary, to combat pulmonary edema.

Pulmonary and Vascular Complications

Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome) have been reported in women treated with gonadotropins. In addition, thromboembolic events both in association with, and separate from, the Ovarian Hyperstimulation Syndrome have been reported following gonadotropin therapy . Intravascular thrombosis, which may originate in venous or arterial vessels, can result in reduced blood flow to vital organs or the extremities. Sequelae of such events have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb. In rare cases, pulmonary complications and/or thromboembolic events have resulted in death.

Multiple Births

Reports of multiple births have been associated with Follistim® treatment. The patient and her partner should be advised of the potential risk of multiple births before starting treatment. In clinical trials with Follistim® and Metrodin®, multiple gestation rates in ART patients were 31% and 38%, respectively, and in ovulation induction patients, the rates were 8% in both groups.

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 usingS. typhimurium and E. coli tester strains and did not produce chromosomal aberrations in an in vitro assay using human lymphocytes.

Pregnancy

Pregnancy Category X: (SeeCONTRAINDICATIONS).

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 within 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.

Assisted Reproductive Technologies (ART)

A starting dose of 150 to 225 IU of Follistim® (follitropin beta for 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. In clinical studies with patients who are responding, it was shown that daily maintenance dosages ranging from 75 to 300 IU for six to twelve days are sufficient, although longer treatment may be necessary. However, in patients that were low or poor responders, maintenance doses of 375 to 600 IU were administered according to individual response. This later category comprised approximately 10% of the women evaluated during clinical studies. The maximum, individualized, daily dose of Follistim® that has been used in clinical studies is 600 IU. 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 5,000 IU to 10,000 IU. Oocyte (egg) retrieval is performed 34 to 36 hours later. The administration of hCG must be withheld in cases where the ovaries are abnormally enlarged on the last day of Follistim® therapy; this will reduce the chance of developing OHSS.

Ovulation Induction

There are a variety of treatment protocols available for ovulation induction. In studies using Follistim®, a stepwise gradually increasing dosing scheme was used. The starting dose was 75 IU of Follistim® for up to 14 days. The dose was then increased by 37.5 IU of Follistim® at weekly intervals until follicular growth and/or serum estradiol levels indicated an adequate response. The maximum, individualized, daily dose of Follistim® that has been safely used for ovulation induction patients during clinical trials is 300 IU. The patient should be treated until ultrasonic visualizations and/or serum estradiol determinations indicate pre-ovulatory conditions equivalent to or greater than those of the normal individual followed by hCG, 5,000 IU to 10,000 IU. If the ovaries are abnormally enlarged on the last day of Follistim® therapy, hCG must be withheld during this course of treatment; this will reduce the chances of developing OHSS.

During treatment with Follistim® and during a two week post-treatment period, patients should be examined at least every other day for signs of excessive ovarian stimulation. It is recommended that Follistim® administration be stopped if the ovaries become abnormally enlarged or abdominal pain occurs. Most OHSS occurs after treatment has been discontinued and reaches its maximum at about seven to ten days post-ovulation.

For ovulation induction, the couple should be encouraged to have intercourse daily, beginning on the day prior to the administration of hCG and until ovulation becomes apparent from the indices employed for the determination of progestational activity (see PRECAUTIONS-Laboratory Tests). Care should be taken to insure insemination. In the light of the foregoing indices and parameters mentioned, it should become obvious that, unless a physician is willing to devote considerable time to these patients and be familiar with and conduct these necessary laboratory studies, he/she should not use Follistim®.

Directions for using Follistim®

1. Wash hands thoroughly with soap and water.
2. Before injections, the septum tops of the vials should be wiped with an aseptic solution to prevent contamination of the contents.
3. To prepare the Follistim® solution, inject 1 mL of Sterile Water for Injection, USP into the vial of Follistim®. DO NOT SHAKE, but gently swirl until the solution is clear. Generally, the Follistim® dissolves immediately. Check the liquid in the container. If it is not clear or has particles in it, DO NOT USE IT.
4. For patients requiring a single injection from multiple vials of Follistim®, up to 4 vials can be reconstituted with 1 mL of Sterile Water for Injection, USP. This can be accomplished by reconstituting a single vial as described above (see step 3). Then draw the entire contents of the first vial into a syringe, and inject the contents into a second vial of lyophilized Follistim®. Gently swirl the second vial, as described above, once again checking to make sure the solution is clear and free of particles. This step can be repeated with 2 additional vials for a total of up to 4 vials of lyophilized Follistim® into 1 mL of diluent.
5. Immediately ADMINISTER the reconstituted Follistim® either SUBCUTANEOUSLY or INTRAMUSCULARLY. Any unused reconstituted material should be discarded.
6. Draw the reconstituted Follistim® into an empty, sterile syringe.
7. Hold the syringe pointing upwards and gently tap the side to force any air bubbles to the top; then squeeze the plunger gently until all the air has been expelled and only Follistim® solution is left in the syringe.
8. Follistim® only works if it is injected SUBCUTANEOUSLY or INTRAMUSCULARLY. The most convenient sites for SUBCUTANEOUS injection are either in the abdomen around the navel where there is a lot of loose skin and layers of fatty tissue or in the upper thigh. Pinch up a large area of skin between the finger and thumb. You should vary the injection site a little with each injection. The best site for INTRAMUSCULAR injection of Follistim® is the upper outer quadrant of the buttock muscle. This area contains a large volume of muscle with few blood vessels and major nerves. Stretching the skin helps the needle to go in more easily and pushes the tissue beneath the skin out of the way. This helps the solution disperse correctly.
9. The injection site should be swabbed with a disinfectant to remove any surface bacteria. Clean about two inches around the point where the needle will go in and let the disinfectant dry for at least one minute before proceeding.
10. For SUBCUTANEOUS injection the needle should be inserted at the base of the pinched-up skin at an angle of 45˚ to the skin surface. The needle for INTRAMUSCULAR injection should be inserted right up to the hilt at an angle of 90˚ to the skin surface. Pushing in with a quick thrust causes the least discomfort.
11. If the needle is correctly positioned it will be difficult to draw back on the plunger. Any blood drawn into the syringe means the needle tip has penetrated a vein or artery. If this happens, remove the syringe, cover the injection site with a swab containing disinfectant and apply pressure; the site should stop bleeding in a minute or two.
12. Once the needle is properly placed, depress the plunger slowly and steadily, so the solution is correctly injected and the skin or muscle tissue is not damaged.
13. Pull the syringe out quickly and apply pressure to the site with a swab containing disinfectant. A gentle massage of the site—while still maintaining pressure—helps disperse the Follistim® solution and relieve any discomfort.
14. Use the disposable syringe only once and dispose of it properly.

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