follistim (follitropin beta)
[Organon USA, Inc.]
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.
Follistim® (follitropin beta for injection) stimulates ovarian follicular growth in women who do not have primary ovarian failure. FSH, the active component of Follistim®, is required for normal follicular growth, maturation, and gonadal steroid production. In the female, the level of FSH is critical for the onset and duration of follicular development, and consequently for the timing and number of follicles reaching maturity. 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 the administration of Follistim® when patient monitoring indicates that appropriate follicular development parameters have been reached.
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 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 of gonadotropin-deficient, but otherwise healthy women. Peak (Cmax) serum FSH levels in these women were 4.3 ± 1.7 IU/L (mean ± SD) and it occurred approximately 27 hours after intramuscular administration.
A multiple, dose proportionality, pharmacokinetic study of Follistim® was completed in healthy, pituitary-suppressed, female subjects given intramuscular doses of 75 IU, 150 IU 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 IU, 150 IU, 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 IU, 150 IU, 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 (C min). Peak blood concentrations with the 75 IU, 150 IU, 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 approximately 8 L.
The recombinant FSH in Follistim® is biochemically very similar to urinary FSH and it is therefore anticipated that it is metabolized in the same manner.
The elimination half-life 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 IU, 150 IU or 225 IU was 26.9 ± 7.8 hours (mean ± SD), 30.1 ± 6.2 and 28.9 ± 6.5, respectively.
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).
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.
Results from a randomized, assessor-blind, group comparative, multicenter safety and efficacy study of Follistim® (Protocol 37608) in 981 infertile women treated for one cycle with in vitro fertilization with Follistim® or Metrodin® after pituitary suppression with a GnRH agonist are summarized in Table I.
|Total number of oocytes recovered||10.9||9.0|
|Number of mature oocytes recovered||9.1||7.3|
|Maximum serum estradiol before
|Treatment duration (days)||11.0
|Ongoing‡ pregnancy rate/attempt||22.2%||18.2%|
Metrodin® is a registered trademark of Serono Laboratories, Inc., Randolph, MA 02368.
The outcomes of the 286 clinical pregnancies (179 in Follistim® and 107 in Metrodin®) are shown in Table II:
|Did not result in live birth||50 (28%)||35 (33%)|
|Single birth||87 (49%)||43 (40%)|
|Multiple birth||42 (23%)||29 (27%)|
Results from a randomized, assessor-blind, group comparative, single center safety and efficacy study of Follistim® (Protocol 37604) in 89 infertile women treated with in vitro fertilization with Follistim® or Humegon® without pituitary suppression with a GnRH agonist are summarized in Table III.
|Total number of oocytes recovered||9.9||7.6|
|Number of mature oocytes recovered||9.4||6.9|
|Maximum serum estradiol before hCG (pmol/L)†||3791||3087|
|Treatment duration (days)||5.8
|Ongoing‡ pregnancy rate/attempt||22.2%||17.1%|
|Ongoing‡ pregnancy rate/transfer §||30.8%||22.2%|
The outcomes of the 22 clinical pregnancies (14 in Follistim® and 8 in Humegon® ) are shown in Table IV:
|Did not result in live birth||2 (14%)||2 (25%)|
|Single birth||7 (50%)||4 (50%)|
|Multiple birth||5 (36%)||2 (25%)|
Results 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 Tables V, VI, and VII.
|First treatment cycle||72%||63%|
|Second treatment cycle||82%||79%|
|Third treatment cycle||85%||82%|
|First treatment cycle||14%||10%|
|Second treatment cycle||19%||18%|
|Third treatment cycle||23%||19%|
The outcomes of the 56 clinical pregnancies (35 in Follistim® and 21 in Metrodin®) are shown in Table VII:
|Did not result in live birth||11 (31%)||8 (38%)|
|Single birth||22 (63%)||12 (57%)|
|Multiple birth||2 (6%)||1 (5%)|
Follistim® (follitropin beta for injection) is indicated for the development of multiple follicles in ovulatory patients participating in an Assisted Reproductive Technology (ART) program. Follistim® 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.
Before treatment with Follistim® is instituted:
Follistim® (follitropin beta for injection) is contraindicated in women who exhibit:
Follistim® (follitropin beta for injection) should be used only by physicians who are experienced in infertility treatment. Follistim® is a potent gonadotropic substance capable of causing Ovarian Hyperstimulation Syndrome (OHSS) (see WARNINGS-Overstimulation of the Ovary During Follistim® Therapy) with or without pulmonary or vascular complications (see WARNINGS-Pulmonary and Vascular Complications) and multiple births (see WARNINGS-Multiple Births). Gonadotropin therapy requires the availability of appropriate monitoring facilities (see PRECAUTIONS-LaboratoryTests).
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.
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.
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.
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).
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.
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.
No drug/drug interaction studies have been performed.
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 Category X: (See CONTRAINDICATIONS).
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.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of Follistim® did not include subjects aged 65 and over.
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.
|Ovarian Hyperstimulation Syndrome||5.2%||4.3%|
|Injection site pain||1.7%||0.5%|
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.
|Ovarian Hyperstimulation Syndrome||7.6%||4.5%|
|Abdominal pain, lower||2.9%||1.5%|
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.
There have been no reports of abuse or dependence with Follistim® (follitropin beta for injection).
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).
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.
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®.
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:
Lyophilized powder may be stored refrigerated or at room temperature (2o-25oC/36o-77oF). Protect from light. Use immediately after reconstitution. Discard unused material.
West Orange, NJ 07052
Diluent manufactured by
Luitpold Pharmaceuticals, Inc.
Shirley, NY 11967
|Follistim (follitropin beta)|
Data are from FDA and U.S. National Library of Medicine.