ORG_MostPrescrAd 5/10/07 10:27 Page 19
Laboratory Tests
In most instances, treatment with Follistim
®
AQ 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
®
AQ
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 develop-
ment of follicles, timing hCG administration, as well as minimizing the risk of OHSS and multiple gestations.
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,
FOR SUBCUTANEOUS OR INTRAMUSCULAR USE ONLY
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
BRIEF SUMMARY determining if ovulation has occurred. Sonographic evidence of ovulation may include the following:
Please see package insert for full prescribing information. a) Fluid in the cul-de-sac,
INDICATIONS AND USAGE
b) Follicle showing marked decrease in size, and
Follistim
®
AQ (follitropin beta injection) is indicated for the development of multiple follicles in ovulatory patients participat-
c) Collapsed follicle.
ing in an Assisted Reproductive Technology (ART) program. Follistim
®
AQ is also indicated for the induction of ovulation Drug Interactions
and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not due to primary ovarian No drug-drug interaction studies have been performed.
failure.
Carcinogenesis and Mutagenesis, Impairment of Fertility
Selection of Patients Long-term toxicity studies in animals have not been performed with Follistim
®
to evaluate the carcinogenic potential of the
Before treatment with Follistim
®
AQ is instituted: drug. Follistim
®
was not mutagenic in the Ames test using S. typhimurium and E. coli tester strains and did not produce
1. A thorough gynecologic and endocrinologic evaluation of the patient must be performed. The evaluation should include chromosomal aberrations in an in vitro assay using human lymphocytes.
a hysterosalpingogram (to rule out uterine and tubal pathology) and documentation of anovulation by means of review-
Pregnancy
ing a patient’s history, performing a physical examination, determining serum hormonal levels as indicated, and option-
Pregnancy Category X: (See CONTRAINDICATIONS).
ally performing an endometrial biopsy. Patients with tubal pathology should receive Follistim
®
AQ only if enrolled in
an ART program.
Nursing Mothers
2. Primary ovarian failure should be excluded by the determination of circulating gonadotropin levels.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because
3. Careful examination should be made to rule out early pregnancy.
of the potential for serious adverse reactions in the nursing infant from Follistim
®
AQ, a decision should be made whether
4. Evaluation of the partner’s fertility potential should be included in the workup procedure.
to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
CONTRAINDICATIONS
Pediatric Use
Follistim
®
AQ (follitropin beta injection) is contraindicated in women who exhibit:
Safety and effectiveness in pediatric patients have not been established.
1. Prior hypersensitivity to recombinant hFSH products. Geriatric Use
2. High levels of FSH indicating primary ovarian failure. Clinical studies of Follistim
®
did not include subjects aged 65 and over.
3. Uncontrolled thyroid or adrenal dysfunction.
ADVERSE REACTIONS
4. Tumor of the ovary, breast, uterus, hypothalamus or pituitary gland.
Assisted Reproductive Technologies (ART)
5. Pregnancy.
Rates of adverse events from a randomized, assessor-blind, group comparative, multicenter safety and efficacy study of
6. Heavy or irregular vaginal bleeding of undetermined origin.
Follistim
®
in 989 infertile women treated with in vitro fertilization with Follistim
®
or urofollitropin after pituitary suppression
7. Ovarian cysts or enlargement not due to polycystic ovary syndrome (PCOS).
with a GnRH agonist are summarized in Table 5.
8. Hypersensitivity reactions to streptomycin or neomycin. Follistim
®
AQ may contain traces of these antibiotics and may
cause hypersensitivity reactions in susceptible persons.
Table 5. Incidence of Adverse Clinical Experiences (>1%)
WARNINGS
Adverse Event Follistim
®
(n=591) Adverse Event Follistim
®
(n=591)
Follistim
®
AQ (follitropin beta injection) should be used only by physicians who are experienced in infertility treatment. Miscarriage 11.0% Abdominal pain 2.5%
Follistim
®
AQ is a potent gonadotropic substance capable of causing Ovarian Hyperstimulation Syndrome (OHSS) (see
WARNINGS-Overstimulation of the Ovary During Follistim
®
AQ Therapy) with or without pulmonary or vascular complications
Ovarian Hyperstimulation Injection site pain 1.7%
(see WARNINGS-Pulmonary and Vascular Complications) and multiple births (see WARNINGS-Multiple Births). Gonado-
Syndrome 5.2%
Vaginal hemorrhage 1.5%
tropin therapy requires the availability of appropriate monitoring facilities (see PRECAUTIONS-Laboratory Tests).
Ectopic pregnancy 3.0%
Overstimulation of the Ovary During Follistim
®
AQ Therapy
Ovulation Induction
In order to minimize the hazards associated with the occasional abnormal ovarian enlargement that may occur with
Rates of adverse events from a randomized, assessor-blind, group comparative, multicenter safety and efficacy study of
Follistim
®
AQ therapy, the lowest effective dose should be used (see DOSAGE AND ADMINISTRATION in the full pre-
Follistim
®
in 172 chronic anovulatory women who failed to ovulate and/or conceive during clomiphene citrate treatment are
scribing information). Use of ultrasound monitoring of ovarian response and/or measurement of serum estradiol levels
summarized in Table 6.
can further minimize the risk of overstimulation.
Table 6. Incidence of Adverse Clinical Experiences (>1%)
If the ovaries are abnormally enlarged on the last day of Follistim
®
AQ therapy, hCG should not be administered in this
course of treatment; to reduce the chances of developing Ovarian Hyperstimulation Syndrome (OHSS).
Adverse Event Follistim
®
(n=105) Adverse Event Follistim
®
(n=105)
The Ovarian Hyperstimulation Syndrome (OHSS): OHSS is a medical entity distinct from uncomplicated ovarian enlarge-
Miscarriage 9.5% Abdominal pain, lower 2.9%
ment and may progress rapidly to become a serious medical event. OHSS is characterized by a dramatic increase in vas- Ovarian Hyperstimulation Abdominal pain 1.9%
cular permeability, which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the Syndrome 7.6%
pericardium. The early warning signs of OHSS developing are severe pelvic pain, nausea, vomiting, and weight gain. The
Ovarian cyst 2.9%
following symptoms have been reported in cases of OHSS: abdominal pain, abdominal distension, gastrointestinal symp-
Abdominal discomfort 2.9%
toms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria. Clinical
The following adverse events have been reported in women treated with gonadotropins: pulmonary and vascular complica-
evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effu-
tions (see WARNINGS), hemoperitoneum, adnexal torsion (as a complication of ovarian enlargement), dizziness, tachy-
sions, hydrothorax, acute pulmonary distress, and thromboembolic events (see WARNINGS-Pulmonary and Vascular
cardia, dyspnea, tachypnea, febrile reactions, flu-like symptoms including fever, chills, musculoskeletal aches, joint pains,
Complications). Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied
nausea, headache and malaise, breast tenderness, and dermatological symptoms (dry skin, erythema, body rash, hair loss,
by morphologic changes on liver biopsy, have been reported in association with Ovarian Hyperstimulation Syndrome (OHSS).
and hives).
During clinical trials with Follistim
®
therapy, OHSS occurred in 53 (5.2%) of the 1029 women treated and of these 29 (2.8%)
There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone
were hospitalized. Cases of OHSS are more common, more severe, and more protracted if pregnancy occurs; therefore,
multiple drug regimens for ovulation induction; however, a causal relationship has not been established.
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,
Congenital Anomalies
OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be developing prior to
The incidence of congenital malformations after Assisted Reproductive Technologies (ART) may be slightly higher than
hCG administration (see PRECAUTIONS-Laboratory Tests), the hCG must be withheld.
after spontaneous conception. This slightly higher incidence is thought to be related to differences in parental characteris-
tics (e.g., maternal age, sperm characteristics) and to the higher incidence of multiple gestations after ART. There are no
If serious OHSS occurs, treatment should be stopped and the patient should be hospitalized. Treatment is primarily symp-
indications that the use of gonadotropins during ART is associated with an increased risk of congenital malformations.
tomatic 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 thor-
Storage
oughly assessed in the following manner: 1) fluid intake and output; 2) weight; 3) hematocrit; 4) serum and urinary electro-
Store refrigerated, 2–8°C (36–46°F) until dispensed. Upon dispensing, the product may be stored by the patient at 2–8°C
lytes; 5) urine specific gravity; 6) BUN and creatinine; 7) total proteins with albumin: globulin ratio; 8) coagulation studies;
(36–46°F) until the expiration date, or at or below 25°C (77°F) for 3 months or until expiration date, whichever occurs first.
9) electrocardiogram to monitor for hyperkalemia and 10) abdominal girth. These determinations should be performed
Protect from light, keep container in carton. Do not freeze.
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
For more detail regarding the information contained in this leaflet call 1-866-836-5633.
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
www.follistim.com
possible. Intercourse should be prohibited in patients with significant ovarian enlargement after ovulation because of the
Follistim
®
is a registered trademark of N.V. Organon.
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
c5287only
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. Treat-
ment 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
Manufactured for Organon USA Inc.
be limited by instituting severe potassium, sodium, and fluid restriction.
Roseland, NJ 07068
Resolution Phase: A fall in hematocrit and an increasing urinary output without an increased intake are observed due to the
by Organon (Ireland) Ltd.
return of the third space fluid to the intravascular compartment. Peripheral and/or pulmonary edema may result if the kid-
Swords, Co. Dublin, Ireland
neys are unable to excrete third space fluid as rapidly as it is mobilized. Diuretics may be indicated during the resolution
©2005 Organon USA Inc. FAQ-8007 1184 9/05 21
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 Hyper-
stimulation 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
Multiple births have been reported for all FSH treatments including Follistim
®
AQ (follitropin beta injection) treatment. The
patient and her partner should be advised of the potential risk of multiple births before starting treatment.
PRECAUTIONS
General
Careful attention should be given to the diagnosis of infertility and in the selection of candidates for Follistim
®
AQ
(follitropin beta injection) therapy (see INDICATIONS AND USAGE-Selection of Patients).
Information for Patients
Prior to therapy with Follistim
®
AQ, 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 pos-
sible adverse reactions (see ADVERSE REACTIONS) should be discussed.
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