Included as part of the PRECAUTIONS section.
Follistim AQ Cartridge should be used only by physicians who are experienced
in infertility treatment. Follistim AQ Cartridge contains a potent gonadotropic
substance capable of causing Ovarian Hyperstimulation Syndrome (OHSS) with or without pulmonary or vascular complications and multiple births.
Gonadotropin therapy requires the availability of appropriate monitoring facilities.
Careful attention should be given to the diagnosis of infertility and in the
selection of candidates for Follistim AQ Cartridge therapy [see INDICATIONS
AND USAGE and DOSAGE AND ADMINISTRATION].
Switching to Follistim AQ Cartridge from other brands (manufacturer), types
(recombinant, urinary), and/or methods of administration (Follistim Pen, conventional
syringe) may necessitate an adjustment of the dose [see DOSAGE AND ADMINISTRATION].
Abnormal Ovarian Enlargement
In order to minimize the hazards associated with abnormal ovarian enlargement
that may occur with Follistim AQ therapy, treatment should be individualized
and 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 is important to minimize the risk of overstimulation.
If the ovaries are abnormally enlarged on the last day of Follistim AQ therapy,
hCG should not be administered in order to reduce the chances of developing
Ovarian Hyperstimulation Syndrome (OHSS). Intercourse should be prohibited in
patients with significant ovarian enlargement after ovulation because of the
danger of hemoperitoneum resulting from ruptured ovarian cysts.
Ovarian Hyperstimulation Syndrome (OHSS)
OHSS is a medical entity distinct from uncomplicated ovarian enlargement and
may progress rapidly to become a serious medical condition. 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. Abdominal pain, abdominal distension, gastrointestinal
symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement,
weight gain, dyspnea, and oliguria have been reported with OHSS. Clinical evaluation
may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites,
hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and
thromboembolic reactions. Transient liver
function test abnormalities suggestive of hepatic dysfunction with or without
morphologic changes on liver biopsy have also been reported in association with
OHSS occurs after gonadotropin 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 a
risk for OHSS evident prior to hCG administration,
the hCG must be withheld. Cases of OHSS are more common, more severe, and more
protracted if pregnancy occurs; therefore, women should be assessed for the
development of OHSS for at least two weeks after hCG administration.
If serious OHSS occurs, gonadotropins, including hCG, should be stopped and
consideration should be given as to whether the patient needs to be hospitalized.
Treatment is primarily symptomatic and overall should consist of bed rest, fluid
and electrolyte management, and analgesics (if needed). 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. The management of
OHSS may be divided into three phases as follows:
- Acute Phase
Management should be directed at preventing hemoconcentration due to loss
of intravascular volume to the third space and minimizing the Â risk of thromboembolic
phenomena and kidney damage. Fluid intake and output, weight, hematocrit,
serum and urinary electrolytes, urine Â specific gravity, BUN and creatinine,
total proteins with albumin: globulin ratio, coagulation studies, electrocardiogram
to monitor for hyperkalemia, and abdominal girth should be thoroughly assessed
daily or more often based on the clinical need. Treatment, consisting of limited
intravenous fluids, electrolytes, and human serum albumin 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.
- Chronic Phase
After the acute phase is successfully managed as above, excessive fluid accumulation
in the third space should be limited by instituting severe potassium, sodium,
and fluid restriction.
- Resolution Phase
As third space fluid returns to the intravascular compartment, a fall in hematocrit
and increasing urinary output are observed in the absence of any increase
in intake. 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
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
Â uch 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
During clinical trials with Follistim or Follistim AQ Cartridge therapy, OHSS
occurred in 7.6% of 105 women (OI) and 6.4% of 751 women (IVF or ICSI) treated
with Follistim and Follistim AQ Cartridge, respectively.
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 reactions both in association with, and separate from OHSS 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. Women with generally recognized risk factors
for thrombosis, such as a personal or family history, severe obesity, or thrombophilia,
may have an increased risk of venous or arterial thromboembolic events, during
or following treatment with gonadotropins. Sequelae of such reactions have included
venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral
vascular occlusion (stroke), and arterial occlusion resulting in loss of limb
and rarely in myocardial infarction. In rare cases, pulmonary complications
and/or thromboembolic reactions have resulted in death. In women with recognized
risk factors, the benefits of ovulation induction, in vitro fertilization
(IVF) or intracytoplasmic sperm injection (ICSI) treatment need to be weighed
against the risks. It should be noted, that pregnancy itself also carries an
increased risk of thrombosis.
Ovarian torsion has been reported after treatment with Follistim AQ Cartridge
and after intervention with other gonadotropins. This may be related to OHSS,
pregnancy, previous abdominal surgery, past history of ovarian torsion, previous
or current ovarian cyst and polycystic ovaries. Damage to the ovary due to reduced
blood supply can be limited by early diagnosis and immediate detorsion.
Multi-fetal Gestation and Birth
Multi-fetal gestation and births have been reported with all gonadotropin treatments
including Follistim AQ Cartridge treatment. The woman and her partner should
be advised of the potential risk of multi-fetal gestation and births before
The incidence of congenital malformations after IVF or ICSI may be slightly
higher than after spontaneous conception. This slightly higher incidence is
thought to be related to differences in parental characteristics (e.g., maternal
age, sperm characteristics) and to the higher incidence of multi-fetal gestations
after IVF or ICSI. There are no indications that the use of gonadotropins during
IVF or ICSI is associated with an increased risk of congenital malformations.
Since infertile women undergoing IVF or ICSI often have tubal abnormalities,
the incidence of ectopic pregnancies might be increased. Early confirmation
of an intrauterine pregnancy should be determined by β-hCG testing and
The risk of spontaneous abortions (miscarriage) is increased with gonadotropin
products. However, causality has not been established. The increased risk may
be a factor of the underlying infertility.
There have been infrequent reports of ovarian neoplasms, both benign and malignant,
in women who have undergone multiple drug regimens for controlled ovarian stimulation;
however, a causal relationship has not been established.
In most instances, treatment with Follistim AQ Cartridge 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 Cartridge or when clinical assessment indicates that sufficient
follicular maturation has occurred. The degree of follicular maturation and
the timing of hCG administration can both be determined with the use of sonographic
visualization of the ovaries and endometrial lining in conjunction with measurement
of serum estradiol levels. The combination of transvaginal ultrasonography and
measurement of serum estradiol levels is also useful for minimizing the risk
of OHSS and multi-fetal gestations.
The clinical confirmation of ovulation is obtained by the following direct
or indirect indices of progesterone production as well as sonographic evidence
Direct or indirect indices of progesterone production are:
- Urinary or serum luteinizing hormone (LH) rise
- A rise in basal body temperature
- Increase in serum progesterone
- Menstruation following the shift in basal body temperature
The following provide sonographic evidence of ovulation:
- Collapsed follicle
- Fluid in the cul-de-sac
- Features consistent with corpus luteum formation
Sonographic evaluation of the early pregnancy is also important to rule out
Clinical monitoring for spermatogenesis utilizes the following indirect or
- Serum testosterone level
- Semen analysis
The Follistim Pen is intended only for use with Follistim AQ Cartridge. The
Follistim Pen is not recommended for the blind or visually impaired without
the assistance of an individual with good vision who is trained in the proper
use of the injection device.
Patient Counseling Information
“See FDA-Approved Patient Labeling (PATIENT INFORMATION)”
Dosing and Use of Follistim AQ Cartridge with Pen
Instruct women and men on the correct usage and dosing of Follistim AQ Cartridge
in conjunction with the Follistim Pen. Make sure that individuals who have used
other gonadotropin products delivered by a syringe are aware of differences
arising from use of the pen. Women and men should read and follow all instructions
in the Follistim Pen “Instructions for Use” Manual prior to administration
of Follistim AQ Cartridge.
Advise women and men of the number of doses which can be extracted from the
full unused Follistim AQ Cartridge that you have prescribed.
Therapy Duration and Necessary Monitoring in Women and Men Undergoing Treatment
Prior to beginning therapy with Follistim AQ Cartridge, inform women and men
about the time commitment and monitoring procedures necessary to undergo treatment
[see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
Instructions on a Missed Dose
Inform women and men that if they miss or forget to take a dose of Follistim
AQ Cartridge, the next dose should not be doubled and they should call the healthcare
provider for further dosing instructions.
Ovarian Hyperstimulation Syndrome
Inform women regarding the risks with use of Follistim AQ Cartridge of Ovarian
Hyperstimulation Syndrome [see WARNINGS AND PRECAUTIONS] and associated
symptoms including lung and blood vessel problems [see WARNINGS AND PRECAUTIONS]
and ovarian torsion [see WARNINGS AND PRECAUTIONS].
Multi-fetal Gestation and Birth
Inform women regarding the risk of multi-fetal gestations with the use of Follistim
AQ Cartridge [see WARNINGS AND PRECAUTIONS].
Carcinogenesis, Mutagenesis, 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 using S. typhimurium and E. coli tester strains and did not
produce chromosomal aberrations in an in vitro assay using human lymphocytes.
Use In Specific Populations
Pregnancy Category X: Follistim AQ Cartridge should not be used during pregnancy
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 AQ Cartridge, 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.