Included as part of the PRECAUTIONS section.
BRAVELLE® should only be used by physicians who
are experienced in infertility treatment. BRAVELLE® contains
gonadotropic substances capable of causing in women, Ovarian Hyperstimulation
Syndrome [OHSS] with or without pulmonary or vascular complications and multiple births.
Gonadotropin therapy requires the availability of appropriate monitoring
facilities. Use the lowest effective
Hypersensitivity And Anaphylactic Reactions
Hypersensitivity/anaphylactic reactions associated with
urofollitropins for injection, purified administration have been reported in
some patients. These reactions presented as generalized urticaria, facial
edema, angioneurotic edema, and/or dyspnea suggestive of laryngeal edema. The
relationship of these symptoms to uncharacterized urinary proteins is
Abnormal Ovarian Enlargement
In order to minimize the hazard associated with abnormal
ovarian enlargement that may occur with BRAVELLE® 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 is important to minimize the risk of ovarian stimulation.
If the ovaries are abnormally enlarged on the last day of
BRAVELLE® therapy, hCG should not be administered in order to reduce the
chances of development of the Ovarian Hyperstimulation Syndrome. Prohibit intercourse in women with significant ovarian
enlargement because of the danger of hemoperitoneum resulting from rupture of
Ovarian Hyperstimulation Syndrome (OHSS)
OHSS: OHSS is a medical event distinct from uncomplicated
ovarian enlargement. OHSS may progress rapidly to become a serious medical
event. It is characterized by an apparent 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 development of OHSS 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 events. Transient liver
function test abnormalities suggestive of hepatic dysfunction, which may be
accompanied by morphologic changes on liver biopsy, have been reported in
association with OHSS.
OHSS occurs after treatment has been discontinued and
reaches its maximum at about 7 to 10 days after treatment. Usually, OHSS
resolves spontaneously with the onset of menses. If there is evidence that OHSS
may be developing prior to hCG administration,
the hCG must be withheld.
Cases of OHSS are more common, more severe and more
protracted if pregnancy occurs. OHSS develops rapidly; therefore patients
should be followed for at least two weeks after hCG administration.
If severe OHSS occurs, gonadotropins, including hCG, must
be stopped and consideration should be given as to whether the woman needs 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 risk of thromboembolic
phenomena and kidney damage. Fluid intake and output, weight, hematocrit, serum
and urinary electrolytes, urine 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, 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
- 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
Do not remove ascitic, pleural, and pericardial fluid
unless there is the necessity to relieve symptoms such as pulmonary distress or
OHSS increases the risk of injury to the ovary. Pelvic
examination or intercourse may cause rupture of an ovarian cyst, which may
result in hemoperitoneum, and should 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. A physician experienced in the management of this
syndrome, or who is experienced in the management of fluid and electrolyte
imbalances, should be consulted.
In a clinical study of induction of ovulation indication,
6 of 72 (8.33%) BRAVELLE® treated women developed OHSS and 2 were
classified as severe. In a clinical study for the development of multiple
follicles as part of an IVF cycle, 3 of 60 women treated with BRAVELLE® developed
OHSS and 1 was classified as severe.
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 in
women treated with gonadotropins. Intravascular thrombosis and embolism, which
may originate in venous or arterial vessels, can result in reduced blood flow
to critical organs or the extremities. Women with generally recognized risk
factors for thrombosis, such as 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 infarctions. In rare cases,
pulmonary complications and/or thromboembolic events have resulted in death. In
women with recognized risk factors, the benefits of ovulation induction and
assisted reproductive technology need to be weighed against the risks.
Pregnancy also carries an increased risk of thrombosis.
Ovarian torsion has been reported after treatment with
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 therapy including therapy with BRAVELLE® .
In a controlled study of 72 patients undergoing induction
of ovulation, 66.7% of pregnancies of women treated with subcutaneous BRAVELLE®
were multiples, while 28.6% of pregnancies in women treated with
intramuscular BRAVELLE® were multiples.
In a controlled study of 60 patients undergoing IVF,
34.8% of pregnancies of women treated with subcutaneous BRAVELLE® were
multiples. Before beginning treatment with BRAVELLE®, advise the
woman and her partner of the potential risk of multi-fetal gestation and birth.
The incidence of congenital malformations after some ART
[specifically in vitro fertilization (IVF) or intracytoplasmic sperm injection
(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, maternal and paternal genetic background,
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
Since infertile women undergoing ART often have tubal
abnormalities, the incidence of ectopic pregnancy may be increased. Early
confirmation of intrauterine pregnancy should be determined by β-hCG
testing and transvaginal ultrasound.
The risk of spontaneous abortion (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 had multiple drug therapy for
controlled ovarian stimulation; however, a causal relationship has not been
In most instances, treatment of women with BRAVELLE® will
result only in follicular growth and maturation. In the absence of an endogenous
LH surge, hCG is given when monitoring of the woman indicates that sufficient
follicular development has occurred. This may be estimated by ultrasound alone
or in combination with measurement of serum estradiol levels. The combination
of both ultrasound and serum estradiol measurement are useful for monitoring
follicular growth and maturation, timing of the ovulatory trigger, detecting
ovarian enlargement and minimizing the risk of the Ovarian Hyperstimulation
Syndrome and multiple gestation.
The clinical confirmation of ovulation is obtained by
direct or indirect indices of progesterone production as well as sonographic
evidence of ovulation.
Direct or indirect indices of progesterone production:
- Urinary or serum luteinizing hormone (LH) rise
- A rise in basal body temperature
- Increase in serum progesterone
- Menstruation following the shift in basal body
Sonographic evidence of ovulation:
- Collapsed follicle
- Fluid in the cul-de-sac
- Features consistent with corpus luteum formation
- Secretory endometrium
Patient Counseling Information
See FDA-approved patient
labeling (Patient Information and Instructions for Use)
Dosing and Use
Instruct women on the correct
usage and dosing of MENOPUR® [see DOSAGE AND ADMINISTRATION].
Caution women not to change the dosage or the schedule of administration unless
she is told to do so by her healthcare provider.
Duration and Monitoring Required
Prior to beginning therapy with
BRAVELLE®, inform women about the time commitment and monitoring
procedures necessary for treatment.
Instructions Regarding a Missed
Dose Inform the woman that if she misses or forgets to take a
dose of BRAVELLE®, the next dose should not be doubled and she
should call her healthcare provider for further dosing instructions.
Inform women regarding the
risks of OHSS [see WARNINGS AND PRECAUTIONS] and OHSS-associated
symptoms including lung and blood vessel problems [see WARNINGS AND
ovarian torsion [see WARNINGS AND PRECAUTIONS] with the use of BRAVELLE®
Multi-fetal Gestation and Birth
Inform women regarding the risk
of multi-fetal gestation and birth with the use of BRAVELLE® [see WARNINGS
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term toxicity studies in
animals and in vitro mutagenicity tests have not been performed to evaluate the
carcinogenic potential of urofollitropin for injection, purified.
Use In Specific Populations
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 BRAVELLE®, 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.
Renal and Hepatic Insufficiency
Safety and effectiveness in
women with renal and hepatic sufficiency have not been established.