Bravelle(Urofollitropin)

Dosage Forms And Strengths

Lyophilized powder for Injection containing 82.5 International Units of FSH, to deliver 75 International Units of FSH after reconstituting with the diluent, supplied in sterile vials with diluent vials and Q•Cap® vial adapters.

BRAVELLE® (urofollitropin for injection, purified) is supplied in a sterile, lyophilized, single dose vial containing 82.5 International Units of FSH, to deliver 75 International Units FSH after reconstituting with the diluent.

Each vial is available with an accompanying vial of sterile diluent containing 2 mL of 0.9% Sodium Chloride Injection, USP.

75 International Units FSH activity, supplied as:

NDC 55566-8505-2: Box of 5 vials + 5 vials diluent.
NDC 55566-8505-6: Box of 5 vials + 5 vials diluent + 5 Q•Cap® vial adaptors.

Storage and Handling

Lyophilized powder may be stored refrigerated or at room temperature (3° to 25° C/37° to 77°F). Protect from light. Use immediately after reconstitution. Discard unused material.

Manufactured for: Ferring Pharmaceuticals Inc. Parsippany, NJ 07054. Revised 02/2014

Induction Of Ovulation In Women Who Have Previously Received Pituitary Suppression

Prior to initiation of treatment with BRAVELLE®:

• Perform a complete gynecologic and endocrinologic evaluation
• Exclude a diagnosis of primary ovarian failure
• Exclude the possibility of pregnancy
• Demonstrate tubal patency
• Evaluate the fertility status of the male partner

Development Of Multiple Follicles As Part Of An Assisted Reproductive Technology (ART) Cycle In Ovulatory Women Who Have Previously Received Pituitary Suppression

Prior to initiation of treatment with BRAVELLE®:

• Perform a complete gynecologic and endocrinologic evaluation, and diagnose the cause of infertility
• Exclude the possibility of pregnancy
• Evaluate the fertility status of the male partner
• Exclude women with primary ovarian failure

General Dosing Information

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
• Administer BRAVELLE® subcutaneously in the abdomen or intramuscularly as described in Instructions for Use.
• A healthcare provider should administer BRAVELLE® intramuscularly.

Recommended Dosing For Induction Of Ovulation

The dosing scheme is stepwise and is individualized for each woman.

• For women who have received GnRH agonist or antagonist pituitary suppression, a starting dose of 150 International Units per day of BRAVELLE® is administered subcutaneously or intramuscularly for 5 days in the first cycle of treatment.
• In subsequent cycles of treatment, the starting dose (and dosage adjustments) of BRAVELLE® should be determined based on the history of the ovarian response to BRAVELLE®.
• The following should be considered when planning the woman's individualized dose of BRAVELLE®:
  • Appropriate BRAVELLE® dose adjustment(s), based on clinical monitoring (including serum estradiol levels and vaginal ultrasound results), should be used to prevent multiple follicular growth and cycle cancellation.
  • Do not make adjustments in dose more frequently than once every 2 days and do not exceed more than 75 to 150 International Units per adjustment.
  • Use the lowest dose of BRAVELLE® that will achieve desired results.
  • The maximum, individualized, daily dose of BRAVELLE® is 450 International Units per day.
  • In general, do not exceed 12 days of treatment.
• When pre-ovulatory conditions are reached, administer human chorionic gonadotropin (hCG) to induce final oocyte maturation and ovulation.
• Withhold hCG in cases where the ovarian monitoring on the last day of BRAVELLE® treatment suggests an increased risk of ovarian hyperstimulation syndrome (OHSS).
• Encourage the woman and her partner to have intercourse daily, beginning on the day prior to the administration of hCG and until ovulation becomes apparent.

Discourage intercourse when the risk for OHSS is increased.

Recommended Dosing For Assisted Reproduction Technology

The recommended dosing scheme for patients undergoing IVF follows a stepwise approach and is individualized for each woman. The recommended initial dose of BRAVELLE® for women who have received a GnRH agonist for pituitary suppression is 225 International Units. BRAVELLE® may be administered together with MENOPUR® (menotropins for injection, USP), and the total initial dose when the products are combined should not exceed 225 International Units (150 International Units of BRAVELLE® and 75 International Units of MENOPUR® or 75 International Units of BRAVELLE® and 150 International Units of MENOPUR®).

• Beginning on cycle day 2 or 3, a starting dose of 225 International Units of BRAVELLE® is administered subcutaneously daily until sufficient follicular development, as determined by ultrasound in combination with measurement of serum estradiol levels, is attained. In most cases, therapy should not exceed 12 days.
• Adjust the dose after 5 days based on the woman's ovarian response, as determined by ultrasound evaluation of follicular growth and serum estradiol levels.
• Do not make additional dosage adjustments more frequently than every 2 days or by more than 75 -150 International Units at each adjustment.
• Continue treatment until adequate follicular development is evident, and then administer hCG.
• Withhold the administration of hCG in cases where the ovarian monitoring suggests an increased risk of OHSS on the last day of BRAVELLE® therapy.
• Do not administer daily doses of BRAVELLE® or BRAVELLE® in combination with MENOPUR® that exceed 450 International Units.

BRAVELLE® is contraindicated in women who exhibit:

• Prior hypersensitivity to BRAVELLE® or urofollitropins
• High levels of FSH indicating primary ovarian failure
• Pregnancy BRAVELLE® may cause fetal harm when administered to a pregnant woman. BRAVELLE® is contraindicated in women who are pregnant. If this drug is used during pregnancy, or if the woman becomes pregnant while taking this drug, the woman should be apprised of the potential hazard to a fetus.
• Presence of uncontrolled non-gonadal endocrinopathies (e.g., thyroid, adrenal, or pituitary disorders)
• Sex hormone dependent tumors of the reproductive tract and accessory organ
• Tumors of pituitary gland or hypothalamus
• Abnormal uterine bleeding of undetermined origin
• Ovarian cysts or enlargement of undetermined origin, not due to polycystic ovary syndrome

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 dose.

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 uncertain.

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. 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 cysts.

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 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 edema.

Do not remove ascitic, pleural, and pericardial fluid unless there is the necessity to relieve symptoms such as pulmonary distress or cardiac tamponade.

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

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.

Congenital Malformations

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 malformations.

Ectopic Pregnancy

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.

Spontaneous Abortion

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.

Ovarian Neoplasms

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 established.

Laboratory Tests

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 temperature

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®. 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.

Ovarian Hyperstimulation Syndrome (OHSS)

Inform women regarding the risks of OHSS and OHSS-associated symptoms including lung and blood vessel problems and ovarian torsion 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®.

Nonclinical Toxicology

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

Teratogenic effects

Pregnancy Category X.

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 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.

Pediatric Use

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.

SIDE EFFECTS

The following serious adverse reactions are discussed elsewhere in the labeling:

• Hypersensitivity and Anaphylactic Reactions
• Abnormal Ovarian Enlargement
• Ovarian Hyperstimulation Syndrome
• Thromboembolic events
• Ovarian Torsion
• Multi-fetal Gestation and Birth
• Congenital Malformations
• Ectopic Pregnancy
• Spontaneous Abortion
• Ovarian Neoplasms

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

The safety of BRAVELLE® was examined in four clinical studies that enrolled a total of 222 women who received BRAVELLE®.

Ovulation Induction

In a randomized, multi-center, active controlled study, a total of 72 women received BRAVELLE® (35 in a subcutaneous administration arm and 37 in an intramuscular administration arm) for induction of ovulation. Adverse reactions occurring at an incidence of ≥ 2% incidence in women receiving BRAVELLE® are shown in Table 1.

Table 1: Ovulation Induction Safety Profile

Assisted Reproductive Technology

Three studies examined the safety profile of BRAVELLE® in ART. A total of 150 women received treatment with BRAVELLE® in these studies. Adverse reactions occurring at an incidence of ≥ 2% incidence for this integrative assessment are presented in Table 2.

Table 2: Integrated IVF Safety Profile

Postmarketing Experience

The following adverse reactions have been reported during postmarketing use of gonadotropins. Because these reactions were reported voluntarily from a population of uncertain size, the frequency or a causal relationship to BRAVELLE® cannot be reliably determined.

Gastrointestinal disorders: Abdominal pain, Nausea, Vomiting, Abdominal distension, Abdominal discomfort, Diarrhea, Constipation

General disorders and administration site conditions: Pain, Injection site reactions (redness, bruising, swelling and/or pruritus)

Infections and infestations: Urinary tract infection, Nasopharyngitis

Musculoskeletal and connective tissue disorders: Muscle spasm

Nervous system disorders: Headache

Reproductive system disorders: Vaginal hemorrhage, OHSS , Pelvic pain, Breast tenderness, Vaginal discharge. Ovarian enlargement, Multiple pregnancies

Skin and subcutaneous tissue disorders: Rash

Vascular disorders: Hot flushes

DRUG INTERACTIONS

No drug/drug interaction studies in humans have been conducted for BRAVELLE®.

Teratogenic effects

Pregnancy Category X.

The following serious adverse reactions are discussed elsewhere in the labeling:

• Hypersensitivity and Anaphylactic Reactions
• Abnormal Ovarian Enlargement
• Ovarian Hyperstimulation Syndrome
• Thromboembolic events
• Ovarian Torsion
• Multi-fetal Gestation and Birth
• Congenital Malformations
• Ectopic Pregnancy
• Spontaneous Abortion
• Ovarian Neoplasms

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

The safety of BRAVELLE® was examined in four clinical studies that enrolled a total of 222 women who received BRAVELLE®.

Ovulation Induction

In a randomized, multi-center, active controlled study, a total of 72 women received BRAVELLE® (35 in a subcutaneous administration arm and 37 in an intramuscular administration arm) for induction of ovulation. Adverse reactions occurring at an incidence of ≥ 2% incidence in women receiving BRAVELLE® are shown in Table 1.

Table 1: Ovulation Induction Safety Profile

Assisted Reproductive Technology

Three studies examined the safety profile of BRAVELLE® in ART. A total of 150 women received treatment with BRAVELLE® in these studies. Adverse reactions occurring at an incidence of ≥ 2% incidence for this integrative assessment are presented in Table 2.

Table 2: Integrated IVF Safety Profile

Postmarketing Experience

The following adverse reactions have been reported during postmarketing use of gonadotropins. Because these reactions were reported voluntarily from a population of uncertain size, the frequency or a causal relationship to BRAVELLE® cannot be reliably determined.

Gastrointestinal disorders: Abdominal pain, Nausea, Vomiting, Abdominal distension, Abdominal discomfort, Diarrhea, Constipation

General disorders and administration site conditions: Pain, Injection site reactions (redness, bruising, swelling and/or pruritus)

Infections and infestations: Urinary tract infection, Nasopharyngitis

Musculoskeletal and connective tissue disorders: Muscle spasm

Nervous system disorders: Headache

Reproductive system disorders: Vaginal hemorrhage, OHSS , Pelvic pain, Breast tenderness, Vaginal discharge. Ovarian enlargement, Multiple pregnancies

Skin and subcutaneous tissue disorders: Rash

Vascular disorders: Hot flushes

Aside from possible ovarian hyperstimulation and multiple gestations , little is known concerning the consequences of acute overdosage with BRAVELLE®.

Single doses of 225 International Units and multiple daily doses (7 days) of 150 International Units of BRAVELLE® were administered to healthy volunteer female subjects while their endogenous FSH was suppressed. Sixteen subjects received BRAVELLE® subcutaneously and 12 received the drug intramuscularly. Serum FSH concentrations were determined. Based on the steady state ratio of FSH C max and AUC, subcutaneous and intramuscular administration of BRAVELLE® were not bioequivalent. Multiple doses of BRAVELLE® intramuscular resulted in C max and AUC of 77.7% and 81.8% compared to multiple doses of BRAVELLE® subcutaneous. The FSH pharmacokinetic parameters for single and multiple dose BRAVELLE®, administered subcutaneously and intramuscularly are in Table 3.

Table 3: FSH Pharmacokinetic Parameters (Mean ± SD) Following BRAVELLE® Administration

Absorption

The subcutaneous route of administration trends toward greater bioavailability than the IM route for single and multiple doses of BRAVELLE®.

Distribution

Human tissue or organ distribution of FSH has not been studied for BRAVELLE®.

Metabolism

Metabolism of FSH has not been studied for BRAVELLE® in humans.

Elimination

The mean elimination half-lives of FSH for subcutaneous and intramuscular single dosing are 31.8 and 37 hours, respectively. However, following multiple dosing (X 7 days) they are 20.6 and 15.2 hours for SC and IM, respectively.