Drug: Bravelle
BRAVELLE® is a product containing a highly purified preparation of human follicle stimulating hormone (hFSH) extracted from the urine of postmenopausal women. Human FSH is a gonadotropin and consists of two non-covalently linked glycoproteins designated as the α and β subunits. The α subunit has 92 amino acids of which two are modified by attachment of carbohydrates. The β subunit has 111 amino acids of which two are modified by attachment of carbohydrates. BRAVELLE® is a sterile, lyophilized powder intended for subcutaneous or intramuscular injection after reconstitution with sterile 0.9% Sodium Chloride Injection, USP. Each vial of BRAVELLE® contains 82.5 International Units (IU) of Follicle Stimulating Hormone (FSH) activity, 23 mg Lactose Monohydrate, 0.005 mg Polysorbate 20, and Sodium Phosphate buffer (Sodium Phosphate dibasic, Heptahydrate and Phosphoric acid) for pH adjustments, which, when reconstituted with diluent, will deliver 75 International Units of FSH. BRAVELLE® contains up to 2% luteinizing hormone (LH) activity based on bioassay. Human Chorionic Gonadotropin (hCG) is not detected in BRAVELLE®. When stored at 3° to 25°C, up to 40% of the α-subunits may be oxidized. The in vivo biological activity of urofollitropin for injection, purified is determined by using reference standards calibrated against the First International Standard for follicle-stimulating hormone, (FSH, Urofollitropin), Urinary, Human for Bioassay, National Institute for Biological Standards and Control (NIBSC) at its 46th meeting in 1995. FSH is a glycoprotein that is acidic and water-soluble. BRAVELLE® has been mixed in vitro with MENOPUR® with no evidence of aggregation. Therapeutic class: Infertility
Source: http://www.rxlist.com
The following serious adverse reactions are discussed elsewhere in the labeling:
Adverse Events (%) All Patients with Adverse Events ≥ 2% BRAVELLE® subcutaneous
N=35 BRAVELLE® intramuscular
N=37 Genitourinary/Reproductive OHSS 4 (11.4) 2 (5.4) Vaginal Hemorrhage 3 (8.6) 0 (0.0) Ovarian Disorder (Pain, Cyst) 1 (2.9) 3 (8.1) Urinary tract infection 0 1 (2.7) Cervix disorder 1 (2.9) 0 Gastrointestinal Nausea 2 (5.7) 0 (0.0) Enlarged Abdomen 1 (2.9) 1 (2.7) Abdominal Pain 1 (2.9) 2 (5.4) Vomiting 0 1 (2.7) Constipation 0 1 (2.7) Diarrhea 0 1 (2.7) Metabolic/Nutritional Dehydration 0 1 (2.7) Weight gain 1 (2.9) 0 Skin/Appendages Acne 1 (2.9) 0 Exfoliative dermatitis 0 1 (2.7) Other Body Systems Headache 4 (11.4) 3 (8.1) Pain 2 (5.7) 0 (0.0) Neck pain 0 1 (2.7) Respiratory Disorder 2 (5.7) 0 (0.0) Hot Flashes 2 (5.7) 0 (0.0) Fever 0 1 (2.7) Hypertension 0 1 (2.7) Emotional lability 0 1 (2.7) Depression 0 1 (2.7) Accidental injury 0 1 (2.7) 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
All Patients with Adverse Events ≥ 2% Adverse Events (%) BRAVELLE® subcutaneous
N=150 Genitourinary/Reproductive Vaginal hemorrhage 7 (4.7) Post retrieval pain 12 (8.0) Pelvic pain/cramps 10 (6.7) OHSS 9 (6.0) Uterine spasms 4 (2.7) Vaginal spotting 4 (2.7) Urinary tract infection 5 (3.3) Ovarian disorder 3 (2.0) Breast tenderness 3 (2.0) Vaginal Discharge 4 (2.7) Infection fungal 3 (2.0) Gastrointestinal Abdominal cramps 21 (14.0) Nausea 13 (8.7) Abdominal pain 7 (4.7) Abdominal fullness/enlargement 10 (6.7) Constipation 3 (2.0) Other Body Systems Headache 19 (12.7) Pain 8 (5.3) Rash 4 (2.7) Respiratory disorder 6 (4.0) Sinusitis 3 (2.0) Injection site reaction 6 (4.0) Hot flash 6 (4.0) Emotional lability 3 (2.0) 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 [see WARNINGS AND PRECAUTIONS], Pelvic pain, Breast tenderness, Vaginal discharge. Ovarian enlargement, Multiple pregnancies [see WARNINGS AND PRECAUTIONS] Skin and subcutaneous tissue disorders: Rash Vascular disorders: Hot flushes Read the Bravelle (urofollitropin injection) Side Effects Center for a complete guide to possible side effectsLearn More »
- Hypersensitivity and Anaphylactic Reactions [see WARNINGS AND PRECAUTIONS]
- Abnormal Ovarian Enlargement [see WARNINGS AND PRECAUTIONS]
- Ovarian Hyperstimulation Syndrome [see WARNINGS AND PRECAUTIONS]
- Thromboembolic events [see WARNINGS AND PRECAUTIONS]
- Ovarian Torsion [see WARNINGS AND PRECAUTIONS]
- Multi-fetal Gestation and Birth [see WARNINGS AND PRECAUTIONS]
- Congenital Malformations [see WARNINGS AND PRECAUTIONS]
- Ectopic Pregnancy [see WARNINGS AND PRECAUTIONS]
- Spontaneous Abortion [see WARNINGS AND PRECAUTIONS]
- Ovarian Neoplasms [see WARNINGS AND PRECAUTIONS]
Adverse Events (%) All Patients with Adverse Events ≥ 2% BRAVELLE® subcutaneous
N=35 BRAVELLE® intramuscular
N=37 Genitourinary/Reproductive OHSS 4 (11.4) 2 (5.4) Vaginal Hemorrhage 3 (8.6) 0 (0.0) Ovarian Disorder (Pain, Cyst) 1 (2.9) 3 (8.1) Urinary tract infection 0 1 (2.7) Cervix disorder 1 (2.9) 0 Gastrointestinal Nausea 2 (5.7) 0 (0.0) Enlarged Abdomen 1 (2.9) 1 (2.7) Abdominal Pain 1 (2.9) 2 (5.4) Vomiting 0 1 (2.7) Constipation 0 1 (2.7) Diarrhea 0 1 (2.7) Metabolic/Nutritional Dehydration 0 1 (2.7) Weight gain 1 (2.9) 0 Skin/Appendages Acne 1 (2.9) 0 Exfoliative dermatitis 0 1 (2.7) Other Body Systems Headache 4 (11.4) 3 (8.1) Pain 2 (5.7) 0 (0.0) Neck pain 0 1 (2.7) Respiratory Disorder 2 (5.7) 0 (0.0) Hot Flashes 2 (5.7) 0 (0.0) Fever 0 1 (2.7) Hypertension 0 1 (2.7) Emotional lability 0 1 (2.7) Depression 0 1 (2.7) Accidental injury 0 1 (2.7) 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
All Patients with Adverse Events ≥ 2% Adverse Events (%) BRAVELLE® subcutaneous
N=150 Genitourinary/Reproductive Vaginal hemorrhage 7 (4.7) Post retrieval pain 12 (8.0) Pelvic pain/cramps 10 (6.7) OHSS 9 (6.0) Uterine spasms 4 (2.7) Vaginal spotting 4 (2.7) Urinary tract infection 5 (3.3) Ovarian disorder 3 (2.0) Breast tenderness 3 (2.0) Vaginal Discharge 4 (2.7) Infection fungal 3 (2.0) Gastrointestinal Abdominal cramps 21 (14.0) Nausea 13 (8.7) Abdominal pain 7 (4.7) Abdominal fullness/enlargement 10 (6.7) Constipation 3 (2.0) Other Body Systems Headache 19 (12.7) Pain 8 (5.3) Rash 4 (2.7) Respiratory disorder 6 (4.0) Sinusitis 3 (2.0) Injection site reaction 6 (4.0) Hot flash 6 (4.0) Emotional lability 3 (2.0) 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 [see WARNINGS AND PRECAUTIONS], Pelvic pain, Breast tenderness, Vaginal discharge. Ovarian enlargement, Multiple pregnancies [see WARNINGS AND PRECAUTIONS] Skin and subcutaneous tissue disorders: Rash Vascular disorders: Hot flushes Read the Bravelle (urofollitropin injection) Side Effects Center for a complete guide to possible side effectsLearn More »
Source: http://www.rxlist.com
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.
- 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) [see WARNINGS AND PRECAUTIONS].
- 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.
- 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 [see WARNINGS AND PRECAUTIONS].
- Do not administer daily doses of BRAVELLE® or BRAVELLE® in combination with MENOPUR® that exceed 450 International Units.
Source: http://www.rxlist.com
No drug/drug interaction studies in humans have been conducted for BRAVELLE® . Last reviewed on RxList: 2/28/2014
This monograph has been modified to include the generic and brand name in many instances.
This monograph has been modified to include the generic and brand name in many instances.
Source: http://www.rxlist.com
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
- 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
Source: http://www.rxlist.com
BRAVELLE® is contraindicated in women who exhibit:
This monograph has been modified to include the generic and brand name in many instances.
- Prior hypersensitivity to BRAVELLE® or urofollitropins
- High levels of FSH indicating primary ovarian failure [see INDICATIONS AND USAGE]
- Pregnancy BRAVELLE® may cause fetal harm when administered to a pregnant woman [see Use In Specific Populations]. 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) [see INDICATIONS AND USAGE]
- 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
This monograph has been modified to include the generic and brand name in many instances.
Source: http://www.rxlist.com
Aside from possible ovarian hyperstimulation [see WARNINGS AND PRECAUTIONS] and multiple gestations [see WARNINGS AND PRECAUTIONS], little is known concerning the consequences of acute overdosage with BRAVELLE® .
Source: http://www.rxlist.com
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 Last reviewed on RxList: 2/28/2014
This monograph has been modified to include the generic and brand name in many instances.
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 Last reviewed on RxList: 2/28/2014
This monograph has been modified to include the generic and brand name in many instances.
Source: http://www.rxlist.com
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 [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 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:
This monograph has been modified to include the generic and brand name in many instances.
- 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.
- 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
- Collapsed follicle
- Fluid in the cul-de-sac
- Features consistent with corpus luteum formation
- Secretory endometrium
This monograph has been modified to include the generic and brand name in many instances.
Source: http://www.rxlist.com
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