Bravelle Information
Bravelle (Urofollitropin) Description
Bravelle (Urofollitropin) is a product containing a highly purified preparation of human follicle stimulating hormone (hFSH) extracted from the urine of postmenopausal women. Human FSH 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 (Urofollitropin) is a sterile, lyophilize powder intended for subcutaneous (SC) or intramuscular (IM) injection after reconstitution with sterile 0.9% Sodium Chloride Injection, USP Each vial of Bravelle (Urofollitropin) 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 IU of FSH. Bravelle (Urofollitropin) contains up to 2% luteinizing hormone (LH) activity based on bioassay. Human Chorionic Gonadotropin (hCG) is not detected in Bravelle (Urofollitropin) . 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.
Therapeutic class: Infertility.
Bravelle (Urofollitropin) Clinical Pharmacology
Bravelle (Urofollitropin) administered for 7 to 12 days produces ovarian follicular growth in women who do not have primary ovarian failure. Treatment with Bravelle (Urofollitropin) in most instances results only in follicular growth and maturation. When sufficient follicular maturation has occurred, hCG must be given to induce ovulation.
Bravelle (Urofollitropin) Contraindications
Bravelle (Urofollitropin) is contraindicated in women who have:
Bravelle (Urofollitropin) Warnings
Bravelle (Urofollitropin) is a drug that should only be used by physicians who are thoroughly familiar with infertility problems. It is a potent gonadotropic substance capable of causing Ovarian Hyperstimulation Syndrome [OHSS] with or without pulmonary or vascular complications in women. Bravelle (Urofollitropin) therapy requires a certain time commitment by physicians and supportive health professionals, and its use requires the availability of appropriate monitoring facilities (see ). Bravelle (Urofollitropin) should be used with a great deal of care.
Ovarian Enlargement: Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distension and/or abdominal pain occurs in approximately 20% of those treated with follitropin and hCG, and generally regresses without treatment within two or three weeks.
In order to minimize the hazard associated with the occasional abnormal ovarian enlargement, which may occur with FSH - hCG therapy, the lowest dose consistent with expectation of good results should be used. Careful monitoring of ovarian response can further minimize the risk of overstimulation.
If the ovaries are abnormally enlarged on the last day of Bravelle (Urofollitropin) therapy, hCG should not be administered in the course of therapy; this will reduce the chances of development of the Ovarian Hyperstimulation Syndrome.
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. The following symptomatology has been seen with cases of OHSS: abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events (see "" below). 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 the Ovarian Hyperstimulation Syndrome (OHSS).
In a clinical study of ovulation induction, 6 of 72 (8.33%) Bravelle (Urofollitropin) treated women developed OHSS and two were classified as severe. In a clinical study for multiple follicular development during IVF, 3 of 60 Bravelle (Urofollitropin) treated women developed OHSS and 1 was classified as severe. 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. Most often, OHSS occurs after treatment has been discontinued and reaches its maximum at about 7 to 10 days after treatment. Usually, in cases where OHSS may be developing prior to hCG administration (see ), the hCG should be withheld.
If severe OHSS occurs, treatment be stopped and the patient should be hospitalized.
A physician experienced in the management of the syndrome, or who is experienced in the management of fluid and electrolyte imbalances should be consulted.
Multiple pregnancies have occurred following treatment with Bravelle (Urofollitropin) SC and IM.
Pregnancy outcomes in a controlled study of 72 patients undergoing ovulation induction with Bravelle (Urofollitropin) are shown in Table 4.
The pregnancy outcomes in a controlled study of 60 patients undergoing treatment with Bravelle (Urofollitropin) in IVF are shown in Table 5.
The patient and her partner should be advised of the potential risk of multiple births before starting treatment.
Hypersensitivity/Anaphylactic Reactions Hypersensitivity/anaphylactic reactions associated with follitropins 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.
Bravelle (Urofollitropin) Precautions
The combination of both estradiol levels and ultrasonography are useful for monitoring the growth and development of follicles, timing hCG administration, as well as minimizing the risk of the Ovarian Hyperstimulation Syndrome and multiple gestations.
The clinical confirmation of ovulation, is determined by:
a. A rise in basal body temperature,b. Increase in serum progesterone, andc. 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 determining if ovulation has occurred. Sonographic evidence of ovulation may include the following:
a. Fluid in the cul-de-sac, b. Ovarian stigmata, and c. Collapsed follicle.
Because of the subjectivity of the various tests for the determination of follicular maturation and ovulation, it cannot be overemphasized that the physician should choose tests with which he/she is thoroughly familiar.
Pregnancy Category X:
Bravelle (Urofollitropin) Adverse Reactions
The safety of Bravelle (Urofollitropin) was examined in four clinical studies that enrolled a total of 222 patients receiving Bravelle (Urofollitropin) including 72 for ovulation induction and 150 for IVF.
All adverse events (without regard to causality assessment) occurring ≥ 2 % incidence in the clinical study patients receiving Bravelle (Urofollitropin) are listed in Table 6, (FPI FSH 99-03 study for ovulation induction) and Table 7 (FPI FSH 99-04, FPI FSH 99-05 and FPI FSH 2001-01 studies for IVF).
Bravelle (Urofollitropin) Drug Abuse And Dependence
There have been no reports of abuse or dependence with follitropins.
Bravelle (Urofollitropin) Overdosage
Aside from possible ovarian hyperstimulation (see ) and multiple gestations (see little is known concerning the consequences of acute overdosage with Bravelle (Urofollitropin)
Bravelle (Urofollitropin) Dosage And Administration
1) Wash hands thoroughly with soap and water.2) Before injections, the septum tops of the vials should be wiped with an aseptic solution to prevent contamination of the contents.3) To prepare the Bravelle (Urofollitropin) solution, inject 1 mL of Sterile Saline for Injection, USP into the vial of Bravelle (Urofollitropin) . but gently swirl until the solution is clear. Generally, the Bravelle (Urofollitropin) dissolves immediately. Check the liquid in the container. If it is not clear or has particles in it, 4) For patients requiring a single injection from multiple vials of Bravelle (Urofollitropin) , up to 6 vials can be reconstituted with 1 mL of Sterile Saline for Injection, USP. This can be accomplished by reconstituting a single vial as described above (see step 3). Then draw the entire contents of the first vial into a syringe, and inject the contents into a second vial of lyophilized Bravelle (Urofollitropin) . Gently swirl the second vial, as described above, once again checking to make sure the solution is clear and free of particles. This step can be repeated with 4 additional vials for a total of up to 6 vials of lyophilized Bravelle (Urofollitropin) into 1 mL of diluent.5) Immediately the reconstituted Bravelle (Urofollitropin) either (for ovulation induction or multifollicular development during ART) or (for ovulation induction). Any unused reconstituted material should be discarded.6) Draw the reconstituted Bravelle (Urofollitropin) into an empty, sterile syringe.7) Hold the syringe pointing upwards and gently tap the side to force any air bubbles to the top; then squeeze the plunger gently until all the air has been expelled and only Bravelle (Urofollitropin) solution is left in the syringe.8) Bravelle (Urofollitropin) works if it is injected (for ovulation induction or multifollicular development during ART) or (for ovulation induction). The recommended sites for SC injection are either side of the lower abdomen in alternating fashion with the actual injection site varied a little with each injection. SC injection of Bravelle (Urofollitropin) into the thigh is not recommended unless the lower abdomen is not usable because of scarring, surgical deformity or other medical conditions.
The best site for IM injection of Bravelle (Urofollitropin) is the upper outer quadrant of the buttock muscle near the hip. This area contains few blood vessels and major nerves. Stretching the skin helps the needle to go in more easily and pushes the tissue beneath the skin out of the way. This helps the solution disperse correctly.
9) The injection site should be swabbed with a disinfectant to remove any surface bacteria. Clean about two inches around the point where the needle will go in and let the disinfectant dry for at least one minute before proceeding.10) For injection, the needle should be inserted at a 90° angle to the skin surface.
For injection, the needle should be inserted at a 90° angle to the skin surface. Pushing in with a quick thrust causes the least discomfort.
11) If the needle is correctly positioned, it will be difficult to draw back on the plunger. Any blood drawn into the syringe means the needle tip has penetrated a vein or artery. If this happens, remove the syringe, cover the injection site with a swab containing disinfectant and apply pressure; the site should stop bleeding in a minute or two.12) Once the needle is properly placed, depress the plunger and steadily, so the solution is correctly injected and the skin or muscle tissue is not damaged.13) Pull the syringe out quickly and apply pressure to the site with a swab containing disinfectant. A gentle massage of the site - while still maintaining pressure - helps disperse the Bravelle (Urofollitropin) solution and relieve any discomfort.14) Use the disposable syringe only once and dispose of it properly.
Bravelle (Urofollitropin) How Supplied
Bravelle (Urofollitropin) (urofollitropin for injection, purified) is supplied in a sterile, lyophilized, single dose vial containing 82.5 IU of FSH, to deliver 75 IU 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 IU FSH activity, supplied as:NDC 55566-8505-2: of 5 vials + 5 vials diluent. NDC 55566-8505-6: of 5 vials + 5 vials diluent + 5 Q●Capvial adaptors.
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.
Q●Cap manufactured by Bioject Inc., Tualatin, OR 97062
Manufactured for:FERRING PHARMACEUTICALS INC. SUFFERN, NY 10901 By: CARDINAL HEALTH Albuquerque, New Mexico 87107 6048-046-D6048FR-0408/04
