Bravelle

Browse PDR's full list of drug information

Bravelle

Classes

Gonadotropins
Pituitary Hormones

Administration

NOTE: Urofollitropin should be used only by health care prescribers who are experienced in managing endocrine or fertility disorders and only in facilities where appropriate clinical and endocrinology evaluations are available. Close monitoring of estrogenic activity and ovarian size is necessary.
Hazardous Drugs Classification
NIOSH (Draft) 2020 List: Table 2
Approved by FDA after NIOSH 2016 list published.
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.

Injectable Administration

Fertinex is for subcutaneous (SC) administration only.
Bravelle is for intramuscular (IM) or subcutaneous (SC) administration; however, most patients will prefer SC administration.
It is recommended to use the same brand of urofollitropin in any one treatment cycle.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
 
Preparation of injection:
Fertinex: Inject 0.5—1 ml of sterile saline for injection, USP into the vial. Do not shake, but gently swirl until the solution is clear. Generally, the powder dissolves immediately. Check the liquid in the container. If it is not clear or has particles in it, do not use it. For a single injection from multiple vials, follow directions above and then draw the entire contents of the first vial into a syringe, and inject the contents into a second vial. Gently swirl the second vial, as described above, once again checking to make sure the injection is clear and free of particles. This step can be repeated with as many vials as needed as long as the concentration does not exceed 225 IU/0.5 ml. Use immediately after reconstitution. Discard any unused product.
Bravelle Q-Cap: Twist the Q-Cap onto the syringe, push the tip through the diluent vial's rubber stopper, and pull back on the plunger to remove the diluent. Place the Q-Cap™ on the vial containing the urofollitropin, FSH powder, push the tip into the rubber stopper, and slowly inject the diluent into the vial. Gently swirl until the solution is clear; if it is not clear or has particles in it, do not use it. For a single injection from multiple vials, follow directions above and then draw the entire contents of the first vial into a syringe, and inject the contents into a second vial. Gently swirl the second vial, as described above, once again checking to make sure the injection is clear and free of particles. This step can be repeated with 4 additional vials for a total of up to 6 vials into 1 ml of diluent, the final concentration should not exceed 450 IU/ml. Use immediately after reconstitution. Discard any unused product.
Bravelle: Inject 1 ml of sterile saline for injection, USP into the vial. Do not shake, but gently swirl until the solution is clear. Generally, the powder dissolves immediately. Check the liquid in the container. If it is not clear or has particles in it, do not use it. For a single injection from multiple vials, follow directions above and then draw the entire contents of the first vial into a syringe, and inject the contents into a second vial. Gently swirl the second vial, as described above, once again checking to make sure the injection is clear and free of particles. This step can be repeated with 4 additional vials for a total of up to 6 vials into 1 ml of diluent, the final concentration should not exceed 450 IU/1 ml. Use immediately after reconstitution. Discard any unused product.

Intramuscular Administration

Intramuscular injection (Bravelle only):
Inject deeply into a large muscle. Detailed instructions are found in manufacturer's package label.

Subcutaneous Administration

Subcutaneous injection (Bravelle):
When administered via subcutaneous injection, Bravelle and Menopur (menotropins) may be mixed and administered in the same syringe.
The most convenient sites for subcutaneous injection are either in the abdomen (preferably) around the navel where there is a lot of loose skin and layers of fatty tissue or in the upper thigh. Follow specific manufacturer directions.
Inject subcutaneously taking care not to inject intradermally.
 
Subcutaneous injection (Fertinex):
The most convenient sites for subcutaneous injection are either in the abdomen (preferably) around the navel where there is a lot of loose skin and layers of fatty tissue or in the upper thigh. Follow specific manufacturer directions.
Inject subcutaneously taking care not to inject intradermally.

Adverse Reactions
Severe

ovarian hyperstimulation syndrome / Delayed / 5.0-11.4
exfoliative dermatitis / Delayed / 2.7-2.7
pleural effusion / Delayed / Incidence not known
thrombosis / Delayed / Incidence not known
anasarca / Delayed / Incidence not known
pericardial effusion / Delayed / Incidence not known
pulmonary edema / Early / Incidence not known
thromboembolism / Delayed / Incidence not known
oliguria / Early / Incidence not known
ectopic pregnancy / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
stroke / Early / Incidence not known
acute respiratory distress syndrome (ARDS) / Early / Incidence not known
new primary malignancy / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
laryngeal edema / Rapid / Incidence not known

Moderate

ovarian enlargement / Delayed / 20.0-20.0
vaginal bleeding / Delayed / 2.7-8.6
hot flashes / Early / 4.0-5.7
constipation / Delayed / 2.0-2.7
depression / Delayed / 2.7-2.7
hypertension / Early / 2.7-2.7
dehydration / Delayed / 2.7-2.7
uterine contractions / Early / 2.7-2.7
ascites / Delayed / Incidence not known
hypovolemia / Early / Incidence not known
hypoalbuminemia / Delayed / Incidence not known
dyspnea / Early / Incidence not known
hypotension / Rapid / Incidence not known
phlebitis / Rapid / Incidence not known

Mild

headache / Early / 8.1-12.7
nausea / Early / 5.7-8.7
pelvic pain / Delayed / 6.7-6.7
abdominal pain / Early / 2.9-5.4
injection site reaction / Rapid / 4.0-4.0
acne vulgaris / Delayed / 2.9-2.9
diarrhea / Early / 2.7-2.7
vomiting / Early / 2.7-2.7
fever / Early / 2.7-2.7
vaginal discharge / Delayed / 2.7-2.7
rash / Early / 2.7-2.7
leukorrhea / Delayed / 2.7-2.7
emotional lability / Early / 2.0-2.7
sinusitis / Delayed / 2.0-2.0
mastalgia / Delayed / 2.0-2.0
weight gain / Delayed / Incidence not known
dyspepsia / Early / Incidence not known
xerosis / Delayed / Incidence not known
dizziness / Early / Incidence not known
malaise / Early / Incidence not known
pruritus / Rapid / Incidence not known
musculoskeletal pain / Early / Incidence not known
alopecia / Delayed / Incidence not known
chills / Rapid / Incidence not known
menstrual irregularity / Delayed / Incidence not known
flatulence / Early / Incidence not known
urticaria / Rapid / Incidence not known
gynecomastia / Delayed / Incidence not known

Common Brand Names

Bravelle

Dea Class

Rx

Description

Human-derived urinary gonadotropin; lower cost than recombinant FSH; primarily contains FSH with negligible (< 0.1 IU) LH activity per 1000 IU of FSH activity; used for infertility protocols for ovulation induction; also used for spermatogenesis induction in men with reproductive failure due to hypothalamic or pituitary dysfunction or hypogonadotropic hypogonadism.

Dosage And Indications
For the treatment of infertility in females.
NOTE: During urofollitropin treatment and during a 2-week post-treatment period, females should be examined at least every other day for signs of excessive ovarian stimulation. Ovarian hyperstimulation syndrome (OHSS) usually occurs after discontinuation of urofollitropin and reaches its maximum at about 7—10 days post-ovulation.
For the development of multiple follicles in the ovulatory female patient participating in an Assisted Reproductive Technology (ART) program. Subcutaneous dosage (Bravelle only) Adult females

Initially, the manufacturer recommends 225 IU SC daily for the first 5 days of treatment for those patients who have received GnRH agonist or antagonist pituitary suppression. Urofollitropin (Bravelle) may be administered together with menotropins (Menopur) with a total initial dose not to exceed 225 IU SC (150 IU urofollitropin, 75 IU menotropins OR 75 IU urofollitropin, 150 IU menotropins). Adjust subsequent dosing to individual patient response. Adjustments in dose should not be made more frequently than once every 2 days and should not exceed more than 75 to 150 IU per adjustment. The maximum dose is 450 IU/day (urofollitropin alone or in combination with menotropins) and in most cases therapy beyond 12 days is not recommended. If adequate follicular development is evident, hCG (5000 to 10,000 USP units) should be given to induce final follicular maturation in preparation for oocyte retrieval. Withhold hCG if the ovaries are abnormally enlarged or if abdominal pain occurs. These precautions may reduce the risk of OHSS. Literature has been published regarding the use of Bravelle in IVF. In this study, if hCG criteria were not met after 12 days of stimulation, the patient was allowed a maximum of 2 additional days to try and meet criteria. Patients should be followed closely for at least 2 weeks after hCG administration. If there is inadequate follicle development or ovulation without subsequent pregnancy, the course of treatment may be repeated.

Subcutaneous dosage (Fertinex only) Adult females

The dosage should be individualized for each patient. Initiate therapy in the early follicular phase (cycle day 2 or 3) at a dose of 150 IU SC once daily until sufficient follicular development is attained. In most cases, therapy should not exceed 10 days.

For the induction of ovulation and pregnancy in the anovulatory infertile patient in whom the cause of infertility is functional and not due to primary ovarian failure. Subcutaneous or Intramuscular dosage (Bravelle only) Adult females

Initially, the manufacturer recommends 150 IU SC or IM daily for the first 5 days of treatment for those patients who have received GnRH agonist or antagonist pituitary suppression. Adjust subsequent dosing to individual patient response. Adjustments in dose should not be made more frequently than once every 2 days and should not exceed more than 75 to 150 IU per adjustment. The maximum dose is 450 IU/day and in most cases therapy beyond 12 days is not recommended. If patient response to FSH is appropriate, hCG (5000 to 10,000 USP units) should be given 1 day following the last dose of Bravelle. Withhold hCG if the serum estradiol is > 2000 pg/ml, if the ovaries are abnormally enlarged or if abdominal pain occurs. Advise the patient to refrain from intercourse. These precautions may reduce the risk of OHSS and multiple gestation. Patients should be followed closely for at least 2 weeks after hCG administration. If there is inadequate follicle development or ovulation without subsequent pregnancy, the course of treatment may be repeated.

Subcutaneous dosage (Fertinex only) Adult females

75 international units (IU) SC once daily. A response is usually evident after 5—7 days. A dosage adjustment may be considered at this time. The dose should not be increased more than twice in any cycle or by more than 75 IU per adjustment. To complete follicular development and effect ovulation in the absence of an endogenous LH surge, administer HCG (5000—10,000 units) one day after the last dose of urofollitropin. HCG should be withheld if the serum estradiol level is > 2000 pg/ml. If the ovaries are enlarged, treatment with urofollitropin should be discontinued, HCG should not administered, and the patient should be advised not to have intercourse. The initial dose in subsequent cycles should be individualized for each patient based on her response in the preceding cycle. Doses larger than 300 IU/day are not routinely recommended. HCG (5000—10,000 units) must be given 1 day after the last dose of urofollitropin.

For the treatment of infertility in males (for the stimulation of spermatogenesis in males with primary or secondary hypogonadotropic hypogonadism and resultant oligospermia).
NOTE: Fertinex brand of urofollitropin is designated an orphan drug by the FDA for this indication.
NOTE: Pretreatment with hCG is required prior to combination treatment with urofollitropin. Various hCG dosages have been advocated; continue hCG for a period sufficient to achieve normal serum testosterone levels. Such pretreatment may require 3—6 months (see HCG monograph).
Subcutaneous dosage (Fertinex only; combined with hCG therapy) Adults

After normal serum testosterone levels with hCG have been reached, urofollitropin is given 150 IU SC three times per week in combination with hCG at the dose required to maintain normal serum testosterone levels IM/SC three times per week (administered at a separate site). The lowest dose of urofollitropin which induces spermatogenesis should be utilized. If azoospermia persists, the urofollitropin dose may be increased to 300 IU three times per week. Combination therapy should be continued for at least 4 months to ensure detection of spermatozoa in the ejaculate and to increase testicular volume.

Dosing Considerations
Hepatic Impairment

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Drug Interactions

There are no drug interactions associated with Urofollitropin, FSH products.

How Supplied

Bravelle Intramuscular Inj Pwd F/Sol: 75IU
Bravelle Subcutaneous Inj Pwd F/Sol: 75IU

Maximum Dosage

No specific maximum dosage limit recommendations are available. Dosage regimens of urofollitropin depend upon the patient's age, sex, weight, condition being treated, the formulation used, and the prescribing clinician's judgment. Therefore, doses may vary widely and must be carefully individualized.

Mechanism Of Action

Mechanism of Action: Urofollitropin contains primarily follicle-stimulating hormone (FSH). Urofollitropin mimics the actions of endogenous FSH, which is required for normal follicular growth, maturation, and gonadal steroid production. In the female, the concentration of FSH is critical for the onset and duration of follicular development, and consequently for the timing and number of follicles reaching maturity. Urofollitropin replaces deficient or abnormal FSH serum concentrations in patients experiencing ovulatory function impairment not due to primary ovarian failure, providing the necessary FSH activity to stimulate follicle recruitment, growth, and maturation. Because highly purified urofollitropin does not possess clinically significant luteinizing hormone (LH)-like activity, human chorionic gonadotropin (hCG) is administered in order to mimic the endogenous LH surge.

Pharmacokinetics

Urofollitropin is administered subcutaneously or intramuscularly. Based on the steady state ratio of the peak plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC), subcutaneous (SC) and intramuscular (IM) administration of urofollitropin are not bioequivalent. Metabolism of urofollitropin has not been studied in humans.

Intramuscular Route

Multiple doses of urofollitropin IM resulted in Cmax and AUC of 77.7% and 81.8% compared to multiple doses of urofollitropin SC. Peak blood concentrations after 150 IU daily injections for 7 days was 11.5 IU/L for IM administration. The maximum plasma concentration was obtained at approximately 10 hours following intramuscular administration. The elimination half-life is roughly 15 hrs after 7 days of IM administration.

Subcutaneous Route

Peak blood concentrations after 150 IU daily injections for 7 days was 14.8 IU/L for SC administration. The maximum plasma concentration was obtained at approximately 10 hours following SC administration. The elimination half-life is roughly 20 hrs after 7 days of SC administration.

Pregnancy And Lactation
Pregnancy

Urofollitropin is classified in FDA pregnancy risk category X and is contraindicated after conception has occurred. Pregnancy should be ruled out prior to the administration of urofollitropin with each fertility treatment course. Urofollitropin is unnecessary and not recommended during pregnancy. Ovarian hyperstimulation syndrome, which may be induced by FSH therapy, is more common, more severe, and protracted in patients who conceive. In addition to potential effects on the fetus, including congenital malformation and spontaneous abortion, protocols using FSH inherently increase the risk of multiple gestation and the risks associated with such pregnancies.

It is not known whether urofollitropin is distributed into breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the nursing baby from urofollitropin exposure, a decision should be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother.