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Mechanism of Action
US Drug Names
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.
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.
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.
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.
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.
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).
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.
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Description: Urofollitropin is a parenteral, human derived urinary gonadotropin formulation used in infertility treatments. The key differences in human-derived FSH (i.e., urofollitropin) and genetically engineered FSH (i.e., r-FSH) are product sources and cost. Urofollitropin treatments are highly purified follitropins extracted from the urine of postmenopausal women. Urofollitropin contains primarily follicle stimulating hormone (FSH). The highly purified preparations of urofollitropin contain negligible (< 0.1 IU) luteinizing hormone (LH) activity per 1000 IU of FSH activity. By comparison, recombinant products are derived from the secretions from Chinese hamster ovary cells that are cultured in fetal calf or other mammalian serum, and approximate human FSH (see separate Follitropin, r-FSH monograph). Both urofollitropin and r-FSH are manufactured in compliance with strict standards. One advantage of urofollitropin is the lower cost compared to r-FSH products; however, there may be advantages to choosing r-FSH products for some patients (e.g., supply needs or history of sensitivity to urofollitropin).
In females, urofollitropin and hCG are given in a sequential manner and are used for follicular recruitment and development and the induction of ovulation in patients with polycystic ovary syndrome and infertility, who have failed to respond or conceive following adequate clomiphene citrate therapy. The drugs may also be used to stimulate the development of multiple follicles in ovulatory patients undergoing assisted reproductive technologies (ART) such as in vitro fertilization (IVF). Fertinex® (urofollitropin for injection, purified) was approved by the FDA August 23, 1996 for ovulation induction in females, but was discontinued by the manufacturer (Serono) in mid-2003. In males, Fertinex® was designated an orphan drug for spermatogenesis induction for those men with reproductive failure due to hypothalamic or pituitary dysfunction or hypogonadotropic hypogonadism. In May 2002, the FDA granted approval to Ferring Pharmaceuticals to market Bravelle™ (urofollitropin for injection, purified), a highly purified, human-derived follicle-stimulating hormone, for the treatment of infertility following pituitary suppression (e.g., with a GnRH agonist); in December 2002 Bravelle™ received approval for use for multifollicular development in women undergoing in vitro fertilization (IVF). Ferring has also completed Phase III trials for Bravelle™ that evaluate the use of Bravelle™ together with the company's Repronex® (menotropins, HMG) product, in the same syringe. These studies represent the first time a mixed-drug single daily dose regimen has been used for ovulation induction, and the company plans to pursue additional indications for the Bravelle™ product based on these trials.
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.
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
Preparation of injection:
Intramuscular injection (Bravelle only):
Subcutaneous injection (Bravelle):
Subcutaneous injection (Fertinex):
Urofollitropin therapy can result in mild to moderate uncomplicated ovarian enlargement; it occurs in approximately 20% of those treated with urofollitropin and hCG. Ovarian enlargement usually subsides within 2 or 3 weeks without treatment and can be accompanied by abdominal pain and/or distension. In trials, 2.9—5.4% had abdominal pain, 6.7% had pelvic pain, 2.7—6.7% had an enlarged abdomen, 14% had abdominal cramps, 5.7—8.7% had nausea, 2.7% had vomiting, and 2.7% had diarrhea. In order to minimize the hazard associated with the occasional abnormal ovarian enlargement, carefully monitor ovarian response and use the lowest dose consistent with expectation of good results. If substantial ovarian enlargement occurs after ovulation, sexual intercourse should be prohibited because of the risk of hemoperitoneum due to ruptured ovaries. Severe ovarian hyperstimulation syndrome (OHSS) can also occur while receiving urofollitropin therapy. Of 72 women, 8% developed OHSS and two were classified as severe. In another study, 5% of 60 women developed OHSS and 1 was classified as severe. In trials, 5.4—11.4% had OHSS. Do not administer hCG if the ovaries are abnormally enlarged on the last day of urofollitropin, FSH therapy, as this will reduce the chances of development of the OHSS. This syndrome is a medical event distinct from uncomplicated ovarian enlargement and may progress rapidly to become a serious medical event. The syndrome is associated with a marked increase in vascular permeability, which results in rapid accumulation of fluid in the peritoneal, pleural, and pericardial cavities. Some early warning signs include abdominal pain and distention, pelvic pain, nausea, vomiting, diarrhea, and weight gain. Severe cases produce clinical signs such as gross ovarian enlargement, gastrointestinal symptoms, ascites, dyspnea, oliguria, and pleural effusion. Other reported OHSS symptoms include pericardial effusion, anasarca, hydrothorax, acute abdomen, hypotension, renal failure, pulmonary edema, intraperitoneal and ovarian hemorrhage, deep venous thrombosis, adnexal torsion. Elevated urinary steroid levels, electrolyte imbalance, hypovolemia, hemoconcentration, and hypoalbuminemia may also occur. Hemoconcentration, hypovolemic shock, and thromboembolism have been fatal. If severe OHSS occurs, discontinuation of therapy and hospitalization are required. A physician experienced in the management of the syndrome or who is experienced in the management of fluid and electrolyte imbalances should be consulted. Cases of OHSS are more common, more severe, and more protracted if pregnancy occurs. Pelvic examinations should be performed in patients who complain of abdominal pain during drug therapy, and dosages of the drug should be reduced if ovarian enlargement occurs (manifested as abdominal pain). Abdominal and pelvic examination should be done carefully in severe cases of OHSS due to the fragility of the enlarged ovaries. Urofollitropin therapy should not be reinstated until ovarian size has returned to normal. Patients should be examined at least every other day for signs of excessive ovarian stimulation during therapy and during the 2 weeks following treatment with urofollitropin. Most often, OHSS occurs after treatment has been discontinued and reaches its maximum at about 7 to 10 days after treatment.
Adverse drug reactions that may occur with urofollitropin therapy include acne vulgaris (2.9%), breast tenderness/mastalgia (2%), constipation (2—2.7%), dehydration (2.7%), depression (2.7%), dermatological symptoms (alopecia, skin rash (unspecified) (2.7%), exfoliative dermatitis (2.7%), pruritus, xerosis), dizziness, dyspepsia, emotional lability (2—2.7%), flatulence, flu-like symptoms (including chills, cough, fever (2.7%), headache (8.1—12.7%), malaise, and musculoskeletal pain), ectopic pregnancy, hot flashes (4—5.7%), hypertension (2.7%), injection site reaction (4%), leukorrhea (white vaginal discharge, 2.7%), menstrual irregularity, ovarian cyst (2.9—8.1%), sinusitis (2%), vaginal bleeding (2.7—8.6%), and uterine spasm or uterine contractions (2.7%).
Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome (ARDS), and exacerbation of asthma) have been reported in women treated with gonadotropins like urofollitropin. In addition, thromboembolic events both in association with, and separate from OHSS have been reported. Intravascular thrombosis and thromboembolism can result in reduced blood flow to critical organs or the extremities. Sequelae of such events have included venous phlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb. In rare cases, pulmonary complications and/or thromboembolic events have resulted in fatalities.
Some observational studies and a number of case reports gave rise to the speculation that infertility treatments might enhance the risk of new primary malignancy in women (i.e, breast cancer or ovarian cancer). However, infertility alone is an independent risk factor for the development of either breast or ovarian cancer. Case reports and observational studies suggesting an association of cancer to fertility treatments rarely control for other independent confounding factors such as delay in parity or family history. In one long-term cohort study of 1,197 infertile women, the incidence of ovarian or breast cancer was not significantly elevated in the groups receiving fertility treatments versus those not treated. The breast cancer rate, in particular, was not significantly different in either group versus the general female population. While certainly more studies are needed, the current data do not support an association between the use of fertility drugs like urofollitropin and increased cancer risk.
Hypersensitivity or anaphylactic reactions such as anaphylactoid reactions associated with urofollitropin administration have been reported in some patients. These reactions may present as generalized urticaria, facial edema, angioedema, and/or dyspnea suggestive of laryngeal edema. The relationship of these symptoms to uncharacterized urinary proteins is uncertain.
Very little information regarding side effects associated with urofollitropin use in males is available. Follitropin, r-FSH, has been more widely used in men, compared to urofollitropin; side effects reported in men using follitropin and that could be expected with the use of urofollitropin include acne vulgaris, breast pain/ mastalgia, fatigue, and gynecomastia. Injection site reactions can be expected at a rate similar to that in female patients receiving urofollitropin. Other serious events are less common, such as testicular surgery for cryptorchidism, hemoptysis, an infected pilonidal cyst, and lymphadenopathy associated with an Epstein-Barr viral infection.
Urofollitropin is contraindicated for use in any patient with a prior history of urofollitropin hypersensitivity.
It has been suggested that the use of fertility drugs might increase the risk of certain cancers in women. Some observational studies and a number of case reports gave rise to the speculation that the increased number of ovulatory follicles and/or high gonadotropin and estrogen levels induced by infertility treatment might enhance the development of breast carcinoma or ovarian carcinoma. However, infertility alone is an independent risk factor for the development of either breast or ovarian cancer. Also, case reports rarely control for other independent confounding factors such as delay in parity or family history. In one long-term cohort study of 1,197 infertile women, the incidence of ovarian or breast cancer was not significantly elevated in the groups receiving fertility treatments versus those not treated. The breast cancer rate, in particular, was not significantly different in either group versus the general female population. While more studies are needed, current data do not support an association between the use of fertility drugs and increased cancer risks.
Urofollitropin is contraindicated in any other cause of infertility other than anovulation.
Urofollitropin is not indicated for use in children.
All patients should be advised to use caution when driving or operating machinery while receiving urofollitropin. This drug can cause dizziness.
Use urofollitropin cautiously in patients with asthma. This condition may be exacerbated.
Urofollitropin is contraindicated in patients with uncontrolled adrenal insufficiency, uncontrolled thyroid disease, or an intracranial lesion such as a sex-hormone-dependent pituitary adenoma. Increasing sex-hormone concentrations may exacerbate these conditions.
Urofollitropin is contraindicated in men with normal serum gonadotropin concentrations, which indicates normal pituitary function; in primary testicular failure (indicated by increased serum gonadotropin concentrations); and in infertility other than that resulting from hypogonadotropic hypogonadism.
Urofollitropin should not be used in patients with primary ovarian failure because it is ineffective in these patients.
The use of urofollitropin in patients with dysfunctional uterine bleeding or vaginal bleeding of unknown origin is contraindicated. This may indicate the presence of endometrial hyperplasia or carcinoma which can be exacerbated by increased estrogen serum concentrations due to ovulation. Any possibility of uterine neoplasms should be ruled out before use. Endometrial growth may be stimulated by these fertility protocols; they should be used cautiously in patients with uterine leiomyomata (fibroids) or endometriosis.
Clinical studies of urofollitropin for the treatment of infertility in women typically do not include geriatric females. Use with caution in elderly females who are undergoing assisted reproductive technology (ART) procedures.
Prior to initiation of urofollitropin in women, a full gynecologic exam and endocrine assessment should be performed. Except for those patients enrolled in ART programs, this should include an exam to rule out tubal pathology. Urofollitropin is contraindicated in patients with ovarian enlargement or a preexisting ovarian cyst that is not due to polycystic ovarian syndrome (PCOS). Urofollitropin therapy should not be initiated until the diagnostic cause of the cyst or enlargement has been determined and ovary size has returned to normal.
All female patients undergoing urofollitropin treatment should be instructed to report symptoms of ovarian enlargement, including abdominal pain or pelvic pain; nausea; vomiting; ascites (fluid and distension in the abdomen); or weight gain immediately. The current cycle of fertility agents should be halted if ovarian enlargement or ovarian hyperstimulation syndrome (OHSS) occurs or if an ovarian cyst develops; maximal ovarian enlargement may not be evident until several days after fertility drug discontinuation. Sexual intercourse should be avoided to limit trauma risk. hCG administration should not occur in these patients or in patients with symptoms or signs of abnormal ovarian enlargement on the last day of follitropin therapy. However, withholding of hCG does not ensure that OHSS will not occur. Fertility therapy should not be reinstated until ovary size has returned to normal. Complete pelvic exams, including pelvic ultrasounds, should be repeated in all female patients during and prior to each fertility drug cycle. Some patients with polycystic ovary syndrome (PCOS) are unusually sensitive to gonadotropins and may have an exaggerated response to ovarian hyperstimulation protocols.
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.
Rarely, thromboembolic events have been reported in females receiving medications for fertility protocols. Urofollitropin should be used with extreme caution in those patients with a a personal or family history of thrombophlebitis or other active thromboembolic disease, and in patients with severe obesity. These patients may have an increased risk of venous or arterial thromboembolic events during or following treatment with gonadotropins. This warning does not apply to the use of urofollitropin treatment in males.
Tobacco smoking is a lifestyle choice that may decrease fertility or the effectiveness of fertility treatments in some women and/or men. Patients should be encouraged to avoid tobacco consumption and pursue smoking cessation while pursuing fertility therapies such as the use of urofollitropin.
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.
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.
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.
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.
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