Pharmacological Classifications: Pituitary Hormone; Fertility Agent
General Information: 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 vitrofertilization (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.
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.
Route-Specific Pharmacokinetics: 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.
Indications: FSH is primarily indicated for the treatment of female infertility as it stimulates ovarian follicular growth in women who do not have primary ovarian failure.12 FSH is also indicated in the treatment of male infertility with adult-onset idiopathic hypogonadotropic hypogonadism.3
Contraindications and Precautions: Your health care provider needs to know if you have any of these conditions: abnormal or unusual vaginal bleeding, asthma, brain tumor or certain other kinds of cancer, conditions affecting your adrenal gland or thyroid gland, enlarged ovaries or ovarian cyst, failure of the ovaries to produce eggs, obstruction of the fallopian tubes, an unusual or allergic reaction to follitropin beta, neomycin, streptomycin, other hormones, medicines, foods, dyes, or preservatives, pregnant, and breast feeding. You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how this medicine affects you. It is important to keep all records required by your health care professional on body temperature and intercourse, and to carefully follow any directions for urine or blood testing or ultrasound exams. If you think you have become pregnant, contact your doctor or health care professional at once. Certain fertility treatments increase your chances of having multiple babies, like twins or triplets.
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.4
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.5
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.5
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.5 This warning does not apply to the use of urofollitropin treatment in males.
Drinking alcoholic beverages, including ethanol intoxication, or tobacco smoking are two lifestyle choices that may decrease fertility or the effectiveness of fertility treatments in some women and/or men. Patients should avoid excessive alcohol or tobacco consumption while pursuing fertility therapy with urofollitropin.
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.5
Breast-Feeding: 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.5
Interactions: Urofollitropin has no drug interactions that are known to be clinically significant.
Some herbal or alternative therapies may have effects on hypothalamic-pituitary function or hormone concentrations and thus may interfere with fertility therapies. Chasteberry, chaste tree fruit, Vitex agnus-castus may interfere with the therapeutic activity of infertility drugs. A case of ovarian hyperstimulation syndrome and multiple follicular development has been reported in a woman who took chasteberry prior to one of her IVF protocol cycles; serum gonadotropin and hormone levels were disordered and pregnancy was not accomplished.6 Due to a lack of data, herbal therapies touted for women's health are not recommended for use with prescribed fertility treatments.
Black cohosh, Cimicifuga racemosa, is a phytomedicinal that may potentially suppress luteinizing hormone (LH).789 It could potentially antagonize certain fertility agents that augment gonadotropin release. Due to a lack of data, any herbal therapies touted for women's health are not recommended for use with prescribed fertility treatments.
Adverse Reactions/Side Effects: 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.5
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%).5
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.5
Some observational studies and a number of case reports gave rise to the speculation that infertility treatments might enhance the risk of secondary 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.10 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.5
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.
How is this medication best taken? This medicine is for injection under the skin. If you get this medicine at home, you will be taught how to prepare and give this medicine. Use exactly as directed. Take your medicine at regular intervals. Do not take it more often than directed. It is important that you put your used needles and syringes in a special sharps container: do not put them in a trash can. If you do not have a sharps container, call your local pharmacy or healthcare provider to get one.
What do I do if I miss a dose? If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take your next regularly scheduled dose. Do not take two doses at the same time.
Storage: Keep this medicine in a refrigerator at 2°-8°C (36°-46°F). Keep all medicine out of the reach of children. Throw away any unused medicine after the expiration date. Do not flush unused medications or pour down a sink or drain.
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- 2. Arce JC, Nyboe Andersen A, Fernandez-Sanchez M, Visnova H, Bosch E, Garcia Velasco JA, Barri P, de Sutter P, Klein BM, Fauser BC. Ovarian response to recombinant human follicle-stimulating hormone: a randomized antimullerian hormone-stratified, dose-response trial in women undergoing in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril. 2014 Dec; 102(6): 1633-1640.e5.
- 3. Kobori Y, Suzuki K, Iwahata T, Shin T, Sato R, Nishio K, yagi H, Arai G, Soh S, Okada H. Hormonal therapy (hCG and rhFSH) for infertile men with adult-onset idiopathic hypogonadotropic hypogonadism. Syst Biol Reprod Med. 2014 Dec 18: 1-3.
- 4. Potashnik G, Lerner-Gava L, Genkin L, et al. Fertility drugs and the risk of breast and ovarian cancers: results of a long-term follow-up study. Fertil Steril 1999;71:853-859.
- 5. Bravelle (urofollitropin) package insert. Parsippany, NJ: Ferring Pharmaceuticals Inc.; 2014 Feb.
- 6. Cahill DJ, Fox R, Wardle PG, et al. Multiple follicular development associated with herbal medicine. Hum Reprod1994;9:1469—70.
- 7. Duker EM, Kopanski L, Jarry H, et al. Effects of extracts from Cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats. Planta Med 1991;57:420—4.
- 8. Eagon PK, Tress NB, Ayer HA, et al. Medicinal botanicals with hormonal activity (abstract 1073). Proc Amer Assoc Cancer Res 1999:40.
- 9. Lieberman S. A review of Cimicifuga racemosa (black cohosh) for the symptoms of menopause. Journal of Women's Health 1998;7:525—9.
- 10. Potashnik G, Lerner-Gava L, Genkin L, et al. Fertility drugs and the risk of breast and ovarian cancers: results of a long-term follow-up study. Fertil Steril 1999;71:853-859.