Urofollitropin (Systemic)


BAN:
Urofollitrophin {03} .

VA CLASSIFICATION
Primary: HS106

Note: Controlled substance classification—

Note: Controlled substance classification


U.S.—Schedule IV (controlled substance in some states in the U.S.){21}
Commonly used brand name(s): Fertinex; Fertinorm HP; Metrodin.

Other commonly used names are
follicle-stimulating hormone (FSH) and urofollitrophin .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Gonadotropin—

infertility therapy adjunct—

Indications

Accepted

Infertility, female (treatment)—Urofollitropin is indicated, in conjunction with human chorionic gonadotropin (hCG), for stimulation of ovulation and induction of pregnancy in patients with polycystic ovary syndrome who have an elevated luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio and who have failed to respond to adequate clomiphene citrate therapy {20} {23} {37} {38} {40} {44} {46}. Urofollitropin is not useful in patients with primary ovarian failure. {04} {20}

Reproductive technologies, assisted1—Urofollitropin is indicated, in conjunction with hCG, to stimulate the development of multiple oocytes in ovulatory patients who are attempting to conceive by means of assisted reproductive technologies, such as gamete intrafallopian transfer (GIFT) or in vitro fertilization (IVF). {04} {06} {29} {40} {47}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Extracted from urine of postmenopausal women {04}.

Mechanism of action/Effect:

Urofollitropin contains follicle-stimulating hormone (FSH). The combination of FSH and luteinizing hormone (LH) stimulates follicular growth and maturation {20} {23} {39} {46} {48}. Chorionic gonadotropin (hCG), whose actions are nearly identical to those of LH, is administered following urofollitropin treatment to mimic the naturally occurring surge of LH that triggers ovulation {20} {29} {39} {43} {46} {51}.


Precautions to Consider

Carcinogenicity

Long-term studies have not been done in animals to evaluate the carcinogenic potential of urofollitropin. {04} {20} {48}

Pregnancy/Reproduction
Fertility—
Use of urofollitropin to stimulate ovulation is associated with a high incidence of multiple gestations and births {04} {20} {23} {24} {25} {26} {28} {29} {31} {36} {48}. As a result, this may increase the risk of neonatal prematurity, as well as other complications associated with multiple gestations {04} {20} {23} {24} {25} {26} {28} {29} {31} {36} {48}.

Pregnancy—
Although problems in humans have not been documented, use of urofollitropin during pregnancy is unnecessary {04} {06} {07} {09} {11} {12} {13} {14} {48}.

Ovarian hyperstimulation syndrome (OHS), which may be induced by urofollitropin therapy, is more common, more severe, and protracted in patients who conceive. {04} {09} {33}

FDA Pregnancy Category X.

Breast-feeding

It is not known whether urofollitropin is distributed into breast milk {20}. However, urofollitropin is not indicated during the course of breast-feeding {48}.

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Abnormal vaginal bleeding, undiagnosed{04}{20}{48}{49}    (may indicate the presence of endometrial hyperplasia or carcinoma, which may be exacerbated by urofollitropin-induced increases in estrogen serum concentrations {48}; other possible endocrinopathies should also be ruled out {48})


» Ovarian cyst or enlargement not associated with polycystic ovary syndrome{20}{48}    (risk of further enlargement {04} {48})


Risk-benefit should be considered when the following medical problem exists
Sensitivity to urofollitropin or other gonadotropins

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Estradiol{17}{18}{20}{23}{29}{43}{44}{45}{46}{47}{48}{50}    (measurement of serum concentrations is recommended as needed, continuing through the day of chorionic gonadotropin administration {04} {06} {08} {09} {10} {12} {18} {20} {48}; recommended to determine optimal dose and to lessen the risk of ovarian hyperstimulation syndrome {04} {18} {20} {48})


» Ultrasound examination{18}{20}{23}{29}{42}{43}{44}{45}{46}{47}{48}    (recommended during urofollitropin therapy and prior to administration of chorionic gonadotropin to provide information on the number and size of mature follicles, to follow follicular development, and to lessen the risk of ovarian hyperstimulation syndrome and multiple gestation {04} {06} {18} {20} {48})


Daily basal body temperature{18}{46}{48}    (can be used to determine if ovulation has occurred {04} {18} {19} {48}; pregnancy test is recommended if basal body temperature following a cycle of treatment is biphasic and not followed by menses {18})


Progesterone{18}{29}{41}{44}{46}{48}    (measurement of serum or urine concentrations can be used prior to urofollitropin therapy to confirm anovulation {04} {18} {19} {34} {41} {48}; serum concentrations can be used after urofollitropin therapy to detect luteinized ovarian follicles {04} {18} {19} {42} {44} {46} {48})




Side/Adverse Effects

Note: Thromboembolism has not been reported in patients who have received urofollitropin, but has occurred with menotropins (LH/FSH) both in association with and separate from ovarian hyperstimulation syndrome. {04} {20} Complications resulting from thromboembolism have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, stroke, arterial occlusion necessitating limb amputation, and (rarely) death. {04}
Serious respiratory complications have not been reported in patients who have received urofollitropin, but have occurred with menotropins (LH/FSH) therapy. {04} These conditions included atelectasis and acute respiratory distress syndrome. {04} Rarely, death has resulted. {04}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
—about 10 to 20%    
Uncomplicated, mild to moderate ovarian enlargement or{04}{20}{43} ovarian cysts{04}{20} (mild bloating, abdominal or pelvic pain{20}{23})
    
redness, pain, or swelling at injection site{04}{20}{23}

Note: Ovarian enlargement is usually mild to moderate and abates within 2 or 3 weeks {04} {20}. Ovarian cysts have also occurred, though less frequently {04} {20}.


Incidence less frequent or rare
    
Severe ovarian hyperstimulation syndrome{04}{20}{23}{38}{43}{46} (severe abdominal or stomach pain; feeling of indigestion; moderate to severe bloating; decreased amount of urine; continuing or severe nausea, vomiting, or diarrhea; severe pelvic pain; rapid weight gain; swelling of lower legs; shortness of breath){04}{20}{23}
    
fever and chills{20}
    
skin rash or hives{04}{20}{23}

Note: In clinical trials, ovarian hyperstimulation syndrome (OHS) occurred in 6% of patients treated with urofollitropin for anovulation due to polycystic ovary syndrome and 0.25% of patients given urofollitropin for in vitro fertilization. {04} OHS may often occur 7 to 10 days after ovulation or completion of therapy {04} {20}. OHS differs from uncomplicated ovarian enlargement and can progress rapidly to cause serious medical problems. {04} With OHS, a marked increase in vascular permeability results in rapid accumulation of fluid in the peritoneal, pleural, and pericardial cavities (third spacing of fluids). {04} {33} {43} Medical complications ultimately arising from this increased vascular permeability may include hypovolemia, hemoconcentration, electrolyte imbalance, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events. {04} {33} {43} OHS is more common, more severe, and protracted in patients who conceive. {04} {09} {33}




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent or rare
    
Breast tenderness{20}{23}
    
diarrhea, mild{04}{20}
    
nausea{04}{20}
    
vomiting{04}{20}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Urofollitropin (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to urofollitropin or other gonadotropins
Other medical problems, especially abnormal vaginal bleeding or ovarian cyst or enlargement

Proper use of this medication

» Proper dosing

Precautions while using this medication
» Importance of close monitoring by physician

» Importance of following physician's instructions for recording of basal body temperature and timing of intercourse, when recommended by physician


Side/adverse effects
Signs of potential side effects, especially ovarian cysts, enlargement, or hyperstimulation syndrome


General Dosing Information
Patients receiving urofollitropin should be under the supervision of a physician experienced in the treatment of gynecologic or endocrine disorders. {04}

Dosage varies considerably and must be adjusted to meet the individual requirements of each patient, on the basis of clinical response {23} {32}.

Conception should be attempted within 48 hours of administration of hCG {30} {48}. It is recommended that the couple have intercourse or insemination be performed daily beginning the day after hCG is administered, until ovulation is thought to have occurred. {20} {48}

If ovulation does not occur after any cycle of therapy, the therapeutic regimen employed should be re-evaluated {07} {42} {46}. After 3 to 6 cycles of non-ovulatory menses, the appropriateness of continuing the use of urofollitropin for ovulation induction should be reconsidered. {07} {27} {42} {46}

For treatment of adverse effects
Ovarian enlargement or ovarian cyst formation

   • Discontinuing therapy until ovarian size has returned to baseline. {04} Human chorionic gonadotropin should also be withheld for that cycle {51}.
   • Prohibiting intercourse until ovarian size has returned to baseline to prevent cyst rupture. {04}
   • Reducing dosage in next course of therapy. {04}


Ovarian hyperstimulation syndrome (OHS):


Acute phase—
   • Discontinuing therapy. {04}
   • Prohibiting intercourse until ovarian size has returned to baseline to prevent cyst rupture. {04} {16}
   • Most cases of OHS will spontaneously resolve when menses begins. {04} In selected cases, hospitalization of the patient and bed rest may be necessary {51}.
   • Utilizing therapy to prevent hemoconcentration and minimize risk of thromboembolism and renal injury. {43}
   • Correcting (cautiously) electrolyte imbalance while maintaining acceptable intravascular volume {04}; in the acute phase, intravascular volume deficit cannot be completely corrected without increasing third space fluid volume. {04}
   • Monitoring fluid intake and output, body weight, hematocrit, serum and urine electrolytes, urine specific gravity, blood urea nitrogen (BUN), creatinine, and abdominal girth daily or as often as required. {04} {43} {51}
   • Monitoring serum potassium concentrations for development of hyperkalemia. {04}
   • Limiting performance of pelvic examinations since they may result in rupture of ovarian cysts and hemoperitoneum. {04} {07} {51}
   • Administering intravenous fluids, electrolytes, and human serum albumin as needed to maintain adequate urine output and to avoid hemoconcentration. {04} {51}
   • Administering analgesics as needed. {04}
   • Avoiding diuretic use since it reduces intravascular volume further. {04}
   • Removing ascitic, pleural, or pericardial fluid only if it is imperative for relief of symptoms such as respiratory distress or cardiac tamponade; to do so may increase risk of injury to the ovary. {04}
   • In patients who require surgery to control bleeding from ovarian cyst rupture, employing surgical measures that also maximally conserve ovarian tissue. {04}



Intermediate phase—
   • Once patient is stabilized, minimizing third spacing of fluids by cautiously replacing potassium, sodium, and fluids as required, based on monitoring of serum electrolyte concentrations. {04} {51}
   • Avoiding diuretic use. {04}



Resolution phase—
   • The third space fluid shifts to intravascular compartment, resulting in decreased hematocrit value and increased urinary output. {04}
   • Peripheral and/or pulmonary edema may result if third space fluid volume mobilized exceeds renal output. {04}
   • Administering diuretics when required, to manage pulmonary edema. {04}




Parenteral Dosage Forms

UROFOLLITROPIN FOR INJECTION

Note: According to the manufacturer, the purified product will replace this formulation of urofollitropin in 1997.


Usual adult dose
Infertility, female
Intramuscular, 75 Units once a day, usually for seven or more days, followed by 5000 to 10,000 Units of human chorionic gonadotropin (hCG) one day after the last dose of urofollitropin {20} {37} {44} {46} {51}. If necessary, the dosage may then be increased to 150 Units once a day, usually for seven or more days. {20} {51}

Reproductive technologies, assisted1
Intramuscular, 150 Units once a day, beginning in the early follicular phase (cycle Day 2 or 3), until sufficient follicular development occurs, followed by 5000 to 10,000 Units of hCG one day after the last dose of urofollitropin {07} {29} {32} {47}.


Note: Dosage regimen may vary according to physician preference or patient response {07} {10} {23} {51}.
If the ovaries are abnormally enlarged or if serum estradiol concentrations are excessively elevated on the last day of urofollitropin therapy, human chorionic gonadotropin should not be given for that cycle. {04} {20} {23} {42} {44}


Size(s) usually available:
U.S.—


75 Units (Rx) [Metrodin{04}{22}]


150 Units (Rx) [Metrodin{04}{22}]

Canada—


75 Units (Rx) [Metrodin{20}]


150 Units (Rx) [Metrodin{04}{22}]

Packaging and storage:
Store between 3 and 25 °C (37 and 77 °F), unless otherwise specified by manufacturer. Protect from light.

Preparation of dosage form:
Using standard aseptic technique, reconstitute by adding 1 to 2 mL of Sodium Chloride Injection USP to the contents of 1 ampul of Urofollitropin for Injection.

Stability:
Use immediately after reconstitution; discard any unused portion.


UROFOLLITROPIN FOR INJECTION (Purified)

Usual adult dose
Infertility, female
Subcutaneous, 75 Units once a day, usually for seven or more days, followed by 5000 to 10,000 Units of human chorionic gonadotropin (hCG) one day after the last dose of urofollitropin {20} {37} {44} {46} {51}. If necessary, the dosage may then be increased to 150 Units once a day, usually for seven or more days. {20} {51}
Reproductive technologies, assisted1
Subcutaneous, 150 Units once a day, beginning in the early follicular phase (cycle Day 2 or 3), until sufficient follicular development occurs, followed by 5000 to 10,000 Units of hCG one day after the last dose of urofollitropin {07} {29} {32} {47}.


Note: Dosage regimen may vary according to physician preference or patient response {07} {10} {23} {51}.
If the ovaries are abnormally enlarged or if serum estradiol concentrations are excessively elevated on the last day of urofollitropin therapy, human chorionic gonadotropin should not be given for that cycle {04} {20} {23} {42} {44}.
Canadian labeling states that purified urofollitropin for injection can be given subcutaneously or intramuscularly {02}; the subcutaneous route is less painful to the patient.



Size(s) usually available:
U.S.—


75 Units (Rx) [Fertinex{01}]


150 Units (Rx) [Fertinex{01}]

Canada—


75 Units (Rx) [Fertinorm HP{02}]


150 Units (Rx) [Fertinorm HP{02}]

Packaging and storage:
Store between 3 and 25 °C (37 and 77 °F), unless otherwise specified by manufacturer. Protect from light.

Preparation of dosage form:
Using standard aseptic technique, reconstitute by adding 0.5 to 1 mL of Sodium Chloride Injection USP to the contents of 1 or more ampules. Do not exceed a strength of 225 Units urofollitropin per 0.5 mL {01}.

Stability:
Use immediately after reconstitution; discard any unused portion {01} {02}.



Revised: 08/07/1997



References
  1. Fertinex package insert (Serono—US), Rev 2/96, Rec 6/97.
  1. Fertinorm HP product monograph (Serono—Canada), Rev 95, Rec 6/97.
  1. Fleeger CA, editor. USP dictionary of USAN and international drug names 1997. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1996. p. 752.
  1. Metrodin package insert (Serono—US), Rev 5/88, Rec 7/88.
  1. FDA Drug and Device Product Approvals. Vol. 11(3). March 1988. NDA No. 19-415/Date 3/1/88.
  1. Panel comments, 7/21/87.
  1. Panel comment, 10/88.
  1. Panel comment, 10/88.
  1. Panel comment, 10/88.
  1. Panel comment, 10/88.
  1. Panel comment, 10/88.
  1. Panel comment, 10/88.
  1. Panel comment, 10/88.
  1. Panel comment, 10/88.
  1. Panel comment, 10/88.
  1. Panel comment, 10/88.
  1. Panel comments, 10/88.
  1. Panel comments, 3/12/90 and 4/16/90, respectively.
  1. Panel comment, 4/16/90.
  1. Metrodin product labeling (Pharmascience), Rev 1988. In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 25th ed. Ottawa: Canadian Pharmaceutical Association, 1990: 628-9.
  1. Florida Dept. of Professional Regulation. Board of Pharmacy Newsletter 1988 Feb; 6(1): 1, 5.
  1. Metrodin package insert (Serono—US), Rev 1/89, Rec 10/25/90.
  1. American Fertility Society. Ovulation drugs: a guide for patients. Birmingham, AL: Author, 1990.
  1. Shoham Z, Zosmer A, Insler V. Early miscarriage and fetal malformations after induction of ovulation (by clomiphene citrate and/or human menotropins), in vitro fertilization, and gamete intrafallopian transfer. Fertil Steril 1991; 55(1): 1-11.
  1. Collins MS, Bleyl JA. Seventy-one quadruplet pregnancies: management and outcome. Am J Obstet Gynecol 1990; 162(6): 1384-92.
  1. Steer C, Campbell S, Davies M, Mason B, Collins W. Spontaneous abortion rates after natural and assisted conception. Br Med J 1989; 299: 1317-8.
  1. Seibel MM, Ranous C, Kearnan M. In vitro fertilization: how much is enough? [letter]. N Engl J Med 1989; 321(15): 1052-3.
  1. MRC Working Party on Children Conceived by In Vitro Fertilization. Births in Great Britain resulting from assisted conception, 1978-1987. Br Med J 1990; 300: 1229-33.
  1. Seibel MM. A new era in reproductive technology: in vitro fertilization, gamete intrafallopian transfer, and donated gametes and embryos. N Engl J Med 1988; 318(13): 828-34.
  1. American College of Obstetricians and Gynecologists. Technical bulletin #120: medical induction of ovulation. Wash., D.C.: Author, Sep. 1988.
  1. Hill GA, Bryan S, Herbert III CM, Shah DM, Colston Wentz A. Complications of pregnancy in infertile couples: routine treatment versus assisted reproduction. Obstet Gynecol 1990; 161(2): 381-2.
  1. Benadiva CA, Ben-Rafael Z, Strauss III JF, Mastroianni L, Flickinger GL. Ovarian responses of individuals to different doses of human menopausal gonadotropins. Fertil Steril 1988; 49(6): 997-1001.
  1. Kingsland CR, Collins JV, Rizk B, Mason BA. Ovarian hyperstimulation presenting as acute hydrothorax after in vitro fertilization. Am J Obstet Gynecol 1989; 161(2): 381-2.
  1. American Fertility Society. Investigation of the infertile couple. Birmingham, AL: Author, 1986.
  1. American Fertility Society. IVF & GIFT: a patient's guide to assisted reproductive technology. Birmingham, AL: Author, 1989.
  1. Medical Research Laboratories, Society for Assisted Reproductive Technology, and The American Fertility Society. In vitro fertilization-embryo transfer (IVF-ET) in the United States: 1989 results from the IVF-ET Registry. Fertil Steril 1991; 55(1): 14-23.
  1. Sagle MA, Hamilton-Fairley D, Kiddy DS, Franks S. A comparative, randomized study of low-dose human menopausal gonadotropin and follicle-stimulating hormone in women with polycystic ovarian syndrome. Fertil Steril 1991; 55(1): 56-60.
  1. Blankstein J, Quigley MM. Induction of ovulation in the patient with polycystic ovarian disease. Endocrinol Metab Clin North Am 1988; 17(4): 733-49.
  1. Hodgen GD. Neuroendocrinology of the normal menstrual cycle. J Reprod Med 1989; 34(1 Supp): 68-75.
  1. Dodson WC. Role of gonadotropin releasing hormone agonists in ovulation induction. J Reprod Med 1989; 34(1 Supp): 76-80.
  1. Blackwell RE. The infertility workup and diagnosis. J Reprod Med 1989; 34(1 Supp): 81-5.
  1. Bonaventura LM. Practice management for ovulation induction. J Reprod Med 1989; 34(1 Supp): 86-9.
  1. Goldfarb AF (moderator). Panel discussion. J Reprod Med 1989; 34(1 Supp): 90-4.
  1. Caldwell BV. Monitoring gonadotropin therapy. J Reprod Med 1989; 34(1 Supp): 95-9.
  1. March CM. Experience with ultrasound. J Reprod Med 1989; 34(1 Supp): 100-3.
  1. Marut EL. The polycystic ovary syndrome. J Reprod Med 1989; 34(1 Supp): 104-7.
  1. Scott RT, Rosenwaks Z. Ovulation induction for assisted reproduction. J Reprod Med 1989; 34(1 Supp): 108-14.
  1. Panel consensus, 11/18/91.
  1. Panel consensus, 11/18/91.
  1. Panel consensus, 11/18/91.
  1. Panel consensus, 2/20/92.
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