Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution Reconstituted, Injection:
Bravelle: 75 units (1 ea [DSC])
Pharmacology
Mechanism of Action
Urofollitropin is a preparation of highly purified follicle-stimulating hormone (FSH) extracted from the urine of postmenopausal women. Follitropins stimulate ovarian follicular growth in women who do not have primary ovarian failure. FSH is required for normal follicular growth, maturation, gonadal steroid production, and spermatogenesis.
Pharmacokinetics/Pharmacodynamics
Time to Peak
IM: 17 hours (single dose), 11 hours (multiple doses)
SubQ: 21 hours (single dose), 10 hours (multiple doses)
Half-Life Elimination
IM: 37 hours (single dose), 15 hours (multiple doses)
SubQ: 32 hours (single dose), 21 hours (multiple doses)
Use: Labeled Indications
Multifollicular development during Assisted Reproductive Technologies: Development of multiple follicles with Assisted Reproductive Technologies (ART) in women who have previously received pituitary suppression.
Limitations of use: Prior to therapy, perform a complete gynecologic exam and endocrinologic evaluation and diagnose cause of fertility; exclude the possibility of pregnancy; evaluate the fertility status of the male partner; exclude women with primary ovarian failure
Ovulation induction: Ovulation induction in women who previously received GnRH agonist or antagonist for pituitary suppression.
Limitations of use: Prior to therapy, perform a complete gynecologic exam (including demonstration of tubal patency) and endocrinologic evaluation; exclude the possibility of pregnancy; evaluate the fertility status of the male partner; exclude a diagnosis of primary ovarian failure
Contraindications
Hypersensitivity to follitropins or any component of the formulation; high levels of FSH indicating primary ovarian failure; uncontrolled nongonadal endocrinopathies (eg, thyroid, adrenal, or pituitary disorders); sex hormone-dependent tumors of the reproductive tract and accessory organ; tumors of pituitary gland or hypothalamus; abnormal uterine bleeding of undetermined origin; ovarian cysts or enlargement not due to polycystic ovary syndrome; pregnancy
Dosage and Administration
Dosing: Adult
Note: Dose should be individualized. Use the lowest dose consistent with the expectation of good results. Over the course of treatment, doses may vary depending on individual patient response.
Assisted reproductive technologies (ART): Adults: Females: SubQ: Starting on day 2 or 3 of cycle, administer 225 units once daily for the first 5 days; urofollitropin may be administered together with menotropins and the total initial dose of both products combined should not exceed 225 units (menotropins 150 units and urofollitropin 75 units; or menotropins 75 units and urofollitropin 150 units). Adjust dose after 5 days based on ultrasound monitoring of ovarian response and measurement of serum estradiol levels. Do not make additional adjustments more frequently than once every 2 days or by >75 to 150 units. Maximum daily dose: 450 units (of urofollitropin, or menotropins plus urofollitropin); treatment >12 days is not recommended; once adequate follicular development is evident, hCG should be administered. Withhold the hCG dose if ovarian monitoring suggests an increased risk of OHSS.
Ovulation induction: Adults: Females: IM, SubQ: Initial: 150 units once daily for 5 days in the first cycle of treatment. After 5 days, dose adjustments up to 75 to 150 units can be made every ≥2 days based on ultrasound monitoring of ovarian response and/or measurement of serum estradiol levels; maximum daily dose: 450 units; treatment >12 days is not recommended. If response to follitropin is appropriate, administer hCG; withhold the hCG dose if ovarian monitoring suggests an increased risk of OHSS and advise the patient to refrain from intercourse. For subsequent cycles, the starting dose and dosage adjustments should be determined based on historical ovarian response.
Reconstitution
Dissolve contents of vial in sodium chloride 0.9% 1 mL (provided); gently swirl (do not shake). Do not use if solution is not clear or contains particles. If more than 1 vial is required for a single dose, up to 6 vials can be reconstituted with sodium chloride 0.9% 1 mL and administered as a single injection. This is done by first reconstituting 1 vial with sodium chloride 0.9% as previously described, withdrawing the entire contents of the reconstituted vial, and (using this as the diluent for the second vial) injecting into the second vial, etc. Use immediately after reconstitution. May mix with Menopur (menotropins for injection).
Administration
Administer IM or SubQ.
IM administration should be given by a health care provider.
SubQ: Administer to alternating sites on lower abdomen.
Storage
Lyophilized powder may be stored in the refrigerator or at room temperature of 3°C to 25°C (37°F to 77°F). Protect from light. Discard unused portion.
Drug Interactions
There are no known significant interactions.
Adverse Reactions
Percentage may vary by indication or route of administration.
>10%:
Central nervous system: Headache
Endocrine & metabolic: Ovarian hyperstimulation syndrome, ovary enlargement
Gastrointestinal: Abdominal cramps
1% to 10%:
Cardiovascular: Hypertension
Central nervous system: Depression, emotional lability, pain (including post-retrieval pain)
Dermatologic: Acne vulgaris, exfoliative dermatitis, skin rash
Endocrine & metabolic: Dehydration, hot flash, ovarian disease (cyst, pain), weight gain
Gastrointestinal: Abdominal pain, constipation, diarrhea, enlargement of abdomen, nausea, vomiting
Genitourinary: Breast tenderness, cervix disease, pelvic cramps, pelvic pain, spotting, urinary tract infection, uterine spasm, vaginal discharge, vaginal hemorrhage
Infection: Infection
Local: Injection site reaction
Neuromuscular & skeletal: Neck pain
Respiratory: Respiratory tract disease, sinusitis
Miscellaneous: Fever
Warnings/Precautions
Concerns related to adverse effects:
- Hypersensitivity: Hypersensitivity and anaphylactic reactions have been reported; discontinue use for serious reactions and treat appropriately.
- Ovarian enlargement: May be accompanied by abdominal distention and/or abdominal pain. If ovaries are abnormally enlarged on the last day of treatment, withhold hCG to reduce the risk of ovarian hyperstimulation syndrome (OHSS). Intercourse should be avoided with significant ovarian enlargement.
- Ovarian hyperstimulation syndrome: Ovarian hyperstimulation syndrome (OHSS) is a rare exaggerated response to ovulation induction therapy (Fiedler 2012; SOGC-CFAS 2011). This syndrome may begin within 24 hours of treatment but may become most severe 7 to 10 days after therapy (SOGC-CFAS 2011). Symptoms of mild/moderate OHSS may include abdominal distention/discomfort, diarrhea, nausea, and/or vomiting. Severe OHSS symptoms may include severe abdominal pain, anuria/oliguria, ascites, severe dyspnea, hypotension, or nausea/vomiting (intractable). Decreased creatinine clearance, hemoconcentration, hypoproteinemia, elevated liver enzymes, elevated WBC, and electrolyte imbalances may also be present (ASRM 2016; Fiedler 2012; SOGC-CFAS 2011). Treatment is primarily symptomatic and includes fluid and electrolyte management, analgesics, and prevention of thromboembolic complications (ASRM 2016; SOGC-CFAS 2011). Therapy with gonadotropins should be stopped.
- Ovarian neoplasms: Benign and malignant neoplasms have been reported (infrequently) in women receiving multiple-drug therapy for controlled ovarian stimulation; causal effect has not been established.
- Ovarian torsion: Has been reported following gonadotropin treatment; may be related to OHSS, prior ovarian torsion, prior or current ovarian cyst, polycystic ovaries, pregnancy, or prior abdominal surgery. Early diagnosis and prompt detorsion may limit the extent of ovarian damage.
- Pulmonary effects: Serious pulmonary conditions (atelectasis, acute respiratory distress syndrome, and exacerbation of asthma) have been reported.
- Thromboembolic events: In association with and separate from ovarian hyperstimulation syndrome (OHSS), thromboembolic events have been reported. Use caution in women with personal or family risk factors for thrombosis.
Disease-related concerns:
- Hepatic impairment: Use with caution in patients with hepatic impairment; safety and efficacy have not been established.
- Renal impairment: Use with caution in patients with renal impairment; safety and efficacy have not been established.
Other warnings/precautions:
- Appropriate use: To minimize risks, use only at the lowest effective dose. Monitor ovarian response with serum estradiol and vaginal ultrasound on a regular basis.
- Experienced physician: These medications should only be used by physicians who are thoroughly familiar with infertility problems and their management.
- Multiple births: May result from the use of these medications; advise patient of the potential risk of multifetal gestation and multiple births before starting the treatment.
Monitoring Parameters
Monitor sufficient follicular growth and maturation. This may be directly estimated by transvaginal sonographic visualization of the ovaries and endometrial lining. The combination of both ultrasonography and measurement of estradiol levels is useful for monitoring for the growth and development of follicles and timing hCG administration.
The clinical evaluation of estrogenic activity (changes in vaginal cytology and changes in appearance and volume of cervical mucus) provides an indirect estimate of the estrogenic effect upon the target organs and, therefore, it should only be used adjunctively with more direct estimates of follicular development (ultrasonography and serum estradiol determinations).
The clinical confirmation of ovulation is obtained by direct and indirect indices of progesterone production as well as sonographic evidence of ovulation. Direct or indirect indices of progesterone production most generally used are: rise in serum or urine LH, rise in basal body temperature, increase in serum progesterone, and menstruation following the shift in basal body temperature. Sonographic evidence of ovulation includes collapsed follicle, fluid in the cul-de-sac, features consistent with corpus luteum formation, and secretory endometrium.
Monitor for signs and symptoms of OHSS for at least 2 weeks following hCG administration.
OHSS: Monitoring of hospitalized patients should include abdominal circumference, albumin, cardiorespiratory status, electrolytes, fluid balance, hematocrit, hemoglobin, serum creatinine, urine output, urine specific gravity, vital signs, weight (all daily or as necessary) and liver enzymes (weekly) (SOGC-CFAS 2011).
Pregnancy
Pregnancy Risk Factor
X
Pregnancy Considerations
Ectopic pregnancy, congenital abnormalities, spontaneous abortion, and multi-fetal gestations/births have been reported. The incidence of congenital abnormality may be slightly higher after ART than with spontaneous conception; higher incidence may be related to parental characteristics (maternal age, genetics, sperm characteristics). Urofollitropin is used for the induction of ovulation and with ART; use is contraindicated in women who are already pregnant.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience injection site irritation, nausea, headache, abdominal pain, bloating, abdominal cramps, or hot flashes. Have patient report immediately to prescriber signs of ovarian hyperstimulation syndrome (severe abdominal pain or bloating; severe nausea, vomiting, or diarrhea; excessive weight gain; shortness of breath; or change in how much urine is passed), signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood), abnormal vaginal bleeding, or pelvic pain (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
