Urofollitropin

G03G - Gonadotropins and other ovulation stimulants ATC G03GA04 Unknown approved 1986 Parenteral

JFDA label: Bravelle

Mechanism of Action

Agonist of Follicle-stimulating hormone receptor — Follicle stimulating hormone receptor agonist

Target	Action	Gene / class
Follicle-stimulating hormone receptor efficacy	AGONIST	FSHR

Indications

Approved

Multifollicular development during ART
Ovulation induction

Contraindications

Source: Lexicomp

Hypersensitivity to follitropins or any component of the formulation Absolute
abnormal uterine bleeding of undetermined origin Absolute
high levels of FSH indicating primary ovarian failure Absolute
ovarian cysts or enlargement not due to polycystic ovary syndrome Absolute
sex hormone–dependent tumors of the reproductive tract and accessory organ Absolute
tumors of pituitary gland or hypothalamus Absolute
uncontrolled nongonadal endocrinopathies (eg, thyroid, adrenal, or pituitary disorders) Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (1)

Common Hypertension

Nervous system disorders (4)

Very Common Headache

Common Depression · emotional lability · pain (including post-retrieval pain)

Renal and urinary disorders (9)

Common Breast tenderness · cervix disease · pelvic cramps · pelvic pain · spotting · urinary tract infection · uterine spasm · vaginal discharge · vaginal hemorrhage

Metabolism and nutrition disorders (6)

Very Common Ovarian hyperstimulation syndrome · ovary enlargement

Common Dehydration · hot flash · ovarian disease (cyst, pain) · weight gain

Gastrointestinal disorders (7)

Very Common Abdominal cramps

Common Abdominal pain · constipation · diarrhea · enlargement of abdomen · nausea · vomiting

Skin and subcutaneous tissue disorders (3)

Common Acne vulgaris · exfoliative dermatitis · skin rash

Musculoskeletal and connective tissue disorders (1)

Common Neck pain

Infections and infestations (1)

Common Infection

General disorders and administration site conditions (2)

Common Fever · Injection site reaction

Respiratory, thoracic and mediastinal disorders (2)

Common Respiratory tract disease · sinusitis

Dosing

Source: Lexicomp

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 >75-150 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 75-150 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.

There are no dosage adjustments provided in manufacturer’s labeling (has not been studied).

Warnings & Precautions

Source: Lexicomp

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.

Pregnancy & Lactation

Pregnancy

FDA category X Contraindicated

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.

Lactation

It is not known if urofollitropin is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother.

Monitoring

Clinical pearl	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 b

Clinical pearl

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 b

Chemistry & Properties

Formula	C42H65N11O12S2
Molecular weight	980.2 g/mol
IUPAC name	(2R)-1-[(4S,7S,10S,16R,19S)-19-amino-7-(2-amino-2-oxoethyl)-13-[(2R)-butan-2-yl]-10-[(1S)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]-N-[(2R)-1-[(2-amino-2-oxoethyl)amino]-4-methyl-1-oxopentan-2-yl]pyrrolidine-2-carboxamide
CAS	97048-13-0
PubChem CID	73759969
InChIKey	`ZDRRIRUAESZNIH-JLSAMJFVSA-N`
logP	-1.5 (XLogP -1.5)
Polar surface area	427.0 Å²
H-bond acceptors / donors	15 / 12

SMILES

CCC(C)C1C(=O)NC(C(=O)NC(C(=O)NC(CSSCC(C(=O)NC(C(=O)N1)CC2=CC=C(C=C2)O)N)C(=O)N3CCCC3C(=O)NC(CC(C)C)C(=O)NCC(=O)N)CC(=O)N)C(C)O

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	1.988 h
Volume of distribution	0.33 L/kg
Protein binding	10.3%
BBB penetrant	No

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (1, DDInter)

Interacting drug	Severity	Management
Ganirelix	moderate

Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Bravelle	Tablet 75 IU	10 amp	Petra Drug Store	122.420