follitropin alfa (Rx)

Frequency Not Defined

GONAL-f

• Intermenstrual bleeding
• Ovarian hyperstimulation
• Abdominal pain
• Acne
• Flatulence
• Diarrhea
• Back pain
• Emotional lability

Gonal-f RFF Pen

• Diarrhea
• Dizziness
• OHSS (for ovulation induction)
• Flatulence
• Acne
• Toothache
• Intermenstrual bleeding
• Breast pain, Injection site reactions, Ovarian cyst, Nausea, Sinusitis

Postmarketing Reports

Asthma exacerbation

Thromboembolism

Contraindications

Prior hypersensitivity to recombinant FSH preparations

High levels of FSH indicating primary gonadal failure

Presence of uncontrolled non-gonadal endocrinopathies (thyroid, adrenal, or pituitary disorders)

Sex hormone-dependent tumors of the reproductive tract and accessory organs

Tumors of pituitary gland or hypothalamus

Gonal-F: Women with abnormal uterine bleeding of undetermined origin; ovarian cyst or enlargement of undetermined origin

Cautions

In the postmarketing experience, serious systemic hypersensitivity reactions, including anaphylaxis, reported with use and symptoms have included dyspnea, facial edema, pruritis, and urticaria; if an anaphylactic or other serious allergic reaction occurs, initiate appropriate therapy including supportive measures if cardiovascular instability and/or respiratory compromise occur, and discontinue further use

Ovarian torsion reported after treatment with gonadotropins, including this drug; this may be related to OHSS, pregnancy, previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst and polycystic ovaries; early diagnosis and immediate detorsion limit damage to ovary due to reduced blood supply

Multi-fetal gestation and births reported with all gonadotropin therapy, including therapy with this drug; during clinical trials multiple births occurred in 20% of live births in women receiving therapy for ovulation induction and 35.1% of live births in women undergoing ART; advise the woman and her partner of potential risk of multi-fetal gestation and birth before beginning therapy with this drug

Since infertile women undergoing ART often have tubal abnormalities, the incidence of ectopic pregnancy may be increased in women who become pregnant as result of ART; advise women who become pregnant following ART and have: abdominal/pelvic pain (particularly on one side); shoulder, neck or rectal pain; and nausea and vomiting to seek immediate medical attention; confirm presence of an intrauterine pregnancy early by β-hCG testing and transvaginal ultrasound

The risk of spontaneous abortion (miscarriage) is increased with gonadotropin products, including this drug; however, causality has not been established; the increased risk may be a factor of underlying infertility

There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have had multiple drug therapy for controlled ovarian stimulation, however, a causal relationship has not been established

Ovarian hyperstimulation syndrome (OHSS)

• This syndrome is a medical entity distinct from uncomplicated ovarian enlargement and may progress rapidly to become a serious medical event; OHSS is characterized by a dramatic increase in vascular permeability, which can result in rapid accumulation of fluid in peritoneal cavity, thorax, and potentially, the pericardium
• The early warning signs of development of OHSS are severe pelvic pain, nausea, vomiting, and weight gain; abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement weight gain, dyspnea, and oliguria have been reported with OHSS
• Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic reactions
• Transient liver function test abnormalities suggestive of hepatic dysfunction with or without morphologic changes on liver biopsy, reported in association with OHSS
• OHSS occurs after gonadotropin treatment discontinued and it can develop rapidly, reaching its maximum about seven to ten days following treatment
• Usually, OHSS resolves spontaneously with onset of menses; if there is evidence that OHSS may be developing prior to hCG administration withhold hCG; cases of OHSS are more common, more severe, and more protracted if pregnancy occurs; therefore, assess women for development of OHSS for at least two weeks after hCG administration
• If serious OHSS occurs, stop gonadotropins, including this medication and hCG, and consider whether the woman needs to be hospitalized; treatment is primarily symptomatic and overall consists of bed rest, fluid and electrolyte management, and analgesics (if needed); because the use of diuretics can accentuate the diminished intravascular volume, avoid diuretics exceptin the late phase of resolution as described below
• The management of OHSS is divided into three phases as follows:

• Acute phase:

  • Management is directed at preventing hemoconcentration due to loss of intravascular volume to third space and minimizing risk of thromboembolic phenomena and kidney damage
  • Thoroughly assess daily or more often, based on clinical need,fluid intake and output, weight, hematocrit, serum and urinary electrolytes, urine specific gravity, BUN and creatinine, total proteins with albumin: globulin ratio, coagulation studies, electrocardiogram to monitor for hyperkalemia, and abdominal girth
  • Treatment, consisting of limited intravenous fluids, electrolytes, human serum albumin, is intended to normalize electrolytes while maintaining an acceptable but somewhat reduced intravascular volume
  • Full correction of the intravascular volume deficit may lead to an unacceptable increase in the amount of third space fluid accumulation

• Chronic phase

  • After acute phase is successfully managed as above, excessive fluid accumulation in the third space should be limited by instituting severe potassium, sodium, and fluid restriction

• Resolution phase

  • As third space fluid returns to intravascular compartment, a fall in hematocrit and increasing urinary output are observed in absence of any increase in intake
  • Peripheral and/or pulmonary edema may result if the kidneys are unable to excrete third space fluid as rapidly as it is mobilized; diuretics may be indicated during resolution phase, if necessary, to combat pulmonary edema
  • Do not remove ascitic, pleural, and pericardial fluid, unless there is necessity to relieve symptoms such as pulmonary distress or cardiac tamponade
• OHSS increases risk of injury to ovary; avoid pelvic examination or intercourse, as these may cause rupture of an ovarian cyst, which may result in hemoperitoneum
• If bleeding occurs and requires surgical intervention, control the bleeding and retain as much ovarian tissue as possible; a physician experienced in management of this syndrome, or who is experienced in management of fluid and electrolyte imbalances should be consulted

Pulmonary vascular complications

• Serious pulmonary conditions (for example, atelectasis, acute respiratory distress syndrome, and exacerbation of asthma) reported in women treated with gonadotropins, including this medication
• In addition, thromboembolic events both in association with, and separate from OHSS reported in women treated with gonadotropins, including this medication
• Intravascular thrombosis and embolism, which may originate in venous or arterial vessels, can result in reduced blood flow to critical organs or extremities
• Women with generally recognized risk factors for thrombosis, such as personal or family history, severe obesity, or thrombophilia, may have an increased risk of venous or arterial thromboembolic events, during or following treatment with gonadotropins
• Sequelae of such reactions have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb and rarely in myocardial infarctions
• In rare cases, pulmonary complications and/or thromboembolic reactions have resulted in death. In women with recognized risk factors, the benefits of ovulation induction and assisted reproductive technology (ART) need to be weighed against risks; it should be noted that pregnancy also carries an increased risk of thrombosis

Abnormal ovarian enlargement

• In order to minimize hazards associated with abnormal ovarian enlargement that may occur with therapy, individualize treatment and use lowest effective dose; use of ultrasound monitoring of ovarian response and/or measurement of serum estradiol levels is important to minimize risk of ovarian stimulation
• If ovaries are abnormally enlarged on last day of therapy, do not administer hCG in order to reduce chance of developing OHSS; prohibit intercourse for women with significant ovarian enlargement after ovulation because of danger of hemoperitoneum resulting from rupture of ovarian cysts

Embryofetal toxicity

• .Incidence of congenital malformations after some ART, specifically in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), may be slightly higher than after spontaneous conception
• This slightly higher incidence is thought to be related to differences in parental characteristics (eg, maternal age, maternal and paternal genetic background, sperm characteristics) and to higher incidence of multi-fetal gestations after IVF or ICSI; there are no indications that the use of gonadotropins during IVF or ICSI is associated with an increased risk of congenital malformations.

Pregnancy

Drug not indicated in pregnant women

The incidence of congenital malformations after some assisted reproductive technology, specifically in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)], maybe slightly higher than that after spontaneous conception; this slightly higher incidence is thought to be related to differences in parental characteristics (eg, maternal age, maternal and paternal genetic background, sperm characteristics) and to a higher incidence of multi-fetal gestations after IVF or ICSI; there is no human data that the use of gonadotropins (including drug alone or as part of IVF or ICSI cycles, increases risk of congenital malformations

Risk of spontaneous abortion (miscarriage) is increased in women who have used gonadotropins products (including GONAL-F) to achieve pregnancy

Verify a negative pregnancy test before administering drug

Animal data

• In animal studies, the continuous administration of recombinant human FSH during pregnancy resulted in a decrease in number of viable fetuses and difficult and prolonged delivery; no teratogenic effect observed

Lactation

There are no data on presence of drug in human milk, effects on breastfed infant, or on milk production; because secretion of prolactin during lactation can result in inadequate response to ovarian stimulation, advise women not to breastfeed during treatment

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Recombinant follicle stimulating hormone (FSH); stimulate ovarian follicular growth in women who do not have primary ovarian failure;

Stimulates spermatogenesis in men with hypogonadotrophic hypogonadism

Pharmacokinetics

Onset: 2.7-18 months (spermatogenesis); within cycle (females)

Vd: 10 L

Bioavailability: 66-76% (healthy female volunteers)

Half-life: 50 hr (IM in healthy female volunteers); 24 hr (SC in healthy female volunteers)

Peak plasma time: 8-16 hr (SC in females); 25 hr (IM in females); 11-20 hr (IM in males)

SC Administration

Gonal-f RFF Pen is a SC self-injectable pen for women

Remove pen from refridgerator at least 30 min before injection to warm to room temperature

Inject SC in abdomen

Storage

Pharmacy: Store the Gonal-f RFF Redi-ject refrigerated 2-8°C (36-46°F) until dispensed

Upon dispensing, store refrigerated 2-8°C (36-46°F) until the expiration date, or at room temperature 20-25°C (68-77°F) for up to 3 months or until the expiration date, whichever occurs first

After the first injection, store refrigerated 2-8°C (36-46°F) or at room temperature 20-25°C (68-77°F) for up to 28 days

Protect from light

Do not freeze

Once opened or stored at room temperature, discard unused material after 28 days