Follitropin alfa

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# Overview
Follitropin alfa is an endocrine-metabolic agent that is FDA approved for the treatment of female infertility, Ovulation induction.   Common adverse reactions include abdominal pain, nausea, headache,cyst of ovary.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

# Indications
- Follitropin alfa (follitropin alfa for injection) is indicated for the induction of ovulation and pregnancy in the oligo-anovulatory infertile patient in whom the cause of infertility is functional and not due to primary ovarian failure. Follitropin alfa is also indicated for the development of multiple follicles in the ovulatory patient participating in an Assisted Reproductive Technology (ART) program.

# Selection of Patients
- Before treatment with follitropin alfa is instituted, a thorough gynecologic and endocrinologic evaluation must be performed. This should include an assessment of pelvic anatomy. Patients with tubal obstruction should receive follitropin alfa only if enrolled in an in vitro fertilization program.
- Primary ovarian failure should be excluded by the determination of gonadotropin levels.
- Appropriate evaluation should be performed to exclude pregnancy.
- Patients in later reproductive life have a greater predisposition to endometrial carcinoma as well as a higher incidence of anovulatory disorders. A thorough diagnostic evaluation should always be performed in patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities before starting follitropin alfa therapy.
- Evaluation of the partner's fertility potential should be included in the initial evaluation.

# Dosage
Infertile Patients with oligo-anovulation
- The dose of follitropin alfa (follitropin alfa for injection) to stimulate development of the follicle must be individualized for each patient.
- The lowest dose consistent with the expectation of good results should be used. Over the course of treatment, doses of follitropin alfa may range up to 300 IU per day depending on the individual patient response. Follitropin alfa should be administered until adequate follicular development is indicated by serum estradiol and vaginal ultrasonography. A response is generally evident after 5 to 7 days. Subsequent monitoring intervals should be based on individual patient response.
- It is recommended that the initial dose of the first cycle be 75 IU of follitropin alfa per day, administered subcutaneously. An incremental adjustment in dose of up to 37.5 IU may be considered after 14 days. Further dose increases of the same magnitude could be made, if necessary, every seven days. Treatment duration should not exceed 35 days unless an E2 rise indicates imminent follicular development. To complete follicular development and effect ovulation in the absence of an endogenous LH surge, chorionic gonadotropin, hCG, should be given after the last dose of follitropin alfa. Chorionic gonadotropin should be withheld if the serum estradiol is greater than 2,000 pg/mL. If the ovaries are abnormally enlarged or abdominal pain occurs, follitropin alfa treatment should be discontinued, hCG should not be administered, and the patient should be advised not to have intercourse; this may reduce the chance of development of the ovarian hyperstimulation syndrome and, should spontaneous ovulation occur, reduce the chance of multiple gestation. A follow-up visit should be conducted in the luteal phase.
- The initial dose administered in the subsequent cycles should be individualized for each patient based on her response in the preceding cycle. Doses larger than 300 IU of FSH per day are not routinely recommended. As in the initial cycle, hCG must be given after the last dose of follitropin alfa to complete follicular development and induce ovulation. The precautions described above should be followed to minimize the chance of development of the ovarian hyperstimulation syndrome.
- The couple should be encouraged to have intercourse daily, beginning on the day prior to the administration of hCG until ovulation becomes apparent from the indices employed for the determination of progestational activity. Care should be taken to ensure insemination. In light of the indices and parameters mentioned, it should become obvious that, unless a physician is willing to devote considerable time to these patients and be familiar with and conduct the necessary laboratory studies, he/she should not use follitropin alfa.
Assisted Reproductive Technologies
- As in the treatment of patients with oligo-anovulatory infertility, the dose of follitropin alfa to stimulate development of the follicle must be individualized for each patient. For Assisted Reproductive Technologies, therapy with follitropin alfa should be initiated in the early follicular phase (cycle day 2 or 3) at a dose of 150 IU per day, until sufficient follicular development is attained. In most cases, therapy should not exceed ten days. In patients undergoing ART under 35 years old, whose endogenous gonadotropin levels are suppressed, follitropin alfa should be initiated at a dose of 150 IU per day. In patients 35 years old and older whose endogenous gonadotropin levels are suppressed, follitropin alfa should be initiated at a dose of 225 IU per day. Treatment should be continued until adequate follicular development is indicated as determined by ultrasound in combination with measurement of serum estradiol levels. Adjustments to dose may be considered after five days based on the patient's response; subsequently dosage should be adjusted no more frequently than every 3-5 days and by no more than 75-150 IU additionally at each adjustment. Doses greater than 450 IU per day are not recommended. Once adequate follicular development is evident, hCG should be administered to induce final follicular maturation in preparation for oocyte retrieval. The administration of hCG must be withheld in cases where the ovaries are abnormally enlarged on the last day of therapy. This should reduce the chance of developing OHSS.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Follitropin alfa in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Follitropin alfa in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Follitropin alfa in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Follitropin alfa in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Follitropin alfa in pediatric patients.

# Contraindications
- Follitropin alfa (follitropin alfa for injection) is contraindicated in women who exhibit:
- Prior hypersensitivity to recombinant FSH preparations or one of their excipients.
- High levels of FSH indicating primary gonadal failure.
- Uncontrolled thyroid or adrenal dysfunction.
- Sex hormone dependent tumors of the reproductive tract and accessory organs.
- An organic intracranial lesion such as a pituitary tumor.
- Abnormal uterine bleeding of undetermined origin.
- Ovarian cyst or enlargement of undetermined origin.
- Pregnancy.

# Warnings
- Follitropin alfa (follitropin alfa for injection) should only be used by physicians who are thoroughly familiar with infertility problems and their management. Follitropin alfa is a potent gonadotropic substance capable of causing ovarian hyperstimulation syndrome (OHSS) in women with or without pulmonary or vascular complications. Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, and requires the availability of appropriate monitoring facilities. Safe and effective use of follitropin alfa in women requires monitoring of ovarian response with serum estradiol and vaginal ultrasound on a regular basis. The lowest effective dose should be used.

# Overstimulation of the Ovary During FSH Therapy
Ovarian Enlargement
- Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distention and/ or abdominal pain occurs in approximately 20% of those treated with urofollitropin and hCG, and generally regresses without treatment within two or three weeks. Careful monitoring of ovarian response can further minimize the risk of overstimulation.
- If the ovaries are abnormally enlarged on the last day of follitropin alfa therapy, hCG should not be administered in this course of therapy. This will reduce the chances of development of ovarian hyperstimulation syndrome.
Ovarian Hyperstimulation Syndrome (OHSS)
- OHSS is a medical event distinct from uncomplicated ovarian enlargement. Severe OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event. It is characterized by an apparent dramatic increase in vascular permeability which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium. The early warning signs of development of OHSS are severe pelvic pain, nausea, vomiting, and weight gain. The following symptomatology has been seen with cases of OHSS: abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea]], severe ovarian enlargement, weight gain, dyspnea, and oliguria. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events. Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with Ovarian Hyperstimulation Syndrome (OHSS).
- OHSS occurred in 6 of 83 (7.2%) follitropin alfa treated women in Study 22240 (ovulation induction); none were classified as severe. In Study 21884 (ART), OHSS occurred in 11 of 237 (4.6%) follitropin alfa treated women and 1 (0.42%) was classified as severe. OHSS may be more severe and more protracted if pregnancy occurs. OHSS develops rapidly; therefore, patients should be followed for at least two weeks after hCG administration. Most often, OHSS occurs after treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be developing prior to hCG administration.
- If severe OHSS occurs, treatment must be stopped and the patient should be hospitalized. A physician experienced in the management of this syndrome, or who is experienced in the management of fluid and electrolyte imbalances should be consulted.
Pulmonary and Vascular Complications
- Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome and exacerbation of asthma) have been reported. In addition, thromboembolic events both in association with, and separate from Ovarian hyperstimulation syndrome have been reported.
- Intravascular thrombosis and embolism can result in reduced blood flow to critical organs or the extremities. Sequelae of such events have included venous thrombophlebitis, 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 death.
Multiple Births
- Reports of multiple births have been associated with follitropin alfa treatment. In Study 22240 for women receiving follitropin alfa over three treatment cycles, 20% of live births were multiple births. In Study 21884, 35.1% of live births were multiple births in women receiving follitropin alfa. The rate of multiple births is dependent on the number of embryos transferred. The patient should be advised of the potential risk of multiple births before starting treatment.

# Adverse Reactions

## Clinical Trials Experience
- The safety of follitropin alfa was examined in two clinical studies .
- Adverse events (without regard to causality assessment) occurring in at least 2.0% of patients in Study 22240 (ovulation induction) are listed in Table 4.
- Headache occurred in greater than 20% of patients receiving follitropin alfa in this study.
- Adverse events (without regard to causality assessment) occurring in at least 2.0% of patients in Study 21884 (ART) are listed in Table 5.
- Headache and abdomen enlargement occurred in more than 10% of patients and abdominal pain occurred in more than 20% of patients.
- The following medical events have been reported subsequent to pregnancies resulting from Gonadotropins in controlled clinical studies:
- Spontaneous Abortion
- Ectopic Pregnancy
- Premature Labor
- Postpartum Fever
- Congenital Abnormalities
- There are no indications that use of gonadotropins during ART is associated with an increased risk of congenital malformations.
- The following adverse reactions have been previously reported during follitropin alfa therapy:
- Pulmonary and vascular complications
- Adnexal torsion (as a complication of ovarian enlargement),
- Mild to moderate ovarian enlargement,
- Hemoperitoneum
- There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for ovulation induction; however, a causal relationship has not been established.

## Postmarketing Experience
- In addition to adverse events reported from clinical trials, the following events have been reported during postmarketing use of follitropin alfa. Because these reactions were reported voluntarily from a population of uncertain size, the frequency or a causal relationship to follitropin alfa can not be reliably determined.
- Body as a Whole - General: Hypersensitivity reactions including anaphylactoid reactions.
- Respiratory System: asthma

# Drug Interactions
There is limited information regarding Follitropin alfa Drug Interactions in the drug label.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Follitropin alfa in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Follitropin alfa during labor and delivery.

### Nursing Mothers
There is no FDA guidance on the use of Follitropin alfa with respect to nursing mothers.

### Pediatric Use
There is no FDA guidance on the use of Follitropin alfa with respect to pediatric patients.

### Geriatic Use
There is no FDA guidance on the use of Follitropin alfa with respect to geriatric patients.

### Gender
There is no FDA guidance on the use of Follitropin alfa with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Follitropin alfa with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Follitropin alfa in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Follitropin alfa in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Follitropin alfa in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Follitropin alfa in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Subcutaneously
- Dissolve the contents of one or more single-dose vials of follitropin alfa in 1.0 mL of Sterile Water for Injection, USP (concentration should not exceed 450 IU/mL) and administer subutaneously immediately. Any unused reconstituted material should be discarded.

### Monitoring
There is limited information regarding Monitoring of Follitropin alfa in the drug label.
- Description

# IV Compatibility
There is limited information regarding IV Compatibility of Follitropin alfa in the drug label.

# Overdosage
- Aside from possible ovarian hyperstimulation and multiple gestations, there is no information on the consequences of acute overdosage with follitropin alfa (follitropin alfa for injection).

# Pharmacology

## Mechanism of Action
There is limited information regarding Follitropin alfa Mechanism of Action in the drug label.

## Structure
- Follitropin alfa (follitropin alfa for injection) is a human follicle stimulating hormone (FSH) preparation of recombinant DNA origin, which consists of two non-covalently linked, non-identical glycoproteins designated as the - and -subunits. The - and -subunits have 92 and 111 amino acids, respectively, and their primary and tertiary structure are indistinguishable from those of human follicle stimulating hormone. Recombinant FSH production occurs in genetically modified Chinese Hamster Ovary (CHO) cells cultured in bioreactors. Purification by immunochromatography using an antibody specifically binding FSH results in a highly purified preparation with a consistent FSH isoform profile, and a high specific activity. The biological activity of follitropin alfa is determined by measuring the increase in ovary weight in female rats. The in vivo biological activity of follitropin alfa has been calibrated against the first International Standard for recombinant human follicle stimulating hormone established in 1995 by the Expert Committee on Biological Standards of the World Health Organization. Follitropin alfa contains no luteinizing hormone (LH) activity. Based on available data derived from physico-chemical tests and bioassays, follitropin alfa and follitropin beta, another recombinant follicle stimulating hormone product, are indistinguishable.
- Follitropin alfa is a sterile, lyophilized powder intended for subcutaneous injection after reconstitution.
- Each follitropin alfa single-dose vial is filled with 82 IU (6 g) follitropin alfa to deliver 75 IU (5.5 g) and contains 30 mg sucrose, 1.11 mg dibasic sodium phosphate dihydrate, 0.45 mg monobasic sodium phosphate monohydrate, 0.1 mg methionine, and 0.05 mg polysorbate 20. Phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for pH adjustment. Vials are reconstituted with Sterile Water for Injection, USP.
- Under current storage conditions, follitropin alfa may contain up to 10% of oxidized follitropin alfa.
- Therapeutic Class: Infertility

## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Follitropin alfa in the drug label.

## Pharmacokinetics
- Single-dose pharmacokinetics of follitropin alfa were determined following subcutaneous administration of 300 IU follitropin alfa to 21 pre-menopausal healthy female volunteers who were pituitary down-regulated with a GnRH agonist.
- The descriptive statistics for the pharmacokinetic parameters are presented in Table 1.
Absorption
- The absorption rate of follitropin alfa following subcutaneous administration is slower than the elimination rate. Hence, the pharmacokinetics of follitropin alfa are absorption rate-limited.
Distribution
- Human tissue or organ distribution of FSH has not been determined for follitropin alfa.
Metabolism/Excretion
- FSH metabolism and excretion following administration of follitropin alfa have not been studied in humans.
Special populations
- Safety, efficacy, and pharmacokinetics of follitropin alfa in patients with renal or hepatic insufficiency have not been established.
Drug-Drug Interactions
- No drug-drug interaction studies have been conducted

## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Follitropin alfa in the drug label.

# Clinical Studies
- The safety and efficacy of follitropin alfa have been examined in two clinical studies: one study (Study 22240) for ovulation induction and one study (Study 21884) for assisted reproductive technologies (ART).
Ovulation Induction (OI)
- Study 22240 was a phase III, assessor-blind, randomized, comparative, multinational, multicenter study in oligo-anovulatory infertile women undergoing ovulation induction. Patients were randomized to either follitropin alfa (n=83), administered subcutaneously, or a comparator recombinant human FSH. The use of insulin-sensitizing agents was allowed during the study. Efficacy was assessed using the mean ovulation rate in the first cycle of treatment. The cycle 1 ovulation rate (primary outcome) for follitropin alfa is presented in Table 2. Additionally, this table includes cumulative secondary outcome results from cycle 1 through 3. Study 22240 was not powered to demonstrate differences in these secondary outcomes.
Assisted Reproductive Technologies (ART)
- Study 21884 was a phase III, assessor-blind, randomized, comparative, multinational, multicenter study in ovulatory, infertile women undergoing stimulation of multiple follicles for Assisted Reproductive Technologies (ART) after pituitary down-regulation with a GnRH agonist. Patients were randomized to either follitropin alfa (n=237), administered subcutaneously, or a comparator recombinant human FSH. Randomization was stratified by insemination technique . Efficacy was assessed using the mean number of fertilized oocytes the day after insemination. The initial doses of follitropin alfa were 150 IU a day for patients < 35 years old and 225 IU for patients  35 years old. The maximal dose allowed for both age groups was 450 IU per day. Treatment outcomes for follitropin alfa are summarized in Table 3.

# How Supplied
- Follitropin alfa (follitropin alfa for injection) is supplied in a sterile, lyophilized form in single-dose vials containing 82 IU with diluent (Sterile Water for Injection, USP) in a pre-filled syringe. Following reconstitution with the diluent as described, upon administration each vial will deliver a dose of 75 IU.
- Lyophilized vials may be stored refrigerated or at room temperature (2- 25C/36-77F). Protect from light. Use immediately after reconstitution. Discard unused material.
- Sterile Water for Injection, USP is provided in a pre-filled syringe. Separate needles are provided for reconstitution (18 G) and administration (29 G).
- Note: No antimicrobial or other substance has been added to the Sterile Water for Injection for the single-dose vials. Sterile Water for Injection is not suitable for intravascular injection without its first having been made approximately isotonic by the addition of a suitable solute.
- The following package combinations are available:
- 1 vial follitropin alfa 75 IU and 1 pre-filled syringe Sterile Water for Injection, USP, 1 mL, 1 reconstitution needle (18 gauge), 1 administration needle (29 gauge), NDC 44087-9005-1 10 vials follitropin alfa 75 IU and 10 pre-filled syringes Sterile Water for Injection, USP, 1 mL, 10 reconstitution needles (18 gauge), 10 administration needles (29 gauge), NDC 44087-9005-6

## Storage
There is limited information regarding Follitropin alfa Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Follitropin alfa in the drug label.

# Precautions with Alcohol
- Alcohol-Follitropin alfa interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- GONAL-F RFF 

# Look-Alike Drug Names
There is limited information regarding Follitropin alfa Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price