Cinnal-f®


(follitropin alfa)

The Right Choice for Fertility


INDICATIONS AND USAGE

Women

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

Selection of Patients

  1. Before treatment with Cinnal-f 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 Cinnal-f only if enrolled in an in vitro fertilization program.

  2. Primary ovarian failure should be excluded by the determination of gonadotropin levels.

  3. Appropriate evaluation should be performed to exclude pregnancy.

  4. 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 Cinnal-f therapy.

  5. Evaluation of the partner's fertility potential should be included in the initial evaluation.

Men

Cinnal-f (follitropin alfa) is indicated for the induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism in whom the cause of infertility is not due to primary testicular failure.

Selection of Patients

  1. Before treatment with Cinnal-f is instituted for azoospermia, a thorough medical and endocrinologic evaluation must be performed.

  2. Hypogonadotropic hypogonadism should be confirmed, and primary testicular failure should be excluded by the determination of gonadotropin levels.

  3. Prior to Cinnal-f therapy for azoospermia in patients with hypogonadotropic hypogonadism, serum testosterone levels should be normalized.

DOSAGE AND ADMINISTRATION

One or more ampules of Cinnal-f® should be dissolved in one mL of Sterile Water for Injection, (concentration should not exceed 225 IU/0.5 mL) and administered subcutaneously immediately.

Dosage

Infertile Patients with oligo-anovulation

The dose of Cinnal-f (follitropin alfa) 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 Cinnal-f may range up to 300 IU per day depending on the individual patient response. Cinnal-f 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 Cinnal-f 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, (5,000 USP units) should be given 1 day after the last dose of Cinnal-f. 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, Cinnal-f 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, 5,000 USP units of hCG must be given 1 day after the last dose of Cinnal-f 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 Cinnal-f.

Assisted Reproductive Technologies

As in the treatment of patients with oligo-anovulatory infertility, the dose of Cinnal-f to stimulate development of the follicle must be individualized for each patient. For Assisted Reproductive

Technologies, therapy with Cinnal-f 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, whose endogenous gonadotropin levels are suppressed, Cinnal-f 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 75150 IU additionally at each adjustment. Doses greater than 450 IU per day are not recommended. Once adequate follicular development is evident, hCG (5,000 to 10,000 USP units) 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.

Male Patients with Hypogonadotropic Hypogonadism

The dose of Cinnal-f (follitropin alfa for injection) to induce spermatogenesis must be individualized for each patient. Cinnal-f must be given in conjunction with hCG. Prior to concomitant therapy with Cinnal-f and hCG, pretreatment with hCG alone (1,000 to 2,250 USP units two to three times per week) is required. Treatment should continue for a period sufficient to achieve serum testosterone levels within the normal range. Such pretreatment may require 3 to 6 months and the dose of hCG may need to be increased to achieve normal serum testosterone levels. After normal serum testosterone levels are reached, the recommended dose of Cinnal-f is 150 IU administered subcutaneously three times a week and the recommended dose of hCG is 1,000 USP units (or the dose required to maintain serum testosterone levels within the normal range) three times a week. The lowest dose of Cinnal-f which induces spermatogenesis should be utilized. If azoospermia persists, the dose of Cinnal-f may be increased to a maximum dose of 300 IU three times per week. Cinnal-f may need to be administered for up to 18 months to achieve adequate spermatogenesis.

Administration

One or more ampules of Cinnal-f® should be dissolved in one mL of Sterile Water for Injection, (concentration should not exceed 225 IU/0.5 mL) and administered subcutaneously immediately.

Patients should be instructed to use the accompanying syringes, calibrated in FSH units (IU FSH) for administration. The doctor, nurse, or pharmacist should show the patient how to locate the syringe marking that corresponds to the prescribed dose.

DOSAGE FORMS AND STRENGTHS

Each Cinnal-f® package contains:

1.  One ampoule of solvent contains 1 ml water for injection

2.  One vial of powder contains 5.5 micrograms of follitropin alfa, equivalent to 75 IU

CONTRAINDICATIONS

Cinnal-f (follitropin alfa for injection) is contraindicated in women and men who exhibit:

  1. Prior hypersensitivity to recombinant FSH preparations or one of their excipients.
  2. High levels of FSH indicating primary gonadal failure.
  3. Uncontrolled thyroid or adrenal dysfunction.
  4. Sex hormone dependent tumors of the reproductive tract and accessory organs.
  5. An organic intracranial lesion such as a pituitary tumor. And in women who exhibit:
  6. Abnormal uterine bleeding of undetermined origin.
  7. Ovarian cyst or enlargement of undetermined origin.
  8. Pregnancy.

WARNINGS AND PRECAUTIONS

Cinnal-f (follitropin alfa) should only be used by physicians who are thoroughly familiar with infertility problems and their management.

Cinnal-f 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 (see "Precautions/Laboratory Tests"). Safe and effective use of Cinnal-f 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 Cinnal-f 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 (see "Pulmonary and Vascular Complications"). 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 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 (see "Precautions/Laboratory Tests"), the hCG must be withheld.

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 ovulation induction clinical trials, 12.3% of live births were multiple births in women receiving recombinant follitropin alfa and 14.5% of live births were multiple births in women receiving urofollitropin. In IVF/ET clinical trials, 44.0% of live births were multiple births in women receiving recombinant follitropin alfa and 41.0% of live births were multiple births in women receiving urofollitropin and is dependent on the number of embryos transferred. The patient should be advised of the potential risk of multiple births before starting treatment.

Laboratory Tests

In most instances, treatment of women with Cinnal-f results only in follicular recruitment and development. In the absence of an endogenous LH surge, hCG is given when monitoring of the patient indicates that sufficient follicular development has occurred. This may be estimated by ultrasound alone or in combination with measurement of serum estradiol levels. The combination of both ultrasound and serum estradiol measurement are useful for monitoring the development of follicles, for timing of the ovulatory trigger, as well as for detecting ovarian enlargement and minimizing the risk of the Ovarian Hyperstimulation Syndrome and multiple gestation. It is recommended that the number of growing follicles be confirmed using ultrasonography because plasma estrogens do not give an indication of the size or number of follicles.

The clinical confirmation of ovulation, with the exception of pregnancy, is obtained by direct and indirect indices of progesterone production. The indices most generally used are as follows:

  1. A rise in basal body temperature;
  2. Increase in serum progesterone; and
  3. Menstruation following a shift in basal body temperature.

When used in conjunction with the indices of progesterone production, sonographic visualization of the ovaries will assist in determining if ovulation has occurred. Sonographic evidence of ovulation may include the following:

  1. Fluid in the cul-de-sac;
  2. Ovarian stigmata;
  3. Collapsed follicle; and
  4. Secretory endometrium.

Accurate interpretation of the indices of follicle development and maturation require a physician who is experienced in the interpretation of these tests.

ADVERSE REACTIONS

Percentage may vary by indication, product formulation

>10%:

Cardiovascular: Varicocele (15%)

Central nervous system: Headache (13% to 27%)

Dermatologic: Acne vulgaris (males 59%)

Endocrine & metabolic: Ovarian cyst (4% to 15%)

Gastrointestinal: Abdominal pain (9% to 23%), nausea (4% to 14%), enlargement of abdomen (1% to 14%)

Genitourinary: Mastalgia (males 14%)

Local: Injection site reaction (males 15%; females 1% to 4%),

Respiratory: Upper respiratory tract infection (4% to 12%)

1% to 10%:

Cardiovascular: Chest pain (1% to 2%), hypotension (1% to 2%), palpitations (1% to 2%)

Central nervous system: Fatigue (males 9%; females 1% to 2%), pain (2% to 6%), emotional lability (5%), migraine (1% to 4%), dizziness (1% to 3%), malaise (2%), anxiety (1% to 2%), drowsiness (1% to 2%), nervousness (1% to 2%), paresthesia (1% to 2%)

Dermatologic: Acne vulgaris (females 4%), pruritus (1% to 2%)

Endocrine & metabolic: Gynecomastia (9%), intermenstrual bleeding (4% to 9%), ovarian hyperstimulation syndrome (5% to 7%; severe: <1%), weight gain (4%), menstrual disease (3%), hot flash (2%), ovarian disease (2%), increased thirst (1% to 2%)

Gastrointestinal: Diarrhea (1% to 8%), flatulence (4% to 7%), toothache (1% to 4%), vomiting (1% to 3%), aphthous stomatitis (2%), constipation (2%), dyspepsia (2%), anorexia (1% to 2%)

Genitourinary: Pelvic pain (7%), mastalgia (females 4% to 6%), vaginal hemorrhage (1% to 6%), cervical lesion (3%), genital candidiasis (3%), dysmenorrhea (1% to 3%), cystitis (2%), gynecological pain (2%), urinary frequency (2%), urinary tract infection (2%), uterine hemorrhage (2%), leukorrhea (1% to 2%)

Infection: Viral infection (2%)

Local: Bruising at injection site (10%), pain at injection site (3% to 9%), inflammation at injection site (1% to 4%), swelling at injection site (3%)

Neuromuscular & skeletal: Back pain (4% to 5%), myalgia (1% to 2%)

Respiratory: Rhinitis (≤7%), pharyngitis (3% to 7%), sinusitis (5% to 6%), flu-like symptoms (4%), cough (2% to 3%), asthma (1% to 2%), dyspnea (1% to 2%)

Miscellaneous: Fever (2% to 4%)

Postmarketing and/or case reports (Limited to important or life-threatening): Anaphylactoid reaction, anaphylaxis, depression, Epstein-Barr infection, hemoperitoneum, hemoptysis, hypersensitivity reaction, ovarian neoplasm, ovarian torsion, ovary enlargement, pulmonary complications (including atelectasis, acute respiratory distress syndrome, exacerbation of asthma), thromboembolism, vascular disease

DRUG INTERACTIONS

No drug/drug interaction studies have been performed.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category X.

See CONTRAINDICATIONS.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the nursing infant from Cinnal-f, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

OVERDOSAGE

Aside from possible ovarian hyperstimulation and multiple gestations (see "Warnings"), there is no information on the consequences of acute overdosage with follitropin alfa.

DESCRIPTION

Cinnal_f (follitropin alfa) is a human follicle stimulating hormone (FSH) preparation of recombinant DNA origin. Recombinant FSH production occurs in genetically modified Chinese Hamster Ovary (CHO) cells cultured in bioreactors. The biological activity of follitropin alfa is determined by measuring the increase in ovary weight in female rats. Cinnal_f contains no luteinizing hormone (LH) activity.

Each Cinnal-F Multi-Dose vial is filled with 75 IU (5.5 mcg) follitropin alfa. Multiple Dose vials are reconstituted with Bacteriostatic Water for Injection (0.9% benzyl alcohol), USP.

Therapeutic Class: Infertility

CLINICAL PHARMACOLOGY

Cinnal-f (follitropin alfa) stimulates ovarian follicular growth in women who do not have primary ovarian failure. FSH, the active component of Cinnal-f is the primary hormone responsible for follicular recruitment and development. In order to effect final maturation of the follicle and ovulation in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given following the administration of Cinnal-f when monitoring of the patient indicates that sufficient follicular development has occurred. There is interpatient variability in response to FSH administration. The physico-chemical, immunological, and biological activities of recombinant FSH (r-hFSH) are comparable to those of pituitary and human menopausal urine-derived FSH. Cinnal-f (follitropin alfa), when administered with hCG, stimulates spermatogenesis in men with hypogonadotropic hypogonadism. FSH, the active component of Cinnal-F, is the primary hormone responsible for spermatogenesis.

Pharmacokinetics

Absorption

The absorption rate of follitropin alfa following subcutaneous or intramuscular administration was found to be 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.

After intravenous administration to pituitary down-regulated, healthy female volunteers, the serum profile of FSH appears to be described by a two compartment open model with a distribution half-life of about 2-2.5 hours. Steady-state serum levels were reached after 4 to 5 days of daily administration.

Metabolism/Excretion

FSH metabolism following administration of follitropin alfa has not been studied in humans. Total clearance after IV administration in healthy females was 0.6 L/hr; mean residence time was 17-20 hours. FSH renal clearance was 0.07 L/hr after intravenous administration representing approximately 1/8 of total clearance.

Special populations

Safety, efficacy, and pharmacokinetics of follitropin alfa in patients with renal or hepatic insufficiency have not been established.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long- term studies in animals have not been performed to evaluate the carcinogenic potential of follitropin alfa. However, follitropin alfa showed no mutagenic activity in a series of tests performed to evaluate its potential genetic toxicity including, bacterial and mammalian cell mutation tests, a chromosomal aberration test and a micronucleus test.

Impaired fertility has been reported in rats, exposed to pharmacological doses of follitropin alfa (≥40 IU/kg/day) for extended periods, through reduced fecundity.

HOW SUPPLIED/STORAGE AND HANDLING

Storage

1. Keep out of reach of children.

2. Should be stored at 2 - 8˚C.

3. Should not be exposed to direct light.

4. Should not be used, after the expiry date on the label.

5. Any unused portion should be discarded.

6. Do not use the liquid obtained after reconstitution if it is not clear or you can see particles floating in it.

FAQs

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