Gonal f (Follitropin alfa) is a recombinant human follicle-stimulating hormone that is used in the treatment of male and female infertility. It is used for the induction of ovulation in females and spermatogenesis in males.

Gonal f (Follitropin alfa) Uses:

• Multifollicular development during Assisted Reproductive Technology (ART):

  • Used to stimulate the development of multiple follicles with ART

• Ovulation induction:

  • Induction of ovulation and pregnancy in oligo anovulatory infertile patients in whom the cause of infertility is functional and not caused by primary ovarian failure

• Spermatogenesis induction (Gonal-f only):

  • Induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism in whom the cause of infertility is not due to primary testicular failure

Gonal f (Follitropin alfa) Dose in Adults

Note:

• The dose should be individualized.
• Use the lowest dose consistent with the expectation of good results.
• Over the course of treatment, doses may vary based on individual patient response.

Gonal f (Follitropin alfa) Dose in Ovulation induction:

• Females:

  • SubQ:
    • Initial: 75 units daily;
    • incremental dose adjustments of up to 37.5 units may be considered after 14 days;
    • further dose increases of the same magnitude can be made if required, every weak (maximum dose: 300 units in a day).
    • Treatment should be continued until follicular growth and/or serum estradiol levels indicate an adequate ovarian response.
    • If the response to follitropin is appropriate, hCG is given a day following the last dose to induce final oocyte maturation and ovulation.
    • Withhold hCG if serum estradiol is more than 2000 pg per mL;
    • Discontinue if the ovaries are abnormally enlarged, or if abdominal pain occurs. In general, therapy should not exceed 35 days.

Gonal f (Follitropin alfa) Dose in the Multifollicular development during ART:

• Females:

  • SubQ:
    • Start therapy with follitropin alfa in the early follicular phase (cycle day 2 or day 3) at a dose of 150 units each day, until sufficient follicular development is attained.
    • In most cases, therapy should not be exceeded to  10 days.
    • In patients of 35 or more than 35 years whose endogenous gonadotropin levels are suppressed, initiate follitropin alfa at a dose of 225 units each day.
    • Continue treatment until adequate follicular development is indicated as determined by ultrasound in combination with the measurement of serum estradiol levels.
    • Recommend adjustments to dose after 5 days based on the patient's reply;
    • adjust subsequent dosage every 3-5 days by ≤75 to 150 units additionally at each adjustment.
    • Doses more than 450 units each day are not necessary.
    • Once adequate follicular development is evident, administer hCG to induce final follicular maturation in preparation for oocyte retrieval.
    • Withhold hCG if the ovaries are abnormally enlarged.

Gonal f (Follitropin alfa) Dose in the Spermatogenesis induction:

• Males:

  • Gonal-f:
    • SubQ: Therapy should begin with hCG pretreatment until serum testosterone is in a  normal range, then initiate Gonal-f at 150 units thrice in a weak with hCG thrice in a weak;
    • continue with the smallest dose  required  to induce spermatogenesis (maximum dose: 300 units thrice in a weak);
    • may be given for up to 18 months

Use in Children:

Not indicated.

Gonal f (Follitropin alfa) Pregnancy Risk Category: X

• Multiple births, spontaneous abortion, ectopic pregnancy and congenital abnormalities have all been reported.
• Congenital abnormalities may be more common after ART than spontaneous conception.
• This may be due to parental characteristics (maternal and sperm characteristics)
• Women who are pregnant or nearing the end of their pregnancy should not use this medication.
• Follitropin alfa is used to induce ovulation.

Follitropin alfa use during breastfeeding:

• It is unknown if breast milk contains follitropin alfa.
• There is a risk of serious adverse reactions in nursing babies. It is important to decide whether to stop nursing or stop using the drug.

Gonal f (Follitropin alfa) Dose in Kidney Disease:

There is no dosage adjustment provided in the manufacturer's labeling (has not been studied).

Gonal f (Follitropin alfa) Dose in Liver disease:

There is no dosage adjustment provided in the manufacturer's labeling (has not been studied).

Common Side Effects of Gonal f (Follitropin alfa):

• Cardiovascular:

  • Varicocele

• Central Nervous System:

  • Headache

• Dermatologic:

  • Acne Vulgaris

• Endocrine & Metabolic:

  • Ovarian Cyst

• Gastrointestinal:

  • Abdominal Pain
  • Nausea
  • Enlargement Of Abdomen

• Genitourinary:

  • Mastalgia

• Local:

  • Injection Site Reaction

• Respiratory:

  • Upper Respiratory Tract Infection

Less Common Side Effects Of Gonal f (Follitropin alfa):

• Cardiovascular:

  • Chest Pain
  • Hypotension
  • Palpitations

• Central Nervous System:

  • Fatigue
  • Pain
  • Emotional Lability
  • Migraine
  • Dizziness
  • Malaise
  • Anxiety
  • Drowsiness
  • Nervousness
  • Paresthesia

• Dermatologic:

  • Acne Vulgaris
  • Pruritus

• Endocrine & Metabolic:

  • Gynecomastia
  • Intermenstrual Bleeding
  • Ovarian Hyperstimulation Syndrome
  • Weight Gain
  • Menstrual Disease
  • Hot Flash
  • Ovarian Disease
  • Increased Thirst

• Gastrointestinal:

  • Diarrhea
  • Flatulence
  • Toothache
  • Vomiting
  • Aphthous Stomatitis
  • Constipation
  • Dyspepsia
  • Anorexia

• Genitourinary:

  • Pelvic Pain
  • Mastalgia
  • Vaginal Hemorrhage
  • Cervical Lesion
  • Genital Candidiasis
  • Dysmenorrhea
  • Cystitis
  • Gynecological Pain
  • Urinary Frequency
  • Urinary Tract Infection
  • Uterine Hemorrhage
  • Leukorrhea

• Infection:

  • Viral Infection

• Local:

  • Bruising At Injection Site
  • Pain At Injection Site
  • Inflammation At Injection Site
  • Swelling At Injection Site

• Neuromuscular & Skeletal:

  • Back Pain
  • Myalgia

• Respiratory:

  • Rhinitis
  • Pharyngitis
  • Sinusitis
  • Flu-Like Symptoms
  • Cough
  • Asthma
  • Dyspnea

• Miscellaneous:

  • Fever

Contraindications to Gonal f (Follitropin alfa):

• Sex hormone-based cancers of the reproductive tract or accessory organs
• High levels of FSH can indicate primary gonadal dysfunction (ovarian or testicular).
• Hypersensitivity to any component of the formula or follitropins;
• Undetermined cause of abnormal uterine bleeding
• Intracranial lesions (eg pituitary and hypothalamus tumors);
• Uncontrolled adrenal, thyroid, or pituitary dysfunction
• ovarian cysts and enlargements of undetermined origin that are not caused by polycystic Ovarian Syndrome;
• pregnancy

Warnings and precautions

• Abortion

  • Gonadotropins can increase the risk of spontaneous abortion.
  • It has not been proven that causality exists.

• Ectopic pregnancy

  • Women with tubal abnormalities may be at greater risk of ectopic pregnancy. Early confirmation with hCG testing or transvaginal ultrasound is essential to confirm intrauterine pregnancy.

• Hypersensitivity

  • Reports of severe hypersensitivity reactions, including anaphylaxis, have been made. Stop using the medication and get treatment.

• Ovarian enlargement:

  • This condition may be accompanied with abdominal distention or pain. It occurs in approximately 20% of people treated with urofollitropin or hCG and usually regresses within 2 to 3 week.
  • To reduce the effect of ovarian hyperstimulation syndrome, (OHSS), withhold hCG if the ovaries become abnormally large on the last day.

• Ovarian hyperstimulation syndrome (OHSS):

  • OHSS can be a rare, exaggerated reaction to ovulation-induction therapy.
  • It can begin as soon as the treatment is completed, but it may get worse within 7-10 days.
  • Symptoms of mild/moderate OHSS may include abdominal distention/discomfort, diarrhea, nausea, and/or vomiting.
  • Severe symptoms of OHSS may include severe abdominal pain and anuria/oliguria ascites, severe dyspnea or hypotension, nausea/vomiting (intractable), or severe dyspnea.
  • You may also experience decreased hemoconcentration, hypoproteinemia and creatinine clearance.
  • Stop using gonadotropins.
  • The primary treatment is supportive and includes fluid and electrolyte management, analgesia and management and prevention for thromboembolic complications.

• Ovarian neoplasms

  • Women who have received multiple drugs for controlled ovarian stimulation have occasionally been diagnosed with malignant and benign neoplasms.
  • However, the causal relationship has not been established.

• Ovarian torsion

  • This condition has been reported after gonadotropin treatment. It may be due to OHSS or prior or current ovarian cysts, polycystic ovaries or pregnancy.
  • Early diagnosis and prompt detorsion can limit the severity of ovarian problems.

• Effects on the pulmonary system:

  • There have been reports of serious pulmonary conditions, including acute respiratory distress syndrome, exacerbation and atelectasis.

• Events that are thromboembolic:

  • Thromboembolic events have been reported in association with and apart from ovarian hyperstimulation Syndrome (OHSS).

Monitoring parameters:

• Monitor sufficient follicular maturation.
• This may be directly estimated by sonographic visualization of the ovaries and endometrial lining or measuring serum estradiol levels.
• 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 or by sonographic evidence.

The indices of progesterone production most  generally used are:

• urinary or serum luteinizing hormone (LH) rise, increase in serum progesterone, rise in basal body temperature, and menstruation following the shift in basal body temperature.

The indices of sonographic evidence of ovulation include:

• Collapsed follicle, fluid in the cul-de-sac, features consistent with corpus luteum formation, or secretory endometrium.
• Monitor for signs and symptoms of OHSS for at least 2 weeks following hCG administration.

OHSS:

• Monitoring parameters for hospitalized patients should include, cardiorespiratory status, electrolytes, fluid balance, abdominal circumference, albumin hematocrit, hemoglobin, serum creatinine, urine specific gravity, vital signs, urine output, weight (all daily or as necessary), and liver enzymes (weekly).

Spermatogenesis:

• Monitor serum testosterone levels and sperm count.

How to administer Gonal f (Follitropin alfa)?

SubQ:

• Administer SubQ. Contents of multidose vials (Gonal-f or Gonal-f RFF) should be administered using the calibrated syringes provided by the manufacturer.
• Allow any bubbles to settle prior to administration. Allow Gonal-f RFF Rediject to warm to room temperature for at least half an hour prior to administration to avoid discomfort from the cold injection.
• Do not mix other medications inside of the Gonal-f RFF Rediject device.

Mechanism of action of Gonal f (Follitropin alfa):

• Follitropin alfa, a human FSH preparation with recombinant DNA origin, is known as Follitropin. 
• Follitropins stimulate ovarian growth in women without primary ovarian failure, and stimulate spermatogenesis for hypogonadotropic hypogonadism men.
• FSH is necessary for normal follicular development, maturation, gonadal steroids production and spermatogenesis.

The onset of action: Peak effect:

• Spermatogenesis, median: 6.8 to 12.4 months (range 2.7-18.1 months)
• Follicle development: Within the cycle

Absorption: SubQ:

• Absorption rate is slower than the elimination rate

Bioavailability:

• ~66 percent  to 76 percent in healthy female volunteers;
• 10 percent in vitro fertilization/embryo transfer patients

Half-life elimination:

• SubQ: 24 to 53 hours in healthy female volunteers;
• 32 to 41 hours in healthy male volunteers

Time to peak: In healthy volunteers:

• Females: SubQ: 8 to 16 hours
• Males: SubQ: 11 to 20 hours

International Brand Names of Follitropin alfa:

• Gonal-f
• Gonal-f RFF
• Gonal-f RFF Rediject
• Gonal-f Pen
• Bemfola
• Forielle
• Gonal-F
• Gonalef
• Ovaleap

Follitropin alfa Brand Names in Pakistan: