Follitropin Beta (Follistim, Puregon) is a recombinant FSH (follicle-stimulating hormone) that is used to treat females and male patients with infertility secondary to a pituitary problem (hypogonadotropic hypogonadism).

Follitropin beta Uses:

• Females:
  • Induction of ovulation and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not caused by primary ovarian failure;
  • induction of pregnancy in normal ovulatory women undergoing Assisted Reproductive Technology (ART) (eg, in vitro fertilization [IVF], intracytoplasmic sperm injection [ICSI])
• Males:
  • Induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism in whom the cause of infertility is not due to primary testicular failure.

Follitropin Beta Dose in Adults

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.

Follitropin Beta Dose in the induction of Ovulation:

• Females:

  • Follistim AQ (vials): IM, SubQ:
    • Stepwise approach:
      • Initiate therapy with 75 units per day for at least the first 7 days.
      • Increase the dose by 25 or 50 units at weekly intervals until follicular growth or serum estradiol levels indicate an adequate response.
      • The maximum (individualized) daily dose that has been safely used for ovulation induction in patients during clinical trials is 300 units.
      • If the response to follitropin is appropriate, hCG is given 1 day following the last dose to induce final oocyte maturation and ovulation.
      • Withhold hCG if the ovaries are abnormally enlarged, or if abdominal pain occurs.
  • Follistim AQ Cartridge: SubQ:
    • Stepwise approach:
      • Initiate therapy with 50 units per day for at least the first 7 days.
      • Increase the dose by 25 or 50 units at weekly intervals until follicular growth and/or serum estradiol levels indicate an adequate response.
      • The maximum (individualized) daily dose that has been safely used for ovulation induction in patients during clinical trials is 250 units.
      • If the response to follitropin is appropriate, hCG is given 1 day following the last dose to induce final oocyte maturation and ovulation.
      • Withhold hCG if the ovaries are abnormally enlarged, or if abdominal pain occurs.
  • Puregon (vials) [Canadian product] (IM, SubQ), Puregon Cartridge [Canadian product] (SubQ):
    • Stepwise approach:
      • Initiate therapy with 50 units per day for at least the first 7 days.
      • Increase the dose gradually until follicular growth and/or plasma estradiol levels indicate an adequate response (a daily increase of estradiol levels of 40 percent to 100 percent is considered optimal).
      • If the response to follitropin is appropriate, hCG is given 1 day following the last dose to induce final oocyte maturation and ovulation.
      • Decrease hCG dose if the number of responding follicles is too high or estradiol levels increase too rapidly (eg, greater than daily doubling for estradiol for 2 or 3 consecutive days);
      • Withhold hCG if the ovaries are abnormally enlarged or if abdominal pain occurs.

Follitropin Beta Dose in the ART:

• Females:

  • Follistim AQ (vials): IM, SubQ:
    • Stepwise approach:
      • The initial dose of 150 to 225 units is recommended for at least the first 4 days of treatment.
      • The dose may be adjusted for the individual patient based upon their ovarian response.
      • The maximum daily dose used in clinical studies is 600 units. When a sufficient number of follicles of adequate size are present, the final maturation of the follicles is induced by administering hCG.
      • Oocyte retrieval is performed 34 to 36 hours later.
      • Withhold hCG in cases where the ovaries are abnormally enlarged on the last day of follitropin beta therapy.
  • Puregon vials [Canadian product] (IM, SubQ), Puregon Cartridge [Canadian product] (SubQ):
    • A starting dose of 150 to 225 units is recommended for at least the first 4 days of treatment.
    • The dose may be adjusted for the individual patient based upon their ovarian response. The maximum daily dose safely used in clinical studies is 450 units (limited experience with higher doses).
    • When a sufficient number of follicles of adequate size are present, the final maturation of the follicles is induced by administering hCG 30 to 40 hours after the last follitropin beta dose.
    • Withhold hCG in cases where the ovaries are abnormally enlarged on the last day of follitropin beta therapy.
  • Follistim AQ Cartridge: SubQ:
    • Stepwise approach:
      • The initial dose of 200 units is recommended for at least the first week of treatment.
      • The dose may be adjusted for the individual patient based upon their ovarian response.
      • The maximum daily dose used in clinical studies is 500 units.
      • When a sufficient number of follicles of adequate size are present, the final maturation of the follicles is induced by administering hCG.
      • Oocyte retrieval is performed 34 to 36 hours later.
      • Withhold hCG in cases where the ovaries are abnormally enlarged on the last day of follitropin beta therapy.

Follitropin Beta Dose in the induction of spermatogenesis:

• Males:

  • Puregon (vials) [Canadian product], Follistim AQ (vials), Follistim AQ Cartridge, Puregon Cartridge [Canadian product]:
  • Note:
    • Pretreatment with hCG monotherapy is required prior to concomitant therapy with follitropin beta and hCG. Follitropin beta therapy may be initiated after normal serum testosterone levels have been reached.
  • SubQ: 450 units every week (administered as 225 units two times in a weak or 150 units thrice time in a weak).
  • A lower dose of Follistim AQ Cartridge may be considered.

Note:

• Dose adjustment for follitropin beta pen with cartridge:
  • When administered using the pen, the follitropin cartridge delivers on average 18 percent more follitropin beta when compared to dissolved lyophilized follitropin beta administered by a conventional syringe.
  • If the above starting doses were previously used when administering a recombinant lyophilized gonadotropin product via a conventional syringe, lower initiating and maintenance doses should be considered when switching to follitropin pen with the cartridge.
  • The following dose conversion may be used:

Follitropin Beta Dosing Conversion1

Use in Children:

Not indicated.

Pregnancy Risk Factor X

• Multiple births, congenital abnormalities and ectopic pregnancies have all been reported.
• Follitropin beta is used to induce ovulation. Women who are pregnant or planning to become pregnant should not use it.
• Congenital abnormalities may be more common after ART than spontaneous conception.
• This may be due to parental characteristics (maternal and sperm characteristics).

Use of Follitropin beta during breastfeeding

• It is unknown if breast milk contains follitropin beta.
• There is a risk of serious adverse reactions in breastfeeding infants. It is important to decide whether to stop breastfeeding or to take the drug.

Dose in Kidney Disease:

The manufacturer's labeling doesn't provide any dosage adjustments (has not been studied).

Dose in Liver disease:

The manufacturer's labeling doesn't provide any dosage adjustments (has not been studied).

Side Effects of Follitropin beta:

• Central Nervous System:

  • Headache
  • Fatigue

• Dermatologic:

  • Acne Vulgaris
  • Skin Rash

• Endocrine & Metabolic:

  • Ovarian Hyperstimulation
  • Ovarian Cyst
  • Gynecomastia

• Gastrointestinal:

  • Nausea
  • Abdominal Pain
  • Abdominal Distress

• Genitourinary:

  • Pelvic Symptoms
  • Pelvic Pain

• Local:

  • Injection Site Reaction
  • Pain At Injection Site

Contraindications to Follitropin beta:

• Hypersensitivity to streptomycin,follitropins, neomycin, or any component of the formulation;
• High levels of FSH indicate primary gonadal dysfunction;
• Uncontrolled nongonadal hormone disorders (eg pituitary or thyroid disorders, adrenal)
• Tumor of the breast, ovary, uterus or pituitary gland

Additional contraindications for females

• Undetermined cause of abnormal vaginal bleeding
• ovarian cysts and enlargements not caused by polycystic-ovary syndrome
• pregnancy

Canadian labeling: Additional contraindications not in the US labeling

• Lactation;
• Conditions that are incompatible with pregnancy (e.g., uterine fibrid tumors, malformations of reproductive organs).
• use in children.

Warnings and precautions

• Ovarian enlargement:

  • To reduce the risk of ovarian hyperstimulation syndrome, (OHSS), withhold hCG if the ovaries become abnormally large on the last day.

• Ovarian hyperstimulation syndrome:

  • Ovarian hyperstimulation Syndrome (OHSS), is a rare, exaggerated response for ovulation-induction therapy.
  • Severe symptoms of OHSS may include severe stomach pain, severe dyspnea or hypotension, severe dyspnea and ascites.
  • You may also experience decreased creatinine clearance, increased liver enzymes, hemoconcentration and hypoproteinemia.
  • This syndrome can develop within 24 hours after treatment, but it may get more severe 7-10 days later.
  • Symptoms of mild/moderate OHSS may include diarrhea, nausea, abdominal distention/discomfort, and/or vomiting.
  • The treatment is primarily symptomatic. It includes fluid and electrolyte management as well as analgesics and prevention of thromboembolic complications. Stop using gonadotropins.

• Ovarian torsion

  • This may occur in connection to OHSS or pregnancy, previous or current ovarian surgery, polycystic ovaries and history of ovarian damage.

• Effects on the pulmonary system:

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

• Events that are thromboembolic:

  • There have been reports of thromboembolic events, both in association with and apart from ovarian hyperstimulation Syndrome.

Monitoring parameters:

Females:

• 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 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,
• rise in basal body temperature,
• increase in serum progesterone, 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 ovarian hyperstimulation syndrome (OHSS) for at least 2 weeks following hCG administration.

OHSS:

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

Males:

• Monitor for sufficient spermatogenesis.
• This can be directly estimated by semen analysis, or indirectly estimated by serum testosterone level.
• Semen analysis is recommended 4 to 6 months after starting treatment.
• Therapy should continue for 3 to 4 months before improvement in spermatogenesis can be expected.

How to administer Follitropin beta?

SubQ injection may be given in the abdomen just below the navel or upper thigh. IM injection may be given in the upper outer quadrant of the buttock. Avoid areas that are red, bruised tender, or hard.

• Follistim AQ, Puregon [Canadian product]: Vials:
  • Administer by IM or SubQ injection.
• Follistim AQ Cartridge, Puregon Cartridge [Canadian product]:
  • Cartridge: Administer by SubQ injection only, using the Follistim Pen or the Puregon Pen, which can be set to deliver the appropriate dose.

Mechanism of action of Follitropin beta:

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

Onset of action:

• Peak effect:
  • Females: Follicle development: Within cycle

Absorption:

• Females:
  • IM: 76 percent ;
  • SubQ: 78 percent .

Half-life elimination:

• Females:
  • IM: 44 hours (single dose), 27-30 hours (multiple doses);
  • SubQ: 33 hours (single dose)

Time to peak:

• Females: SubQ: 13 hours

International Brands of Follitropin beta:

• Follistim AQ
• Puregon
• Follistim
• Recagon

Follitropin beta Brand Names in Pakistan:

There is no brand available in Pakistan.