Follitropins and Menotropins

Number: 1082

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Brand Selection for Medically Necessary Indications for Commercial Medical Plans

Follitropins

As defined in Aetna commercial policies, health care services are not medically necessary when they are more costly than alternative services that are at least as likely to produce equivalent therapeutic or diagnostic results. Follistim AQ (follitropin beta) is more costly to Aetna than other follicle-stimulating hormone (FSH) products. There is a lack of reliable evidence that Follistim AQ is superior to other lower cost FSH products for medically necessary indications. Therefore, Aetna considers Follistim AQ to be medically necessary only for members who have a contraindication, intolerance, or ineffective response to an adequate one-month trial of the available equivalent alternative Gonal-F (follitropin alfa). 

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses injectable follitropins and menotropins for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of Follistim AQ (follitropin beta), Gonal-F (follitropin alfa), Gonal-F RFF (follitropin alfa), or Menopur (menotropins) required of all Aetna participating providers and members in applicable plan designs. For precertification, call (866) 782-2779 or fax (860) 754-2515. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Note: Medical/Pharmacy Benefit Alignment of Coverage for Infertility Drugs and Procedures:

Medical necessity review of infertility drugs by Aetna Specialty Pharmacy Guideline Management may be bypassed for infertility ART drugs that are for use with infertility medical procedures if the infertility procedure has been approved for coverage under the member’s Aetna medical benefit plan. During precertification, a medical authorization number and confirmation of the approval of the infertility procedures will be required to bypass medical necessity review by Specialty Pharmacy Guideline Management. Note: Some plans may require medical necessity review of all infertility drugs by Aetna Specialty Guideline Management. Members of these plans must undergo Specialty Pharmacy Guideline Management medical necessity review of all infertility drugs regardless of whether the drugs are for use with approved infertility medical procedures. For additional information, see CPB 0327 - Infertility.

1. Criteria for Initial Approval

   1. Follitropins

      Aetna considers follitropins (e.g., follitropin alfa [Gonal-F]; follitropin beta [Follistim AQ]) medically necessary for the following indications when criteria are met:

      1. Follicle stimulation - for members undergoing assisted reproductive technology (ART) or ovulation induction who meet any of the following criteria:

         1. Member has completed three or more previous cycles of clomiphene or letrozole; or
         2. Member has a risk factor for poor ovarian response to clomiphene or letrozole; or
         3. Member has a contraindication or exclusion to clomiphene or letrozole; or
         4. Member is 37 years of age or older; or

      2.  Treatment of hypogonadotropic hypogonadism in members who meet both of the following criteria:

         1. Low pretreatment testosterone levels; and
         2. Low or low-normal follicle stimulating hormone (FSH) or luteinizing hormone (LH) levels; or

   2. Menotropins

      Aetna considers menotropins (Menopur) medically necessary for follicle stimulation in members undergoing assisted reproductive technology (ART) or ovulation induction who meet any of the following criteria:

      1. Member has completed three or more previous cycles of clomiphene or letrozole; or
      2. Member has a risk factor for poor ovarian response to clomiphene or letrozole; or
      3. Member has a contraindication or exclusion to clomiphene or letrozole; or
      4. Member is 37 years of age or older.

      Aetna considers all other indications as experimental, investigational, or unproven.

2. Continuation of Therapy

   Aetna considers continuation of follitropin or menotropin therapy medically necessary for all members (including new members) requesting reauthorization who meet all initial authorization criteria.

3. Policy Limitations and Exclusions

   1. Many plans exclude coverage for infertility injectable medications; other plans may limit coverage of ovulation induction cycles with menotropins to a maximum number per lifetime. Please check plan documents for details.
   2. Under most Aetna benefit plans, self-administered prescription medications are covered under the pharmacy benefit. Please check benefit plan descriptions.

4. Related Policies 

   1. CPB 0001 - Transrectal Ultrasound
   2. CPB 0007 - Erectile Dysfunction
   3. CPB 0020 - Injectable Medications
   4. CPB 0327 - Infertility
   5. CPB 0532 - Scrotal Ultrasonography

Dosage and Administration

The dosage regimen for follitropin and menotropin products used in any particular case will depend upon the indication for use. Refer to the Full Prescribing Information of the requested product for additional information.

Experimental, Investigational, or Unproven 

Aetna considers the following indications experimental, investigational, or unproven because there is insufficient evidence for the use of hCG for these indications (not an all-inclusive list):

• Follitropins or menotropins solely for endometrium preparation for frozen embryo transfer (FET), see CPB 0327 -  Infertility
• Menotropins for treatment of male infertility

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
58974	Embryo transfer, intrauterine [Not covered for solely for endometrium preparation for frozen embryo transfer (FET)]
89255	Preparation of embryo for transfer (any method) [Not covered for solely for endometrium preparation for frozen embryo transfer (FET)]
HCPCS codes covered if selection criteria are met:
S0122	Injection, menotropins, 75 IU
S0126	Injection, follitropin alfa, 75 IU
S0128	Injection, follitropin beta, 75 IU

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications for Follitropins

• Follitropin beta injection (Follistim AQ) is indicated for:

  • Induction of ovulation and pregnancy in anovulatory infertile women in whom the cause of infertility is functional and not due to primary ovarian failure.
  • Pregnancy in normal ovulatory women undergoing controlled ovarian stimulation as part of an in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle.
  • Induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism (HH) in whom the cause of infertility is not due to primary testicular failure.
    
    

• Follitropin alfa injection (Gonal-F) is indicated for:

  • Induction of ovulation and pregnancy in oligio-anovulatory women in whom the cause of infertility is functional and not due to primary ovarian failure.
  • Development of multiple follicles in ovulatory women as part of an ART cycle.
  • Induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism in whom the cause of infertility is not due to primary testicular failure.
    

Follicle-stimulating hormone (FSH), the active component in Follistim AQ Cartridge (Merck & Co, Inc.), is required for normal follicular growth, maturation, and gonadal steroid production. In women, the level of FSH is critical for the onset and duration of follicular development, and consequently for the timing and number of follicles reaching maturity. Follistim AQ Cartridge stimulates ovarian follicular growth in women who do not have primary ovarian failure. In order to effect the final phase of follicle maturation, resumption of meiosis and rupture of the follicle in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given following treatment with Follistim AQ Cartridge when patient monitoring indicates appropriate follicular development parameters have been reached. In men, Follistim, when administered with hCG, stimulates spermatogenesis in men with hypogonadotropic hypogonadism. FSH, the active component of Follistim, is the pituitary hormone responsible for spermatogenesis.

Per the FDA-approved label, Follistim AQ Cartridge is contraindicated in women and men who exhibit prior hypersensitivity to recombinant hFSH products, high levels of FSH indicating primary gonadal failure, presence of uncontrolled non-gonadal endocrinopathies, hypersensitivity reactions related to streptomycin or neomycin, tumors of the ovary, breast, uterus, testis, hypothalamus or pituitary gland. Follistim AQ is also contraindicated in women who exhibit pregnancy, heavy or irregular vaginal bleeding of undetermined origin, and ovarian cysts or enlargement not due to polycystic ovary syndrome (PCOS).

Follistim AQ carries the following warnings and precautions: abnormal ovarian enlargement, oarian hyperstimulation syndrome (OHSS), pulmonary and vascular complications, ovarian torsion, multi-fetal gestation and birth, congenital anomalies, ectopic pregnancy, spontaneous abortion, and ovarian neoplasms.

Gonal-F (EMD Serono, Inc.) stimulates ovarian follicular growth in women who do not have primary ovarian failure. In order to bring about 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 Gonal-F, when monitoring of the patient indicates that sufficient follicular development is achieved. Gonal-F stimulates spermatogenesis in men with hypogonadotropic hypogonadism when administered with hCG. 

Gonal-F is available as Gonal-F RFF Redi-Ject or Gonal-F multi-dose vials.

Per the FDA-approved label, Gonal-F is contraindicated in women and men who exhibit prior hypersensitivity to recombinant FSH products or one of their excipients, high levels of FSH indicating primary gonadal failure, uncontrolled non-gonadal endocrinopathies, sex hormone dependent tumors of the reproductive tract and accessory organs, tumors of pituitary gland or hypothalamus. Gonal-f is also contraindicated in women who exhibit abnormal uterine bleeding of undetermined origin, and ovarian cyst or enlargement of undetermined origin.

Gonal-F carries the following warnings and precautions: hypersensitivity reactions and anaphylaxis, ovarian hyperstimulation syndrome, pulmonary and vascular complications (e.g., venous or arterial thromboembolic events), ovarian torsion, abnormal ovarian enlargement, multi-fetal gestation and births, embryofetal toxicity (note: there is no evidence that the use of gonadotropins during in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) is associated with an increased risk of congenital malformations), ectopic pregnancy, spontaneous abortion, and ovarian neoplasm (both benign and malignant ovarian neoplasms are reported in women who have had multiple drug therapy for controlled ovarian stimulation, however, causality has not been established).

The most common adverse reactions (2% or more) in ovulation induction include: headache, abdominal pain, ovarian hyperstimulation, injection site pain, diarrhea, flatulence nausea, ovarian cyst, and injection site inflammation. The most common adverse reactions (2% or more) in development of multiple follicles in assisted reproduction technology (ART) include: abdominal pain, headache, abdominal enlargement, injection site bruising, nausea, injection site pain, ovarian hyperstimulation, injection site inflammation, injection site reaction, and injection site edema.

U.S. Food and Drug Administration (FDA)-Approved Indications for Menotropins

• Menopur is indicated for development of multiple follicles and pregnancy in ovulatory women as part of an assisted reproductive technology (ART) cycle.

Menotropins for injection is branded as Menopur (Ferring Pharmaceuticals, Inc.). Menopur, administered for 7 to 20 days, produces ovarian follicular growth and maturation in women who do not have primary ovarian failure. Treatment with Menopur in most instances results only in follicular growth and maturation. When sufficient follicular maturation has occurred, hCG must be given to induce ovulation. 

Menopur is available as lyophilized powder for injection containing 75 IU FSH and 75 IU of luteinizing hormone (LH) activity, supplied as lyophilized powder or pellet in sterile vials with diluent vials and Q•Cap vial adapters.

Per the FDA-approved label, Menopur is contraindicated in women who exhibit prior hypersensitivity to Menopur or menotropins products or one of their excipients, high levels of FSH indicating primary ovarian failure, pregnancy, presence of uncontrolled non-gonadal endocrinopathies, sex hormone dependent tumors of the reproductive tract and accessory organ, tumors of pituitary gland or hypothalamus, abnormal uterine bleeding of undetermined origin, ovarian cyst or enlargement of undetermined origin, not due to polycystic ovary syndrome.

Menopur carries warnings and precautions for abnormal ovarian enlargement, ovarian hyperstimulation syndrome (OHSS), pulmonary and vascular complications, ovarian torsion, multi-fetal gestation and birth, congenital malformation, ectopic pregnancy, spontaneous abortion, and ovarian neoplasm.

The most common adverse reactions (2% or more) in assisted reproduction technology (ART) include: abdominal cramps, abdomen enlarged, abdominal pain, headache, injection site pain and reaction, injection site inflammation, and OHSS.

Endometrium Preparation for Frozen Embryo Transfer

There are no guidelines or peer-reviewed literature supporting the use of follitropins (recombinant FSH) or menotropins (hMG) for frozen embryo transfer (FET) cycles without follicle stimulation in assisted reproductive technology (ART).

The use of gonadotropins (follitropins or menotropins) is reserved for cycles where follicular stimulation is required, such as in anovulatory women or those with irregular cycles, to induce ovulation and create a corpus luteum. In women with regular ovulatory cycles, natural or modified natural cycles are preferred, and mild stimulation with gonadotropins does not improve live birth or implantation rates compared to natural cycles.

The American Society for Reproductive Medicine (ASRM) does not provide guidance or recommendation on the use of follitropins (recombinant FSH) or menotropins (hMG) for endometrial preparation in FET cycles in the absence of follicle stimulation.

Current evidence suggests that using these exogenous gonadotropins solely for FET offers no established benefit and introduces unnecessary cost and risk (Peeraer et al, 2015; Zhang et al, 2023).

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References