Drug Therapy Guidelines Fertility Medications: Bravelle®, Cetrotide®, Clomid, clomiphene, Follistim AQ®, Ganirelix®, Gonal-F®, human chorionic , leuprolide,

Menopur®, Novarel®, Ovidrel®, Pregnyl®, Crinone®,

Applicable* Endometrin®, First-Progesterone®, progesterone in oil Medical Benefit x Effective: 08/03/2021 Pharmacy- Formulary 1 x Next Review: 6/22 Pharmacy- Formulary 2 x Date of Origin: 7/00 Pharmacy- Formulary 3/Exclusive x Review Dates: 7/12/00, 5/8/01, 1/15/02, 5/6/03, 12/16/03, 6/8/04, Pharmacy- Formulary 4/AON x 12/16/05, 2/1/06, 10/15/06, 7/20/07, 11/5/07, 12/15/08, 12/09, 9/10, 1/11, 9/11, 9/12, 9/13, 9/14, 6/15, 6/16, 6/17, 6/18, 6/19, 9/19, 3/20, 6/20, 9/20, 3/21, 6/21

I. Medication Description

Gonadotropin Releasing Hormone (GnRH) Agonists are indicated for the inhibition of premature (LH) surges in women undergoing controlled ovarian stimulation. GnRH Antagonists are indicated for inhibition of premature luteinizing hormone (LH) surges in women undergoing controlled ovarian stimulation. , FSH, or combination of FSH/LH are indicated for stimulation of ovarian follicular growth. Human chorionic gonadotropins (hCG) are indicated for inducing . Clomiphene is a selective- receptor-modulator (SERM) used for inducing ovulation.

Therapeutic Class Agents GnRH Agonists leuprolide GnRH Antagonists Cetrotide®, Ganirelix® Gonadotropins Follitropin alfa: Gonal-F®, Gonal-F RFF® (non-preferred) Follitropin beta: Follistim AQ® (preferred) : Menopur® Urofollitropins: Bravelle® hCG human chorionic gonadotropin, Novarel®, Ovidrel®, Pregnyl® Progestin Injection progesterone oil for injection Vaginal Progesterone Crinone, Endometrin, First-Progesterone Selective-estrogen receptor- Clomid*, Clomiphene* modulator (SERM)

II. Position Statement

Coverage is determined through a prior authorization process with supporting clinical documentation for every request.

Contractual limitations may also apply to coverage of fertility medications.

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Drug Therapy Guidelines Fertility Medications Last Review Date: 6/2021

Uses outside of infertility treatment and fertility preservation will be considered on a case-by-case basis depending on FDA approval or the corporate Off-Label Drug Use Policy and Procedure.

*Medications may be reviewed in accordance with New York State requirements.

III. Policy

Coverage can be provided when the following criteria are met:

Vaginal Progesterone products (Crinone, Endometrin, First-Progesterone):  Coverage is available for FDA approved diagnoses or diagnoses with compendial support.

Female** Fertility:  Coverage is available for members who are trying to conceive when ONE of the following has been met: o Member has been diagnosed with infertility, defined as meeting ANY of the following: . Failure to establish a clinical pregnancy after twelve months of regular, unprotected sexual intercourse or therapeutic donor insemination in females** younger than thirty- five years of age OR . Failure to establish a clinical pregnancy after six months of regular, unprotected sexual intercourse or therapeutic donor insemination for a female** thirty-five years of age or older OR o Member’s circumstances are not expected to result in a clinical pregnancy as determined by an appropriate fertility specialist (coverage decisions will be made on a case by case basis) AND  Coverage is requested by an appropriate fertility specialist (e.g. reproductive endocrinologist) AND  Prior to starting sequential hormone therapy for female** infertility: o An infertility work-up needs to be performed (if not previously done) AND o For IUI use only: . Primary ovarian failure and tubal obstruction are ruled out AND . Complete semen analysis is performed and sample is deemed appropriate for use AND  One of the following apply, based on the medication requested: o For coverage of hCG and clomiphene: Medication is being used as part of a covered procedure OR o For coverage of gonadotropins: Hypothalamic amenorrhea (HA) is documented OR o For coverage of GnRH antagonists, GnRH agonists, progestin injection, or gonadotropins, at least ONE of the following conditions is met: . Documented severe (Stage 4) is confirmed OR . Documented diminished ovarian function (DOR) such as elevation in 3-day FSH level (above 10-14 mIU/ml) is confirmed OR . Documented oral therapy failure (with clomiphene, metformin, or letrozole) is confirmed, as defined by one of the following:  Failure to become pregnant after 3 ovulatory cycles of therapy  Failure to ovulate after 3 consecutive cycles of therapy  Patient experienced intolerable side effects from oral therapy

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Drug Therapy Guidelines Fertility Medications Last Review Date: 6/2021

 Coverage of non-preferred medication Gonal-F® or Gonal-F RFF® can be considered if the following criteria are met: o When requesting coverage of a brand medication for which a plan-preferred A/B rated generic is available, there is sufficient evidence that the use of the A/B rated generic equivalent has resulted in inadequate results AND o Coverage will be provided after a trial with plan-preferred medication Follitropin AQ® has resulted in either a treatment failure or intolerable side effects OR when at least ONE of the following criteria have been met: . The plan-preferred medications are contraindicated or will likely cause an adverse reaction by or physical or mental harm to the member. . The plan-preferred medications are expected to be ineffective based on the known clinical history and conditions of the member and the member’s prescription drug regimen. . The member has tried the plan-preferred medications or another prescription drug in the same pharmacologic class or with the same mechanism of action and such prescription drug was discontinued due to lack of efficacy or effectiveness, diminished effect, or an adverse event. . The member is stable on the medication selected by their healthcare professional for the medical condition under consideration (where “stable” is defined as receiving the medication for an adequate period of time, have achieved optimal response, and continued favorable outcomes are expected UNLESS the medication was initially selected solely due to the availability of a drug sample or a coupon card and the member does not otherwise meet the definition of “stable”). . The plan-preferred medication is not in the best interest of the member because it will likely cause a significant barrier to the member’s adherence or to compliance with the member’s plan of care, will likely worsen a comorbid condition of the member, or will likely decrease the member’s ability to achieve or maintain reasonable functional ability in performing daily activities.

**Female term is being utilized to represent biological sex; not gender.

Male*** Fertility:  Coverage is requested by an appropriate fertility specialist (e.g. reproductive endocrinologist) AND  Prior to starting sequential hormone therapy for male*** infertility: o An infertility work-up needs to be performed (if not previously done) AND o Complete semen analysis is performed AND o Resultant diagnosis is deemed amenable to hormonal infertility treatment AND  One of the following apply, based on the medication requested: o For coverage of hCG: There is a confirmed diagnosis of hypogonadotropic hypogonadism not associated with primary testicular failure o For coverage of follitropins: . There is a confirmed diagnosis of hypogonadotropic hypogonadism not associated with primary testicular failure AND Page 3 of 7

Drug Therapy Guidelines Fertility Medications Last Review Date: 6/2021

. Pretreatment with hCG has first normalized serum testosterone levels AND . Medication must be given in conjunction with hCG AND . Coverage of non-preferred medication Gonal-F® or Gonal-F RFF® can be considered if the following criteria are met:  When requesting coverage of a brand medication for which a plan-preferred A/B rated generic is available, there is sufficient evidence that the use of the A/B rated generic equivalent has resulted in inadequate results AND  Coverage will be provided after a trial with plan-preferred medication Follistim AQ® has resulted in either a treatment failure or intolerable side effects OR when at least ONE of the following criteria have been met: o The plan-preferred medications are contraindicated or will likely cause an adverse reaction by or physical or mental harm to the member. o The plan-preferred medications are expected to be ineffective based on the known clinical history and conditions of the member and the member’s prescription drug regimen. o The member has tried the plan-preferred medications or another prescription drug in the same pharmacologic class or with the same mechanism of action and such prescription drug was discontinued due to lack of efficacy or effectiveness, diminished effect, or an adverse event. o The member is stable on the medication selected by their healthcare professional for the medical condition under consideration (where “stable” is defined as receiving the medication for an adequate period of time, have achieved optimal response, and continued favorable outcomes are expected UNLESS the medication was initially selected solely due to the availability of a drug sample or a coupon card and the member does not otherwise meet the definition of “stable”). o The plan-preferred medication is not in the best interest of the member because it will likely cause a significant barrier to the member’s adherence or to compliance with the member’s plan of care, will likely worsen a comorbid condition of the member, or will likely decrease the member’s ability to achieve or maintain reasonable functional ability in performing daily activities. o For coverage of menotropins: . There is a confirmed diagnosis of hypogonadotropic hypogonadism not associated with primary testicular failure AND . Pretreatment with hCG has first normalized serum testosterone levels AND . Medication must be given in conjunction with hCG.

Fertility Preservation  Coverage is requested by an appropriate fertility specialist (e.g. reproductive endocrinologist) AND

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Drug Therapy Guidelines Fertility Medications Last Review Date: 6/2021

 Member will be undergoing or receiving a medical treatment that may directly or indirectly cause iatrogenic infertility (iatrogenic infertility is defined as the impairment of fertility by surgery, radiation, chemotherapy or other medical treatment affecting reproductive organs or processes) AND  Planned procedure is not deemed experimental according to the standards and guidelines established by the American College of Obstetricians and Gynecologists (ACOG) and the American Society for Reproductive Medicine (ASRM). ***Male term is being utilized to represent biological sex; not gender.

IV. Quantity Limitations

Coverage is available for quantities to afford dosing within FDA-approved dosing regimens.

V. Coverage Duration

 Coverage for use in conjunction with IVF is provided for duration of 2 month to allow coverage for 1 IVF cycle and may be renewed. o Certain plan contracts may limit coverage to 3 cycles of IVF per lifetime.  Coverage for progesterone in oil in conjunction with IVF: up to 12 weeks gestation  Coverage for all other situations is provided for 6 months and may be renewed.

VI. Coverage Renewal Criteria

Re-evaluation will be required after the initial authorization period and consideration can be granted for extended therapy if:  Requested by a fertility specialist with clinical rationale for continuation AND  Planned procedure has been documented and is coverable AND  Eligibility for coverage still applies as outlined in the governing plan contract.

VII. Billing/Coding Information

n/a

VIII. Summary of Policy Changes

 4/11/11: Follistim® becomes preferred agent over Gonal-F®  1/1/12: no changes  12/15/12: no changes  12/15/13: hCG now covered without failure of oral therapy when used for a covered procedure  1/1/15: o coverage of hCG clarified to include pretreatment workup and testing o appropriate fertility specialist prescriber required for coverage

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Drug Therapy Guidelines Fertility Medications Last Review Date: 6/2021

o discontinued meds (Lupron, Luveris) removed from policy; clarification of coverage criteria for the treatment of male infertility made based on FDA approved indication o removal of azoospermia as a condition for which male infertility treatment is not covered  7/1/15: formulary distinctions made  9/15/15: progestins added to policy  7/19/16: no policy changes  5/3/17: step edit criteria added  6/21/17: clarified oral agents requirement  8/15/18: clarified renewal criteria  8/15/19: no policy changes  11/15/19: updated Position Statement; updated coverage criteria and coverage duration to include IVF and fertility preservation  5/1/20: policy name changed from “Injectable Fertility Medications” to “Fertility Medications;”Clomid and clomiphene added to policy; these drugs may be reviewed in accordance with New York State requirements; changed coverage duration for IVF to 2 months to allow medication utilization for 1 cycle  8/1/20: clarified criteria for IUI use  1/1/21: clarified progesterone in oil coverage duration  5/28/21: clarified gender definitions  8/30/21: added coverage for Crinone, Endometrin and First-Progesterone

IX. References

1. Al-Inany H. Gonadotropin-releasing hormone antagonists for assisted conception (Cochrane Review) Cochrane Library 4, 2001. 2. Al-Inany H. GnRH Antagonist in assisted reproduction (Cochrane Review) Cochrane Library 2002; Vol 17(4): 847-885. 3. Bates GW, Bates SR, The economics of infertility: Developing an infertility managed-care plan. Am J Obstet Gynecol 1996; 174(4):1200-1207. 4. Bouloux, P, Warne, D, et al. Efficacy and safety of recombinant human follicle-stimulating hormone in men with isolated hypogonadotropic hypogonadism. Fertility and Sterility Feb 2002; 77(2):270-27 5. Depenbusch, M, et al. Maintenance of spermatogenesis in hypogonadotropic hypogonadal men with human chorionic gonadotropin alone. Eur J Endocrinol Nov 2002; 147(5):617-24 6. Drug Facts and Comparisons. St. Louis 2003 7. Management of Infertility caused by ovulatory dysfunction, Practice Bulletins-Gynecology #34. Obstet Gynecol 2002; 99:347 8. Clinical Pharmacology. Accessed 4/2021. 9. Micromedex. Accessed 4/2021. 10. Bravelle® Product Information. Ferring Pharmaceuticals, Inc., Parsippany, NJ 07054. Revised 2/2014. 11. Cetrotide® Product information. EMD Serono, Inc, Rockland, MA 02370. Revised 7/2017. 12. Follistim® Product Information. Merck & Co., Inc., Whitehouse Station, NJ 08889. Revised 12/2014. 13. Ganirelix® Product information. Merck & Co., Inc., Whitehouse Station, NJ 08889. Revised 2/2019. 14. Gonal-F® Product Information. EMD Serono, Inc, Rockland, MA 02370. Revised 1/2017. 15. Menopur® Product Information. Ferring Pharmaceuticals, Inc., Parsippany, NJ 07054. Revised 5/2018. 16. Novarel® Product Information. Ferring Pharmaceuticals, Inc., Parsippany, NJ 07054. Revised 5/2018. 17. Ovidrel® Product information. EMD Serono, Inc, Rockland, MA 02370. Revised 6/2018. 18. Pregnyl® Product Information. Merck & Co., Inc., Whitehouse Station, NJ 08889. Revised 1/2015. Page 6 of 7

Drug Therapy Guidelines Fertility Medications Last Review Date: 6/2021

19. Patient education: Ovulation induction with clomiphene (Beyond the Basics). Uptodate web site. http://www.uptodate.com/contents/ovulation-induction-with-clomiphene-beyond-the-basics. Updated July 14, 2015. Accessed 5, 2017 20. Oktay K, Harvey BE, Partridge AH, et al. Fertility Preservation in Patients With Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol 2018; 36:1994. 21. Practice Committee of the American Society for Reproductive Medicine. Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion. Fertility and Sterility, Volume 100, Issue 5, 1214 – 1223 22. Infertility Workup for the Women’s Health Specialist. ACOG Committee Opinion No 781. American College of Obstetricians and Gynecologists. Obstet Gynecol 2019; 133: e377-384. 23. Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility: a committee opinion. Fertil Steril. 2012 Sep;98(3):591-8. doi: 10.1016/j.fertnstert.2012.05.031. PMID: 22704630. 24. Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril. 2012 Aug;98(2):302-7. doi: 10.1016/j.fertnstert.2012.05.032. PMID: 22698637. 25. Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women: a committee opinion. Fertil Steril. 2013 Aug;100(2):341-8. doi: 10.1016/j.fertnstert.2013.05.033. PMID: 23809505. 26. Practice Committee of the American Society for Reproductive Medicine. Effectiveness and treatment for unexplained infertility. Fertil Steril. 2006 Nov;86(5 Suppl 1):S111-4. doi: 10.1016/j.fertnstert.2006.07.1475. PMID: 17055802. 27. L. Gianaroli, C. Racowsky, J. Geraedts, M. Cedars, A. Makrigiannakis, R. Lobo, Best practices of ASRM and ESHRE: a journey through reproductive medicine, Human Reproduction, Volume 27, Issue 12, December 2012, Pages 3365–3379, https://doi.org/10.1093/humrep/des338 28. Fertility Preservation for Patients with Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2013;31:2500-2510. 29. Gianaroli, Luca & Racowsky, Catherine & Geraedts, Joep & Cedars, Marcelle & Makrigiannakis, Antonis & A Lobo, Roger. (2012). Best practices of ASRM and ESHRE: A journey through reproductive medicine. Fertility and sterility. 98. 10.1016/j.fertnstert.2012.07.1164. 30. Myers ER, Eaton JL, McElligott KA, et al. Management of Infertility. Comparative Effectiveness Review No. 217. (Prepared by the Duke Evidence-based Practice Center under Contract No. 290-2015-00004-I.) AHRQ Publication No. 19-EHC014-EF. Rockville, MD: Agency for Healthcare Research and Quality; May 2019. DOI: https://doi.org/10.23970/AHRQEPCCER217. 31. Centers for Medicare and Medicaid Services. Medicare Benefit Policy Manual: Chapter 15. (CMS Publication No. 100-02). Retrieved from http://www.cms.hhs.gov.

*These guidelines are not applicable to benefits covered under Medicare Advantage. Medicare Advantage benefit coverage requests are reviewed in accordance with the guidance set forth in Chapter 15 Section 50 of the Centers for Medicare & Medicaid Services Medicare Benefit Policy Manual.

The Plan fully expects that only appropriate and medically necessary services will be rendered. The Plan reserves the right to conduct pre-payment and post-payment reviews to assess the medical appropriateness of the above-referenced therapies.

The preceding policy applies only to members for whom the above named pharmacy benefit medications are included on their covered formulary. Members with closed formulary benefits are subject to trying all appropriate formulary alternatives before a coverage exception for a non-formulary agent will be considered.

The preceding policy is a guideline to allow for coverage of the pertinent medication/product, and is not meant to serve as a clinical practice guideline.

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