Archived Policies - Prescription Drugs


Gonadotropin-Releasing Hormone (GnRH) Analogs, Hormones and Antagonists

Number:RX501.041

Effective Date:07-15-2008

End Date:02-28-2009

Coverage:

NOTE:  This policy addresses the singular use of GnRH analogue ALONE.  This policy does not address the combined use of luteinizing hormone-releasing hormone (LHRH) agonists AND anti-androgens.

Gonadotropin-Releasing Hormone (GnRH) analogs, hormones and antagonists are addressed individually by brand names and may be considered medically necessary for the indications listed beneath each drug and:

  • When based on the U.S. Food and Drug Administration (FDA) label indications, or
  • FDA Orphan Drug Designation, or
  • As an off-label listing within a standard reference compendia (The United States Pharmacopoeia Drug Information (USPDI).

Off-label use of FDA approved drugs is considered not medically necessary:

  • When the FDA has determined its use to be contra indicated for a specific condition, or
  • When off-label uses cannot be validated by standard reference compendia or peer reviewed literature.

Plenaxis™ (Abarelix) may be considered medically necessary for the palliative treatment of men with advanced symptomatic prostate cancer, in whom LHRH agonist therapy is not appropriate and who refuse surgical castration, and have one or more of the following:

  • risk of neurological compromise due to metastases, and/or
  • ureteral or bladder outlet obstruction due to local encroachment or metastatic disease, and/or
  • severe bone pain from skeletal metastases persisting and are on narcotic analgesia.

Cetrotide (Antagon) [ganirelix acetate] may be considered medically necessary for infertility treatment to inhibit luteinizing hormone (LH) surges.  (Check member benefit contracts for coverage).

Eligard (Lupron, Viadur) may be considered medically necessary for the following:

A.  Oncology Uses:

  • Prostate cancer patients:
    1. Palliative treatment of advanced prostate cancer, including metastasis, as an alternative to surgery or estrogen administration; or
    2. Advanced prostate cancer, including metastasis, when other hormone therapies are intolerable, surgical castration is not an option, and there are no alternate therapies available; or
    3. Prostate cancer treatment; Stage B2 through C locally confined.
  • Breast cancer patients who are not on concurrent aromatase inhibitor therapy for:
    1. Treatment of advanced or metastatic breast cancer in premenopausal and perimenopausal women; or
    2. Treatment in premenopausal women with hormone receptor positive disease with or without concurrent tamoxifen or ovarian suppression.

B.  Gynecology Uses:

  • Endometriosis:  For pain relief and reduction of lesions for duration of therapy (management of chronic pelvic pain).

NOTE:  The following recommendations from ACOG are based on Level A scientific evidence:  When relief of pain from treatment with a GnRH agonist supports continued therapy, the addition of add-back therapy reduces or eliminates GnRH-induced bone mineral loss without reducing the efficacy of pain relief.

NOTE: The following recommendations are from the Lupron Drug Insert:  If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month course of LUPRON DEPOT and norethindrone acetate 5 mg daily may be considered.  Retreatment beyond this one six-month course cannot be recommended.  It is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits.  Retreatment with LUPRON DEPOT alone is not recommended

  • Uterine Leiomyomata (fibroid):  With iron therapy as a preoperative measure for six months.
  • Infertility:  Treatment to inhibit luteinizing hormone surges (check member benefit contracts for allowance of coverage).

C.  Endocrine Uses:

  • Central precocious puberty (CPP), gonadotropin-dependent, male or female,
  • Endometrial thinning prior to endometrial ablation for dysfunctional uterine bleeding.

Lupron is contraindicated in women who are or may become pregnant while receiving the drug.  Lupron may cause fetal harm when administered to a pregnant woman.

Lutrepulse (Factrel): may be considered medically necessary for the following:

A.   Pituitary:

  • Primary hypothalamic amenorrhea testing or treatment following pituitary surgery; or 
  • Functional capacity and response of gonadotropes of anterior pituitary; or
  • Testing for the luteinizing hormone response for suspected gonadotropin insufficiency.

B.   Endometriosis:  For pain relief and reduction of lesions for duration of therapy (management of chronic pelvic pain).

C.  Breast Cancer:  Palliative treatment of breast cancer in pre- or post-menopausal women.

Zoladex: may be considered medically necessary for the following indications:

A.   Oncology Uses:

  • Prostate Cancer Patients:
    1. Palliative treatment of advanced prostate cancer, including metastasis, as an alternative to surgery or estrogen administration; or
    2. Advanced prostate cancer, including metastasis,  when other hormone therapies are intolerable, surgical castration is not an option, and there are no other alternative therapies available; or
    3. Prostate cancer treatment; Stage B2 through C locally confined.
  • Breast Cancer Patients:  Palliative treatment of breast cancer in pre- or post-menopausal women.

B.   Gynecology Uses:

  • Endometriosis for pain relief and reduction of lesions for up to six months; or
  • Endometriosis for pain relief and reduction of lesions for duration of therapy (the management of chronic pelvic pain); or
  • Endometrial thinning prior to endometrial ablation for dysfunctional uterine bleeding.

Supprelin (Vantas, Histrelin): may be considered medically necessary for the following indications:

A.   Prostate Cancer Patients:

  • Palliative treatment of advanced prostate cancer, including metastasis, as an alternative to surgery or estrogen administration; or
  • Advanced prostate cancer, including metastasis, when other hormone therapies are intolerable, surgical castration is no longer an option, and there are no other alternative therapies available.

BEndocrine Uses:  Central precocious puberty (CPP), gonadotropin-dependent, male or female.

Synarel: may be considered medically necessary for the following indications:

A.  Gynecology Uses:

  • Endometriosis for pain relief and reduction of lesions for up to six months; or
  • Endometriosis for pain relief and reduction of lesions for duration of therapy (the management of chronic pelvic pain).

BEndocrine Uses:  Central precocious puberty (CPP), gonadotropin-dependent, male or female.

Trelstar Depot: may be considered medically necessary for the following indications:

  • Palliative treatment of advanced prostate cancer, including metastasis, as an alternative to surgery or estrogen administration; or
  • Advanced prostate cancer, including metastasis, when other hormone therapies are intolerable, surgical castration is no longer an option, and there are no other alternative therapies available.

Administration of GnRH analogs, hormones and antagonists are considered not medically necessary for the following:

A.  Gynecology Uses:

  • Hypogonadism; or
  • Anovulation with or without accompanying polycystic ovarian disease; or
  • Menstrual cycle regulation with or without amenorrhea; or
  • Menopause; or
  • Delayed puberty; or
  • Advanced metastatic ovarian malignancy or endometrial cancer; or
  • Menstrually related mood disorder.

B.  Prostate Cancer Patients:

  • Benign prostate hypertrophy, or
  • Chemically induced male castration; or
  • Male contraceptive agents or oligospermia.

C.  Miscellaneous Clinical Conditions:

  • Skin conditions (such as itching, redness, dryness, wrinkling, roughness); or
  • Liver cancer; or
  • Non-specific chronic intestinal diseases (such as, pseudo obstruction, functional disease, or hollow visceral neuropathy).

NOTE:  Check contract or legislative provisions which may mandate benefits.

Description:

Acting on the pituitary gland in the brain, GnRH suppresses function of the ovaries and testes, blocking the production of testosterone in males and estrogen in females.  Repeated monthly injections of these drugs cause gonadal hormone dependent tissues or organs to reduce or cease activity, such as the normal prostrate gland that is dependent on testosterone for growth and function.  This effect is reversible on discontinuation of the drug therapy.

Although GnRH products may differ in specific labeled indications and dosing requirements, clinical evidence does not support differential effectiveness of one product over the other for FDA approved clinical indications.

Plenaxis (Abarelix) has been approved for marketing under a voluntary risk management program (RMP) to patients with advanced prostate cancer.  RMP is a strict Prescribing Program, part of an expedited drug approval pathway, to reserve specific pharmaceuticals to patients where the medical benefits outweigh the risks. RMP requirements generally include all of the following:

  • Restricted dispensing of the medication directly to the physician, and
  • Completed educational programs by the physician and patient, and
  • Maintenance of physician and patient registries.

Cetrotide® (cetrorelix acetate [ganirelix acetate] for injection) a synthetic decapeptite analog of gonadotropin-releasing hormone (GnRH), is a GnRH antagonist.  It is used as a component of infertility regimens (recombinant FSH or human menopausal gonadotropin (hMG), centrorelix, and human chorionic gonadotropin (hCG) to inhibit premature luteinizing hormone (LH) surges in women undergoing controlled ovarian stimulation (COS).

Leuprolide acetate (Eligard, Lupron, Viadur) is a synthetic analog of naturally occurring gonadotropin releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone.  Because of its inhibitory effect on gonadotropin secretion and androgen or estrogen synthesis, leuprolide inhibits growth of hormone-dependent tumors.  Leuprolide has reduced the size of the prostate gland and has inhibited prostatic tumor growth. There is also evidence to suggest that leuprolide inhibits the growth of estrogen-dependent mammary tumors mainly by inhibiting ovarian function and estrogen synthesis.

Lutrepulse (Factrel) is another form of gonadotropin-releasing hormone (GnRH) that is naturally released from the hypothalamus gland. GnRH causes the pituitary gland to release other hormones LH and follicle-stimulating hormone [FSH]).  LH and FSH control development in children and fertility in adults.

Supprelin (Vantas) is a GnRH antagonist that lowers the male hormone testosterone in blood.  These two drugs have been designated as an orphan drug.  The orphan designation by the FDA was devised to provide financial incentives to drug manufacturers for research and development of drugs with a small target treatment population (less than 200,000); it does not constitute final FDA approval.  Orphan designation may also be known as “grant-supported products which have marketing approval.” 

Synarel (Nafarelin) is used in the palliative treatment of endometriosis.  This drug like other GnRH analogs produces reversible hypo estrogenic state, which is thought to be principally responsible for the beneficial effects observed in endometriosis.  A six month course of therapy can provide symptomatic relief and a reduction in endometrial lesions.

Synarel (Nafarelin) is also used for the treatment of central (via activation of the hypothalmic-pituitary-gonadal axis) precocious puberty (true precocious puberty GnRH-dependent precocious puberty, complete isosexual precocity) in children of both sexes and has been designated an orphan drug by the FDA for use in this condition.  Precocious puberty is generally defined as the onset of sexual characteristics in girls or boys younger than eight or nine years of age respectively.  The principle goals of therapy with GnRH analogs in this condition are to halt the premature development of secondary sexual characteristics and achieve a near normal adult height by slowing linear growth and skeletal maturation.   

Trelstar is indicated in the palliative treatment of advanced prostate cancer.  It offers an alternative treatment for prostate cancer when orchiectomy or estrogen administration is either not indicated or unacceptable to the patient.

Rationale:

The FDA approves drugs for specific indications that are included in the drug's labeling.  When a drug is used for an indication other than those specifically included in the labeling, it is referred to as an off-label, unlabeled use, or grant supported orphan drug use with marketing approval.  When coverage is allowed for GnRH therapies, it is done based solely on the FDA labeled indications.

Coverage for treatment of breast cancer beyond the approved FDA labeled indications has been based on two clinical studies, over a two year period, comparing ovarian suppression hormones, such as GnRH analogs to conventional chemotherapeutic agents, such as a combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF).  Five years after the completion of one study, no difference between goserelin (Zoladex) and CMF was established in the final outcome review.  Converting patients from an estrogen receptor (ER) positive to negative state, CMF induces significantly better disease free survival and overall survival.

The American College of Obstetrics and Gynecology (2004) recommended the use of gonadotropin-releasing hormone agonists as a treatment option for chronic pelvic pain since they have been demonstrated to relieve endometriosis-associated pelvic pain.  Guidelines from the Royal College of Obstetricians and Gynaecologists (2005) state women with cyclical pelvic pain should be offered a therapeutic trial, using the combined oral contraceptive pill or a GnRH agonist for a period of three- to six-months before having a diagnostic laparoscopy.  The Ling (1999) study represents the one small short-term RCT used for support of empiric therapy for management of chronic pelvic pain.

A MEDLINE search through (October 2007) indicated a lack of peer reviewed scientific literature from which conclusions could be made concerning the safety and efficacy of treatment of various other indications mentioned which were not labeled indications by the FDA, including, but not limited to: premenstrual syndrome; menopause or mood related disorders; chronic intestinal disease; cancer of the endometrium, ovary, or liver; benign prostatic hypertrophy; menstrual cycle regulation; and male castration.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

None


Medicare Coverage:

The information contained in this section is for informational purposes only.  HCSC makes no representation as to the accuracy of this information.  It is not to be used for claims adjudication for HCSC Plans.

Medicare (CMS) does have a national coverage position.

A national coverage position for Medicare may have been developed or changed since this medical policy document was written.  See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

Martikainen, H., Penttinen, J., et al.  Gonadotropin-releasing hormone agonist analog therapy effective in ovarian granulosa cell malignancy.  Gynecologic Oncology (1989 December) 35(3):406-8.

Corrnillie, F.J., Osterlynck, D., et al.  Deeply infiltrating pelvic endometriosis: histology and clinical significance.  Fertility and Sterility (1990 June) 53(6):978-83.

Koninckx, P.R., Meuleman, C., et al.  Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain. Fertility and Sterility (1991 April) 55(4):759-65.

Gallagher, C.J., Oliver, R.T., et al.  Gonadotropin-releasing hormone analog treatment for recurrent progestogen-resistant endometrial cancer.  British Journal of Cancer (1992) 65(Supplement 16):15.

Koninckx, P.R. and D.C. Martin.  Deep endometriosis: a consequence of infiltration or retraction or possibly adenomyosis externa?  Fertility and Sterility (1992 November) 58(5):924-8.

Clemons, R.D., Kappy, M.S., et al.  Long-term effectiveness of depot gonadotropin-releasing hormone analogue in the treatment of children with central precocious puberty.  American Journal of Diseases of Children (1993 June) 147(6):653-7.

Cirkel, U., Ochs, H., et al.  Estrogen and progesterone receptor content of enucleated uterine myomata after luteinizing hormone-releasing hormone.  Analogue depot therapy.  ACTA Obstetrics and Gynecology Scandinavia (1994 April) 73(4):328-32.

Gutmann, J.N., Thornton, K.L., et al.  Evaluation of leuprolide acetate treatment of histopathology of uterine myomata.  Fertility and Sterility (1994 April) 61(4):622-6.

Mathias, J.R., Clench, M.H., et al.  Effect of leuprolide acetate in patients with functional bowel disease.  Long-term follow-up after double-blind, placebo-controlled study.  Digestive Diseases & Sciences (1994 June) 39(6):1155-62 and 1163-70.

Stovall, T.G., Summit, R.L. Jr., et al.  Gonadotropin-releasing hormone agonist used before hysterectomy.  American Journal of Obstetrics (1994 June) 170(6):1744-8.

Kiltz, R.J., Rutgers, J., et al.  Absence of a dose-response effect of leuprolide acetate on leiomyomata uteri size.  Fertility and Sterility (1994 June) 61(6):1021-6.

Rivlin, M.E., Patel, R. B., et al.  Leuprolide acetate depot for the treatment of uterine leiomyomas.  Changes in bone density, uterine volume, and uterine vascular resistive index. Journal of Reproductive Medicine (1994 September) 39(9):663-6.

De Aloysio, D., Altieri, P., et al.  The combined effect of a GnRH analog in premenopausal estrogen deficiency for the treatment of uterine leiomyomas in perimenopausal women. Gynecologic and Obstetric Investigation (1995) 39(2):115-9.

Watanabe, Y. and G. Nakamura.  Effects of two different doses of leuprolide acetate depot on uterine cavity area in patients with uterine leiomyomata.  Fertility and Sterility (1995 March) 63(3):487-90.

Demco, L.  Mapping the source and character of pain due to endometriosis by patient-assisted laparoscopy.  The Journal of the American Association of Gynecologic Laparoscopists (1998 August) 5(3):241-5.

Ling, F.W.  Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis.  Obstetrics and Gynecology (1999 January) 93(1): 51-8.

van der Kwast, T.H., Tetu, B., et al.  Prolonged neoadjuvant combined androgen blockade leads to a further reduction of prostate tumor volume: three versus six months of endocrine therapy. Urology (1999 March) 53(3):523-9.

Medical Management of Endometriosis – Position paper.  Washington, D.C.: ACOG Practice Bulletin (1999 December) (11):1-14.

Cada, Dennis J., Pharm, D., et al. of the Editorial Advisory Panel. 2000. Drugs, Facts and Comparisons, St. Louis, Facts and Comparisons, A Wolters Kluwer Company, (2000 January).

Van Poppel, H.  Neoadjuvant hormone therapy and radical prostatectomy: the jury is still out. European Urology (2001) 39 Supplement 1:10-4.

Osuga, Y., Yano, T., et al.  Effects of gonadotropin-releasing hormone analog treatment on skin condition.  Gynecological Endocrinology (2002 February) 16(1): 57-61.

Bono, A.V., Salvadore, M., et al.  Gonadotropin-releasing hormone receptors in prostate tissue. Analytical and Quantitative Cytology and Histology (2002 August) 24(4): 221-7.

Review by United States Pharmacopeial Convention, Inc.  2003 Edition Drug Information for the Health Care Professional. Volume 1. Colorado: Thomason MICROMEDEX (2003).

Miller, N.L., Bissonette, E.A., et al.  Impact of novel neoadjuvant and adjuvant hormone-deprivation approach on quality of life, voiding function, and sexual function after prostate brachytherapy. Cancer (2003 March 1) 97(5):1203-10.

Pollack, A., Grignon, D.J., et al.  Prostate cancer DNA ploidy and response to salvage hormone therapy after radiotherapy with or without short-term total androgen blockade: an analysis of RTOG 8610.  Journal of Clinical Oncology (2003 April 1) 21(7):1238-48.

Tiguert, R., Rigaud, J., et al.  Neoadjuvant hormone therapy before salvage radiotherapy for an increasing post-radical prostatectomy serum prostate specific antigen level.  Journal of Urology (2003 August) 170(2 Part 1):447-50.

McEvoy, G.K., Miller, J., eds. et al.  American Society of Health-System Pharmacists, American Hospital Formulary Service (AHFS). Bethesda, Maryland: Drug Information (2003).

Lupron Depot, Lupron Depot-Ped, Lupron Depot- 3 Month, Lupron Depot- 4 Month): 1057;

Vantas (histrelin acetate) – Product information. Cranbury, New Jersey: Valera Pharmaceuticals (2004 October).

Drug Information for the Health Care Professional (USPDI) 25th edition.  Thompson MICROMEDEX.  Greenwood Village, Colorado: 2005 edition.

ACS – Histrelin Acetate Implant, Vantas. 2004. American Cancer Society – Cancer Drug Guide (2005 May 26) <http://www.cancer.org>.

Chronic Pelvic Pain – Position paper.  Washington, D.C.: ACOG Practice Bulletin (2004 March) (51):1-16.

Borgsdorf, Lawrence R., et al. of the Editorial Advisory Panel. 2006. Drugs, Facts and Comparisons, St. Louis, Missouri: Facts and Comparisons. A Wolters Kluwer Company (2006 January).

Cantineau, A.E., Cohlen, B.J., et al.  Ovarian stimulation protocols (anti-oestrogens, gonadotrophins with and without GnRH agonists/antagonists) for intrauterine insemination

(IUI) in women with subfertility.  Cochrane Database System Review (2007) (2):CD005356.

Kastrup, E.K, ed., et al.  Drugs Facts and Comparisons, St. Louis, Missouri: Facts and Comparisons, Inc.  A Wolters Kluwer Company (2005-2007) GnRH (2007 October).

Policy History:

7/15/2008        Coverage Revised

4/15/2008        Revised/Updated Entire Document

7/15/2007        Coverage Revised

11/15/2006      Revised/Updated Entire Document

1/1/2006          Coverage Revised

7/1/2005          Codes Revised/Added/Deleted

3/29/2005        Coverage Revised

10/1/2004        Revised/Updated Entire Document

6/2001             Codes Revised/Added/Deleted

9/1996             Revised/Updated Entire Document

5/1996             Document number change

7/1995             Revised/Updated Entire Document

10/1994           Revised/Updated Entire Document

7/1993             Revised/Updated Entire Document

7/1992             Revised/Updated Entire Document

4/1992             Revised/Updated Entire Document

5/1990             New Medical Document

Archived Document(s):

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