Archived Policies - Prescription Drugs


Gonadotropin-Releasing Hormone (GnRH) Therapy for Cancer and Human Reproduction

Number:RX501.041

Effective Date:11-15-2006

End Date:07-14-2007

Coverage:

Gonadotropin-Releasing Hormone (GnRH) Analogs, Hormones, and Antagonists (listed by their brand names with their accompanying CPT/HCPCS code, if available) may be considered medically necessary (MN) and services may be eligible for reimbursement:

  • When (based upon the U.S. Food and Drug Administration (FDA) label indications or by FDA Orphan Drug Designation OR
  • As an off-label listing within a standard reference compendia (SRC) or supported by clinical research that appears in peer-reviewed literature (PRL) specific for the indication in question) the uses are intended for the various clinical conditions provided in the following grid. 

Those allowed services are identified in the grid by *MN* with or without an accompanying directive for further review notes or provisions below the grid.

Off-Label use of FDA approved drugs is considered not medically necessary (NMN):

  • When the FDA has determined its use to be contraindicated for treatment of the condition for which coverage is requested OR
  • When off-label uses can not be validated by SRC or PRL documentation. 

Those not allowed services are identified in the grid by NMN.

SPECIAL COMMENT ON OFF-LABEL USE INDICATION DOCUMENTATION REQUIREMENT:

SRC or PRL documentation is required when the administration of the GnRH drug is provided for a MN service and is not indicated as an off-label use on the following grid.  PRL is a published scientific study including a trial that is preferably large, multi-centered and prospective, double blinded and randomized.  PRL does not include publications or research studies that are sponsored to a significant extent by a pharmaceutical company or financially interested parties.

 

 

Clinical Conditions:

Gonadotropin-Releasing Hormones:

Plenaxis

Cetrotide or Antagon

Lutrepulse or Factrel   

Zoladex

Supprelin

or Vantas

Eligard

or Lupron or Viadur

Synarel

Trelstar

Palliative treatment of advanced prostate cancer, including metastasis, as an alternative to surgery or estrogen administration

*MN*

see Note 1

NMN

NMN

*MN*

*MN*

Using Vantas only, not Supprelin.

*MN*

NMN

*MN*

Advanced prostate cancer, including metastasis,  when other hormone therapies are intolerable, surgical castration is no longer an option, and no other alternative therapies available

*MN*

see Note 1

NMN

NMN

*MN*

*MN*

Using Vantas only, not Supprelin.

 

*MN*

 

NMN

*MN*

Prostate cancer treatment; Stage B2 through C locally confined

NMN

NMN

NMN

*MN*

NMN

*MN*

see Note 2

NMN

NMN

Primary hypothalamic amenorrhea testing or treatment following pituitary surgery or irradiation OR functional capacity and response of gonadotropes of anterior pituitary OR testing for the luteinizing hormone response for suspected gonadotropin insufficiency

NMN

NMN

*MN*

see Note 3

Using Factrel used for Testing OR Lutrepulse for Treatment

NMN

NMN

NMN

NMN

NMN

Endometriosis for pain relief and reduction of lesions for up to 6 (six) months

NMN

NMN

NMN

*MN*

Based on SRC Label Use. See Notes 4 & 5

NMN

*MN*

see Notes 3 & 4

*MN*

see Notes 3 & 4

NMN

Endometriosis for pain relief and reduction of lesions for duration of therapy (the management of chronic pelvic pain)

NMN

NMN

*MN*

see Note 6

*MN*

Based on SRC Label Use. See Note 6

NMN

*MN*

Based on SRC Label Use. See Note 6

*MN*

Based on SRC Label Use. See Note 6

NMN

Endometrial thinning prior to endometrial ablation for dysfunctional uterine bleeding

NMN

NMN

NMN

*MN*

see Note 7

NMN

NMN

NMN

NMN

Uterine leiomyomata (fibroid) with iron therapy as a preoperative measure for 6 (six) months

NMN

NMN

NMN

NMN

NMN

*MN*

See Note 8

NMN

NMN

Infertility treatment to inhibit luteinizing hormone surges (check member benefit contracts for allowance of coverage)

NMN

*MN*

NMN

NMN

NMN

*MN*

Using Lupron only, not Eligard or Viadur.

NMN

NMN

Palliative treatment of breast cancer in pre- or post-menopausal women

NMN

NMN

*MN*

Based on SRC Label Use.

 

*MN*

NMN

*MN*

Based on SRC Label Use.

 

NMN

NMN

Central precocious puberty (CPP), gonadotropin-dependent, male or female

NMN

NMN

NMN

NMN

*MN*

see Note 9

Using Supprelin only, not Vantas.

 

*MN*

 

*MN*

NMN

NOTE 1:         Advanced prostate cancer therapy; documentation may be requested verifying  strict adherence to the FDA's Risk Management Program (RMP) guidelines. About 5 to 10% of men with prostate cancer have advanced to the point where they become candidates for Plenaxis.  The drug manufacturer (sponsor) will ensure that patients and providers are fully informed of the risks and benefits of Plenaxis before using it.  The sponsor will only be distributing Plenaxis to providers who attest to certain qualifications and are enrolled in the Praecis' Plenaxis PLUS (Plenaxis User Safety) Program.  The sponsor will be conducting study assessments of the RMP, including an assessment of the prescribing and actual use of Plenaxis.

NOTE 2:         Prostate cancer treatment; early, neoadjuvant or adjuvant hormonal therapy is often used for three to six months prior to, in conjunction with, or as post surgical or radiation management of localized prostate cancer.  Beyond six months, prostate cancer cells may become resistant to the hormonal therapy.  However, there is no limitation in benefit coverage.

NOTE 3:         Post-treatment induced amenorrhea; documentation verified by operative and/or radiological therapy report in a patient who experiences surgical or radiation induced amenorrhea.  Treatment plan may be a temporary measure and allowed up to six months.

NOTE 4:         Endometriosis; documentation of a thorough history and physical in a patient who desires to maintain fertility, having failed conservative medical treatment (including laparoscopic fulguration or laser treatment) and because of medical or surgical problems that preclude performing surgery.  Treatment plan may be a temporary measure and allowed up to six months.

NOTE 5:         Endometriosis (SEVERE); documentation of a thorough history and physical in a patient who desires to maintain fertility and because of medical or surgical problems that preclude performing surgery.  Treatment plan may be a temporary measure and allowed up to six months.

NOTE 6:         Endometriosis (SEVERE) or Chronic Pelvic Pain; documentation of a thorough history and physical in a patient who is not being treated for infertility and is not responsive to conservative medical treatment, such as oral contraceptives, progestins or nonsteroidal inflammatory drugs; and, the patient opts for medical treatment rather than surgical intervention, such as a hysterectomy.  Treatment plan may be a temporary measure and allowed up to six months.  During the six month treatment period, the treatment plan may change every three months.  Records should indicate prior medication treatment failure and/or surgical intervention plans.

NOTE 7:         Endometrial thinning prior to endometrial ablation; documentation of a surgical treatment plan within three months of initiating GnRH treatment.

NOTE 8:         Uterine leiomyomata; documentation of scheduled myomectomy or hysterectomy at the completion of GnRH treatment.  Treatment plan may be a temporary measure and allowed up to six months.

NOTE 9:         Central precocious puberty or centrally mediated precocious puberty; early appearance of secondary sexual characteristics before the age of eight in girls and the age of nine in boys for the conclusion of therapy by age eleven in girls and by age twelve in boys.  The average length of treatment is greater than six months.

Administration of GnRH Analogs, Hormones and Antagonists are considered not medically necessary UNLESS contract or legislative provision mandate benefits (such as those patients who have in-vitro fertilization benefits as menstrual cycle regulation may be a step in the in-vitro fertilization process) for the following, including but not limited to, treatment of the clinical conditions:

  • Hypogonadism; OR
  • Anovulation with or without accompanying polycystic ovarian disease; OR
  • Menstrual cycle regulation with or without amenorrhea.

Administration of GnRH Analogs, Hormones, and Antagonists are considered not medically necessary for the following, including but not limited to, treatment of clinical conditions:

  • Benign prostate hypertrophy (such as, preoperative shrinking of an enlarged prostate in preparation for a transurethral resection prostatectomy); OR
  • Chemically induced male castration; OR
  • Male contraceptive agents or oligospermia; OR
  • Menopause; OR
  • Delayed puberty.

Administration of GnRH Analogs, Hormones, and Antagonists are considered experimental, investigative, or unproven for ALL clinical conditions not listed previously as covered in this policy including, but not limited to:

  • Advanced metastatic ovarian malignancy or endometrial cancer; OR
  • Menstrually related mood disorder; OR
  • Skin conditions (such as redness, itching, dryness, wrinkling, roughness); OR
  • Liver cancer; OR
  • Non-specific chronic intestinal diseases (such as, pseudo obstruction, functional disease, or hollow visceral neuropathy.

Description:

GnRH is a synthetic analogue of naturally occurring GnRH with greater potency than the natural hormone.  Repeated monthly injections of GnRH drugs will suppress the pituitary gland in the brain resulting in gonadal hormone dependent tissues or organs, such as the ovaries or testes, to reduce or cease activity.  This effect is reversible on discontinuation of the drug therapy.

The following is a listing of GnRH products by their generic name with the primary purpose, brand name, and FDA approval date when available:

  • Abaralex Depot (Antagonist), Plenaxis, November 2003
  • Cetrolrelix Acetate (Antagonist), Cetrotide, August 2000
  • Ganirelix Acetate (Antagonist), Antagon, July 1999
  • Gonardorelin Acetate (Hormone), Lutrepulse or Factrel, October 1989
  • Goserelin Acetate (Analog), Zoladex, June 1997
  • Histrelin Acetate (Hormone), Supprelin, December 1991
  • Histrelin Acetate (Hormone), Vantas, October 2004
  • Leuprolide Acetate (Analog), Eligard, pending approval
  • Leuprolide Acetate (Analog), Lupron and Lupron Depot, October 1986
  • Leuprolide Acetate (Analog), Viadur, March 2000
  • Nafarelin Acetate, (Hormone), Synarel, during 1990
  • Triptorelin Pamoate (Analog), Trelstar Depot and Trelstar LA, June 2000.

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 approved clinical indications.

Plenaxis 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,
  • Completed educational programs by the physician and patient, and
  • Maintenance of physician and patient registries.

Plenaxis is being evaluated in phase III clinical studies as a treatment for endometriosis in addition to other indications, such as benign prostatic hypertrophy, breast cancer, and uterine fibroids.

Supprelin and Vantas 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”. 

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

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 positive to negative state, CMF induces significantly better disease free survival and overall survival.

A lack of scientific evidence from which conclusions can be made concerning the safety and efficacy of prescribing for various other indications mentioned as clinical conditions and not a labeled indication by the FDA, such as:

  • premenstrual syndrome, OR
  • menopause or mood related disorders, OR
  • polycystic ovarian disease, OR
  • chronic intestinal disease, OR
  • cancer of the endometrium, ovary, or liver, OR
  • benign prostatic hypertrophy, OR
  • menstrual cycle regulation, OR
  • male castration. 

Further research with randomized, controlled, clinical trials is required to determine achievable outcomes outside the investigational setting.

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:

Relationship between GnRHs and applicable codes:

  • Lutrepulse (or Factrel); J1620 (injection, per 100 mcg)
  • Lupron Depot; J1950 (depot suspension per 3.75 mg)
  • Trelstar Depot; J3315 (injection, 3.75 mg)
  • Zoladex; J9202 (implant, per 3.6 mg)
  • Lupron Depot, Eligard; J9217 (depot suspension per 7.5 mg)
  • Lupron; J9218 (injection, per 1 mg)
  • Lupron; J9219 (implant, 65 mg)
  • Supprelin; Q2020 (injection, 10 mg)
  • Antagon; S0132 (injection, 250 mcg)
  • Vantas; S0133 (implant, 50 mg)
  • Plenaxis; S0165 (injection, 100 mg)
  • Cetrotide, Viadur, Synarel; J3490 (no specific code available)

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.

Except for Abarelix for the treatment of prostate cancer, Medicare does not have a national position on this service. It is subject to local carrier discretion. Please refer to the local carrier for more information.  The Medicare National Coverage Determination allows for use of Abarelix as reasonable and necessary as a palliative treatment for patients with advanced symptomatic prostate cancer.

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 deport 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):

  • Gonadorelin Acetate (Lutrepulse) (2000 January): 253-4;
  • Nafarelin Acetate (Synarel) (2000 January): 254-6;
  • Histrelin Acetate (Supprelin) (2000 January): 256-8;
  • Ganirelix Acetate (Antagon) (2000 November): 258a;
  • Cetrorelix Acetate (Cetrotide) (2000 November): 258b-c;
  • Leuprolide Acetate (Leuprolide Acetate Injection, Lupron, Lupron for Pediatric Use, Lupron Depot, Lupron Depot-Ped, Lupron Depot- 3 Month, Lupron Depot- 4 Month, Viadur) (2001 January): 1909-13;
  • Goserelin Acetate (Zoladex) (2001 January): 1913-5a;
  • Triptorelin Pamoate (Trelstar Depot, Trelstar LA) (2002 November): 1915a-6;
  • Leuprolide Acetate (Eligard) (2002 April): KU-67.

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):

  • Cetrorelix Acetate (Cetrotide): 773;
  • Ganirelix Acetate (Antagon): 1402;
  • Goserelin Acetate (Zoladex): 1430;
  • Leuprolide Acetate (Leuprolide Acetate Injection, Lupron,   Lupron for Pediatric Use, Lupron Depot, Lupron Depot-Ped, Lupron Depot- 3 Month, Lupron Depot- 4 Month): 1704;
  • Leuprolide Acetate (Viadur): 1704;
  • Nafarelin Acetate (Synarel): 1964;
  • Triptorelin Pamoate (Trelstar Depot, Trelstar LA): 2662.

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.

Review by American Society of Health-System Pharmacists. American Hospital Formulary Service, 2003 Drug Information. Maryland: ASHP (2003):

  • Abarelix Depot (Plenaxis): KU-15;
  • Goserelin Acetate (Zoladex): 1010;
  • Leuprolide Acetate (Leuprolide Acetate Injection, Lupron,  Lupron for Pediatric Use, Lupron Depot, Lupron Depot-Ped, Lupron Depot- 3 Month, Lupron Depot- 4 Month): 1057;
  • Triptorelin Pamoate (Trelstar Depot, Trelstar LA): 1150;
  • Nafarelin Acetate (Synarel): 2958;
  • Cetrorelix Acetate (Cetrotide): 3569;
  • Ganirelix Acetate (Antagon): 3628.

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

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, Facts and Comparisons, A Wolters Kluwer Company, (2006 January):

  • Gonadorelin Acetate (Lutrepulse) (2000 January): 253-4;
  • Nafarelin Acetate (Synarel) (2000 January): 254-6;
  • Histrelin Acetate (Supprelin) (2000 January): 256-8;
  • Ganirelix Acetate (Antagon) (2000 November): 258a;
  • Cetrorelix Acetate (Cetrotide) (2000 November): 258b-c;
  • Abarelix (Plenaxis) (2004 February): 258d-e;
  • Leuprolide Acetate (Leuprolide Acetate Injection, Lupron, Lupron for Pediatric Use, Lupron Depot, Lupron Depot-Ped, Lupron Depot- 3 Month, Lupron Depot- 4 Month, Viadur) (2006 April): 1909-13d;
  • Goserelin Acetate (Zoladex) (2001 January): 1914-15;
  • Triptorelin Pamoate (Trelstar Depot, Trelstar LA) (2002 November): 1915a-6;
  • Gonadorelin HCl (Factrel) (2001 August): 1978a;
  • Leuprolide Acetate (Eligard) (2006 April):1909-13d.

Policy History:

Archived Document(s):

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