Archived Policies - Prescription Drugs


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

Number:RX501.041

Effective Date:03-29-2005

End Date:06-30-2005

Coverage:

Gonadotropin-Releasing Hormone (GnRH) Analogs, Hormones, and Antagonists (listed by their brand names with their accompanying CPT/HCPCS code, if available) are considered medically necessary (MN) and services are eligible for reimbursement when (based upon the FDA Label indications OR as a Label/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 provisions.

Off-Label use of FDA approved drugs is 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.

 

 

Clinical Conditions:

Gonadotropin-Releasing Hormones:

Plenaxis

Cetrotide

Antagon

Lutrepulse or Factrel   

Zoladex

Supprelin

Eligard or Lupron or Viadur

Synarel

Trelstar

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

NMN

NMN

NMN

NMN

*MN*

NMN

*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

NMN

NMN

NMN

NMN

NMN

NMN

Prostate cancer treatment; Stage B2 through C locally confined

NMN

NMN

NMN

NMN

*MN*

NMN

*MN*

see Note 2

NMN

NMN

Primary hypothalamic amenorrhea treatment following pituitary surgery or irradiation

NMN

NMN

NMN

*MN*

see Note 3

NMN

NMN

NMN

NMN

NMN

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

NMN

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

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

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

NMN

*MN*

Using Lupron only, not Eligard or Viadur. See Note 8

NMN

NMN

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

NMN

*MN*

*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

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

NMN

*MN*

 

see Note 9

*MN*

Using Lupron or Viadur, not Eligard.

NMN

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 means 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.

NOTE 1:         Advanced prostate cancer therapy; documentation of 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 studies 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 3 (three) to 6 (six) months prior to, in conjunction with, or as post surgical or radiation management of localized prostate cancer.  Beyond 6 (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 6 (six) months.

NOTE 4:         Endometriosis; documentation verified by operative and/or tissue report 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.  For individual consideration may be approved if the treatment is a temporary measure and allowed up to 6 (six) months.

NOTE 5:         Endometriosis (SEVERE); documentation verified by operative and/or tissue report 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 6 (six) months.

NOTE 6:         Endometriosis (SEVERE) or Chronic Pelvic Pain; documentation verified by operative and/or tissue report in a patient who is not being treated for infertility and is not responsive to conservative medical treatment, such as oral contraceptives or progestins; 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 6(six) months.  In addition, up to the 6 (six) months, the treatment plan may change every 3 (three) months.  Records should indicate prior medication treatment failure and surgical intervention plans.

NOTE 7:         Endometrial thinning prior to endometrial ablation; documentation of a confirmed of a surgical treatment plan in 3 (three) months.

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 6 (six) months.

NOTE 9:         Central precocious puberty or centrally mediated precocious puberty; early appearance of secondary sexual characteristics before the age of 8 (eight) in girls and the age of 9 (nine) in boys for the conclusion of therapy by age 11 (eleven) in girls and by age 12 (twelve) in boys.  The average length of treatment is greater than 6 (six) months.

Administration of Gonadotropin-Releasing Hormone (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 Gonadotropin-Releasing Hormone (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 Gonadotropin-Releasing Hormone (GnRH) Analogs, Hormones, and Antagonists are considered experimental, investigative, or unproven for the following, including but not limited to, treatment of clinical conditions:

  • 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.  Using the pituitary gland in the brain, GnRH suppresses functions of the ovaries and testes.

Repeated monthly injections of these drugs cause gonadal hormone dependent tissues/organs to reduce or cease activity, such as the normal prostrate gland that is dependent on testosterone for the growth and function.  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
  • 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 will be done 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 studies as a treatment for endometriosis in addition to other indications, such as benign prostatic hypertrophy, breast cancer, and uterine fibroids.

NOTE:   This policy addresses the singular use of GnRH analogue ALONE.    This policy does not address the combined use of 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 or unlabeled use.  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 CMR was established in the final outcome review.  Converting patients from an estrogen receptor (ER) positive to negative state, CMR 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 treating 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)
  • Plenaxis; S0165 (injection injection, 100 mg)
  • Cetrotide, Viadur, Synarel; J3490 (unclassified drugs, no specific code available)

Medicare Coverage:

Medicare will cover all labeled and bracketed indications of GnRH as documented in the USPDI and/or Physician's Desk Reference.

Coverage of injections is allowable only if the drug is furnished and administered by the physician or by auxiliary personnel under general physician supervision in the physician's office or in the patient's home.

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.

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.

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.

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.

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. AmericanHospitalFormulary 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.

Policy History:

Archived Document(s):

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