BlueCross and BlueShield of Montana Medical Policy/Codes
Gonadotropin-Releasing Hormone (GnRH) Agonists and Antagonists
Chapter: Drugs - Medical Benefit
Current Effective Date: August 27, 2013
Original Effective Date: August 27, 2013
Publish Date: May 27, 2013
Description

Acting on the pituitary gland in the brain, gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), stimulates the function of the testes and ovaries.  GnRH analogs are synthetic peptide drugs modeled after the human hypothalamic GnRH.  Two types of analogs have been distinguished – GnRH agonists and GnRH antagonist.  GnRH agonists drugs interacts with GnRH receptors to elicit its biologic response, the release of pituitary gland hormones – follicle stimulating hormones (FSH) and luteinizing hormone (LH).  GnRH antagonist drugs competitively and reversibly binds to the GnRH receptors in the pituitary gland, blocking or suppressing the release of FSH and LH.  In men, the reduction of LH subsequently leads to rapid suppression of testosterone release from the testes.  In women, the reduction leads to suppression of estrogen release from the ovaries. 

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 U.S. Food and Drug Administration (FDA) approved clinical indications.

Abarelix (Plenaxis) has been approved, as an injectable form of a GnRH antagonist, 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.

NOTE:  Plenaxis was originally approved November 25, 2003, but was withdrawn from the market in May 2005.  Patients who were on Plenaxis before it was withdrawn were “grandfathered”; currently, Plenaxis is only available to patients who have continued on it since being grandfathered

Cetrorelix Acetate (Cetrotide) is a synthetic injectable decapeptide analog of GnRH, a GnRH antagonist.  It is used as a component of infertility regimens (recombinant FSH or human menopausal gonadotropin [hMG], Cetrorelix, and human chorionic gonadotropin [hCG]) to inhibit premature LH surges in women undergoing controlled ovarian stimulation (COS). 

Degarelix Acetate (Firmagon) is a GnRH antagonist injectable for the treatment of adult male patients with advanced hormone-dependent prostate cancer and is administered by subcutaneous injection.  Firmagon reduces levels of prostate specific antigen (PSA) by blocking the GnRH receptors in the pituitary gland.  Blocking these receptors suppresses the luteinizing hormone, which decreases production of testosterone by the testicles.  Since prostate cancer is dependent on testosterone for growth, the growth of prostate cancer slows down.

Ganirelix Acetate (Antagon) injection is a synthetic decapeptide analog of GnRH, like cetrorelix acetate, and a GnRH antagonist.  This drug is used for infertility treatment to inhibit LH surges.

Goseralin Acetate (Zoladex) is a GnRH analog, which is indicated in certain conditions requiring suppression of estrogen or testosterone secretion.  At this time, Zolodex is available as a long acting, continuous releasing subcutaneous implant for a period of 28 days.

Histrelin Acetate (Supprelin LA or Vantas) is a GnRH antagonist that lowers the male hormone testosterone in blood.  Both Supprelin LA and Vantas are available as subcutaneous implants for continuous release of the drug.  Supprelin LA is utilized for treatment of children with central precious puberty, where as Vantas is indicated in the palliative treatment of advanced prostate cancer. 

NOTE:  In 2007, Supprelin (not Supprelin LA) marketing has been discontinued, no longer available.

Leuprolide Acetate (Eligard, Lupron, or Viadur) is a synthetic analog of naturally occurring GnRH or LHRH and an antagonist.  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.  Eligard and Lupron are available as injectables, where as Viadur is an implant. 

Nafarelin Acetate (Synarel), a metered nasal spray, 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 is also used for the treatment of central (via activation of the hypothalamic-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.  

Triptorelin Pamoate (Trelstar®, Trelstar Depot® or Trelstar LA®) injection 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.

Policy

Prior authorization is recommended. To authorize, call Blue Cross and Blue Shield of Montana (BCBSMT) Customer Service at 1-800-447-7828 or fax your request to the Medical Review Department at 406-441-4624. A retrospective review is performed if services are not prior authorized.

Medically Necessary

BCBSMT may consider Gonadotropin-Releasing Hormone (GnRH) agonists and antagonists, addressed individually by generic names with brand names, medically necessary for the indications listed, in the Indications Table below, beside each drug and when:

  • There are FDA approved label indications; or
  • The FDA has granted an Orphan Drug Designation to the drug; or
  • There is an off-label listing within a standard reference compendia (such as the United States Pharmacopoeia Drug Information [USPDI] or the American Society of Health Systems Pharmacists’ American Hospital Formulary Service [AHFS]).

INDICATIONS TABLE

If the drug therapy is:

Then the medically necessary indications may include:

Abarelix Depot (Plenaxis),

For the palliative treatment of men with advanced symptomatic prostate cancer in whom luteinizing-hormone-releasing hormone (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, persistent bone pain from skeletal metastases that is unrelieved by narcotic analgesia.

Cetrorelix Acetate (Cetrotide®),

For the following indications:

  • Infertility treatment to inhibit luteinizing hormone (LH) surges (check member benefit contracts for coverage); or
  • In the treatment of uterine leiomyomas in premenopausal women.

Degarelix Acetate (Firmagon®),

For advanced prostate cancer treatment, including metastasis, when other hormone therapies are intolerable, surgical castration is not an option, and there are no other alternative therapies available.

Ganirelix Acetate (Antagon®),

For infertility treatment to inhibit LH surges (check member benefit contracts for coverage).

Goseralin Acetate (Zoladex®),

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: 
  1. Palliative treatment of breast cancer in pre- or post-menopausal women; or
  2. Adjuvant treatment of hormone receptor-positive, axillary lymph node-positive disease in premenopausal women.

BGynecology Uses:

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

C.  In Vitro Uses:  Infertility treatment to desensitize the pituitary gland prior to ovarian stimulation (check member benefit contracts for coverage).

D.  Endocrine Uses:  Central precocious puberty (CPP), gonadotropin-dependent, with onset of secondary sexual characteristics earlier than nine years for males and eight years for females.

Histrelin Acetate (Supperlin LA® or Vantas®)

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:  CPP, gonadotropin-dependent, with onset of secondary sexual characteristics earlier than nine years for males and eight years for females.

Leuprolide Acetate (Eligard®, Lupron® or Viadur®),

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 alternate therapies available; or
    3. Prostate cancer neoadjuvant 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 peri menopausal women; or
    2. Treatment in premenopausal women with hormone receptor positive disease with or without concurrent tamoxifen or ovarian suppression.
  • Ovarian cancer patients for treatment of ovarian stromal tumors, relapsing granulosa cell tumors of the ovary, recurrent epithelial ovarian cancers, primary peritoneal cancer, and/or fallopian tube cancer.

B.  Gynecology Uses:

  • Endometriosis for pain relief and reduction of lesions for duration of therapy (management of chronic pelvic pain); or
  • In the treatment of uterine leiomyomas in premenopausal women.

C.  Endocrine Uses: 

  • CPP, gonadotropin-dependent, with onset of secondary sexual characteristics earlier than nine years for males and eight years for females; or
  • Endometrial thinning prior to endometrial ablation for dysfunctional uterine bleeding.

D.  In Vitro Uses:  Infertility treatment to inhibit LH surges (check member benefit contracts for coverage).

Nafarelin Acetate (Synarel®),

For the following indications:

A.  Gynecology Uses:

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

B.  Endocrine Uses: 

  • CPP, gonadotropin-dependent, with onset of secondary sexual  characteristics earlier than nine years for males and eight years for females; or
  • Hirsutism due to ovarian androgen hypersecretion.

Triptorelin Pamoate (Trelstar®, Trelstar Depot® or Trelstar LA®),

For the following indications:

A.  Oncology Uses:

  • 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.

B.  Non-Oncology Uses:  Benign fibrocystic mastopathy (fibrocystic disease of the breast) for up to three months.

C.  Gynecology Uses:

  • Endometriosis for pain relief and reduction of lesions for up to six-months of treatment; or
  • Endometriosis for pain relief and reduction of lesions for duration of therapy (the management of chronic pelvic pain) for up to six-months of treatment; or
  • Hyperplastic endometrium; or
  • In the treatment of uterine leiomyomas in premenopausal women.

D.  In Vitro Uses:  Infertility treatment to pituitary suppression prior to ovarian stimulation (check member benefit contracts for coverage);

E.  Endocrine Uses:  CPP, gonadotropin-dependent, with onset of secondary sexual characteristics earlier than nine years for males and eight years for females.

**If pharmacy benefits are handled through a third party vendor, such as Prime Therapeutics, they will handle the reviews, appeals, and process claims for some of these drugs.

Not Medically Necessary

BCBSMT considers administration of GnRH analogs, hormones and antagonists, in addition to the table above, not medically necessary for all other indications, including but not limited to:

  • Anovulation with or without accompanying polycystic ovarian disease;or
  • Benign prostate hypertrophy; or
  • Chemically induced male castration; or
  • Delayed puberty; or
  • Hypogonadism; or
  • Liver cancer; or
  • Male contraceptive agents or oligospermia; or
  • Menopause; or
  • Menstrual cycle regulation with or without amenorrhea; or
  • Menstrually related mood disorder; or 
  • Non-specific chronic intestinal diseases (such as, pseudo obstruction, functional disease; or hollow visceral neuropathy); or
  • Skin conditions (such as itching; redness; dryness; wrinkling; or roughness).

NOTE:  An off-label indication for an FDA approved drug that is not addressed in the coverage table above is considered not medically necessary when:

  • The FDA has determined its use to be contraindicated for a specific condition; or
  • The off-label use cannot be validated by standard reference compendia or peer reviewed literature.

Advanced Member Notice of Financial Liability for Denied Services

When the criteria for coverage is not met, BCBSMT encourages all participating providers to have a member complete and sign an Advanced Member Notification (AMN) form, stating that BCBSMT will not cover this service, supply, device, or drug. If an AMN is signed prior to delivery of the service, participating providers can balance bill the member. If an AMN is not signed, participating providers are financially liable for the service and cannot balance bill the BCBSMT member for denied services. Services deemed Not Medically Necessary, or Investigational that are provided by an out-of-state (Montana) or Out-of-Network provider are the financial responsibility of the member regardless of a completed AMN.

Refer to the Advanced Member Notification medical policy for more information.  The AMN form is available at www.bcbsmt.com (Click on Providers and then Forms).

Policy Guidelines

DOSING TABLE

NOTE:  Drug dosing recommendations in the Medical Policy follow FDA approved dosage in the product label.  A prescription for doses that exceed the product label must be accompanied by citation of clinical studies that support a higher dose regimen.

Drug:

Dosage(s):

Abarelix Depot

(Plenaxis),

The recommended dose of Plenaxis is 100 mg administered intramuscularly on day-one, 15, 29 (week-four) and every four-weeks thereafter.

Cetrorelix Acetate (Cetrotide®),

  • Ovarian stimulation therapy with gonadotropins is started on cycle Day two or three.  The dose of gonadotropins should be adjusted according to individual response.  Cetrotide may be administered subcutaneously either once daily (0.25 mg dose) or once (3 mg dose) during the early- to mid-follicular phase.  In the single dose regimen, 3 mg of Cetrotide is administered when the serum estradiol level is indicative of an appropriate stimulation response, usually on stimulation day seven.  If human chorionic gonadotropin (hCG) has not been administered within four-days after injection of Cetrotide 3 mg, Cetrotide 0.25 mg should be administered once daily until the day of hCG administration.  In the multiple dose regimen, 0.25 mg of Cetrotide is administered on either stimulation day-five (morning or evening) or day-six (morning) and continued daily until the day of hCG administration.
  • In the treatment of uterine leiomyomas in premenopausal women, efficacy has been a loading dose of Cetrocide 5 mg twice daily for two-days, followed by maintenance of Cetrocide 0.8 mg for at least three-months. 

Degarelix Acetate (Firmagon®),

Firmagon is for subcutaneous administration, starting with a dose of 240 mg (as two injections of 120 mg each).  Maintenance doses of 80 mg are administered as a single injection every 28-days.

Ganirelix Acetate (Antagon®),

After initiating follicle-stimulating hormone therapy on day two or three of the cycle, Antagon may be administered subcutaneously once daily during the mid to late portion of the follicular phase.  Injections should be continued daily until the day of hCG administration.

Goseralin Acetate (Zoladex®),

  • Zoladex 3.6 mg should be administered subcutaneously (as an implant) every 28 days.  For the management of endometriosis, the recommended duration of administration is six-months for women 18 years of age and older. 
  • Zoladex, at a dose of 10.8 mg, should be administered subcutaneously (as an implant) every 12 weeks into the anterior abdominal wall.

Histrelin Acetate (Supperlin LA® or Vantas®)

  • The recommended dose of Supprelin LA is one implant every 12 months.  The implant is inserted subcutaneously in the upper arm, providing histrelin acetate for 12 months of hormonal therapy.
  • The recommended dose of Vantas is one implant for 12 months.  Each implant contains 50 mg of histrelin acetate, which is inserted subcutaneously in the upper arm providing 12 months of hormonal therapy.  Vantas must be removed after 12 months.  At the time the implant is removed, another may be inserted to continue therapy.

Leuprolide Acetate (Eligard®, Lupron® or Viadur®),

A.  Eligard is available in several formulations – when used for the palliative treatment of advanced prostatic cancer:

1.      7.5 mg subcutaneously every month,

2.      22.5 mg subcutaneously every three months,

3.      30 mg subcutaneously every four months,

4.      45 mg subcutaneously every six months.

B.   Lupron is available in several formulations:

  • Lupron Depot 3.75 mg – when used for the following indications:

1.       Endometriosis management, including pain relief and reduction of lesions, is given monthly.  Duration of initial treatment or retreatment should be limited to six months.

2.       Uterine Leiomyomata treatment concomitantly with iron therapy is indicated for the preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata.  Prior to Lupron treatment, one-month trial of iron alone to assess patient response.  Lupron may be added if the response to iron alone is considered inadequate.  Recommended duration of therapy with Lupron Depot 3.75 mg is up to three months.

  • Lupron Injection or Depot (varied strengths of 3.75 mg, 7.5 mg, 11.25 mg, 22.5 mg, and 30 mg) – when used for the palliative treatment of advanced prostatic cancer:

1.      When using 3.5 mg, the recommended dose is 1 mg administered daily subcutaneously.  The patient may be supplied with a 14-day patient administration kit, rather than single or multiple vials. 

2.      Lupron 7.5 mg is recommended as a single monthly intramuscular injection. 

3.      Lupron Depot-3-month 22.5 mg is intended as an intramuscular injection to be given every three months or 84 days.  Due to different release characteristics, a fractional dose of this three-month depot formulation is not the equivalent to the same monthly formulation and should not be given.

4.      The recommended dose of Lupron Depot-4-month 30 mg to be administered is one injection every four-months or 16-weeks.  Due to different release characteristics, a fractional dose of this four-month depot formulation is not the equivalent to the same monthly formulation and should not be given.

  • Lupron Depot-Ped (varied dosing based on patient weight) – when used for the treatment of CPP:

1.      The dose of Lupron Depot-Ped must be individualized for each child in the treatment of CPP.  The dose is based on a mg/kg ratio of drug to body weight.  Younger children require higher doses on a mg/kg ratio.  For each dose form, after one to two months of initiating therapy or changing doses, the child must be monitored with a GnRH stimulation test, sex steroids, and Tanner staging to confirm downregulation.  Measurements of bone age for advancement should be monitored every 6- to 12-months.  The dose should be titrated upward until no progression of the condition is noted either clinically and/or by laboratory parameters.  Discontinuation should be considered before age 11 for females and age 12 for males.  The recommended starting dose is 0.3 mg/kg/4 weeks (minimum 7.5 mg) administered in a single intramuscular injection.  The starting dose will be dictated by the child’s weight:

a.    ≤ 25 kg of weight = 7.5 mg,

b.    > 25-37.5 mg of weight = 11.25 mg,

c.    > 37.5 kg of weight = 15 mg.

2.   If down regulation is not achieved, the dose should be titrated  upward in increments of 3.75 mg every four-weeks.  This dose will be considered the maintenance dose.

  • Lupron Injection using the same parameters as Lupron Depot-Ped (varied dosing) – when used for the treatment of CPP:

1.      The dose of Lupron Injection must be individualized for each child in the treatment of CPP.  The dose is based on a mg/kg ratio of drug to body weight.  Younger children require higher doses on a mg/kg ratio.  The same monitoring is utilized as with Lupron Depot-Ped.  The recommended starting dose is 50 mcg/kg/day administered as a single subcutaneous injection.  If downregulation is not achieved, the dose should be titrated upward by 10 mcg/kg/day.  This dose will be considered the maintenance dose.

  • Lupron Depot-Ped-3-Month Administration – when used for the treatment of CPP:

1.       Lupron Depot-Ped 11.25 mg/3-months or 30 mg/3-months should be administered once every three-months (12-weeks) as a single intramuscular injection.  Hormonal and clinical parameters should be monitored during treatment to ensure adequate suppression.  In case of inadequate suppression, other available GnRH agonists indicated for the treatment of CPP should be considered.  Partial depot dosing should not be administered as the depot formulation is not equivalent to monthly injection formulation.

  • The recommended dose of Viadur is one implant for 12 months, which contains 65 mg of leuprolide, for the palliative treatment of advanced prostatic cancer.  The implant is inserted subcutaneously in the upper arm and continuously releases leuprolide for 12 months of hormonal therapy.  Viadur must be removed after 12 months.  At the time the implant is removed, another may be inserted to continue therapy.

Nafarelin Acetate (Synarel®),

For the treatment of CPP, the recommended daily dose of Synarel is 1600 ug (two nasal sprays twice daily).  The dose can be increased to 1800 ug (three nasal sprays three times daily) if adequate suppression cannot be achieved at 1600 up/day.

Triptorelin Pamoate (Trelstar®, Trelstar Depot® or Trelstar LA®),

  • Trelstar is administered as a single intramuscular injection.  Due to different release characteristics, the dosing strengths are not additive and must be selected based upon the desired dosing schedule.  Trelstar dosing and frequency (not Trelstar Depot or Trelstar LA)is as follows:

1.       3.75 mg every four weeks,

2.       11.25 mg every 12 weeks,

3.       22.5 mg every 24 weeks.

  • Trelstar Depot recommended dosing is 3.75 mg, administered monthly as a single intramuscular injection.
  • The recommended dose of Trelstar LA is 11.25 mg incorporated in a long acting formulation administered every 84 days as a single intramuscular injection.

Rationale for Benefit Administration

This medical policy was developed through consideration of peer reviewed medical literature, FDA approval status, accepted standards of medical practice in Montana, Technology Evaluation Center evaluations, and the concept of medical necessity. BCBSMT reserves the right to make exceptions to policy that benefit the member when advances in technology or new medical information become available.

The purpose of medical policy is to guide coverage decisions and is not intended to influence treatment decisions. Providers are expected to make treatment decisions based on their medical judgment. Blue Cross and Blue Shield of Montana recognizes the rapidly changing nature of technological development and welcomes provider feedback on all medical policies.

When using this policy to determine whether a service, supply or device will be covered, please note that member contract language will take precedence over medical policy when there is a conflict.

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 gonadotrophin-releasing hormone (GnRH) therapies, it is done based solely on the U.S. Food and Drug Administration (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 Gynecologists (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 randomized controlled trial 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.

2012 Update

GnRH receptor blockers are the latest addition to the hormonal therapy armamentarium for patients with advanced prostate cancer.  In contrast to GnRH agonists, GnRH blockers have an immediate onset of action and do not cause a surge in testosterone levels that can lead to a flare in patients with advanced disease. 

On December 29, 2008, the FDA approved degarelix acetate (Firmagon), a GnRH receptor blocker for the treatment of hormone-sensitive advanced prostate cancer.  The effectiveness of degarelix was established in a 12-month, comparative, randomized, open-label, parallel-group phase III clinical trial by Klotz (2008) in which a total of 610 patients with cancer of the prostate [median prostate-specific antigen (PSA) level 19.0] were randomized and received treatment with degarelix (starting dose of 240 mg for one-month followed by maintenance doses of either 80 mg or 160 mg monthly) or leuprolide (7.5mg monthly).  At three-days after starting treatment, testosterone levels were ≤ 0.5 ng/ml in 96.l% and 95.5% of patients in the degarelix 240/80 mg and 240/160 mg groups respectively.  The median PSA levels at 14- and 28-days were significantly lower in the degarelix groups than in the leuprolide group.  The authors concluded that degarelix was not inferior to leuprolide at maintaining low testosterone levels over a one-year treatment period; however, degarelix induced testosterone and PSA suppression significantly faster than leuprolide, which was maintained throughout the study.  Furthermore, there was no need for anti-androgen supplements to prevent the possibility of a clinical flare.

A search of peer reviewed literature through October 2011 identified no new clinical trial publications or any additional information that would change the not medically necessary coverage position of this medical policy.  Several preparations have been discontinued from marketing based on diminished market demand and costs of manufacturing.  Those preparations have been removed from the medically necessary indications of this medical policy.

Coding

Disclaimer for coding information on Medical Policies      

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy.  They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers.  Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

158.8-158.9, 174.0-175.9, 183.0, 183.2, 185, 218.0-218.9, 233.0, 233.4, 253.3, 259.1, 282.60-282.69, 607.3, 617.0-617.9, 625.8-625.9, 626.2, 626.3, 627.0, 627.1, 628.0-628.9, V10.3, V10.46, V58.11-V58.12, V86.0, V66.1-V66.2, V66.7

Procedural Codes: J1620, J1675, J1950, J3315, J9155, J9202, J9217, J9218, J9219, J9225, J9226, S0132, S9560
References
  1. 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.
  2. Corrnillie, F.J., Osterlynck, D., et al.  Deeply infiltrating pelvic endometriosis: histology and clinical significance.  Fertility and Sterility (1990 June) 53(6):978-83.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  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.
  8. 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.
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  14. 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.
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  16. 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.
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Gonadotropin-Releasing Hormone (GnRH) Agonists and Antagonists