Archived Policies - Prescription Drugs


Gonadotropin-Releasing Hormone (GnRH) Agonists and Antagonists

Number:RX501.041

Effective Date:04-15-2019

End Date:03-31-2020

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb strength of recommendation or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

When the requested chemotherapeutic agent is being utilized in a regimen in combination with other chemotherapeutic agents, the entire regimen (including dose, frequency, and duration) must be consistent with recommendations in at least one authoritative source, including but not limited to FDA labeling and nationally recognized compendia or clinical guidelines such as National Comprehensive Cancer Network (NCCN) and CMS coverage policy. HCSC may require a provider to submit documentation from nationally recognized compendia, clinical guidelines, or active Phase III clinical trials supporting the requested regimen.

This medical policy does NOT address Gender Reassignment Services (Transgender Services). This medical policy IS NOT TO BE USED for Gender Reassignment Services. Refer to SUR717.001, Gender Assignment Surgery and Gender Reassignment Surgery and Related Services

Special Comment: This policy addresses the singular use of gonadotropin-releasing hormone (GnRH) agonists and antagonists. It does not address the combined use of luteinizing hormone-releasing hormone (LHRH) agonists AND anti-androgens, for which there is no corresponding medical document.

NOTE 1: This is not an all-inclusive listing of all GnRH preparations. Refer to the U.S. Food and Drug Administration (FDA) for all labeled indications of those GnRH preparations not listed in this policy.

ALERT: All self-injectable medications are administered under the pharmacy benefit.

Gonadotropin-releasing hormone (GnRH) agonists and antagonists are addressed individually by generic and brand names (refer to the Indications Table below) and may be considered medically necessary 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 compendium listed in the disclaimer above.

INDICATIONS TABLE

If the drug therapy is:

Then the medically necessary indications may include:

Cetrorelix Acetate (Cetrotide®),

For the following indications:

Gynecology uses:

In the treatment of uterine leiomyomas, including preoperative hematologic improvement for anemia, in premenopausal women.

In vitro fertilization uses:

In vitro fertilization to inhibit premature luteinizing hormone (LH) surges to control ovarian stimulation/induction and/or final maturation of human embryos (check member benefit contracts for coverage).

Degarelix Acetate (Firmagon®),

For the following indications:

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 no longer an option, and there are no other alternative therapies available.

Ganirelix Acetate (Antagon®),

(see NOTE 3 at end of Coverage section)


 

For the following indication:

In vitro fertilization uses:

To inhibit premature luteinizing hormone (LH) surges to control ovarian stimulation/induction and/or final maturation of human embryos (check member benefit contracts for coverage).

Goseralin Acetate (Zoladex®),

For the following indications:

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 neoadjuvant treatment; Stage T2b-T4 (Stage B2-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.

Gynecology uses:

Endometriosis for pain relief and reduction of lesions for up to 6-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 6-months of treatment; or

Dysfunctional uterine bleeding; or

Endometrial thinning (hypoplasia) prior to endometrial ablation for dysfunctional uterine bleeding.

Endocrine uses:

Central precocious puberty (CPP), gonadotropin-dependent, with onset of secondary sexual characteristics earlier than 9-years for males and 8-years for females.

In vitro fertilization uses:

Infertility treatment to desensitize the pituitary gland prior to ovarian stimulation (check member benefit contracts for coverage).

Histrelin Acetate (Supprelin LA®),

For the following indications:

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 no longer an option, and there are no other alternative therapies available.

Endocrine uses:

CPP, gonadotropin-dependent, with onset of secondary sexual characteristics earlier than 9-years for males and 8-years for females.

Histrelin Acetate (Vantas®),

For the following indications:

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 no longer an option, and there are no other alternative therapies available.

Endocrine uses:

CPP, gonadotropin-dependent, with onset of secondary sexual characteristics earlier than 9-years for males and 8-years for females.

Leuprolide Acetate (Eligard® and Lupron®),

For the following indications:

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 T2b-T4 (Stage B2-C) locally confined.

Breast cancer patients:

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.

Gynecology uses:

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

Premenstrual syndrome; or

In the treatment of uterine leiomyomas, including preoperative hematologic improvement for anemia, in premenopausal women.

Endocrine uses:

CPP, gonadotropin-dependent, with onset of secondary sexual characteristics earlier than 9-years for males and 8-years for females; or

Endometrial thinning (hypoplasia) prior to endometrial ablation for dysfunctional uterine bleeding.

In vitro fertilization uses:

Infertility treatment to inhibit premature luteinizing hormone (LH) surges to control ovarian stimulation/induction and/or final maturation of human embryos (check member benefit contracts for coverage).

Nafarelin Acetate (Synarel®),

For the following indications:

Gynecology uses:

Endometriosis for pain relief and reduction of lesions for up to 6-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 6-months of treatment.

Endocrine uses:

CPP, gonadotropin-dependent, with onset of secondary sexual characteristics earlier than 9-years for males and 8-years for females; or

Hirsutism due to ovarian androgen hypersecretion.

Triptorelin Pamoate (Trelstar® and Triptodur®),

For the following indications:

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 no longer an option, and there are no other alternative therapies available.

Non-oncology uses:

Benign fibrocystic mastopathy (fibrocystic disease of the breast) for up to 3-months.

Gynecology uses:

Endometriosis for pain relief and reduction of lesions for up to 6-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 6-months of treatment; or

Hyperplastic endometrium; or

In the treatment of uterine leiomyomas, including preoperative hematologic improvement for anemia, in premenopausal women.

Endocrine uses:

CPP, gonadotropin-dependent, with onset of secondary sexual characteristics earlier than 9-years for males and 8-years for females. (Triptodur® may be administered to pediatric patients as young as 2-years of age for CPP.); or

Gender dysphoria to suppress puberty using drug therapy.

In vitro fertilization uses:

Infertility treatment to inhibit premature luteinizing hormone (LH) surges to control ovarian stimulation/induction and/or final maturation of human embryos (check member benefit contracts for coverage).

An off-label indication for an FDA approved drug that is not addressed in the coverage table below 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 compendium or peer reviewed literature.

All Other Indications

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

Anovulation with or without accompanying polycystic ovarian disease; or

Benign prostate hypertrophy (BPH); or

Chemically induced male castration; or

Cryopreservation of oocytes, spermatozoa, and/or human embryos (including ovarian or testicular tissue) before or during chemotherapy; or

Delayed puberty; or

Endometrial cancer; or

Hypogonadism; or

Irritable bowel syndrome; 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

Obesity; or

Polycystic ovarian disease; or

Premature ovarian failure; or

Skin conditions (such as itching; redness; dryness; wrinkling; or roughness); or

Testicular cancer.

NOTE 2: The following discontinued preparations are no longer on the medical policy and references to them have been removed from the coverage and description sections of this medical policy:

Abarelix Depot (Plenaxis™),

Gonadorelin Acetate (Lutrepulse®/Lutrepulse Kit® or Factrel®),

Histrelin Acetate (Supprelin® only, not Supprelin LA® or Vantas®), and

Leuprolide Acetate (Viadur® only, not Eligard® or Lupron®).

NOTE 3: Ganirelex Acetate (Antagon®), the brand-named version has been discontinued; but, generic preparations may still be available and in use in Europe. Discussion within the coverage and description sections remain on the medical policy.

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.

Background

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 interact 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 administration of these drugs may cause gonadal hormone dependent tissues or organs to reduce or cease activity, such as the normal prostate gland that is dependent on testosterone for growth and function. This effect is reversible on discontinuation of the drug therapy.

Oncological Staging/Grading

In general, cancer is staged to determine the extent of some cancers and what treatment would be ordered. (1) Not all cancers are staged, such as cancers of the blood cells or leukemias. Table 1 displays the basic staging for cancers as outlined from the American Cancer Society (ACS): (1)

Table 1. Cancer Staging (1)

Stage

Characteristics

0

Describes abnormal cells that have not spread to nearby tissues. Also known as “in situ”.

I

This stage is usually a small tumor that has not grown deeply into nearby tissues, lymph nodes or other parts of the body. Also known as early-stage cancer.

II and III

These stages indicate larger tumors that have grown more deeply into nearby tissue or lymph node(s) but has not spread to other parts of the body. The specific criteria for Stages II and III therefore differ according to diagnosis

IV

Cancer has metastases to other organs or regions of the body, also known as advanced or metastatic cancer.

TNM (Tumor, Node, Metastases) Classification

Clinical staging may also be accessed by the tumor, node, and metastasis (TNM) classification staging system developed by the American Joint Committee on Cancer (AJCC) in collaboration with the Union for International Cancer Control (UICC), herein referred to as the AJCC TNM staging system. (2) The AJCC TNM system classifies cancers by:

T – The size and extent of primary (original) tumor:

o TX – Primary tumor cannot be evaluated,

o T0 – No evidence of primary tumor,

o Tis – Carcinoma in situ (early cancer that has spread to neighboring tissue),

o T1-T4 – Size or extent of the primary tumor; and

N – The involvement of regional lymph nodes:

o NX – Regional lymph nodes cannot be evaluated,

o N0 – No regional lymph nodes involvement (no cancer found in the lymph nodes),

o N1-N3 – Involvement in regional lymph nodes (number and/or extent of spread); and

M – The presence or absence of distant metastases:

o M0 – No distant metastasis (cancer has not spread to other parts of the body),

o M1 – Distant metastasis (cancer has spread to other parts of the body).

NOTE 4: TNM classification and staging could be slightly different with additional, specific categories that reflect the differences in a variety of cancers. For example, in the medical policy, prostate cancer TNM classification and staging may not include other oncological T categories listed within the coverage section. Therefore, they may not be used interchangeably.

Prostate Cancer

In the case of prostate cancer and tumor staging, several sources were used, in this medical policy, which have different staging guides – the National Comprehensive Cancer Network (NCCN) (3) and the ACS/AJCC (4). Table 2 describes all systems and each stage used to assess cancer location and extent of spreading used in the NCCN Guidelines for Prostate Cancer. Table 3 displays the grading/staging system from the ACS/AJCC.

Other than TNM staging, other key pieces of information are used to make the determination:

The prostate-specific antigen (PSA) level at the time of diagnosis; and

The Grade Group (based on the Gleason score), which is a measure of how likely the cancer is to grow and spread quickly. This is determined by the results of the prostate biopsy (or surgery).

There are 2 types of T categories that are often used for prostate cancer:

The clinical T category (written as cT) is the physician’s best estimate of the extent of the disease, based on the results of the physical exam (including a digital rectal exam) and prostate biopsy, and any imaging tests.

Once the prostate has been surgically removed, the physician(s) can also determine the pathologic T category (written as pT). The pathologic T is likely to be more accurate than the clinical T, as it is done after the prostate has been examined in the lab.

Table 2. NCCN Prostate Cancer Staging Systems

Stage

NCCN Prostate Cancer Guidelines –

TNM Staging System

NCCN Prostate Cancer Guidelines –

Prognostic Group Staging

NCCN Prostate Cancer Guidelines –

Both Staging Systems

I

TX – Primary tumor cannot be assessed

T0 – No evidence of primary tumor

T1 – Tumor clinically inapparent tumor that is not palpable

T1a – Tumor incidental histologic that is not palpable

T1b – Tumor incidental histologic finding in more than 5% of tissue resected

T1c – Tumor identified by needle biopsy found in one or both sides, but not palpable

A – Tumor is present, but not detectable clinically; found incidentally

A1 – Tissue resembles normal cells; found in a few chips from one lobe

A2 – More extensive involvement

Stage I = T1a-c, T2a, T2, N0, M0

II

T2 – Tumor is palpable and confined within the prostate

T2a – Tumor involves one-half of one side or less

T2b – Tumor involves more than one-half of one side but not both sides

T2c – Tumor involves both sides

B – The tumor can be felt on physical examination but has not spread outside the prostatic capsule

BIN – The tumor can be felt, it does not occupy a whole lobe, and is surrounded by normal tissue

B1 – The tumor can be felt, and it does not occupy a whole lobe

B2 – The tumor can be felt, and it occupies a whole lobe or both lobes

Stage IIA = T1a-c, T2a, T2, T2b, T2c, N0, M0

Stage IIB = T1-2, N0, M0

Stage IIC = T1-2, T2, N0, M0

III

T3 – Extraprostatic tumor that is not fixed or does not invade adjacent structures

T3a – Extraprostatic extension (unilateral or bilateral)

T3b – Tumor invades seminal vesicle(s)

C – The tumor has extended through the capsule

C1 – The tumor has extended through the capsule but does not involve the seminal vesicles

C2 – The tumor involves the seminal vesicles

Stage IIIA = T1-2, N0, M0

Stage IIIB = T3-4, N0, M0

Stage IIIC = Any T, N0, M0

IV

T4 – Tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall

D – The tumor has spread to other organs

Stage IVA = Any T, N0, M0

Stage IVB = Any T, N1, M0

N/A

N0 – No positive regional nodes

N/A

N/A

N/A

M0 – No distant metastases

N/A

N/A

Table Key:

NCCN: National Comprehensive Cancer Network;

TNM: tumor, node, metastasis.

Table 3. ACS Staging/Grading System for Prostate Cancer

AJCC Stage

Stage Grouping

Stage Description

I

cT1, N0, M0

Grade Group 1 (Gleason score 6 or less)

PSA less than 10

The tumor is not palpable or visible with imaging (such as transrectal ultrasound) The tumor was either found during a TURP or was diagnosed by needle biopsy done for a high PSA) [cT1]. The cancer has not spread to nearby lymph nodes [N0] or elsewhere in the body [M0]. The Grade Group is 1, and the PSA level is less than 10.

OR

pT2, N0, M0

Grade Group 1 (Gleason score 6 or less)

PSA less than 10

The prostate has been removed with surgery, and the tumor was still only in the prostate [pT2]. The cancer has not spread to nearby lymph nodes [N0] or elsewhere in the body [M0]. The Grade Group is 1, and the PSA level is less than 10.

cT1, N0, M0

Grade Group 1 (Gleason score 6 or less)

PSA at least 10 but less than 20

The doctor can’t feel the tumor or see it with imaging such as transrectal ultrasound (it was either found during a transurethral resection of the prostate (TURP) or was diagnosed by needle biopsy done for a high PSA level) [cT1]. The cancer has not spread to nearby lymph nodes [N0] or elsewhere in the body [M0]. The Grade Group is 1. The PSA level is at least 10 but less than 20.

IIA

cT2a or pT2, N0, M0

Grade Group 1 (Gleason score 6 or less)

PSA at least 10 but less than 20

The tumor can be felt by digital rectal exam or seen with imaging such as transrectal ultrasound and is in one half or less of only one side (left or right) of the prostate [cT2a]. OR the prostate has been removed with surgery, and the tumor was still only in the prostate [pT2]. The cancer has not spread to nearby lymph nodes [N0] or elsewhere in the body [M0]. The Grade Group is 1. The PSA level is at least 10 but less than 20.

OR

cT2b or cT2c, N0, M0

Grade Group 1 (Gleason score 6 or less)

PSA less than 20

The tumor can be felt by digital rectal exam or seen with imaging such as transrectal ultrasound. It is in more than half of one side of the prostate [cT2b] or it is in both sides of the prostate [cT2c]. The cancer has not spread to nearby lymph nodes [N0] or elsewhere in the body [M0]. The Grade Group is 1. The PSA level is less than 20.

IIB

T1 or T2, N0, M0

Grade Group 2 (Gleason score 3+4=7)

PSA less than 20

The cancer has not yet spread outside the prostate. It might (or might not) be felt by digital rectal exam or seen with imaging such as transrectal ultrasound [T1 or T2]. The cancer has not spread to nearby lymph nodes [N0] or elsewhere in the body [M0]. The Grade Group is 2. The PSA level is less than 20.

IIIA

T1 or T2, N0, M0

Grade Group 1 to 4 (Gleason score 8 or less)

PSA at least 20

The cancer has not yet spread outside the prostate. It might (or might not) be felt by digital rectal exam or seen with imaging such as transrectal ultrasound [T1 or T2]. The cancer has not spread to nearby lymph nodes [N0] or elsewhere in the body [M0]. The Grade Group is 1 to 4. The PSA level is at least 20.

IIIB

T3 or T4, N0, M0

Grade Group 1 to 4 (Gleason score 8 or less)

Any PSA

The cancer has grown outside the prostate and might have spread to the seminal vesicles [T3], or it has spread into other tissues next to the prostate, such as the urethral sphincter (muscle that helps control urination), rectum, bladder, and/or the wall of the pelvis [T4]. It has not spread to nearby lymph nodes [N0] or elsewhere in the body [M0]. The Grade Group is 1 to 4, and the PSA can be any value.

IVA

Any T, N1, M0

Any Grade Group

Any PSA

The tumor might or might not be growing into tissues near the prostate [any T]. The cancer has spread to nearby lymph nodes [N1] but has not spread elsewhere in the body [M0]. The Grade Group can be any value, and the PSA can be any value.

IVB

Any T, any N, M1

Any Grade Group

Any PSA

The cancer might or might not be growing into tissues near the prostate [any T] and might or might not have spread to nearby lymph nodes [any N]. It has spread to other parts of the body, such as distant lymph nodes, bones, or other organs [M1]. The Grade Group can be any value, and the PSA can be any value.

Table Key:

ACS: American Cancer Society;

AJCC: American Joint Committee on Cancer;

c: clinical;

p: pathologic;

PSA: prostate-specific antigen;

TURP: transurethral resection of the prostate;

TNM: tumor, node, metastasis.

According to the Surveillance, Epidemiology, and End Results Program (SEER) (from the National Institutes of Health) Prostate Staging Scheme: (5)

Guidelines for American Staging for Prostate:

Stages A1, B1, C1, D1 correspond to T1, T2, T3, T4.

Stages A and B are localized; Stage C regionalized; Stage D distant.

Categories:

Stage A can be subdivided based on the number of cell clusters (foci) seen on microscopic examination.

The difference between Stage A and Stage B is whether nodule(s) are clinically palpable (or visibly seen) in the prostate.

Dividing line between Stage B and Stage C is capsular invasion microscopically.

Stage D is metastatic disease identified either clinically or microscopically.

The tumor, lymph node, metastasis, and grade status can be combined into four stages of worsening severity.

Breast Cancer

For breast cancer, “Tis” is included in the TNM staging and describes ductal carcinoma in situ (DCIS) or Paget’s disease of the nipple. (Note that lobular carcinoma in situ (LCIS) is a benign disorder and not included in the staging system.) Additionally, in 2018, AJCC explains that these characteristics may be used to described tumor activity: (6)

Local: cancer is confined within the breast;

Regional: lymph nodes, primarily those within the armpit, are involved;

Distant: cancer is found in other parts of the body;

Locally advanced or regionally advanced: large tumors that involve the breast skin, underlying chest structures, changes to the breast’s shape, and lymph node enlargement, which may be visible;

ER status: estrogen receptor found in some breast cancers; if positive, means the cancer cell depends on estrogen for growth;

PR status: progesterone receptor found in some breast cancers; if positive, means the cancer cell depends on progesterone for growth;

Her2 or Her2/neu status: human epidermal growth factor receptor 2: a gene/oncogene that may play a role in breast cancer when it over-expresses/amplifies; and

Grade of the cancer: cancer cells compared to normal breast cells.

Combinations of TNM, ER, PR, Her2 will assist in staging and prognostication of breast cancer from I-IV. Breast cancer staging assignment is not a requirement for coverage determination in this medical policy.

Ovarian Cancer

For ovarian cancer, staging may be determined by using the TNM staging system (described above) released in 2018 by the AJCC (7) or the classification from the International Federation of Gynecology and Obstetrics (FIGO), (8) which is staging for cancers of the female reproductive system. FIGO is the same as the AJCC staging but does not utilize the TNM categories/characteristics. Ovarian cancer staging assignment is not a requirement for coverage determination in this medical policy.

Regulatory Status

Although GnRH products may differ in specific labeled indications and dosing requirements, clinical evidence may not support differential effectiveness of one product over the other for U.S. Food and Drug Administration (FDA) approved clinical indications.

Cetrorelix Acetate (Cetrotide®) is a synthetic injectable decapeptide analog of GnRH, a GnRH antagonist and originally FDA approved August 11, 2000. (1-2) 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. (1) 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. Firmagon® was first approved by the FDA on December 24, 2008.

Ganirelix Acetate (Antagon®) injection is a synthetic decapeptide analog of GnRH, like cetrorelix acetate, and a GnRH antagonist and originally FDA approved July 29, 1999. (1) This drug is used for infertility treatment to inhibit LH surges.

NOTE 5: Antagon® is no longer available in the U.S. but may be marketed for sale in Europe for use in infertility. The FDA does not mention Antagon® in their website.

Goseralin Acetate (Zoladex®) is a GnRH analog, which is indicated in certain conditions requiring suppression of estrogen or testosterone secretion and originally FDA approved July 27, 1989. (1-2) 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. (1) 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, whereas Vantas® is indicated in the palliative treatment of advanced prostate cancer. Supprelin LA® was originally FDA approved May 3, 2007 and Vantas® on October 12, 2004.

NOTE 6: In 2007, Supprelin® only (not Supprelin LA®) marketing has been discontinued and no longer available. (1)

Leuprolide Acetate (Eligard® or Lupron®) is a synthetic analog of naturally occurring GnRH or LHRH and an antagonist. (1-2) 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. FDA approvals for these analogs were January 23, 2002 for Eligard®, January 9, 1998 for Lupron® on March 3, 2000 for Eligard®.

Nafarelin Acetate (Synarel®), is a metered nasal spray, is used in the palliative treatment of endometriosis and originally FDA approved April 12, 2006. (1-2) 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 6-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 8 or 9 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® or Triptodur®) Trelstar® was first FDA approved June 15, 2000, as an injection used in the palliative treatment of advanced prostate cancer. (1-2) It offers an alternative treatment for prostate cancer when orchiectomy or estrogen administration is either not indicated or unacceptable to the patient. Triptodur®, an extended-release injectable suspension, is used for the treatment of pediatric patients 2 years and older with central precocious puberty. Triptodur® was FDA approved on June 29, 2017. (1-2)

Rationale:

This policy was created in 1990 and based on U.S. Food and Drug Administration (FDA)-approved labeled indications and routinely updated with literature searches, particularly for off-label use. The most recent update including searches in the MedLine database and standard reference compendium through February 2019. The following includes a summary of each gonadotropin releasing hormone (GnRH) agonist and antagonist.

Gonadotropin Releasing Hormone (GnRH) for Prostate Cancer

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. (9, 10)

On December 29, 2008, the FDA approved degarelix acetate (Firmagon®), a GnRH receptor blocker for the treatment of hormone-sensitive advanced prostate cancer. (9, 10) The effectiveness of degarelix was established in a 12-month, comparative, randomized, open-label, parallel-group phase III 2008 clinical trial by Klotz et al. 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). (11) After 3 days of treatment, testosterone levels were equal to or lesser than 0.5 ng/ml in 96.l% and 95.5% of patients of 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 1-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.

The utilization of degarelix as first-line therapy for advanced prostate cancer has also been reported in published literature, particularly when bony metastases has occurred. (11-14) This treatment protocol was confirmed in two trials from Crawford et al., (15) a phase III reported in 2011 and Miller et al., (16) a phase II published in 2015. Both studies were open-label and multi-centered with 2 patient arms: first arm was treated with degarelix and second arm was treated with leuprolide or leuprolide as first-line followed by degarelix as second-line. Both studies demonstrated that when cohort cross-over occurred, degarelix worked as well at maintaining disease control benefits; and, the prostate specific antigen progression-free survival hazard rate was decreased significantly after the switch in the leuprolide/degarelix group while the rate in those who continued degarelix was consistent with the rate in treatment year 1. The authors of both studies concluded that degarelix has clearly demonstrated utilization as first-line therapy and an alternative to other GnRH therapies.

GnRH for Breast Cancer

Coverage for treatment of breast cancer beyond the FDA-approved labeled indications has been based on two clinical studies, over a 2-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). (9, 10, 17) 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.

GnRH for Ovarian Cancer

Coverage for treatment of ovarian cancer beyond the FDA-approved labeled indications has been based upon anecdotal opinions well over the last decade. (18, 19) It is known that the ovary is an endocrine and end (targeted) organ and the hormones with their receptors are associated with ovarian cancer. Two publications, used in the National Comprehensive Cancer Network Guidelines, theorized that some data suggests hormonal therapies, such as leuprolide acetate, may influence ovarian cancer. It is acknowledged there is no hormonal therapy approved by the FDA, but further studies, beyond phase II clinical trials, are warranted while it is used as an off-labeled indication.

GnRH for Chronic Pelvic Pain

The 2004 American College of Obstetrics and Gynecology (ACOG) 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. (20) Guidelines from the 2005 Royal College of Obstetricians and Gynecologists, included in an ACOG bulletin, 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 3- to 6-months before having a diagnostic laparoscopy. (21) The 1999 Ling et al. study represents the one small short-term randomized controlled trial used for support of empiric therapy for management of chronic pelvic pain. (22)

GnRH for Cryopreservation

According to the Practice Committee of the American Society for Reproductive Medicine (ASRM) in 2013, over 100,000 patients less than 45 years of age are diagnosed with cancer in the U.S. (23) Advancements of cancer treatments, including chemotherapy regimens, have led to improved outcomes and survival. However, gonadotoxicity is a concern, with a growing interest in expanding fertility options and treatments. Success rates using cryopreserved embryos and mature oocytes have been discussed and should be discussed with each patient with or without a committed partner. There is concern if chemotherapeutic agents affect the reproductive tissue, particularly when cancer treatments were started emergently and concerns about the well-being of future children had not been addressed. Due to the strategy of fertility treatments, such as ovarian stimulation, there is added concern if cryopreservation would interfere or result in unpredictable outcomes when combined with the chemotherapy regimen. Cryopreservation may also result in a lower yield of oocytes, especially when there is an attempt to begin a second or more cycle. There are no human studies that have specifically examined the quality of oocytes or embryos that result following a prior chemotherapy course, as well as concerns regarding the outcomes following cervical, endometrial, or ovarian surgical treatment. (24, 25)

Summary of Evidence

The U.S. Food and Drug Administration (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 gonadotropin-releasing hormone (GnRH) therapies, it is done based solely on the FDA-approved label indications as well as supporting literature from standard reference compendium for off-labeled indications. Utilization of GnRH therapy degarelix for advanced prostate cancer as first-line therapy is shown in published literature to improve health outcomes particularly when bony metastases are involved.

As a result of the searches, there is 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 FDA approved label indications, including, but not limited to: premenstrual syndrome; menopause or mood related disorders; chronic intestinal disease; cancer of the endometrium, ovary, testicles, or liver; benign prostatic hypertrophy; menstrual cycle regulation; non-oncological ovarian conditions, obesity, 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:

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.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

None

HCPCS Codes

J1620, J1675, J1950, J3315, J3316, J9155, J9202, J9217, J9218, J9219, J9225, J9226, S0132, S9560, [Deleted 1/2019: C9016]

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


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.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

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

References:

1. ACS – Stages of cancer (March 25, 2015). Prepared by the American Cancer Society, in conjunction with the American Joint Committee on Cancer. Available at: <https://www.cancer.net> (accessed February 21, 2019).

2. AJCC – Cancer staging system (2019). Prepared by the American Joint Committee on Cancer and the Union for International Cancer Control. Available at: <http://www.cancerstaging.org> (accessed February 21, 2019).

3. NCCN – Prostate Cancer Clinical Practice Guidelines in Oncology (Version 4.2018). Published by the National Comprehensive Cancer Network (August 15, 2018). Available at: <http://www.nccn.org> (accessed February 21, 2019).

4. ACS – Prostate cancer staging (December 18, 2017). Prepared by the American Cancer Society, in conjunction with the American Joint Committee on Cancer. Available at: <https://www.cancer.net> (accessed February 21, 2019).

5. SEER – Prostate staging schemes (American Staging for Prostate Cancer) (2019). Prepared by the National Institutes of Health/National Cancer Institute/ Surveillance, Epidemiology, and End Results Program Training Module. Available at: <https://www.seer.cancer.gov> (accessed February 21, 2019).

6. ACS – Breast cancer staging (December 20, 2017). Prepared by the American Cancer Society, in conjunction with the American Joint Committee on Cancer. Available at: <https://www.cancer.net> (accessed February 21, 2019).

7. ACS – Ovarian cancer staging (April 11, 2018). Prepared by the American Cancer Society, in conjunction with the American Joint Committee on Cancer. Available at: <https://www.cancer.net> (accessed February 21, 2019).

8. FIGO – Ovarian cancer staging (January 1, 2014). Prepared by the International Federation of Gynecology and Obstetrics. Available at: <https://www.sgo.org> (accessed February 21, 2019).

9. FDA – Product Labeling. Food and Drug Administration (FDA) – Drug Approvals and Database/Biologics License Applications (2017). Available at: <http://www.fda.gov> (accessed – August 1996, January 2000, January 2001, April 2002, November 2002, October 2004, January 2006, December 16, 2010, February 1, 2012, February 2, 2015, August 25, 2016, November 6, 2017, and February 16-18, 2019 for new FDA-Approvals):

Plenaxis™ prescribing information/product label. Praecis Pharmaceuticals Inc. Initial FDA-Approval – 2003. (Reaffirmed current label February 16, 2019).

Cetrotide® prescribing information/product label. EMD Serono, Inc. Initial FDA-Approval – 2000. (Reaffirmed current label February 16, 2019).

Firmagon® prescribing information/product label. Ferring Pharmaceuticals Inc. Initial FDA-Approval – 2008. (Reaffirmed current label February 16, 2019).

Antagon® prescribing information/product label. Organon, Inc. Initial FDA-Approval – 1999. (Reaffirmed current label February 16, 2019).

Zoladex® Implant prescribing information/product label. AstraZeneca Pharmaceuticals LP. Initial FDA-Approval – 1989. (Reaffirmed current label February 16, 2019).

Supprelin LA® prescribing information/product label. Endo Pharmaceuticals Solutions Inc. Initial FDA-Approval – 2007. (Reaffirmed current label February 16, 2019).

Vantas® Implant prescribing information/product label. Endo Pharmaceuticals Solutions Inc. Initial FDA-Approval – 2004. (Reaffirmed current label February 16, 2019).

Eligard® prescribing information/product label. TOLMAR Inc. Initial FDA-Approval – 2002. (Reaffirmed current label February 16, 2019).

Lupron® (Lupron®, Lupron® Depot, Lupron® Depot-Peds) prescribing information/product label. TOLMAR Inc. Initial FDA-Approval – 1998. (Reaffirmed current label February 18, 2019).

Viadur® Implant prescribing information/product label. Bayer Pharmaceuticals Corp. Initial FDA-Approval – 2000. (Reaffirmed current label February 18, 2019).

Synarel® Nasal Solution prescribing information/product label. Pfizer/GD Searle LLC. Initial FDA-Approval – 2006. (Reaffirmed current label February 18, 2019).

Trelstar® prescribing information/product label. Debio RP. Initial FDA-Approval – 2000. (Reaffirmed current label February 18, 2019).

Triptodur® Extended Release prescribing information/product label. Arbor Pharmaceuticals, LLC. Initial FDA-Approval – 2017. (Affirmed current label February 18, 2019).

10. Drug Point Summary. In: IBM Micromedex® DRUGDEX® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: <http://www.micromedexsolutions.com/> (cited: February 2, 2015, August 25, 2016, November 6, 2017, and February 16-18, 2019 – FDA-Approvals and Non-FDA Labeled Indications):

Abarelix depot (Plenaxis™) – updated May 8, 2018. (Reaffirmed posting February 18, 2019).

Cetrorelix acetate (Cetrotide®) – updated February 14, 2019. (Reaffirmed posting February 18, 2019).

Degarelix acetate (Firmagon®) – updated February 14, 2019. (Reaffirmed posting February 18, 2019).

Ganirelix acetate (Antagon®) – updated February 14, 2019. (Reaffirmed posting February 18, 2019).

Goserelin acetate (Zoladex®) – updated February 14, 2019. (Reaffirmed posting February 18, 2019).

Histrelin acetate (Supprelin LA®) – updated February 14, 2019. (Reaffirmed posting February 18, 2019).

Leuprolide acetate (Eligard®, Lupron®, Vantas®) – updated February 14, 2019. (Reaffirmed posting February 18, 2019).

Nafarelin acetate (Synarel®) – updated February 14, 2019. (Reaffirmed posting February 18, 2019).

Triptorelin pamoate (Trelstar®, Triptodur®) – updated February 14, 2019. (Reaffirmed posting February 18, 2019).

11. Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. Dec 2008; 102(11):1531-8. PMID 19035858

12. Rick FG, Block NL, Schally AV. Agonists of luteinizing hormone-releasing hormone in prostate cancer. Expert Opin Pharmacother. 2013 Nov; 14(16):2237-47. PMID: 23984804

13. First-line treatment of metastatic prostate cancer. Androgen suppression for symptomatic disease. Prescrire Int. Feb 2013; 22(135):48-51. PMID: 23444510

14. Shore ND. Experience with degarelix in the treatment of prostate cancer. Ther Adv Urol. Feb 2013; 5(1):11-24. PMID: 23372607

15. Crawford ED, Tombal B, Miller K, et al. A phase III extension trial with a 1-arm crossover from leuprolide to degarelix: comparison of gonadotropin-releasing hormone agonist and antagonist effect on prostate cancer. J Urol. Sep 2011; 186(3):889-97. PMID 21788033

16. Miller K, Simson G, Goble S, et al. Efficacy of degarelix in prostate cancer patients following failure on luteinizing hormone-releasing hormone agonist treatment: results from an open-label, multicentre, uncontrolled, phase II trial (CS27). Ther Adv Urol. Jun 2015; 7(3):105-15. PMID 26161141

17. Robertson JF, Blamey RW. The use of gonadotrophin-releasing hormone (GnRH) agonists in early and advanced breast cancer in pre- and perimenopausal women. Eur J Cancer. May 2003; 39(7):861-9. PMID 12706354

18. Rao GG, Miller DS. Hormonal therapy in epithelial ovarian cancer. Expert Rev Anticancer Ther. Jan 2006; 6(1):43-7. PMID 16375643

19. Yokoyama Y, Mizunuma H. Recurrent epithelial ovarian cancer and hormone therapy. World J Clin Cases. Sep 16 2013; 1(6):187-90. PMID 24303498

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

21. ACOG Committee on Practice Bulletins-Gynecology. Chronic Pelvic Pain – ACOG Practice Bulletin (No. 51). Mar 2004; 103(3):589-603. PMID 14990428

22. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Obstet Gynecol. Jan 1999; 93(1):51-8. PMID 9916956

23. Van Poppel H, Klotz L. Gonadotropin-releasing hormone: an update review of the antagonists versus agonists. Int J Urol. Jul 2012; 19(7):594-601. PMID: 22416801

24. The Practice Committee of the American Society for Reproductive Medicine. Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion. Fertil Steril. Nov 2013; 100(5):1214-22. PMID 24011612

25. Rabah DM, El-Nimer N, Rafe BA, et al. Fertility cryopreservation for female cancer patients: attitudes and clinical practices of oncologist in Riyadh, Saudi Arabia. J Reprod Med. Sep-Oct 2012; (9-10):431-4. PMID 23091992

Policy History:

Date Reason
4/15/2019 Document updated with literature review. The following indications were added to coverage: 1) Treatment of prostate cancer with Supprelin LA®; 2) Treatment of central precocious puberty with Vantas®; and 3) Treatment of gender dysphoria with Trelstar® and Triptodur®. The following preparations have changed in coverage: 1) Plenaxis™ was moved from NOTE 3 to NOTE 2, as it is no longer available in the United States; 2) Viadur® was added to NOTE 2, as it is no longer available in the United States; and 3) Antagon® was added to NOTE 3, as it may no longer be available for sale, but generic forms may still be in use in the United States. Cancer staging information for prostate, breast, and ovarian cancer was added to description. References 1-8, 10, 18, 19 were added; none removed.
1/1/2018 Document updated with literature review. The following was changed for Leuprolide Acetate (Eligard®, Lupron® and Viadur®), under oncology uses – breast cancer patients, by removing “who are not on concurrent aromatase inhibitor therapy for.” The following was added “Triptorelin Pamoate (Triptodur®)” as a treatment of central precocious puberty for children 2-years and older.
10/15/2016 Document updated with literature review. The following was changed for Firmagon® (Degarelix Acetate): considered medically necessary “for advanced prostate cancer treatment, including metastasis.”
7/1/2015 Document updated with literature review. The following was added to the coverage section: 1) For in vitro fertilization, clarification to control ovarian stimulation/induction and/or final maturation of human embryos; 2) For Zoladex®, dysfunctional uterine bleeding may be considered medically necessary; 3) For Eligard®, Lupron®, and Viadur®, premenstrual syndrome may be considered medically necessary; and 4) For uterine leiomyomas in premenopausal women, clarification to improve preoperative anemia. The following indications were added to experimental, investigational and/or unproven listing; cryopreservation of oocytes, spermatozoa, and/or human embryos (including ovarian or testicular tissue) before or during chemotherapy; endometrial cancer; irritable bowel syndrome, obesity, polycystic ovarian disease, premature ovarian failure; and testicular cancer.
7/1/2012 Document updated with literature review. Coverage completely revised, with new indications, and all covered indications categorized as first-line therapy or second-line therapy in a table. Entire policy was completely revised. Document title changed from “Gonadotropin-Releasing Hormone (GnRH) Analogs, Hormones, Antagonists and Receptor Blockers.”
11/6/2009 Codes Added
3/1/2009 Codes Revised/Added/Deleted
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
6/1/2001 Codes Revised/Added/Deleted
9/1/1996 Revised/Updated Entire Document
5/1/1996 Document number change
7/1/1995 Revised/Updated Entire Document
10/1/1994 Revised/Updated Entire Document
7/1/1993 Revised/Updated Entire Document
7/1/1992 Revised/Updated Entire Document
4/1/1992 Revised/Updated Entire Document
5/1/1990 New Medical Document

Archived Document(s):

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