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1 Injectablee Testosterone Products Prior Authorization Policy Number: Origination: 07/2014 Last Review: 07/2014 Next Review: 07/2015 Policy BCBSKC will provide coverage for injectable testosterone products when it is determined to be medically necessary because the following criteria are met. When Policy Topic is covered: Coverage of injectable testosterone (e.g., testosterone cypionate, testosteronee enanthate, Aveed, Testopel) is recommended in those who meet the following criteria: Food and Drug Administration (FDA)-Approved Indications 1. Hypogonadism (Primary or Secondary) in Males. Approve in patients with hypogonadism as confirmed by a low for age pre-treatment serum testosterone (total or free) level defined by the normal laboratory reference values. The injectable testosterone products are indicated for primary and secondary hypogonadism (congenital or acquired). Primary hypogonadism is testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, or orchidectomy, Klinefelter s syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. 1-3 Secondary (hypogonadotropic) hypogonadism is an idiopathic gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation. 2. Delayed Puberty or Inductionn of Puberty in Males 14 years of Age or Older. testosterone cypionate, testosterone enanthate, or Testopel for 6 months. Approve Evidencee supports the use of injectable testosterone agents for delayed puberty. 11 efficacy of Aveed in males < 18 years of age have not been established. 7 The safety and 3. Palliative Treatment of Inoperable Metastatic Breast Cancer in Females. Approve testosterone enanthate injection in women for 6 months if it is prescribed by or in consultationn with an oncologist. Testosterone enanthate may be used secondarily in women with advanced inoperable metastatic breast cancer that are 1 to 5 years postmenopausal. 2 The goal of therapy is ablation of ovaries. It can also be used in premenopausal women with breast cancer that have benefited from oophorectomy and are considered to have hormone-res sponsive tumor. Other Uses with Supportive Evidence 4. Female-to-Male (FTM) Gender Reassignment (i.e., Endocrinologic Masculinization). Approve if prescribed by or in consultation with an endocrinologist or a physician who specializes in the treatment of transgender patients. Clinical studies have demonstrated the efficacy of several different androgen preparations (i.e., oral, parenteral, or transdermal testosterone) to induce masculinizationn in FTM transsexual persons. 12

2 Regimens to change secondary sex characteristics follow the general principle of hormone replacement treatment of male hypogonadism. A clinical practice guideline published by the Endocrine Society, recommends that, prior to initiation of hormonal therapy, the treating endocrinologist should confirm the diagnostic criteria for gender identification disorder (GID) or transsexualism and the eligibility and readiness criteria for the endocrine phase of gender transition. The endocrinologist should also review the onset and time course of physical changes induced by cross-sex hormone treatment. When Policy Topic is not covered: Injectable testosterone (e.g., testosterone cypionate, testosterone enanthate, Aveed, Testopel) has not been shown to be effective, or there are limited or preliminary data or potential safety concerns that are not supportive of general approval for the following conditions. Rationale for non-coverage for these specific conditions is provided below. (Note: This is not an exhaustive list of Conditions Not Recommended for Approval.) 1. Use in Females for Indications Other than Female-to-Male (FTM) Gender Reassignment and Palliative Treatment of Metastatic Breast Cancer (see above). All of the injectable testosterone products are contraindicated for use in pregnant women. 1-3 In the 2006 guidelines on androgen therapy in women from the Endocrine Society, despite some short-term efficacy evidence, it recommends against the generalized use of testosterone by women because the indications are inadequate and the evidence of safety in long-term (> 24 weeks) studies is lacking. 13 The American College of Obstetricians and Gynecologists (ACOG) clinical management guidelines for management of female sexual dysfunction (reaffirmed in 2013) mentions testosterone as an option for the short-term treatment (e.g., 6 months) of hypoactive sexual desire disorder. 14 However, the FDA-approved testosterone formulations provide doses larger than the dosages studied in and typically required by women. More data are needed regarding long-term safety of testosterone use in women and patient selection before it can be recommended in this patient population. Testosterone supplementation has also been evaluated in a small number of women for the effect on follicle stimulation with no significant effect noted To Enhance Athletic Performance. Injectable testosterone products are not recommended for approval because this indication is excluded from coverage in a typical pharmacy benefit. 3. Use in Males with Carcinoma of the Breast. All of these testosterone replacement products are contraindicated for use in men with carcinoma of the breast Use in Males with Known or Suspected Carcinoma of the Prostate (excluding males with treated and cured prostate cancer). All of these testosterone replacement products are contraindicated for use in men with known or suspected carcinoma of the prostate. 1-3 Considerations Injectable testosterone products require prior authorization through the pharmacy services department. This Blue Cross and Blue Shield of Kansas City policy Statement was developed using available resources such as, but not limited to: Hayes Medical Technology Directory, Food and Drug Administration (FDA) approvals, Facts and Comparisons, National specialty guidelines, Local medical policies of other health plans, Medicare (CMS), Local providers. Description of Procedure or Service Endogenous androgens are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. 1-3 Some of these effects include alterations in body musculature, maturation of prostate, seminal vesicles, penis and scrotum. Androgens are also responsible for the growth spurt of adolescence and for the eventual termination of linear growth. Exogenous androgens in children can accelerate linear growth rates but may also cause a disproportionate advancement in bone maturation.

3 Testosterone replacement regimens supply exogenous testosterone and restore serum testosterone levels in the normal range (300 to 1,000 ng/dl). 4 The International Society of Andrology (ISA), International Society for the Study of the Aging Male (ISSAM), European Association of Urology (EAU), European Academy of Andrology (EAA), and the American Society of Andrology (ASA) propose 230 ng/dl as the lower limit of serum testosterone at which patients will benefit from testosterone replacement therapy. 5 The Endocrine Society recommends 300 ng/dl, and the American Association of Clinical Endocrinolgoists (AACE) suggests 200 ng/dl as the lower limit for testosterone replacement. Testosterone level increases in males until 17 years of age and stabilizes to a serum level in the range of 300 to 1,000 ng/dl, until about 40 years of age. After this, the levels begin to decline at 1.2% to 2% per year. About 20% of men > 60 years of age and 50% of men > 80 years of age are estimated to have serum testosterone levels that are subnormal compared with younger men. Given this inherent variability in testosterone levels in men based on age, it is also prudent to consider other variables that could affect a lab drawn testosterone level (e.g., time of day when the level is drawn, laboratory specific normal values for testosterone, total vs. free testosterone levels) before initiating replacement therapy. Male hypogonadism is characterized by low serum levels of testosterone and is classified according to the level of the hypothalamus-pituitary-testis axis involvement. 6 It is classified as primary hypogonadism when the main problem involves the testes (elevated lutenizing hormone [LH] and follicle stimulating hormone [FSH]). It is secondary hypogonadism (hypogonadotropic hypogonadism) if the hypothalamus/pituitary axis are involved; low testosterone levels in this case are associated with low or inadequately normal levels of LH and FSH. The diagnosis of male hypogonadism is based on both a clinical suspicion and low testosterone levels. By restoring normal levels of testosterone, the replacement regimens correct symptoms of hypogonadism, which can include malaise, loss of muscle strength, depressed mood, and decreased libido. 4 Testosterone regimens can be administered orally, parenterally, or transdermally. Injectable testosterone replacement products include testosterone cypionate, testosterone enanthate, Aveed, and Testopel, which is implanted subcutaneously. 4,7 These agents are all indicated for congenital or acquired primary hypogonadism and hypogonadotropic hypogonadism (secondary hypogonadism). 1-3 Testopel and testosterone enanthate are also indicated for delayed puberty. 2-3 Testosterone enanthate may also be used secondarily in women with advanced inoperable metastatic mammary cancer that are 1 to 5 years postmenopausal. 2 The primary goal of this therapy is to ablate the ovaries. It can also be used in premenopausal women with breast cancer that have benefited from oophorectomy and are considered to have hormone-responsive tumor. The prescribing information notes that the judgement regarding the use of androgen therapy in females should be made by an oncologist with expertise in the area. Compared to the other two intramuscular injections, Aveed has a longer duration between dosing after it reaches steady state levels. 7 After the first injection, a second injection is administered after 4 weeks. After this second dosing, the subsequent administration are once every 10 weeks. Dose titration is not necessary. The safety and efficacy of Aveed in males < 18 years of age have not been established. Rationale Guidelines American Urological Association (AUA) A white paper published by the American Urological Association (AUA) [2013] notes the challenges in establishing a universally accepted threshold for testosterone concentration that distinguishes eugonadal from hypogonadal men. 8 The AUA notes that there are several different assays for measurement of testosterone levels, and that the performance characteristics, linearity, reproducibility, low level limits of detection, and the pre-analytical requirements differ among the assays. The Endocrine Society recommends that total low testosterone be defined using local, normal assay ranges in the presence of characteristic signs and symptoms diagnostic of hypogonadism. The AUA states that the rigid use of testosterone cut-off value (e.g., 300 ng/dl) may lead to unnecessary treatment of asymptomatic men as well as under-treatment of men with persistent signs and symptoms.

4 Endocrine Society The Endocrine Society guidelines (2010) on testosterone therapy in adult men with androgen deficiency recommend testosterone therapy for symptomatic men with the classical androgen deficiency syndromes who have low testosterone levels. 9 The purpose is to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density. The guidelines also suggest aiming for serum testosterone levels in the midnormal range with testosterone replacement therapy. They list several options for replacement and note that the choice can be based on the patient s preference, consideration of pharmacokinetics, treatment burden, and cost. The options listed are injectable testosterone enanthate or cypionate, nongenital testosterone patches, testosterone gel, bioadhesive buccal testosterone tablet, or oral testosterone undecanoate (not available in the US), injectable testosterone undecanoate (not available in the US), and testosterone pellets. The World Professional Association for Transgender Health (WPATH) The WPATH Standards of Care document (2011) states that exogenous administration of hormone therapy to induce feminizing or masculinizing changes is a medically necessary intervention for many transsexual, transgender, and gender nonconforming individuals with gender dysphoria. 10 Hormone therapy must be individualized based on the patient s goals, risk/benefit ratio of the medications, presence of other co-morbid conditions, and social/economic issues. Hormone therapy alone can provide significant comfort to patients who do not wish to make a social gender role transition, undergo surgery, or in patients unable to have surgery. References: 1. Depo -Testosterone [prescribing information]. New York, NY: Pharmacia & Upjohn Co; September Delatestryl [prescribing information]. Lexington, MA: Indevus Pharmaceuticals, Inc.; July Testopel [prescribing information]. Morrisville, NC: Slate Pharma; January Lee M. Erectile Dysfunction. Urologic Disorders. In: Dipiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A pathophysiologic approach. 8 th ed. New York: McGraw Hill Medical; 2008: Abadilla KA, Dobs AS. Topical testosterone supplementation for the treatment of male hypogonadism. Drugs. 2012;72: Giagulli VA, Triggiani V, Corona G, et al. Evidence-based medicine update on testosterone replacement therapy (TRT) in male hypogonadism: Focus on new formulations. Curr Pharm Des. 2011;17: Aveed [prescribing information0. Malvern, PA: Endo Pharmaceuticals Solutions Inc.; March Paduch DA, Brannigan RE, Fuchs EF, et al. The laboratory diagnosis of testosterone deficiency. White paper. American Urological Association, Inc. Available at: WhitePaper.pdf. Accessed on October 2, Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2010;95(6): Coleman E, Bockting W, Botzer M, et al. Standards of care for the health of transsexual, transgender, and gender nonconforming people. The World Professional Association for Transgender Health. 7 th Version. International Journal of Transgenderism. 2011;13: Palmert MR, Dunkel L. Clinical Practice. Delayed Puberty. N Engl J Med. 2012;366: Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, et al. Endocrine treatment of the transsexual persons: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2009; 94: Wierman ME, Basson R, Davis SR, et al. Androgen therapy in women: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2006;91(10):

5 14. American College of Obstetricians and Gynecologists Committee on Practice Bulletins-Gynecology. ACOG Practice Bulletin No. 119: Female sexual dysfunction. Obstet Gynecol. 2011;117(4): (reaffirmed 2013). 15. Sipe CS, Thomas MR, Stegmann BJ, van Voorhis BJ. Effects of exogenous testosterone supplementation in gonadotrophin stimulated cycles. Hum Reprod. 2010;25(3): Billing Coding/Physician Documentation Information NA Additional Policy Key Words Policy Number: Related Topics N/A Policy Implementation/Update Information 07/2014 New Policy titled Injectable Testosterone Products Prior Authorization This Medical Policy is designed for informational purposes only and is not an authorization, an explanation of benefits, or a contract. Each benefit plan defines which services are covered, which are excluded, and which are subject to dollar caps or other limits. Members and their providers will need to consult the member's benefit plan to determine if there is any exclusion or other benefit limitations applicable to this service or supply. Medical technology is constantly changing and Blue Cross and Blue Shield of Kansas City reserves the right to review and revise medical policy. This information is proprietary and confidential and cannot be shared without the written permission of Blue Cross and Blue Shield of Kansas City.