Medication Policy Manual

Independent licensees of the Blue Cross and Blue Shield Association Medication Policy Manual Topic: Non-preferred, non-transdermal testosterone replacement therapy products (Android, Aveed, Androxy, Methitest, Natesto, Striant, Testopel, Testred, compounded testosterone products, nonpreferred generic products) Policy No: dru297 Date of Origin: March 15, 2013 Committee Approval Date: February 17, 2017 Next Review Date: February 2018 Effective Date: March 1, 2017 IMPORTANT REMINDER This Medication Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status. Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. The purpose of medication policy is to provide a guide to coverage. Medication Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care. Description Testosterone replacement therapy (TRT) products are used in the treatment of hypogonadism (testosterone deficiency). The effectiveness of TRT is monitored by assessing serum testosterone levels, as well as improvement in sexual function, mood, fatigue, bone mineral density, and wellbeing. dru297.8 Page 1 of 12

Policy/Criteria I. Most contracts require prior authorization approval of non-preferred testosterone replacement therapy (TRT) products, as listed in Appendix 1, prior to coverage. For nonpreferred TRT products, except for Aveed (Android, Methitest, Natesto, Striant, Testopel, Testred, non-preferred generic products), products listed in Appendix 1 may be considered medically necessary when criteria A and B below are met. A. Injectable testosterone cypionate or testosterone enanthate has been ineffective, contraindicated, or not tolerated. B. One of the following four conditions (criteria 1 through 4) is met: 1. A diagnosis of primary (Testicular) hypogonadism or secondary (Pituitary-Hypothalamic) hypogonadism caused by a specific medical condition associated with a deficiency or absence of endogenous testosterone including, but not limited to, those listed in Appendix 3, when documentation of at least two low testosterone levels (less than 300 ng/dl for total testosterone, or less than 9 ng/dl for free testosterone) drawn prior to 10 AM on two separate days is provided. This criterion is not met by primary (Testicular) hypogonadism not caused by a specific medical condition. OR 2. Gender dysphoria when all of the following criteria are met: a. Clinical records document that the patient has the capacity to make fully informed decisions and consent for treatment. AND b. A licensed behavioral health practitioner has diagnosed gender dysphoria as defined by the DSM-5 criteria. AND c. At least one of the following criteria must be met for a period of 3 or more months prior to the initiation of hormone therapy i. Documentation of living as the desired gender; and/or OR ii. Psychotherapy with a licensed behavioral practitioner. 3. To induce puberty in males with delayed puberty (Testopel, Android, Methitest, and Testred only). OR 4. Used secondarily in women with inoperable, metastatic breast cancer who are 1 to 5 years postmenopausal (Android, Methitest, and Testred only). dru297.8 Page 2 of 12

II. Administration, Quantity Limitations, and Authorization Period A. Regence Pharmacy Services considers oral, nasal, topical, and transdermal testosterone replacement therapy (TRT) products to be self-administered medications. B. Regence Pharmacy Services does not consider Aveed or Testopel to be selfadministered medications. C. When prior authorization is approved, TRT products may be authorized as follows: TRT Products Transdermal testosterone topical solution (Axiron ); 30 mg per actuation testosterone topical gel 2% (Fortesta ); 10 mg per actuation testosterone topical gel 1% (Testim Gel 50 mg/5 gm tubes) testosterone topical gel 1% (Vogelxo 50 mg /5 gm tube or packet) testosterone topical gel 1% (Vogelxo pump bottle); 12.5 mg per actuation testosterone transdermal patch 2-4 mg/24 hours (Androderm ) Subcutaneous pellet testosterone 75 mg pellet (Testopel ) Quantity Level Limitation (per Month, unless noted) 2 pump bottles (60 actuations/bottle) 2 pump bottles (120 actuations/bottle) 60 tubes 60 tubes or packets pump bottles (60 actuations per bottle) 2-mg/24 hour: 60 patches 4-mg/24 hour: 30 patches 900 mg (12 pellets) every 3 months Oral/Buccal fluoxymesterone 10 mg tablets (Androxy) methyltestosterone 10 mg capsules (Android, Testred) methyltestosterone 10 mg tablets capsules (Methitest) testosterone 30 mg extended-release buccal tablets (Striant ) Nasal gel testosterone nasal gel 4.5% (Natesto metereddose pump bottle); 5.5 mg per actuation 60 tablets 150 capsules 150 tablets 60 tablets 3 pump bottles (60 actuations per bottle) D. Quantities above the listed quantity limits are considered not medically necessary. dru297.8 Page 3 of 12

E. Authorization shall be reviewed in the timeframes defined below: 1. Primary (Testicular) hypogonadism/secondary (Pituitary- Hypothalamic) hypogonadism: Authorization shall be reviewed after 6 months, and then at least annually to assure that both of the following are met: a. The member has a specific medical condition associated with a deficiency or absence of endogenous testosterone. AND b. The testosterone level does not exceed 700 ng/dl. (See Appendix 2, Lab Monitoring Guidelines for TRT Products). For patients with a testosterone level exceeding 700 ng/dl, ongoing coverage of testosterone replacement therapy will be authorized only when there is clinical documentation that the TRT dose will be adjusted for a goal level of less than 700 ng/dl. 2. Gender reassignment therapy, delayed puberty, and metastatic breast cancer: authorization may be reviewed at least annually to confirm that current medical necessity criteria are met and that the medication is effective. III. Non-preferred TRT products, as listed in Appendix 1, are considered not medically necessary for the following non-specific conditions: A. Primary (testicular) hypogonadism, not otherwise specified, including age-related hypogonadism B. Testicular hypofunction, not otherwise specified C. Low libido in men without hypogonadism or women D. Use in women for infertility; sexual dysfunction, cognitive dysfunction, cardiovascular dysfunction, metabolic dysfunction, bone health, or well-being. IV. The use of testosterone undecanoate injection (Aveed) is considered not medically necessary for any indication. V. Non-preferred TRT products, as listed in Appendix 1, are considered investigational for the following conditions: A. Weight gain in HIV-infected men Position Statement - Testosterone replacement therapy (TRT) is commonly used for treatment of hypogonadism in men and as part of gender reassignment therapy. All products are considered effective for increasing serum testosterone levels. - There is no evidence demonstrating that any one TRT product is safer or more effective than less costly generic injectable options. There are no studies that directly compare the clinical effects of different TRT products. dru297.8 Page 4 of 12

- Hypogonadism may be caused either by failure of the testicles to produce testosterone (primary), or by central defects in the hypothalamus or pituitary gland which lead to secondary testicular failure. [1] - A diagnosis of hypogonadism is confirmed by measuring serum testosterone levels. [1] - Testosterone levels vary throughout the day and are highest in the morning. Normal ranges for serum testosterone levels are usually established using morning blood samples. [1] - Threshold testosterone levels below which adverse health symptoms occur are not known. Likewise, optimal levels of testosterone at which TRT improves outcomes are not known. For most symptoms in younger men, the average testosterone threshold corresponds to the lower limit of the normal range. [1] - Because testosterone levels vary significantly due to body rhythms, episodic secretion, and measurement variations, at least two levels should be obtained to confirm a diagnosis of hypogonadism. [1] - Normal ranges for testosterone vary among laboratories and assays. The Endocrine Society recommends that a lower limit for normal testosterone levels is 300 ng/dl for total testosterone and 9.0 ng/dl for free testosterone. [1] - The Endocrine Society Clinical Guideline recommends evaluating patients 3 to 6 months after initiating treatment to evaluate patients for side effects and to make sure total testosterone levels are between 400 ng/dl and 700 ng/dl. [1] - Overall, TRT products are well tolerated. - In March 2015, the FDA released a drug safety communication clarifying that the benefits and safety of TRT have not been established for the treatment of low testosterone levels due to aging, even if a man s symptoms seem related to low testosterone. The communication also stated that there is a possible increased cardiovascular risk associated with testosterone use. [2] - Since the initial drug safety communication, a limitation of use has been added to the prescribing information for multiple testosterone replacement products. The updated labeling states that safety and efficacy has not been established for age-related hypogonadism (also referred to as late-onset hypogonadism). - Primary or Secondary hypogonadism not otherwise specified (NOS), including agerelated hypogonadism, is not a covered indication. For hypogonadism, testosterone replacement may be considered medically necessary when low testosterone levels are due to a documented medical cause as listed in Appendix 3. - Age-related hypogonadism does not have a unique ICD-10 code, and therefore may be billed under a more general code, such as testicular hypofunction or testicular hypogonadism, not otherwise specified (NOS). - Low-dose testosterone therapy is a standard treatment option for the management of delayed puberty in boys. Goals of therapy include the induction of secondary sexual characteristics or growth and the mitigation of psychosocial difficulties. [3] dru297.8 Page 5 of 12

- Testosterone enanthate may be used secondarily in women with advancing inoperable metastatic breast cancer who are one to five years postmenopausal. Although several testosterone products are FDA-approved for this indication, newer, targeted therapies have largely replaced its use in this setting. [4] - While there is limited evidence that testosterone may have some benefit in for sexual dysfunction in post-menopausal women there is insufficient evidence to establish the safety and efficacy of testosterone in this indication. Additionally, the Endocrine Society recommends against the general use of testosterone for the indications of infertility, sexual dysfunction (other than hypoactive sexual desire disorder), cognitive health, cardiovascular health, bone health, or general well-being in women due to limited evidence of efficacy and safety. [5] - Small increases in lean body mass and body weight have been reported in HIV-infected men with weight loss; however, it is uncertain whether the change was clinically meaningful or whether it correlated with clinically relevant endpoints (increased muscle strength and physical functioning, overall quality of life, or improved survival). - While branded TRT products are comparable in price, testosterone cypionate and testosterone enanthate offer members the best value and they are available at preferred copayments. - Due to serious adverse events, such as pulmonary oil microembolism (POME) reactions and anaphylaxis, that are not present with other products, the use of testosterone undecanoate (Aveed) is considered not medically necessary. [6] - TRT should not be started in men who are at high risk for, or who have, prostate cancer. - Due to the availability of injectable formulations, quantities above the quantity limits listed criterion II.B. are considered not medically necessary. The quantity limits listed correspond with the manufacturer s prescribing information for each medication. There is a lack of literature showing improved health outcomes and safety when the maximum dosing is exceeded. Clinical Efficacy No single testosterone replacement therapy (TRT) product has been proven in reliable clinical studies to be more effective than another TRT product. - All TRT products appear to be similarly effective based on pharmacokinetic data. There is pharmacokinetic evidence that all topical testosterone products replete testosterone levels in men with hypogonadism. [7] - The FDA accepts open-label, non-comparative trials of new TRT formulations as sufficient to provide evidence of safety and efficacy. More clinically relevant endpoints would be trials with validated disease outcome measures, showing meaningful improvements in symptoms, such as low mood, sexual function, lean muscle mass, and energy levels. - There are no trials comparing any branded TRT formulation, therefore there is no evidence that one branded TRT product is superior to another. - Long-term health outcomes of TRT, such as decreased incidence of fracture or cardiovascular risk, are uncertain. [2,8] dru297.8 Page 6 of 12

- Clinical guidelines recognize TRT as standard of care and effective for treatment of hypogonadism in men. All products are considered effective in raising testosterone levels. Choice of TRT product is based on pharmacokinetics, patient preference, and cost. However, oral TRT is not recommended due to poor absorption and liver toxicity. [9,10] - The efficacy of TRT has not been established in men with age-related hypogonadism. - There are no valid, reliable, clinically relevant endpoints for studies assessing the effect of testosterone on desire, frequency of sexual activity, erectile function, mood, energy, overall quality of life, body composition (lean and fat body mass), and bone mineral density in men with age-related hypogonadism. Safety [6,7] - Overall, testosterone topical replacement (TRT) is well tolerated. Common adverse effects ( 3%) include acne, gynecomastia, oral irritation (buccal formulation), headache, and enlarged prostate. The most commonly reported adverse event with topical TRT is application site reactions. However, testosterone transdermal patch (Androderm ) is associated with a significantly higher rate of skin reactions, including blistering of the skin. - TRT may be associated with increased risk of adverse cardiovascular outcomes (increased mortality, myocardial infarction, and stroke). Although findings in several large observational studies and meta-analyses are inconsistent, the FDA s Bone, Reproductive and Urologic Drugs Advisory Committee concluded that there is a small signal of risk. Based on conclusions reached in the advisory committee, the FDA subsequently released a drug safety communication related to the CV risk and will require labeling changes for all prescription testosterone products. [2,8-11] - TRT is contraindicated in men with known or suspected prostate cancer. - Testosterone undecanoate (Aveed) has boxed warnings for pulmonary oil microembolism (POME) reactions and anaphylaxis. POME reactions may be life threatening; symptoms include cough, dyspnea, throat tightening, chest pain, dizziness, and syncope. Patients who received testosterone undecanoate (Aveed) must be monitored in a healthcare setting for 30 minute post-dose in case of serious POME reactions or anaphylaxis. - Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. [12] - In 2009, the FDA issued a MedWatch safety alert of inadvertent (secondary) testosterone exposure with topical testosterone gel (Testim and AndroGel), based on eight case reports of exposure in children, age nine months to five years old. Signs of virilization (development of male secondary sexual characteristics) and bone aging were observed. Black box warnings are now required on all topical gel and solution formulations of testosterone, as well as educational REMS programs to reduce secondary exposure. [13] dru297.8 Page 7 of 12

Appendix 1: Non-Preferred Testosterone Replacement Therapy (TRT) Products Topical testosterone topical solution 2% (Axiron ) testosterone topical gel 2% (Fortesta ) testosterone topical gel 1% (Testim Gel ) testosterone topical gel 1% (Vogelxo ) testosterone transdermal patch 2-4 mg/24 hours (Androderm ) Oral/Buccal methyltestosterone 10 mg capsule (Android, Testred ) methyltestosterone 10 mg capsule (Methitest ) testosterone 30 mg extended-release buccal tablets (Striant ) Nasal gel testosterone nasal gel 4.5% (Natesto ) Subcutaneous Pellet testosterone pellets 75 mg (Testopel ) dru297.8 Page 8 of 12

Appendix 2: Lab Monitoring Guidelines for TRT Products Transdermal patches Androderm Measure morning testosterone (following application of the patch the previous evening) Transdermal gels and solutions AndroGel, AndroGel Pump, Testim Fortesta Axiron Vogelxo Measure pre-dose morning testosterone level Measure testosterone 2 hours after application Measure testosterone 2 to 8 hours after application Measure testosterone 4 to 8 hours after application Subcutaneous pellet Testopel Measure pre-dose level and periodically during therapy Buccal tablet Striant Measure pre-dose morning testosterone level Nasal gel Natesto Measure pre-dose level Injectable testosterone cypionate (generics) testosterone enanthate (generics) Measure pre-dose level and periodically during therapy Measure pre-dose level and periodically during therapy dru297.8 Page 9 of 12

Appendix 3: Causes of Primary (Testicular) and Secondary (Pituitary-Hypothalamic) hypogonadism [14,15] Primary (Testicular) Hypogonadism due to testicular dysfunction, including but not limited to the following conditions: a Bilateral Torsion Cryptorchidism Disorders of androgen biosynthesis Klinefelter s syndrome or other chromosomal abnormalities Myotonic dystrophy Orchitis Toxic damage from chemotherapy, alcohol, or heavy metals Trauma to the testicles Vanishing testis syndrome Varicocele Secondary (Pituitary-Hypothalamic) hypogonadism due to pituitary-hypothalamic dysfunction, including but not limited to the following conditions: Congenital GnRH deficiency Hyperprolactinemia Idiopathic gonadotropic or luteinizing hormone-releasing hormone deficiency Kallman Syndrome Pituitary-hypothalamic dysfunction (not otherwise specified) Pituitary-hypothalamic injury from tumors, trauma, or radiation a Primary (Testicular) or Secondary (Pituitary-Hypothalamic) Hypogonadism (not otherwise specified, including age-related) is not a covered indication. dru297.8 Page 10 of 12

Cross References Testosterone Replacement Therapies, BlueCross BlueShield Association Medical Policy, 5.01.23, Issue 12:2014 Transgender Services, Medical Policy. Medicine, Policy No. 153. Testosterone cypionate, testosterone enanthate, Medication Policy Manual, Policy No. dru395 Preferred transdermal testosterone replacement therapy products (AndroGel, AndroGel Pump ), Medication Policy Manual, Policy No. dru411 Non-preferred, transdermal testosterone replacement therapy products, Medication Policy Manual, Policy No. dru415 Codes Number Description HCPCS J3145 Testosterone undecanoate, 1 mg HCPCS S1089 Testosterone pellet, 75 mg References 1. Bhasin, S, Cunningham, GR, Hayes, FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism. 2010;95:2536-59. PMID: 20525905 2. U.S. Food and Drug Administration. Summary Minutes of the Joint Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. [cited 11/7/2014]; Available from: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drug s/reproductivehealthdrugsadvisorycommittee/ucm418144.pdf. 3. Palmert, MR, Dunkel, L. Clinical practice. Delayed puberty. The New England journal of medicine. 2012 Feb 2;366(5):443-53. PMID: 22296078 4. Ellis, M, Naughton, MJ, Ma, CX. Treatment approach to metastatic hormone receptorpositive breast cancer: Endocrine therapy. In: UpToDate, Basow, DS (Ed). UpToDate, Waltham, MA, 2015. 5. Wierman, ME, Arlt, W, Basson, R, et al. Androgen therapy in women: a reappraisal: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism. 2014 Oct;99(10):3489-510. PMID: 25279570 6. Aveed [package insert]. Malvern, PA: Endo Pharmaceuticals; September 2014 7. Micromedex Healthcare Series [internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically. dru297.8 Page 11 of 12

8. U.S. Food and Drug Administration. FDA Briefing Information for the September 17, 2014 Joint Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting. [cited 11/7/2014]; Available from: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drug s/reproductivehealthdrugsadvisorycommittee/ucm412536.pdf. 9. Vigen, R, O'Donnell, CI, Baron, AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA : the journal of the American Medical Association. 2013;310:1829-36. PMID: 24193080 10. Xu, L, Freeman, G, Cowling, BJ, Schooling, CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebocontrolled randomized trials. BMC Med. 2013;11:108. PMID: 23597181 11. Finkle, WD, Greenland, S, Ridgeway, GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014;9:e85805. PMID: 24489673 12. FDA approves new changes to testosterone labeling regarding the risks associated with abuse and dependence of testosterone and other anabolic androgenic steroids (AAS). [cited 1/4/2017]; Available from: http://www.fda.gov/drugs/drugsafety/ucm526206.htm 13. MedWatch. FDA news release: Testosterone Gel Safety Concerns Prompt FDA to Require Label Changes, Medication Guide. 7May2009. [cited 2/16/2011]; Available from: http://www.fda.gov/newsevents/newsroom/pressannouncements/2009/ucm149580.htm. 14. Snyder, PJ. Causes of secondary hypogonadism in males. In: UpToDate, Martin, K.A. (Ed). UpToDate, Waltham, MA, 2015. 15. Snyder, PJ. Causes of primary hypogonadism in males. In: UpToDate, Martin, K.A. (Ed). UpToDate, Waltham, MA, 2015. Revision Date Revision Summary 2/17/2017 Increased Testopel QL, clarified Androxy QL 2/12/2016 Clarified that primary (testicular) hypogonadism and testicular hypofunction not otherwise specified (NOS), including age-related are considered not medically necessary Clarified that Appendix 3 is not an exhaustive list of potential causes of primary (testicular) and secondary (pituitaryhypothalamic) hypogonadism. Updated not medically necessary uses 12/11/2015 Rearranged policy criteria Clarified that the cause of hypogonadism must be caused by a condition listed in appendix 3 Updated appendix 3 with additional causes of hypogonadism Allowed for reauthorization if testosterone levels exceed 700 ng/ml. Reauthorization requires a documented plan to address the high level or adjust the dose. dru297.8 Page 12 of 12