Testosterone Replacement Therapies

Transcription

1 Testosterone Replacement Therapies Policy Number: Last Review: 7/2015 Origination: 7/2015 Next Review: 7/2016 Policy BCBSKC will provide coverage for testosterone replacement therapies when it is determined to be medically necessary because the following criteria are met. When Policy Topic is covered Testosterone replacement therapy may be considered medically necessary under the following conditions: An established diagnosis of hypogonadism with androgen deficiency that includes: o Persistently low testosterone levels, AND o Multiple symptoms of hypogonadism including at least 1 more specific symptom HIV-infected men with low testosterone levels and weight loss; OR Men on chronic steroid treatment with low testosterone levels If medical criteria is met, a Step 1 product is required to be tried and failed prior to a Step 2 product. Commercial: Step 1: AndroGel or Testim Exchange: Step 1: Axiron When Policy Topic is not covered Testosterone replacement therapy is considered investigational in all other situations in which the above criteria are not met, including but not limited to older men with low testosterone levels in the absence of clinical signs and symptoms of hypogonadism. This policy addresses only testosterone replacement therapy and therefore does not apply to those undergoing treatments for gender transition. Considerations Testosterone replacement products require prior authorization through the pharmacy services department. This Blue Cross and Blue Shield of Kansas City policy Statement was developed the Blue Cross and Blue Shield Association policy Diagnosis of Androgen Deficiency An established diagnosis of hypogonadism with androgen deficiency includes appropriate evaluation and diagnostic workup of a man who presents with symptoms of hypogonadism. Clinical Practice Guidelines recommend measuring serum testosterone only in men with consistent clinical manifestations of hypogonadism. Screening in asymptomatic populations is not recommended. Measurement of serum total testosterone is initially used; serum-free testosterone levels can be measured when total testosterone is in the low normal range and alterations of serum hormone-binding globulin are suspected. 1 Once a persistently low testosterone level has been established, diagnostic testing of the hypothalamic-pituitary axis should be performed to distinguish primary hypogonadism from secondary hypogonadism. When secondary hypogonadism is identified, the underlying etiology

2 should be identified, and any reversible causes treated appropriately before consideration of testosterone replacement. Men on chronic steroid treatment would be receiving ongoing treatment for manifestations of a chronic condition, as opposed to episodic treatment for an acute condition or acute flare of a chronic condition. The length of acute episodic steroid treatment may vary from several days to several months, but in most cases will be less than 4 to 6 weeks. Persistently low testosterone levels refers to serum levels that are below the lower limit of normal on at least 2 occasions when measured in the early morning (8 am). The threshold lower limit for serum testosterone levels is not standardized. The Endocrine Society recommends that a lower limit for normal levels is 300ng/dL for total testosterone and 9.0 ng/dl for free testosterone. 1 Joint guidelines by several European and American specialty societies recommend that replacement therapy be considered at serum total testosterone levels less than 350 ng/dl. 2 More specific symptoms of hypogonadism, as classified by the Endocrine Society, include the following 1 : Incomplete or delayed sexual development Decreased libido Decreased spontaneous erections Breast discomfort, gynecomastia Loss of axillar and/or pubic body hair Very small (<5 ml) or shrinking testes Infertility due to low sperm count Height loss due to vertebral fractures, low trauma fractures, low bone density Hot flushes, sweats Description of Procedure or Service Testosterone Dosage Guidelines Dosing of testosterone is variable, depending on age, baseline testosterone levels, comorbid disease, response to initial replacement levels, and adverse reactions. General dosing guidelines are provided by the Endocrine Society Guidelines (see Practice Guidelines and Position Statements section) Specific dosing guidelines for a few of the more commonly used preparations, taken from the product prescribing information, follow: Androgel (1.62%): The recommended starting dose is 40.5 mg/d, corresponding to 2 pumps applied topically. The recommended dose range is between mg (1 pump) and 81 mg (4 pumps) per day. Androderm patch: The suggested starting dosing for Androderm patch is one 4-mg patch applied daily. The usual range of dosing required to achieve and maintain normal levels is between 2 and 6 mg/d. Testopel : The recommended dosing range for Testopel is 150 to 450 mg every 3 to 6 months. For 75-mg pellets, this would correspond to implant of 2 to 6 pellets every 3 to 6 months. The dosing interval is individualized, as some patients will require redosing as early as every 3 months while others may not require redosing for up to 6 months. Monitoring of testosterone replacement should be performed beginning 3 to 6 months after replacement is initiated to ascertain whether serum levels are restored to the normal range, to determine whether clinical symptoms have improved, and to monitor for adverse effects. The goal of testosterone replacement is to raise levels into the mid-normal range. Higher replacement levels are unlikely to improve symptoms further and may increase the incidence and/or severity of AEs. Monitoring Strategies for Patients on Testosterone Therapy Recommendations for monitoring for testosterone-related AEs are provided by the Endocrine Society Guidelines on testosterone therapy in men with androgen deficiency. 1 These recommendations include:

3 Determine a hematocrit at baseline, at 3 to 6 months, and then annually. If the hematocrit is above 54%, stop therapy until the hematocrit decreases to a safe level, evaluate the patient for hypoxia and sleep apnea, and reinitiate therapy at a reduced dose. Repeating bone mineral density of the lumbar spine, femoral neck, and hip after 1 to 2 years of testosterone therapy in hypogonadal men with osteoporosis or low trauma fracture. In men 40 years of age or older who have a baseline prostate-specific antigen (PSA) greater than 0.6 ng/ml, conduct a digital examination of the prostate and PSA measurement before initiating treatment, at 3 to 6 months, and then in accordance with evidence-based guidelines for prostate cancer screening, depending on the age and race of the patient. Obtain urological consultation if there is: o An increase in serum or plasma PSA concentration greater than 1.4 ng/ml within any 12- month period of testosterone treatment. o A PSA velocity of more than 0.4 ng/ml per year using the PSA level after 6 months of testosterone administration as the reference. PSA velocity should be used only if there are longitudinal PSA data for more than 2 years. o Detection of a prostatic abnormality on digital rectal examination. o American Urological Association (AUA)/International Prostate Symptom Score (IPSS) above 19. Rationale Testosterone is produced in males primarily by the testes in response to stimuli from the hypothalamic and pituitary glands. Low testosterone is caused by deficient production of the hormone and is also known as androgen deficiency. Primary androgen deficiency results from failure of testosterone production at the testicular level in the presence of normal hypothalamic and pituitary function. Secondary androgen deficiency results from failure of production of androgen-stimulating hormones (luteinizing hormone, follicle-stimulating hormone) by the pituitary gland. It can be caused by dysfunction at the hypothalamic or pituitary level. Hypogonadism is the clinical syndrome associated with androgen deficiency. The signs and symptoms of hypogonadism depend on the age of onset. In prepubertal males, the hallmark of androgen deficiency is the failure to develop secondary male sex characteristics. In adults, the signs and symptoms are nonspecific, with the most specific symptoms related to sexual functioning such as decreased libido and erectile dysfunction. Symptoms are dependent on age, severity of androgen deficiency, duration of androgen deficiency, individual sensitivity to androgen, and comorbid illness.1 Symptoms and signs other than sexual dysfunction include loss of body hair, hot flushes or sweats, decreased energy, depression, sleep disturbance, reduced muscle mass and strength, and/or increased body fat. These can all occur in the absence of androgen deficiency and, therefore the diagnosis of hypogonadism can be challenging. A 2014 systematic review of studies that reported on risk factors, comorbidities, and consequences of male hypogonadism identified multiple comorbid conditions that were consistently risk factors for hypogonadism, including advanced age, obesity, a diagnosis of metabolic syndrome, and poor general health status. 3 Multiple other conditions, including diabetes, coronary heart disease, hypertension, stroke, and peripheral artery disease were correlated with the presence of hypogonadism, although were not identified as risk factors. Testosterone levels decrease with age beginning in the fourth or fifth decade, and this decrease is sometimes referred to as male andropause. In the European Male Aging Study of 3220 men, there was a decline in serum testosterone levels of 0.4% per year between the ages of 40 and 70.4 Since this decline is gradual and modest, the clinical impact is uncertain. While there are also parallel decreases in androgen-dependent factors with age, such as sexual function, lean body mass, and BMD, the degree to which these changes are due to decreasing testosterone has not been determined with certainty. Because of the decline in testosterone levels with age, more elderly males will have low levels compared with younger men. Using a cutoff of 325 ng/dl as the lower limit of normal testosterone levels, 1 prospective cohort study of 890 men estimated that the rate of low testosterone is 20% for men in their 60s; 30% for men in their 70s; and 50% for men in their 80s. 5 In this study, there were

4 other factors that were associated with decreased testosterone, such as obesity and severe emotional stress. A much lower percentage of men have a combination of low testosterone levels and definite symptoms of hypogonadism. In the European Male Aging Study, this was estimated to be present in 2.3% of men when using a cutoff of at least 3 symptoms potentially related to androgen deficiency. Another factor that makes the diagnosis of hypogonadism challenging is the measurement of testosterone levels. Testosterone levels fluctuate substantially due to a variety of factors. There is a diurnal variation, which is more pronounced in younger men, with peak levels occurring in the early morning. This makes the timing of measurement important and requires repeated measurement before making a determination that testosterone is consistently low. Also, there is a wide range of levels seen in healthy men, and assigning the proper age-appropriate cutoff is controversial. Some men exhibit clear symptoms of hypogonadism with testosterone levels that are in the low normal range, while other men with low levels do not experience any symptoms. Testosterone Replacement There are numerous different Food and Drug Administration (FDA) approved formulations of testosterone that are available for replacement therapy. For most delivery preparations, FDA approval was granted on the ability to increase levels to the normal range and not on demonstration of beneficial clinical outcomes. 6 Oral testosterone: The most common forms of oral testosterone in clinical use are testosterone enanthate and testosterone cypionate, which are generally dosed twice daily. Oral testosterone is readily absorbed from the intestine and is rapidly metabolized by the liver. The rapid metabolism in the liver limits its clinical utility, as it is difficult to maintain steady serum levels. In addition, the first pass through the liver may increase the probability of liver toxicity. Intramuscular testosterone: Testosterone undecanoate is an intramuscular (IM) depot preparation of testosterone that is slowly absorbed into the circulation. It is administered by deep IM injection every 10 to 14 weeks, and thus has the advantage of infrequent dosing. Disadvantages of this preparation include the IM injection route, which can be painful, and inconsistent rates of absorption. Inconsistent absorption can lead to fluctuating testosterone levels, with associated fluctuations in clinical symptoms. Topical patch: Topical testosterone patches are available and can be applied to nongenital skin areas. Patches are generally dosed once per day and result in stable testosterone levels over time. A limiting factor in the use of patches is the development of skin irritation at the patch site in a high percentage of users. Topical gel: A number of topical testosterone gel preparations are commercially available. They range in strength from 1% to 2% and result in stable serum levels. The gel is applied daily on nongenital skin areas. Precautions need to be taken to avoid transmission of the drug to others by direct contact, therefore it is recommended that the gel be placed on covered skin and that handwashing is performed after application. Buccal tablets: Buccal tablets are commercially available and are applied twice per day to the gums over the upper incisors. Testosterone is absorbed through the buccal mucosa into the systemic circulation. Subcutaneous pellets: Another depot formulation of testosterone is a subcutaneous testosterone tablet. These are placed subcutaneously in the buttocks, abdominal wall, or thigh under local anesthesia. They are replaced every 3 to 6 months. Limitations include the need for a minor surgical procedures, and local reactions at the implantation site, such as infections or fibrosis. There are numerous preparations of testosterone that have received FDA approval for use in testosterone replacement therapy. These include IM, oral, topical, subcutaneous and buccal preparations. In January 2014, FDA announced its plan to investigate the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products based on increased risks reported in several studies. 7 In September 2014, at a meeting of the FDA s Bone, Reproductive and Urologic Drugs Advisory

5 Committee, the committee reported that FDA had not concluded that FDA-approved testosterone treatment increases the risk of stroke, heart attack, and death. However, the Advisory Committee voted in favor of changing the current FDA labeling for indications for testosterone therapies, with committee members stating that the indication for testosterone therapy should be limited to men with classical hypogonadism. 8 Guidelines Assessment of efficacy for therapeutic intervention involves a determination of whether the intervention improves health outcomes. The optimal study design for this purpose is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. Intermediate outcome measures, also known as surrogate outcome measures, may also be adequate if there is an established link between the intermediate outcome and true health outcomes. Nonrandomized comparative studies and uncontrolled studies can sometimes provide useful information on health outcomes, but are prone to biases such as noncomparability of treatment groups, the placebo effect, and variable natural history of the condition. There is a large body of literature that evaluates the efficacy of testosterone replacement therapy. This body of evidence is primarily characterized by small- to medium-sized trials of short duration. There is a high degree of variability in the patient populations, dose and delivery method for testosterone replacement, and outcomes measured. There are also numerous systematic reviews of the available evidence. The following evidence review will focus on the impact of testosterone on specific symptoms for adults with androgen deficiency and clinical symptoms of hypogonadism, and on the benefit for specific subpopulations. Emphasis is on the available systematic reviews and larger individual RCTs. Sexual Dysfunction Adults with Androgen Deficiency and Clinical Symptoms There are a large number of RCTs that have evaluated the effect of testosterone replacement on sexual function in men with hypogonadism and low or low-normal testosterone levels. A systematic review of 17 RCTs with placebo control was published in 2007 by Bolona et al.9 Most of the included trials were small, with a combined enrollment of 862 patients. The methodologic quality of these trials was not high, with most trials not reporting methods taken to limit bias. There was also reporting bias noted, with incomplete data on the range of measured outcomes, and high dropout rates in many of the studies. Combined results indicated a strong effect for an increase in libido in men treated with testosterone. On subgroup analysis, the impact of testosterone replacement was substantially greater for studies that enrolled men with low mean testosterone levels compared with studies that enrolled men with low-normal levels. On combined analysis, there was also a positive impact on erectile dysfunction, but the strength of this effect was moderate and not as consistently reported as for changes in libido. There was no significant effect on overall sexual satisfaction in combined analysis. The authors also reported large variability in the results of the studies and wide confidence intervals around the combined results for each outcome. Subgroup analysis was unable to provide adequate explanations for the variability in study results. Another systematic review reported specifically on the impact of testosterone replacement for erectile dysfunction. 10 This review included 16 randomized and nonrandomized studies and limited combined analysis to studies that reported a response rate by predefined criteria. Combined analysis showed that 57% of treated men had a positive response to testosterone. The response rate was higher for men with primary hypogonadism (64%) compared with men with secondary hypogonadism (44%, p<0.001). There was also a higher response rate for patients treated with transdermal preparations (80.9%) compared with patients treated with IM or oral preparations (51.3% and 53.25%, respectively, p<0.001). Since publication of the systematic reviews, Pexman-Fieth et al reported improvements in erectile function and quality of life among 799 men treated with transdermal testosterone over a 6-month period. 11 Body Composition, Muscle Strength, and Physical Function

6 Bhasin et al performed a meta-analysis of 10 trials that evaluated the effect of testosterone replacement on body composition. 12 They reported a mean increase of 1.1 kg in total body mass and a mean increase of 1.7 kg (95% confidence interval [CI], 1.52 to 1.96) in lean body mass. There was a correlation of the increase in lean body mass with the dose of testosterone given, and with circulating testosterone levels. The effects were less consistent for muscle strength and muscle function. The authors reported an increase in leg strength, but no impact on muscle endurance or muscle tension. Bone Mineral Density In a meta-analysis published in 2006, Tracz et al evaluated the impact of testosterone replacement on bone mineral density (BMD). 13 The trials included in this review were small, with a total population of 365 patients, and only1 trial followed patients for more than 1 year. Testosterone given by the IM route led to an 8% increase (95% CI, 4% to 13%) in density of the lumbar spine, although transdermal treatment did not lead to any significant increases. There was also a 4% increase in density at the femoral neck (95% CI, 2% to 9%).In a meta-analysis published in 2006, Tracz et al evaluated the impact of testosterone replacement on bone mineral density (BMD). 13 The trials included in this review were small, with a total population of 365 patients, and only1 trial followed patients for more than 1 year. Testosterone given by the IM route led to an 8% increase (95% CI, 4% to 13%) in density of the lumbar spine, although transdermal treatment did not lead to any significant increases. There was also a 4% increase in density at the femoral neck (95% CI, 2% to 9%). Other Outcomes Evidence on the impact of testosterone replacement on other outcomes, such as depression, quality of life and cognition, is limited. A few small studies have reported benefit in patients with low testosterone and depression. Amiaz et al reported results of an RCT of 100 men with depression treated with selective serotonin reuptake inhibitors and low or low-normal testosterone. After 6 weeks of treatment, there were significant improvements for patients treated with testosterone compared with placebo on the International Index of Erectile Function Scale. The greatest impact was on the subscale for ejaculatory ability. In 2 studies of men with dysthymia, with enrollments of 33 and 23 total patients, treatment with testosterone lead to greater improvements on the Hamilton Rating Scale for depression and a higher remission rate compared with placebo. 14,15 Borst et al reported results from a small prospective RCT assessing the cognitive benefit of testosterone, with or without the 5-reductase inhibitor finasteride, in men aged 60 or older with low serum testosterone and no evidence of cognitive impairment. 16 Patients were randomized to either placebo, testosteroneenanthate with placebo, finasteride with testosterone vehicle (placebo), or testosterone with finasteride. Compared with placebo, testosterone was associated with a small decrease in depressive symptoms as measured by the 15-point Geriatric Depression Scale (absolute score reduction, points; 95% CI, to -0.06; p=0.04). Testosterone was also associated with a moderate increase in visuospatial memory. Androgen Deficiency in Patients With HIV Infection There is a high prevalence of androgen deficiency in patients with HIV infection who are on antiviral treatment, with up to 25% of this population having low testosterone levels. Men with low levels of testosterone have worse outcomes of HIV disease, including increased progression of disease, loss of muscle mass, and declines in physical functioning. 1 A systematic review of testosterone replacement in HIV-infected men with weight loss was performed by Bhasin et al. 17 These authors identified 8 trials of testosterone replacement in HIV-infected patients with weight loss. The trials were of variable quality and heterogeneous in their methodology. Combined analysis of changes in body weight, fat free mass, and lean body mass was performed. There was an estimated increase of 1.1 kg in body weight (95% CI, 0.2 to 2.0), 1.4 kg in fat-free mass (95% CI, 0.7 to 2.1), and 1.3 kg in lean body mass (95% CI, 0.4 to 2.2) associated with testosterone replacement. This systematic review also reviewed the outcomes of muscle strength and depression. Three trials reported on changes in muscle strength, with 2 of the 3 reporting significant improvements with testosterone. Four trials reported on changes in depression, with combined analysis showing a modest increase in depression scores for testosterone-treated patients. There were no significant changes in parameters of HIV infection, such as T lymphocyte or viral load for patients treated with testosterone.

7 Androgen Deficiency in Patients on Chronic Steroid Treatment Patients who are treated with chronic steroid therapy have lower levels of testosterone compared with age-matched patients who are not on steroids. This effect is thought to be due to direct suppression of the hypothalamic-pituitary axis by steroids, as well as a direct suppression of testosterone production in the testes. This hormonal suppression contributes to the increase in abdominal fat and decrease in BMD seen in patients treated chronically with steroids. The systematic review by Bhasin et al identified 2 placebo-controlled RCTs of testosterone replacement in patients on chronic steroid treatment for asthma or chronic obstructive pulmonary disease. 17 The trials were limited by small sample size and short duration of follow-up. Combined analysis of the 2 trials showed a significant increase in lean body mass of 2.3 kg (95% CI, 2.0 to 3.6) and a significant decrease in fat mass of 3.1 kg (95% CI, -2.8 to -3.5). There was also a significant improvement in lumbar bone density of 4% (95% CI, 2% to 7%), although there was no significant improvement found in BMD of the femoral neck. Androgen Deficiency in Patients with Type II Diabetes Cai et al reported results of a systematic review and meta-analysis of RCTs that evaluated the effect of testosterone therapy on metabolic parameters in patients with type 2 diabetes and hypogonadism. 18 Five RCTs, including 351 subjects were identified that met eligibility criteria, 3 of which were doubleblind, placebo-controlled trials and 2 of which were open-label and single-blind, no treatment controlled trials. In pooled analysis, testosterone was associated with reduced fasting plasma glucose levels (mean difference [MD], -1.10; 95% CI, to -0.31), fasting insulin levels (MD, -2.73; 95% CI, to -1.84), hemoglobin A1C (HbA1c; MD, -0.87; 95% CI, to -0.42), and triglyceride levels (MD, -0.35; 95% CI, to -0.07). The authors note that the studies analyzed were limited by relatively few participants and limited discussion of methods. One of the larger RCTs included in the Cai et al meta-analysis enrolled 220 patients with type 2 diabetes and/or metabolic syndrome and hypogonadism. 19 Treatment in the testosterone group was with 60 mg of transdermal testosterone daily. The primary outcome was the change in insulin resistance, as measured by the homeostasis model of insulin resistance (HOMA-IR), and secondary outcomes were changes in body composition, glycemic control, lipids, and sexual dysfunction. There was a 16% reduction in the HOMA-IR at 6-month follow-up (p<0.02), and this difference persisted at 12-month follow-up. Other outcomes were reported at 6-month follow-up. There were statistically significant improvements for the overall group in the International Index of Erectile Function Score for the testosterone group, but no significant improvement in the HgA1C or fasting glucose levels. There were no differences for the overall group on measures of body composition or lipid levels. On subgroup analysis, there was an improvement for patients with metabolic syndrome on the mean low-density lipoprotein level. In an RCT not included in the 2014 Cai et al meta-analysis, Hackett et al randomized 211 patients with type 2 diabetes and hypogonadism to received parenteral testosterone (1000 mg testosterone undecanoate at week 0, week 6, and week 18) or placebo and followed for 30 weeks.20 For the study s primary outcome, change in HbA1c level, testosterone treatment was associated with a significant reduction in HbA1c at 6 weeks of therapy (from 7.74 to 7.50%). At 18 weeks of therapy, with an MD between treatment and control group, after adjustment for covariates, of (95% CI, to -0.05; p=0.007). There was significant reduction in waist circumference, weight, and BMI in men without depression. No major AEs were reported. Older Men With Low Testosterone Levels Without Definite Hypogonadism There have been a few RCTs that have evaluated the impact of testosterone replacement on elderly males with low testosterone levels, without definite evidence of hypogonadism. Most of these have been small and included only a limited range of outcomes. Some of the representative RCTs are discussed next, including 2 of the larger trials. 21,22

8 A trial by Emmelot-Vonk et al was published in 2008 that enrolled 237 men between the ages of 60 to 80 years who had a low testosterone level but were otherwise healthy.21 Patients were randomized to 80 mg of oral testosterone or placebo and followed for 6 months. A range of outcome measures were reported, including functional mobility, body composition, muscle strength, cognitive function, BMD, metabolic parameters, and quality of life. Safety outcomes were also included; prostate-specific antigen (PSA), prostate volume, renal function, liver function, and hematocrit levels. For most of the outcome measures, there was no improvement in the testosterone group compared with placebo. There was an increase in lean body mass and a decrease in the percent body fat. However, these changes were not accompanied by improvements in functional capacity or muscle strength. There were no significant changes in cognitive function, BMD, or quality of life. There was a trend toward worsening metabolic profile, with 47.8% of men in the testosterone group meeting the definition for metabolic syndrome at the end of the study compared with 35.5% of men in the placebo group (p=0.07). There was a significant but small increase in hematocrit from men in the testosterone group and an increase in creatinine that was of borderline significance. Otherwise there were no group differences in the safety outcomes. Another larger trial was a multicenter RCT from Europe that enrolled 322 patients who were 50 years or older, with mild-to-moderate symptoms of hypogonadism, and a low testosterone level. 22 Patients were randomized to 80 mg, 160 mg, or 240 mg of testosterone daily or placebo, and the primary outcome was the change in the Aging Males Symptom (AMS) measure at 6 months. There were no statistically significant differences on the total AMS score between groups at 6 months, although the scores in the testosterone group showed a greater numerical improvement. There was a statistically significant difference in the AMS sexual domain subscore for the 160-mg testosterone group, but not for the 80- or 240-mg group. There were no statistically significant differences in AEs between groups, including the change in PSA level. Several other smaller RCTs have been published, ranging from 13 to 131 patients The most consistent finding reported in these studies was an increase in lean body mass (4 studies) and a decrease in body fat (3 studies). The impact on strength was mixed, with 2 studies reporting an improvement in the testosterone group and 2 studies reporting no difference between groups. An increased in hemoglobin and/or hematocrit was reported in one of the studies, and an increase in BMD also reported in one of the studies. None of these RCTs reported on functional status, quality of life, or sexual performance. Ongoing and Unpublished Clinical Trials There are a large number of ongoing trials of testosterone replacement therapy. A search of ClinicalTrials.gov in October 2014 using the keywords testosterone replacement, and restricted to intervention trials, returned 122 ongoing trials. Most of these are RCTs in various stages of development. They cover a wide range of potential patient populations, from elderly men with low testosterone levels to more specific populations such as men with prostate cancer. They also cover a wide range of different types of testosterone replacement formulations. Practice Guidelines and Position Statements The Endocrine Society published clinical practice guidelines on Testosterone Therapy in Men with Androgen Deficiency in 2006, 17 with an update published in The 2010 guidelines included the following statements on the diagnosis of androgen deficiency and therapy with testosterone replacement: We recommend making the diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. (Strong recommendation; very low quality of evidence) We recommend testosterone therapy for symptomatic men with classical androgen deficiency syndromes aimed at inducing and maintaining secondary sex characteristics and at improving their sexual function, sense of well-being, and bone mineral density (Strong recommendation; low quality of evidence)

9 We recommend against testosterone therapy in patients with breast or prostate cancer. (Strong recommendation; quality of evidence very low for breast cancer, low for prostate cancer) We recommend that clinicians assess prostate cancer risk in men being considered for testosterone therapy. (Strong recommendation; very low quality of evidence) We suggest initiating testosterone therapy with any of the following regimens, chosen on the basis of the patient s preference, consideration of pharmacokinetics, treatment burden, and cost. (Weak recommendation; strength of evidence low) o 75 to 100 mg of testosterone enanthate or cypionate administered IM [intramuscularly] weekly, or 150 to 200 mg administered every 2 weeks. o One or two 5 mg nongenital, testosterone patches applied nightly over the skin of the back, thigh, or upper arms, away from pressure areas. o 5 to 10 g of a 1% testosterone gel applied daily over a covered area of nongenital skin. o 30 mg of a bioadhesive buccal testosterone tablet applied to buccal mucosa every 12 hours. o Testosterone pellets implanted SC [subcutaneous] at intervals of 3 to 6 months; the dose and regimen vary with the formulation used. o Oral testosterone undecanoate, injectable testosterone undecanoate, testosterone-inadhesive matrix patch, and testosterone pellets where available. Joint guidelines on the Investigation, Treatment and Monitoring of Late-Onset Hypogonadism in males were published by the International Society for the Study of Aging Male, the International Society of Andrology, the European Association of Urology, the European Academy of Andrology, and the American Society of Andrology in These guidelines made the following statements: The diagnosis of treatable hypogonadism requires the presence of symptoms and signs suggestive of testosterone deficiency (Grade A recommendation; level of evidence 3). The symptom most associated with hypogonadism is low libido (Grade A recommendation; level of evidence 3). Other manifestations of hypogonadism include erectile dysfunction, decreased muscle mass and strength, increased body fat, decreased bone mineral density and osteoporosis, decreased vitality, and depressed mood. None of these symptoms are specific to the low androgen state but may raise suspicion of testosterone deficiency. One or more of these symptoms must be corroborated with a low serum testosterone level (Grade A recommendation; level of evidence 3). Preparations of natural testosterone should be used for substitution therapy. Currently available intramuscular, subdermal, transdermal, oral, and buccal preparations of testosterone are safe and effective (Grade A recommendation; level of evidence 1b). The selection of the preparation should be a joint decision of an informed patient and physician. References: 1. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. Jun 2010;95(6): PMID Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. Eur Urol. Jan 2009;55(1): PMID Zarotsky V, Huang MY, Carman W, et al. Systematic literature review of the risk factors, comorbidities, and consequences of hypogonadism in men. Andrology. Nov 2014;2(6): PMID Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab. Jul 2008;93(7): PMID Travison TG, Araujo AB, Kupelian V, et al. The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab. Feb 2007;92(2): PMID Cunningham GR, Toma SM. Clinical review: Why is androgen replacement in males controversial? J Clin Endocrinol Metab. Jan 2011;96(1): PMID Food and Drug Administration. FDA evaluating risk of stroke, heart attack and death with FDA-approved testosterone products. Drug Safety Communications 2014; Accessed October 28, 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. 2014; gsadvisorycommittee/ucm pdf. Accessed October 28, 2014.

10 9. Bolona ER, Uraga MV, Haddad RM, et al. Testosterone use in men with sexual dysfunction: a systematic review and metaanalysis of randomized placebo-controlled trials. Mayo Clin Proc. Jan 2007;82(1): PMID Jain P, Rademaker AW, McVary KT. Testosterone supplementation for erectile dysfunction: results of a metaanalysis. J Urol. Aug 2000;164(2): PMID Pexman-Fieth C, Behre HM, Morales A, et al. A 6-month observational study of energy, sexual desire, and body proportions in hypogonadal men treated with a testosterone 1% gel. Aging Male. Mar 2014;17(1):1-11. PMID Bhasin S, Calof OM, Storer TW, et al. Drug insight: Testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Pract Endocrinol Metab. Mar 2006;2(3): PMID Tracz MJ, Sideras K, Bolona ER, et al. Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials. J Clin Endocrinol Metab. Jun 2006;91(6): PMID Shores MM, Kivlahan DR, Sadak TI, et al. A randomized, double-blind, placebo-controlled study of testosterone treatment in hypogonadal older men with subthreshold depression (dysthymia or minor depression). J Clin Psychiatry. Jul 2009;70(7): PMID Seidman SN, Orr G, Raviv G, et al. Effects of testosterone replacement in middle-aged men with dysthymia: a randomized, placebo-controlled clinical trial. J Clin Psychopharmacol. Jun 2009;29(3): PMID Borst SE, Yarrow JF, Fernandez C, et al. Cognitive effects of testosterone and finasteride administration in older hypogonadal men. Clin Interv Aging. 2014;9: PMID 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. Jun 2006;91(6): PMID Cai X, Tian Y, Wu T, et al. Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. Asian J Androl. Jan-Feb 2014;16(1): PMID Jones TH, Arver S, Behre HM, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. Apr 2011;34(4): PMID Hackett G, Cole N, Bhartia M, et al. Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study. J Sex Med. Mar 2014;11(3): PMID Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA. Jan ;299(1): PMID Legros JJ, Meuleman EJ, Elbers JM, et al. Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study. Eur J Endocrinol. May 2009;160(5): PMID Kenny AM, Kleppinger A, Annis K, et al. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, low bone mass, and physical frailty. J Am Geriatr Soc. Jun 2010;58(6): PMID Kenny AM, Prestwood KM, Gruman CA, et al. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci. May 2001;56(5):M PMID Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab. Aug 1999;84(8): PMID Sih R, Morley JE, Kaiser FE, et al. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. Jun 1997;82(6): PMID Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab. Oct 1992;75(4): PMID Fernandez-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. Jun 2010;95(6): PMID Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci. Nov 2005;60(11): PMID Haddad RM, Kennedy CC, Caples SM, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. Jan 2007;82(1): PMID Cui Y, Zhang Y. The effect of androgen-replacement therapy on prostate growth: a systematic review and metaanalysis. Eur Urol. Nov 2013;64(5): PMID Cui Y, Zong H, Yan H, et al. The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. Jun 2014;17(2): PMID Francomano D, Ilacqua A, Bruzziches R, et al. Effects of 5-year treatment with testosterone undecanoate on lower urinary tract symptoms in obese men with hypogonadism and metabolic syndrome. Urology. Jan 2014;83(1): PMID Pearl JA, Berhanu D, Francois N, et al. Testosterone supplementation does not worsen lower urinary tract symptoms. J Urol. Nov 2013;190(5): PMID Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. Jul ;363(2): PMID

11 36. 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. Nov ;310(17): PMID 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(1):e PMID Baillargeon J, Urban RJ, Kuo YF, et al. Risk of Myocardial Infarction in Older Men Receiving Testosterone Therapy. Ann Pharmacother. Jul ;48(9): PMID Kaplan AL, Trinh QD, Sun M, et al. Testosterone replacement therapy following the diagnosis of prostate cancer: outcomes and utilization trends. J Sex Med. Apr 2014;11(4): PMID Billing Coding/Physician Documentation Information J1071 injection, testosterone cypionate, 1mg (medical benefit) J3121 injection, testosterone enanthate, 1mg (medical benefit) J3145 injection, testosterone undecanoate, 1mg (medical benefit) S0189 Testosterone pellet, 75mg (medical benefit) Subcutaneous hormone pellet implantation Additional Policy Key Words Policy Number: Policy Implementation/Update Information 07/2015 New Policy titled Testosterone Replacement Therapies (replaced the archived Injectable Testosterone) 12/2015 Added code Subcutaneous hormone pellet implantation State and Federal mandates and health plan contract language, including specific provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The medical policies contained herein are for informational purposes. The medical policies do not constitute medical advice or medical care. Treating health care providers are independent contractors and are neither employees nor agents Blue KC and are solely responsible for diagnosis, treatment and medical advice. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, photocopying, or otherwise, without permission from Blue KC.