National Medical Policy

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1 National Medical Policy Subject: Implantable Hormone Pellets Policy Number: NMP 507 Effective Date*: January 2012 Updated: July 2015 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate Medicaid Manuals for coverage guidelines prior to applying Health The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* X Other Please refer to Medicare guidelines for Step Therapy : herapy_memo_ pdf None Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Implantable Hormone Pellets Jul 15 1

2 Note: This policy addresses the use of hormone implants to replace hormones and treat conditions resulting from a decrease in naturally occurring hormones. It does not address the use of hormone implants for other indications e.g., contraception, treatment of sexual dysfunction, cancer or precocious puberty. Current Policy Statement I. Health Net Inc. considers implantable estradiol pellets investigational. At this time, there are no commercially made, FDA approved, estradiol pellets for subcutaneous implantation available in the United States. Studies to date do not provide sufficient evidence to evaluate the efficacy and safety of estradiol implants in postmenopausal women. Although studies found that estradiol implant use was associated with statistically significant improvements in bone mineral density (BMD) and some biochemical markers of bone formation, the studies were small and none of them compared estradiol implants with oral or transdermal hormone replacement therapy. II. Health Net Inc. considers implantable testosterone pellets (e.g., Testopel pellets) medically necessary as replacement therapy in males with conditions associated with a deficiency or absence of endogenous testosterone, specifically, for any of the following indications, when there has been a failure or intolerance of topical (e.g., patch, gels) and injectable testosterone: 1. Congenital or acquired primary hypogonadism (i.e., testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testes syndrome or orchidectomy); or 2. Congenital or acquired hypogonadotrophic hypogonadism (i.e., idiopathic or gonadotropic LHRH deficiency, or pituitary- hypothalamic injury from tumors, trauma or radiation) Note: If the above conditions occur prior to puberty, androgen replacement therapy will be needed during the adolescent years for development of secondary sexual characteristics. Prolonged androgen treatment will be required to maintain sexual characteristics in these and other males who develop testosterone deficiency after puberty. 3. Androgens may be used cautiously to stimulate puberty in carefully selected males with clearly delayed puberty. These patients usually have a familial pattern of delayed puberty that is not secondary to a pathological disorder; puberty is expected to occur spontaneously at a relatively late date. Brief treatment with conservative doses may occasionally be justified in these patients if they do not respond to psychological support. The potential adverse effect on bone maturation should be discussed with the patient and parents prior to androgen administration. An X-ray of the hand and wrist to determine bone age should be taken every 6 months to assess the effect of treatment on epiphyseal centers. Health Net Inc. considers implantable testosterone pellets (e.g., Testopel pellets) investigational for routine use in older men with low testosterone levels due to inconclusive evidence in the peer review literature regarding its potential benefits versus unknown long-term risks. Contraindications: Implantable Hormone Pellets Jul 15 2

3 Androgens are contraindicated in men with carcinomas of the breast or with known or suspected carcinomas of the prostate. Definitions HRT Hormone replacement therapy MHT Menopausal hormone therapy QUS Quantitative ultrasound PINP Procollagen type I N-terminal propeptide OC Osteocalcin NTX N-telopeptide of type I collagen ifdpd, Free deoxypyridinoline LS Lumbar spine TH Total hip FN Femoral neck BMD Bone mineral density HPT Hypothalamic-pituitary-testicular Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures will be replaced by ICD-10 code sets. Health Net National Medical Policies will now include the preliminary ICD-10 codes in preparation for this transition. Please note that these may not be the final versions of the codes and that will not be accepted for billing or payment purposes until the October 1, 2015 implementation date. ICD-9 Codes Pituitary hypogonadism Testicular hypogonadism Delay in sexual development and puberty, not elsewhere classified Menopausal and Postmenopausal disorders ICD-10 Codes E23.6 Other disorders of pituitary gland E29-E29.9 Testicular dysfunction E29.1 Testicular hypofunction E30.0 Delayed puberty N92.4 Excessive bleeding in the premenopausal period N95 N95.9 Menopausal and other perimenopausal disorders CPT Codes Subcutaneous hormone pellet implantation (implantation of Estradiol and/or testosterone pellets beneath the skin) HCPCS Codes S0189 Testosterone pellet, 75mg Scientific Rationale Update July 2015 Implantable Hormone Pellets Jul 15 3

4 Smith et al (2013) reported that a variety of modalities for testosterone replacement therapy (TRT) are available, including topical gels, injections, and Testopel subcutaneous testosterone pellets (STP). STP are becoming more commonly utilized in the United States; however, patient preferences, expectations, and usage patterns regarding this therapy remain poorly characterized. The authors sought to identify factors influencing patients' decisions to initiate or discontinue STP. A total of 175 men from an academic urology clinic who were currently using or who had previously used STP for hypogonadism received a 32-item electronic survey. Main outcome measures included assessment of the impact of convenience, efficacy, side effects, cost, and symptom relief on initiation and discontinuation of STP. One hundred and thirteen men (64.6% response rate) of mean age 51.4 years who previously underwent a mean of 2.8 STP implant procedures completed the survey. Fifty-nine (52.2%) and 40 (35.4%) men had switched to STP from topical gel and injection therapy, respectively, whereas 14 (12.4%) men initially started TRT with STP. Convenience (68.8%) was the most important factor in patients' decision to start STP, while cost of the previous form of TRT (14.7%) was least important. At the time of the survey, 32 men (28.3%) had discontinued STP therapy. Cost of therapy (50%) was the primary factor in discontinuing STP. There was no difference in serum testosterone levels between men who continued STP and those who discontinued therapy (642.8 vs ng/dL, P=0.83). Overall, 68.1% of patients continued STP therapy at the time of survey completion. The authors concluded convenience is the most important factor in a patient's decision to initiate STP; however, physician recommendation also plays a substantial role. Cost was the primary reason for discontinuation. Upon survey completion, greater than two-thirds of respondents elected to continue STP therapy. STP are a viable treatment option for hypogonadal men seeking a convenient and efficacious alternative modality of TRT. Scientific Rationale Initial Estrogen: Estradiol is one of the types of estrogen found in the body. While there are several approvals for estradiol for postmenopausal symptoms (e.g., estradiol patches), there are no commercially made, FDA approved estradiol pellets for subcutaneous implantation available in the United States. The pellets or other compounds containing synthetic or plant-derived sources of hormones are available through compounding pharmacies (e.g., bioidentical hormones). The biodegradable pellets are implanted underneath the skin in the lower abdomen or buttock through a small incision using local anesthesia. A new pellet must be implanted every 4 to 8 months, depending on the dosage and rate of release. Studies to date do not provide sufficient evidence to evaluate the efficacy and safety of estradiol implants. Studies have been small and none compare estradiol implants with oral or transdermal hormone replacement therapy (HRT). A Committee Opinion from the American Congress of Obstetricians and Gynecologists (ACOG) on compounded bioidentical hormones (2005, reaffirmed 2007) states, Most compounded products have not undergone rigorous clinical testing for safety or efficacy, and issues regarding purity, potency, and quality are a concern. Compounded hormone products have the same safety issues as those associated with hormone therapy agents that are approved by the U.S. Food and Drug Administration and may have additional risks intrinsic to compounding. There is no scientific evidence to support claims of increased efficacy or safety for individualized estrogen or progesterone regimens. They note further that bioidentical hormones are available in various routes of administration, including oral, sublingual, and percutaneous or as implants, injectables, and suppositories. Implantable Hormone Pellets Jul 15 4

5 In 2010, the Endocrine Society issued a scientific statement on postmenopausal HRT. In reference to bioidentical hormones, they state the following, There are no published studies in peer-reviewed literature that show: 1) that non-fda-approved compounded bioidentical (menopausal hormone therapy) MHT preparations are safer or more effective than the FDA-approved formulations that are the standard of care; 2) that they carry less risk than FDA-approved products; 3) that salivary testing is a reliable measure on which to safely and effectively base dosing; or 4) that they prevent or do not cause breast or uterine cancer. In addition, there are safety concerns about custom-compounded bioidentical hormones due to the paucity of safety and efficacy data available in the literature as well as quality control concerns about purity, predictable blood and tissue levels, and batch-to-batch consistency. Pareda et al (2002) evaluated the anabolic effect of estrogen on bone by comparing the response of markers of bone formation (and resorption) and bone mineral density (BMD) to subcutaneous estradiol implants in a one year double-blind placebo controlled randomized study. Twenty-one hysterectomized postmenopausal women were randomised to 25 mg estradiol implants at baseline and at six months or to have a sham procedure at baseline and six months. BMD and quantitative ultrasound (QUS) were assessed at baseline and one year. Bone alkaline phosphatase (bone ALP), procollagen type I N-terminal propeptide (PINP), osteocalcin (OC), free deoxypyridinoline (ifdpd), N-telopeptide of type I collagen (NTX), serum oestradiol and intact parathyroid hormone (PTH) were measured at baseline, 4, 8, 12 and 24 weeks. Percentage change markers of bone turnover and PTH and change in estradiol levels over first six months and percentage of changes in DXA and QUS over one year. PINP, bone ALP and OC increased by 28%, 7% and 9%, respectively (P < 0.01) during the first four weeks of treatment and then decreased significantly. Lumbar spine (LS) and total hip (TH) BMD increased by 5.4% and 6.0% (P < 0.001), respectively, and femoral neck (FN) BMD by 3.7% (P < 0.05) during the first year of treatment compared with control subjects. The peak serum estradiol level was achieved four weeks after implant insertion. Mean PTH levels increased significantly in subjects receiving subcutaneous estradiol. Hansen et al. (2003) performed a nonrandomized controlled study that compared estradiol implants with no HRT in postmenopausal women. The Estradiol Group consisted of 21 women (mean age 53 ± 5 years, mean waist:hip ratio 0.79 ± 0.04, mean whole body bone mineral density (BMD) 0.95 ± 0.07; mean symptom score 18 ± 8) who underwent 20 mg estradiol pellet implantation at 4-month intervals. The Control Group consisted of 15 women (mean age 56 ± 4 years, mean waist:hip ratio 0.80 ± 0.05, mean whole body BMD 0.98 ± 0.09; mean symptom score 11 ± 5) who did not undergo HRT. Although patients were assigned to the Estradiol and Control Groups based on patient preference, the only statistically significant difference between the treatment groups at baseline was in symptom score (P<0.01). A total of 8 (38%) Estradiol Group and 8 (53%) Control Group patients failed to complete the 64 weeks of follow-up. At 64 weeks, the Estradiol Group had 5.4% to 7.6% increases in mean BMD measured at the lumbar spine, femoral neck, trochanter, and Wards Triangle, and these increases were statistically significant compared with the Control Group (P<0.05). Changes in mean BMD for the Control Group were not reported but were described as minimal. There were no statistically significant differences between the Estradiol and Control Groups in weight, total body fat, or appendicular skeletal muscle mass; however, the mean abdominal fat to lean soft tissue ratio increased 18% for the Estradiol Group versus no change for the Control Group (P<0.05). Vashisht and Studd (2003) observed whether BMD improves over 5 years in older women using estradiol implants. A total of 18 women were selected who had Implantable Hormone Pellets Jul 15 5

6 commenced HRT around the age of 60 years. The median age was 60.9 years (range years). Each woman had a pretreatment bone scan and then received 6- monthly subcutaneous 50 mg estradiol implants. Twelve untreated women were also selected who had had bone scans at baseline and after 5 years. A comparison of the changes in BMD between treated and untreated women was made using the Wilcoxon rank-sum test. All changes at the hip and spine were statistically significant improvements from baseline in the estradiol-treated group. After 5 years of treatment, the estradiol-treated group had significantly improved bone mineral densities compared with the untreated group. At the spine, the plasma estradiol concentration is statistically significantly correlated with the 5-year increase in bone density (r = 0.717, p = 0.004). There was found to be an inverse relationship between the percentage increase in BMD over the 5-year period and initial bone density (r = , p < 0.005). Thus estrogen is seen to have the effect of improving bone density in older women over 5 years of treatment. The increase in vertebral bone density is most marked in those women with the highest plasma estradiol levels and the lowest pretreatment bone density. Results of the available studies do not provide sufficient evidence to evaluate the efficacy and safety of estradiol implants in postmenopausal women. Although these studies found that estradiol implant use was associated with statistically significant improvements in BMD and some biochemical markers of bone formation, the studies were small and none of them compared estradiol implants with oral or transdermal HRT. Furthermore, there are no well-designed clinical trials that evaluate the efficacy and safety of bioidentical hormone therapy for the treatment of menopause symptoms. Additional controlled studies are needed to evaluate the safety and efficacy of estradiol implants for postmenopausal disorders. Testosterone Hypogonadism in men is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone (androgen deficiency) and a normal number of spermatozoa due to disruption of one or more levels of the hypothalamic-pituitary-testicular (HPT) axis. Abnormalities of the HPT axis at the testicular level cause primary testicular failure, whereas central defects of the hypothalamus or pituitary cause secondary testicular failure. Hypogonadism also can reflect dual defects that affect both the testis and the pituitary. Exogenous testosterone replacement therapy with injectable or topical formulations is a wellestablished treatment of hypogonadism. A 2010 clinical guideline from the Endocrine Society states a diagnosis of androgen deficiency in men is made only when there are consistent symptoms and signs and unequivocally low serum testosterone levels. They recommend testosterone therapy for men with symptomatic androgen deficiency to induce and maintain secondary sex characteristics and to improve their sexual function, sense of wellbeing, muscle mass and strength, and bone mineral density. They recommend against starting testosterone therapy in patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen greater than 4 ng/ml or greater than 3 ng/ml in men at high risk for prostate cancer such as African Americans or men with first-degree relatives with prostate cancer without further urological evaluation, hematocrit >50%, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms with International Prostate Symptom Score (IPSS) > 19, or uncontrolled or poorly controlled heart failure. They 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: Implantable Hormone Pellets Jul 15 6

7 mg of testosterone enanthate or cypionate administered intramuscularly (IM) weekly, or mg administered every 2 weeks. One or two 5-mg nongenital, testosterone patches applied nightly over the skin of the back, thigh, or upper arm, away from pressure areas g of a 1% testosterone gel applied daily over a covered area of nongenital skin (patients should wash hands after application). 30 mg of a bioadhesive buccal testosterone tablet applied to buccal mucosa every 12 hours. Testosterone pellets implanted subcutaneously at intervals of 3 to 6 months; the dose and regimen vary with the formulation used. Oral testosterone undecanoate, injectable testosterone undecanoate, testosteronein-adhesive matrix patch, and testosterone pellets where available Per the guidelines, it is recommended to evaluate the patient 3 to 6 months after testosterone treatment initiation to assess whether symptoms have responded to treatment and whether the patient is suffering any adverse effects, and to check compliance. Testopel is a cylindrically shaped pellet for subcutaneous implantation containing 75mg of testosterone. The pellets are implanted into the subdermal fat of the buttocks, lower abdominal wall or thigh with a trocar under sterile conditions using a local anesthetic. According to the manufacturer (Slate Pharmaceuticals), the suggested dosage for androgens varies depending on the age, and diagnosis of the individual patient. The dosage is adjusted according to the patient's response and the appearance of adverse reactions. The dosage guideline for the testosterone pellets for replacement therapy in androgen-deficient males is 150mg to 450mg subcutaneously every 3 to 6 months. Various dosage regimens have been used to induce pubertal changes in hypogonadal males. The chronological and skeletal ages must be taken into consideration, both in determining the initial dose and in adjusting the dose. The use of Testopel is associated with a number of serious risks. Testopel is contraindicated in men with carcinomas of the breast or with known or suspected carcinomas of the prostate, and in pregnant women (as it presents a potential hazard to the fetus). Testopel implantation has much less flexibility for dosage adjustment than oral administration of or intramuscular injections of oil solutions or aqueous suspensions, requires surgical removal if testosterone should be discontinued, and carries a risk of sloughing out of the skin. According to the FDA-approved product labeling (PI), Testopel is approved for the following indication: Males Androgens are indicated for replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone; a. Primary hypogonadism (congenital or acquired) testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome; or orchidectomy. b. Hypogonadotrophic hypogonadism (congenital or acquired) idiopathic gonadotropin or LHRH deficiency, or pituitary hypothalamic injury from tumors, trauma, or radiation. Implantable Hormone Pellets Jul 15 7

8 If the above conditions occur prior to puberty, androgen replacement therapy will be needed during the adolescent years for development of secondary sexual characteristics. Prolonged androgen treatment will be required to maintain sexual characteristics in these and other males who develop testosterone deficiency after puberty. c. Androgens may be used to stimulate puberty in carefully selected males with clearly delayed puberty. These patients usually have a familial pattern of delayed puberty that is not secondary to a pathological disorder; puberty is expected to occur spontaneously at a relatively late date. Brief treatment with conservative doses may occasionally be justified in these patients if they do not respond to psychological support. The potential adverse effect on bone maturation should be discussed with the patient and parents prior to androgen administration. An X-ray of the hand and wrist to determine bone age should be taken every 6 months to assess the effect of treatment on epiphyseal centers. Kaminetsky et al (2011) evaluated the safety and efficacy of testosterone pellets in 28 men over 6 months as a treatment for male hypogonadism in a phase IV, single center, open-label study designed to assess the safety and efficacy of subcutaneous insertion of 8 to 12 testosterone 75 mg pellets (450 mg to 900 mg), during a single implantation procedure in hypogonadal men. Subjects who successfully completed the protocol were allowed to enroll in an extension study that included another implantation and 6 months of follow-up. Safety was determined by investigatorreported adverse events, changes in vital signs, physical exam findings, and laboratory tests. Efficacy was based on serum laboratory tests, physical exams, implantation site evaluations, and vital signs. Secondary objectives were to assess patient preference for testosterone pellets and to maintain optimal total testosterone. Mean testosterone significantly increased and luteinizing hormone (LH) levels significantly decreased from pre-implantation values at weeks 1, 4, and 12, and had returned to pre-implantation levels by week 24. Prostate-specific antigen levels remained unchanged for the duration of the study. Improvements in several symptoms of hypogonadism were determined with multiple questionnaires. Implanted testosterone pellets were generally well tolerated. Investigators concluded implanted testosterone pellets can normalize testosterone and LH levels and improve symptoms for at least 3 months and up to 6 months in men with hypogonadism, and should be considered as a therapeutic option for hypogonadal men. Fennell et al (2010) directly compared two long-acting depot T products, subdermal T implants (TI) and injectable T undecanoate (TU) for maintenance of testosterone replacement therapy TRT. 38 men with organic androgen deficiency undergoing regular TRT at an academic andrology center were recruited for a two period, randomized sequence, cross-over clinical trial without intervening wash-out period of TRT maintenance. For both depot T products, their pharmacokinetics and pharmacodynamics were evaluated using a range of androgen sensitive clinical, laboratory and quality of life measures as well as preference for ongoing treatment after experience of both products. The two depot T products had distinct pharmacokinetics and were not bioequivalent. However, there were no consistent clinical differences in a comprehensive range of pharmacodynamic measures reflecting androgen effects on biochemistry and hematology, muscle mass and strength, and quality of life, mood and sexual function. The majority (91%) of participants chose TU over TI at study completion. Investigators concluded despite significant pharmacokinetic differences, the two depot T products are clinically interchangeable allowing for choice dependent on patient and physician delivery Implantable Hormone Pellets Jul 15 8

9 preference in practice but most patients preferred the injectable over the implantable form. Cavender and Fairall (2009) reported safety and limited efficacy data from their patients treated for testosterone deficiency syndrome with Testopel subcutaneous testosterone pellets in a single-site, retrospective analysis of medical records from December 2003 through April Main Outcome measures were infection with or without pellet extrusion, as determined by longitudinal follow-up. A total of 80 men met inclusion and exclusion criteria. In the 292 implant procedures performed, four adverse events were reported including one implantation site infection. No spontaneous pellet extrusions were reported. Total and free testosterone concentrations were significantly higher at follow-up than at baseline for all patients. Eighty-six percent of patients were satisfied with this treatment modality based on symptom improvement or having subsequent implant procedures. The authors concluded testosterone replacement with long-acting Testopel pellets had a lower rate of infection (0.3%, 1/292 procedures) as compared with historical data from the Organon testosterone pellet ( %). Additionally, the rate of pellet extrusion was substantially lower (0.3%, 1/292 procedures) as compared with historical data (8.5-12%). None of the patients who complied with post-implant procedure instructions experienced infection or pellet extrusion. Patient satisfaction was high and serum hormone values were improved. The low infection and extrusion rates observed may have been the result of the manufacturing process, which results in small, smoothsurfaced pellets; the absence of foreign material within the pellet packaging; and/or differences in the surgical implantation technique used. Though Testopel pellets have been used in the United States for several decades, more research is needed to document their safety and efficacy. Review History January 2012 Medical Advisory Council initial approval January 2013 Update no revisions January 2014 Update no revisions but added reference to review Step Therapy guidelines for Medicare Advantage members July 2014 Update no revisions This policy is based on the following evidence-based guidelines: 1. The Endocrine Society Clinical Guideline. Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes. J Clin Endocrinol Metab, June 2010, 95(6): Available at: actice%20guidelines/final-androgens-in-men-standalone.pdf 2. American Association of Clinical Endocrinologists. Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hypogonadism in Adult Male Patients Endocrine Practice Vol 8 No. 6 November/December Available at: 3. Hayes. Health Technology Brief. Subcutaneous Implantation of Estradiol Pellets for Postmenopausal Disorders. Aug Updated December 30, Updated Dec Updated Dec Update Dec American Congress of Obstetricians and Gynecologists. Compounded Bioidentical Hormones. Number 322, November 2005 (Reaffirmed 2007, Number 387). Committee Opinion. Number 532, August 2012, Replaces Number 387, November 2007 and Number 322, November Updated August Santen RJ, Allred DC, Ardoin SP, et al.; Endocrine Society. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab Jul;95(7 Suppl 1):s1-s The Endocrine Society. Position Statement. Bioidentical Hormones. Oct Implantable Hormone Pellets Jul 15 9

10 7. Hayes. Search & Summary. Testosterone for Low Sexual Desire in Nonsurgically Postmenopausal Women. October 4, Archived Mar Update Feb Hayes Search and Summary. Testopel (Auxilium Pharmaceuticals Inc.) Implantable Testosterone Pellet for Hypogonadism. Nov 2014 References Update July Leung KM, Alrabeeah K, Carrier S. Update on Testosterone Replacement Therapy in Hypogonadal Men. Curr Urol Rep Aug;16(8): Pastuszak AW, Mittakanti H, Liu JS, et al. Pharmacokinetic evaluation and dosing of subcutaneous testosterone pellets. J Androl Sep-Oct;33(5): Smith RP, Khanna A, Coward RM, et al. Factors influencing patient decisions to initiate and discontinue subcutaneous testosterone pellets (Testopel) for treatment of hypogonadism.j Sex Med Sep;10(9): References Update July Kovac JR, Rajanahally S, Smith RP, et al. Patient satisfaction with testosterone replacement therapies: the reasons behind the choices. J Sex Med Feb;11(2): References Update January McCullough AR, Khera M, Goldstein I, et al. A multi-institutional observational study of testosterone levels after testosterone pellet (Testopel) insertion. J Sex Med Feb;9(2): Moskovic DJ, Freundlich RE, Yazdani P, et al. Subcutaneous implantable testosterone pellets overcome noncompliance in adolescents with Klinefelter syndrome. J Androl Jul-Aug;33(4): References Update January Snabes MC, Zborowski J, Simes S. Libigel (testosterone gel) does not differentiate from placebo therapy in the treatment of hypoactive sexual desire disorder in postmenopausal women. Journal of Sexual Medicine. Conference: 11th Annual Meeting of the International Society for the Study of Women's Sexual Health, ISSWSH 2012 Jerusalem Israel. 9 (pp 171), Snabes M.C., Simes S., Zborowski J. Clear pathway to approval for libigel treatment of postmenopausal women with Hypoactive Sexual Desire Disorder (HSDD). Journal of Sexual Medicine. Conference: 11th Annual Meeting of the International Society for the Study of Women's Sexual Health, (pp ), References - Initial 1. Cavender RK, Fairall M. Subcutaneous testosterone pellet implant (Testopel) therapy for men with testosterone deficiency syndrome: a single-site retrospective safety analysis. J Sex Med Nov;6(11): Conners W, Flinn K, Morgentaler A. Outcomes with the "V" Implantation Technique vs. Standard Technique for Testosterone Pellet Therapy. J Sex Med Dec;8(12): Dandona P, Rosenberg MT. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract May;64(6): Edelstein D, Sivanandy M, Shahani S, Basaria S. The latest options and future agents for treating male hypogonadism. Expert Opin Pharmacother. 2007;8(17): Implantable Hormone Pellets Jul 15 10

11 5. Fennell C, Sartorius G, Ly LP, et al. Randomized cross-over clinical trial of injectable vs. implantable depot testosterone for maintenance of testosterone replacement therapy in androgen deficient men. Clin Endocrinol (Oxf). 2010;73(1): Gooren LJ. Advances in testosterone replacement therapy. Front Horm Res. 2009;37: Hansen RD, Raja C, Baber RJ, Lieberman D, Allen BJ. Effects of 20-mg estradiol implant therapy on bone mineral density, fat distribution and muscle mass in postmenopausal women. Acta Diabetol. 2003;40(Suppl 1):S191-S Kaminetsky JC, Moclair B, Hemani M, Sand M. A phase IV prospective evaluation of the safety and efficacy of extended release testosterone pellets for the treatment of male hypogonadism. J Sex Med Apr;8(4): Kazi M, Geraci SA, Koch CA. Considerations for the diagnosis and treatment of testosterone deficiency in elderly men. Am J Med Oct;120(10): Moskovic DJ, Freundlich RE, Yazdani P, et al. Subcutaneous Implantable Testosterone Pellets Overcomes Noncompliance in Adolescent Men with Klinefelter's Syndrome: Case Report and Review of the Literature. J Androl Sep Pereda CA, Hannon RA, Naylor KE, Eastell R. The impact of subcutaneous estradiol implants on biochemical markers of bone turnover and bone mineral density in postmenopausal women. BJOG. 2002;109(7): Slate Pharmaceuticls. Testopel Pellets. Available at: Vashisht A, Studd JW. Five-year changes in bone density, and their relationship to plasma estradiol and pretreatment bone density, in an older population of postmenopausal women using long-term estradiol implants. Gynecol Endocrinol. 2003;17(6): Important Notice General Purpose. Health Net's National Medical Policies (the "Policies") are developed to assist Health Net in administering plan benefits and determining whether a particular procedure, drug, service or supply is medically necessary. The Policies are based upon a review of the available clinical information including clinical outcome studies in the peer-reviewed published medical literature, regulatory status of the drug or device, evidence-based guidelines of governmental bodies, and evidence-based guidelines and positions of select national health professional organizations. Coverage determinations are made on a case-by-case basis and are subject to all of the terms, conditions, limitations, and exclusions of the member's contract, including medical necessity requirements. Health Net may use the Policies to determine whether under the facts and circumstances of a particular case, the proposed procedure, drug, service or supply is medically necessary. The conclusion that a procedure, drug, service or supply is medically necessary does not constitute coverage. The member's contract defines which procedure, drug, service or supply is covered, excluded, limited, or subject to dollar caps. The policy provides for clearly written, reasonable and current criteria that have been approved by Health Net s National Medical Advisory Council (MAC). The clinical criteria and medical policies provide guidelines for determining the medical necessity criteria for specific procedures, equipment, and services. In order to be eligible, all services must be medically necessary and otherwise defined in the member's benefits contract as described this "Important Notice" disclaimer. In all cases, final benefit determinations are based on the applicable contract language. To the extent there are any conflicts between medical policy guidelines and applicable contract language, the contract language prevails. Medical policy is not intended to override the policy that defines the member s benefits, nor is it intended to dictate to providers how to practice medicine. Policy Effective Date and Defined Terms. The date of posting is not the effective date of the Policy. The Policy is effective as of the date determined by Health Net. All policies are subject to applicable legal and regulatory mandates and requirements for prior notification. If there is a discrepancy between the policy effective date and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. * In some states, prior notice or posting on the website is required before a policy is deemed effective. For information regarding the effective dates of Policies, contact your provider representative. The Policies do not include definitions. All terms are defined by Health Net. For information regarding the definitions of terms used in the Policies, contact your provider representative. Policy Amendment without Notice. Implantable Hormone Pellets Jul 15 11

12 Health Net reserves the right to amend the Policies without notice to providers or Members. In some states, prior notice or website posting is required before an amendment is deemed effective. No Medical Advice. The Policies do not constitute medical advice. Health Net does not provide or recommend treatment to members. Members should consult with their treating physician in connection with diagnosis and treatment decisions. No Authorization or Guarantee of Coverage. The Policies do not constitute authorization or guarantee of coverage of particular procedure, drug, service or supply. Members and providers should refer to the Member contract to determine if exclusions, limitations, and dollar caps apply to a particular procedure, drug, service or supply. Policy Limitation: Member s Contract Controls Coverage Determinations. Statutory Notice to Members: The materials provided to you are guidelines used by this plan to authorize, modify, or deny care for persons with similar illnesses or conditions. Specific care and treatment may vary depending on individual need and the benefits covered under your contract. The determination of coverage for a particular procedure, drug, service or supply is not based upon the Policies, but rather is subject to the facts of the individual clinical case, terms and conditions of the member s contract, and requirements of applicable laws and regulations. The contract language contains specific terms and conditions, including pre-existing conditions, limitations, exclusions, benefit maximums, eligibility, and other relevant terms and conditions of coverage. In the event the Member s contract (also known as the benefit contract, coverage document, or evidence of coverage) conflicts with the Policies, the Member s contract shall govern. The Policies do not replace or amend the Member s contract. Policy Limitation: Legal and Regulatory Mandates and Requirements The determinations of coverage for a particular procedure, drug, service or supply is subject to applicable legal and regulatory mandates and requirements. If there is a discrepancy between the Policies and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. Reconstructive Surgery CA Health and Safety Code requires health care service plans to cover reconstructive surgery. Reconstructive surgery means surgery performed to correct or repair abnormal structures of the body caused by congenital defects, developmental abnormalities, trauma, infection, tumors, or disease to do either of the following: (1) To improve function or (2) To create a normal appearance, to the extent possible. Reconstructive surgery does not mean cosmetic surgery," which is surgery performed to alter or reshape normal structures of the body in order to improve appearance. Requests for reconstructive surgery may be denied, if the proposed procedure offers only a minimal improvement in the appearance of the enrollee, in accordance with the standard of care as practiced by physicians specializing in reconstructive surgery. Reconstructive Surgery after Mastectomy California Health and Safety Code requires treatment for breast cancer to cover prosthetic devices or reconstructive surgery to restore and achieve symmetry for the patient incident to a mastectomy. Coverage for prosthetic devices and reconstructive surgery shall be subject to the co-payment, or deductible and coinsurance conditions, that are applicable to the mastectomy and all other terms and conditions applicable to other benefits. "Mastectomy" means the removal of all or part of the breast for medically necessary reasons, as determined by a licensed physician and surgeon. Policy Limitations: Medicare and Medicaid Policies specifically developed to assist Health Net in administering Medicare or Medicaid plan benefits and determining coverage for a particular procedure, drug, service or supply for Medicare or Medicaid members shall not be construed to apply to any other Health Net plans and members. The Policies shall not be interpreted to limit the benefits afforded Medicare and Medicaid members by law and regulation. Implantable Hormone Pellets Jul 15 12