This Coverage Policy applies to Individual Health Insurance Marketplace benefit plans only.

This Coverage Policy applies to Individual Health Insurance Marketplace benefit plans only. GROWTH HORMONE THERAPY POLICY Omnitrope is the EXCLUSIVE growth hormone covered if patient meets criteria. COVERAGE POLICY Growth hormone must be prescribed by a certified endocrinologist or pediatric nephrologist; growth hormone is considered medically necessary for treatment of members in the following diagnostic categories who meet the following criteria: Growth Hormone Deficiency in Children and Adolescents 1. Growth Hormone Deficiency Covered for children and adolescents with growth hormone deficiency (GHD) and growth failure who meet ALL of the following criteria: a. Patient has failed to respond to at least 2 standard GH stimulation tests, defined as a serum GH level (peak level) of < 10 ng/ml, after stimulation with insulin, levodopa, arginine, propranolol, clonidine or glucagon. However, one abnormal GH test is sufficient for children with brain tumors and irradiation with documented multiple pituitary hormone deficiency (MPHD); b. Appropriate imaging (MRI or CT) of the brain to exclude tumor on hypothalamic-pituitary region; c. One of the following criteria are met: i. Child has severe growth retardation with height standard deviation score (SDS) more than 3 SDS below the mean for ii. Child has moderate growth retardation with height SDS between -2 and -3 SDS below the mean chronological age and sex and decreased growth rate (growth velocity measured over one year below 25 th percentile for age and sex); OR iii. Child exhibits severe deceleration in growth rate (growth velocity measured over 1 year 2 SDS iv. COVERAGE POLICY below the mean for age and sex); OR Child has decreasing growth rate combined with a predisposing condition such as previous cranial irradiation or tumor; OR v. Child exhibits evidence of other pituitary hormone deficiencies or signs of congenital GHD (hypoglycemia, microphallus) 2. Chronic Renal Insufficiency Covered for children with chronic renal insufficiency and growth retardation awaiting renal transplantation who meet ALL the following criteria: a. Child s nutritional status has been optimized, metabolic abnormalities have been corrected and steroid usage has been reduced to a minimum; One of the following criteria are met: i. Child has severe growth retardation with height SDS more than 3 SDS below the mean for ii. Child has moderate growth retardation with height SDS between -2 and 3 SDS below the mean for chronological age and sex and decreased growth rate (growth velocity measured over one year below 25 th percentile for age and sex); OR Coventry Health Care, Inc. Page 1

iii. Child exhibits severe deceleration in growth rate (growth velocity measured over one year 2 SDS below the mean for age and sex) Growth hormone should be stopped after renal transplantation. 3. Turner s Syndrome Covered for girls with Turner s Syndrome and growth retardation who meet ALL the following criteria: a. The diagnosis of Turner s Syndrome is confirmed by chromosome analysis; b. One of the following criteria are met: i. Child has severe growth retardation with height SDS more than 3 SDS below mean for ii. Child has moderate growth retardation with height SDS between 2 and 3 SDS below the mean for chronological age and sex and decreased growth rate (growth velocity measure over one year below 25 th percentile for age and sex); OR iii. Child exhibits severe deceleration in growth rate (growth velocity measured over one year 2 SDS below mean for age and sex). 4. Short-Stature Homeobox-Containing Gene (SHOX) Deficiency: Covered for children with SHOX deficiency and growth retardation who meet ALL the following criteria: a. The diagnosis of SHOX deficiency is confirmed by appropriate chromosome analysis; b. One of the following criteria are met: i. Child has severe growth retardation with height SDS more than 3 SDS below mean for ii. Child has moderate growth retardation with height SDS between 2 and 3 SDS below the mean for chronological age and sex and decreased growth rate (growth velocity measure over one year below 25 th percentile for age and sex); OR iii. Child exhibits severe deceleration in growth rate (growth velocity measured over one year 2 SDS below mean for age and sex). 5. Prader Willi Syndrome Covered for children with Prader Willi Syndrome and growth retardation who meet ALL the following criteria: a. The diagnosis of Prader Willi Syndrome is confirmed by appropriate genetic testing, b. The patient has been evaluated for signs of severe respiratory impairment, upper airway obstruction, and sleep apnea before initiation of treatment, and will be routinely monitored for signs of respiratory infection during treatment, c. The patient is not severely obese prior to initiation of GH (ABW <200% above IBW), and an effective weight control program will be in place during treatment with GH, d. At least one (1) of the following criteria are met: i. Child has severe growth retardation with height SDS more than 3 SDS below mean for ii. Child has moderate growth retardation with height SDS between 2 and 3 SDS below the mean for chronological age and sex and decreased growth rate (growth velocity measure over one year below 25 th percentile for age and sex); OR iii. Child exhibits severe deceleration in growth rate (growth velocity measured over one year 2 SDS below mean for age and sex) 6. Small for Gestational Age (SGA) Children Covered for children born small for gestational age (defined as a birth weight < 2,500 g at a gestational age of more than 37 weeks or birth weight or length < 3 rd percentile for gestational age See Appendix I) who meet ALL the following criteria: a. Child with birth weight or length 2 or more standard deviations below the mean gestational age; b. Child fails to manifest catch up growth by age 3 years, defined as height 2 or more standard deviations below mean for age and sex. Coventry Health Care, Inc. Page 2

Review must include evaluation of growth curves from birth to age 3. 7. Noonan Syndrome Covered for children with Noonan Syndrome and growth retardation who meet ALL the following criteria: a. The diagnosis of Noonan Syndrome confirmed by appropriate genetic testing; b. One of the following criteria are met: i. Child has severe growth retardation with height SDS more than 3 SDS below mean for ii. Child has moderate growth retardation with height SDS between 2 and 3 SDS below the mean for chronological age and sex and decreased growth rate (growth velocity measure over one year below 25 th percentile for age and sex); OR iii. Child exhibits severe deceleration in growth rate (growth velocity measured over one year 2 SDS below mean for age and sex). 8. Idiopathic Short Stature (ISS) (only applicable to members insured by a Coventry benefit in the State of Maryland) ISS *additional criteria for members insured by a Coventry benefit in the State of Maryland. *Alternate Criteria for ISS GH therapy as presented by the Lawson Wilkins Pediatric Endocrine Society (LWPES) A trial of GH therapy will be approved for children with otherwise unexplained short stature who pass GH stimulation tests, but who meet most (3/5) of the following criteria: i. Height >2.25 SD below the mean for age or > 2 SD below the mid-parental height percentile; ii. Growth velocity < 25th percentile for bone age; iii. Bone age > 2 SD below the mean for age; iv. Low serum insulin-like growth factor 1 (IGF-1) and/or insulin-like growth factor binding protein 3 (IGFBP-3); v. Other clinical features suggestive of GHD. Growth Hormone Deficiency in Adults 1. Growth hormone deficiency Covered for replacement of endogenous growth hormone in patients with adult GH deficiency who meet ALL the following criteria: a. Adult onset: Patients who have growth hormone deficiency either alone or with multiple hormone deficiencies (hypopituitarism), as a result of EITHER, disease of the pituitary or hypothalamus, OR, injury to either the pituitary or hypothalmus from surgery, radiation therapy, or trauma; OR Childhood onset: Patients who were growth-hormone deficient during childhood who have GH deficiency confirmed as adult before replacement therapy is started. b. Biochemical diagnosis of GH deficiency, by means of a negative response to two standard GH stimulation test [maximum peak < 5 ng/ml when measured by RIA (polyclonal antibody) or < 2.5 ng/ml when measured by IRMA (monoclonal antibody)]. c. Patients already receiving full supplementation of other deficient hormones as required d. Objective measurement of clinical features of growth hormone deficiency: i. Severely decreased QOL (defined as score of at least 11 out of 25) as assessed using the Adult growth hormone deficiency assessment (AGHDA) questionnaire (see Appendix I); ii. EITHER, Reduced bone density of more than 1 SD below the age and gender-specific mean, (which by WHO criteria would predict a relative fracture risk of more than 2.5) provided that other etiologies have been ruled out or maximally treated; Coventry Health Care, Inc. Page 3

OR, Evidence of cardiac decompensation defined as reduced ejection fraction of < 50% provided that other etiologies have been ruled out or maximally treated; e. Growth hormone is initiated at a low dose and titrated slowly upward at monthly interval: i. Usual starting dose for adult onset is between 0.1 and 0.3 mg/day, with titration up to 0.2 0.5 mg/day for male and titration up to 0.4 1.0 mg/day for female; OR ii. Usual starting dose for childhood onset (transition patient) is between 0.4 and 0.8 mg/day, with titration up to 1.2 2.0 mg/day. 2. AIDS related wasting Covered for HIV infected persons who meet ALL the following criteria: a. Involuntary weight loss of > 10% of pre-illness baseline body weight or body mass index (BMI) < 20 kg/m 2, in the absence of a concurrent illness or medical condition other than HIV infection that may cause the weight loss; b. Failed to adequately respond to or are intolerant to anabolic steroids (eg. Megace); c. Been on anti-retroviral therapy for greater than 30 days prior to beginning growth hormone treatment and will continue anti-retroviral therapy throughout treatment AUTHORIZATION PERIOD LIMITATIONS Growth Hormone Deficiency in Children and Adolescents Initial Approval: 6 months Extended Approval: Annual review is required to determine if growth hormone therapy continues to be medically necessary. The annual review should focus on: Response to therapy, Whether discontinuation criteria are met (see below), Whether there are any major changes in clinical status affecting the need for growth hormone therapy, Verification that the member is still under appropriate reevaluations and care of the network provider. Note: As growth velocity begins to slow down OR when the current height is within 3 inches of the target height based on mid-parental height calculation, review must be done every 6 months, using the annual review criteria. Growth Hormone Deficiency in Adults Initial Approval: 6 months Extended Approval: Biannual review (every 6 months) is required to determine if growth hormone therapy continues to be medically necessary. The biannual review should focus on: Evidence of compliance with recommended therapy, Response to therapy, Tolerability of therapy, Whether there are any major changes in clinical status affecting the need for growth hormone therapy, Verification that the member is still under appropriate reevaluations and care of the network provider, (AT THE 12 MONTH EVALUATION ONLY) Whether discontinuation criteria are met (see below) AIDS-related Wasting One Time Approval: 6 months Coventry Health Care, Inc. Page 4

PROCUREMENT Specialty pharmacy source: Aetna Specialty Pharmacy (ASRx) Contact: ASRx toll free number: (866) 782-2779 ASRx toll free fax number: (866) 329-2779 ASRx e-mail address: www.aetnaspecialtypharmacy.com DISCONTINUATION OF THERAPY Growth Hormone Deficiency in Children and Adolescents In children and adolescents, growth hormone therapy is considered NOT medically necessary and is NOT covered if any of the following discontinuation criteria is met: a. Increase in height velocity < 2 cm total growth in one year of therapy; OR b. Expected final adult height, or target height based on mid-parental height calculation, or current absolute height 25th percentile* (defined as 68 inches in males and 63 inches in females), whichever has been reached first; OR c. Evidence of epiphyseal closure; OR d. Poor response to treatment, defined as an increase in growth velocity of less than 50% from baseline, in the first year of therapy. In children with Prader Willi Syndrome, evaluation of response to therapy should also take into account whether body composition (ie. ratio of lean to fat mass) has significantly improved; OR e. Persistent and uncorrectable problems with adherence to treatment, OR f. In children with Prader Willi Syndrome, patient shows signs of severe respiratory impairment, upper airway obstruction (including onset of or increased snoring) and/or new onset sleep apnea. Note: *Use of growth hormone after the absolute height has reached at least 25th percentile is considered cosmetic and therefore NOT covered. Growth Hormone Deficiency in Adults In adults, growth hormone therapy is considered NOT medically necessary and is NOT covered if any of the following discontinuation criteria are met following the first 12 months of treatment: a. No significant improvement in QOL, defined as less than a 7-point improvement compared to pre-treatment score, as assessed using the Adult growth hormone deficiency assessment (AGHDA) questionnaire; OR (Depending on which of the following applied to initiation of treatment) EITHER, b. No significant improvement of bone density at 12 months relative to pre-treatment measurement (defined as failure to achieve 5% increase in bone density; every -1 SD equals a 10 to 12% decrease in bone density), OR c. No significant improvement of cardiac function at 12 months relative to the pre-treatment measurement (defined as failure to improve the ejection fraction by 10%) NON-COVERAGE Growth hormone therapy is considered experimental/investigational and/or considered cosmetic benefit exclusion and/or NOT medically necessary and is NOT covered for the following conditions: a. Constitutional delay of growth and development b. To promote growth of infants or children with intrauterine growth retardation (except SGA as defined in the coverage criteria above) or Russell-Silver syndrome c. Skeletal dysplasias (eg. achondroplasia) d. Osteogenesis imperfecta e. Down Syndrome and other syndromes associated with short stature and malignant diathesis (eg. Bloom Syndrome, Fanconi Syndrome) f. Somatopause in older adults g. Infertility h. Chronic catabolic states, including respiratory failure, pharmacologic glucocorticoid administration, inflammatory bowel disease and short gut syndrome i. Burn injuries Coventry Health Care, Inc. Page 5

j. Obesity k. Hypophosphatemic rickets l. Muscular dystrophy m. Cystic fibrosis n. Noonan Syndrome without short stature o. Spina bifida p. Juvenile rheumatoid arthritis q. Osteoporosis, including osteoporosis related to menopause r. Post-traumatic stress disorder s. Depression t. Hypertension u. Corticosteroid-induced pituitary ablation v. Muscle mass preservation w. Any other genetic diagnoses associated with short stature x. Idiopathic short stature (non GH-deficient short stature) y. Treatment of GHD in children with Prader Willi Syndrome who are obese, have a history of upper airway obstruction or sleep apnea, and/or have severe respiratory impairment. This policy applies to all Coventry members unless superseded by applicable law. PROCEDURE Growth Hormone Therapy must be prior authorized by the Health Plan. Note: In Health Plan(s) where growth hormone coverage is excluded from the benefit, the benefit exclusion will supersede or override any conflicting portion of this Growth Hormone Therapy Policy. APPENDIX I: Fetal-Infant Growth corresponding to Gestational Age Tenth percentile of birth weight (g) for gestational age by gender: United States, 1991, single live births to resident mothers Gestational age, weeks Male Female 20 270 256 21 328 310 22 388 368 23 446 426 24 504 480 25 570 535 26 644 592 27 728 662 28 828 760 29 956 889 30 1117 1047 31 1308 1234 32 1521 1447 33 1751 1675 34 1985 1901 35 2205 2109 36 2407 2300 37 2596 2484 38 2769 2657 39 2908 2796 40 2986 2872 41 3007 2891 42 2998 2884 43 2977 2868 44 2963 2853 Coventry Health Care, Inc. Page 6

Reprinted with permission from the American College of Obstetricians and Gynecologists (Obstetrics and Gynecology, 1996; 87:163). Coventry Health Care, Inc. Page 7

APPENDIX II: AGHDA Scores The AGHDA Questionnaire asks you to say 'yes' if any of the following 25 statements applies to you. Each 'yes' scores 1 point; the higher the score the worse the quality of life. 1. I have to struggle to finish jobs. 2. I feel a strong need to sleep during the day. 3. I often feel lonely even when I am with other people. 4. I have to read things several times before they sink in. 5. It is difficult for me to make friends. 6. It takes a lot of effort for me to do simple tasks. 7. I have difficulty controlling my emotions. 8. I often lose track of what I want to say. 9. I lack confidence. 10. I have to push myself to do things. 11. I often feel very tense. 12. I feel as if I let people down. 13. I find it hard to mix with people. 14. I feel worn out even when I've not done anything. 15. There are times when I feel very low. 16. I avoid responsibilities if possible. 17. I avoid mixing with people I don't know well. 18. I feel as if I'm a burden to people. 19. I often forget what people have said to me. 20. I find it difficult to plan ahead. 21. I am easily irritated by other people. 22. I often feel too tired to do the things I ought to do. 23. I have to force myself to do all the things that need doing. 24. I often have to force myself to stay awake. 25. My memory lets me down. REFERENCES 1. Gharib H, Cook DM, et.al. American association of clinical endocrinologists medical guidelines for clinical practice for growth hormone use in adults and children - 2003 update. Endocrine Practice, 2003; 9(1): 64-76. 2. Cook DM, Yuen KC, et. at. American association of clinical endocrinologists medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition patients - 2009 update. Endocrine Practice, 2009; 15(Suppl 2): 1-22. 3. Richmond EJ, Rogol AD. Diagnosis of growth hormone deficiency in children. UpToDate. 2010. www. uptodate.com. Accessed on 02/09/10. 4. Growth hormone deficiency. MedlinePlus. 2009. http://www.nlm.nih.gov/medlineplus/. Accessed on 02/09/10. 5. Growth failure in children with kidney disease. National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC). 2009. http://www.kidney.niddk.nih.gov/. Accessed on 02/15/10. 6. Tönshoff, B. Growth hormone treatment in children with chronic kidney disease. UpToDate. 2009. www.uptodate.com. Accessed on 02/15/10. 7. Scheimann AO. Clinical features, diagnosis, and treatment of Prader-Willi syndrome. UpToDate. 2009. Accessed 02/16/10. 8. Mandy, G. Small for gestational age infant. UpToDate. www.uptodate.com. Accessed on 02/09/10. 9. Snyder, P. Growth hormone deficiency in adults. UpToDate. www.uptodate.com. Accessed on 02/09/10. 10. Growth hormone in the treatment of HIV-associated wasting. US National Institute of Health. 2007. http://clinicaltrials.gov/ct2/show/nct00489528. Accessed 02/16/10. Coventry Health Care, Inc. Page 8

11. Schambelan M., Mulligan K., et.al. Recombinant human growth hormone in patients with HIVassociated wasting. A randomized, placebo-controlled trial. Serostim Study Group. Annals of Internal Medicine. 1996 Dec 1; 125(11): 873-82. 12. Short stature. MedlinePlus. 2009.ttp://www.nlm.nih.gov/medlineplus/. Accessed on 02/09/10. 13. Alexander G., Himes J, et.al. A United States national reference for fetal growth. Obstetrics and Gynecology. 1996; 87: 163. 14. Fenton TR. A new growth chart for preterm babies: Babson and Benda's chart updated with recent data and a new format. BMC Pediatrics 2003, 3: 13. 15. AGHDA Scores. Pituitary Foundation. 2006. http://www.pituitary.org.uk/. Accessed on 02/15/10. 16. Goldstone AP, Holland AJ, et al., Recommendations for the diagnosis and management of Prader-Willi Syndrome. J Clin Endocrinol Metab, 2008, 93(11):4183-4197 Accessed 7/13/12 17. Prader-Willi Syndrome Association. Growth Hormone Treatment and Prader-Willi Syndrome Clinical Advisory board Consensus Statement, 2009 Accessed 7/13/12 18. Gunay-Aygun M, Schwartz S, et al., The changing purpose of prader-willi Syndrome Clinical Diagnostic Criteria and Proposed Revised Criteria. Pediatrics 2001, 108(5)92 Accessed 7/13/12 19. Mahan JD, Warady BA. Assessment and treatment of short stature in pediatric patients with chronic kidney disease: a consensus statement. Pediatric Nephrology, 2006; 26:917-930 Accessed 7/13/2012 20. Growth hormone in chronic renal disease. Indian Journal of Endocrinology and Metabolism, 2012; 16:2 Accessed 7/13/2012 21. Guest G, Berard E, et al. Effects of growth hormone in short children after renal transplantation. French Society of Pediatric Nephrology. Pediatric Nephrology 1998; 12:437-446 Accessed 7/13/2012 22. Fine RN, Stablein D, et al. Recombinant human growth hormone post-renal transplantation in children: a randomized controlled study of the NAPRTCS Kidney Int 2002, 62:688-696 Accessed 7/13/12 23. Vimalachandra D, Craig JC, et al. Growth hormone treatment in children with chronic renal failure: a meta-analysis of randomized controlled trials. J Pediatr 1998, 139:560-567 Accessed 7/13/12 Disclaimer: Coventry Health Care, Inc. (CHC) medical policies, technology assessments, and medical reviews (collectively CHC Policies ) are developed by CHC to provide guidance in administering plan benefits and constitute neither offers of coverage nor medical advice. Access to CHC Policies is provided for general reference purposes only and does not infer guaranteed coverage. CHC does not provide health care services or supplies. Providers are expected to exercise their independent medical judgment in rendering the most appropriate care. State and federal law, as well as benefit plan terms and conditions and CHC Policies in effect on the date that any service is rendered, including but not limited to definitions and specific inclusions/exclusions, take precedence over clinical policy and must be considered first in determining eligibility for coverage. The terms of the member's benefit plan shall determine coverage. Some benefit plans exclude coverage for services or supplies that Coventry may consider medically necessary. If there is a discrepancy between this policy and a member's benefit plan, the benefit shall govern. Coverage may also differ for CHC Medicare and/or Medicaid members based on any applicable Centers for Medicare & Medicaid Services (CMS) coverage statements including National Coverage Determination (NCD), Local Medical Review Policies (LMRP), and/or Local Coverage Determinations (LCD). As clinical technology is continually updated, CHC policies are subject to periodic updates. Do not rely on printed versions of CHC policies as they may be outdated. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or means without the written consent of CHC. Coventry Health Care, Inc. Page 9