Original Effective Date: 7/5/2007

Transcription

1 Subject: Recombinant Human Growth Hormone (somatropin)_adult Growth Hormone Deficiency GHD HIV/AIDS-associated wasting and cachexia Short Bowel Syndrome (SBS) Policy Number: MCP-004-D Review Dates: 4/28/2010, 4/27/2011, 3/14/2017, 7/10/2018 Original Effective Date: 7/5/2007 Revision Date(s): 4/28/2010, 4/27/2011, 3/14/2017 DISCLAIMER This Molina Clinical Policy (MCP) is intended to facilitate the Utilization Management process. It expresses Molina's determination as to whether certain services or supplies are medically necessary, experimental, investigational, or cosmetic for purposes of determining appropriateness of payment. The conclusion that a particular service or supply is medically necessary does not constitute a representation or warranty that this service or supply is covered (i.e., will be paid for by Molina) for a particular member. The member's benefit plan determines coverage. Each benefit plan defines which services are covered, which are excluded, and which are subject to dollar caps or other limits. Members and their providers will need to consult the member's benefit plan to determine if there are any exclusion(s) or other benefit limitations applicable to this service or supply. If there is a discrepancy between this policy and a member's plan of benefits, the benefits plan will govern. In addition, coverage may be mandated by applicable legal requirements of a State, the Federal government or CMS for Medicare and Medicaid members. CMS's Coverage Database can be found on the CMS website. The coverage directive(s) and criteria from an existing National Coverage Determination (NCD) or Local Coverage Determination (LCD) will supersede the contents of this MCP document and provide the directive for all Medicare members. SUMMARY OF EVIDENCE/POSITION This policy addresses the coverage of recombinant human growth hormone (rhgh, somatotropin) for the treatment of ADULT INDICATIONS [Growth Hormone Deficiency; HIV/AIDS-associated wasting and cachexia; and Short Bowel Syndrome (SBS)] when appropriate criteria are met. The intent of this drug policy is to ensure appropriate selection of patients for therapy based on product labeling, clinical guidelines, and clinical studies. Recombinant human growth hormone (rhgh, somatotropin) is used as replacement therapy in adults with endogenous growth hormone deficiency (GHD), such as those with idiopathic or acquired GHD. Human growth hormone (hgh, somatotropin) is secreted by the anterior pituitary. Most of its anabolic effects are mediated by insulin-like growth factor-i (IGF-I, somatomedin C), which is synthesized in the liver and other tissues in response to growth hormone stimulation. Growth hormone stimulates linear growth in children and influences metabolism of carbohydrates, fats, minerals, and proteins. Somatropin is produced by recombinant DNA technology and has the same amino acid sequence as naturally occurring hgh (a single polypeptide chain of 191 amino acids). The goal of GH replacement in adults is to minimize the symptoms of GHD (e.g., fatigue, poor endurance, and poor sense of well-being), improve the quality of life, and achieve serum insulin like growth factor (IGF- 1) concentration in the normal range for age and sex. The major endpoints of treatment are to improve blood lipid levels, improve the patient s waist-to-hip ratio, improve body composition, improve quality of life, and reduce cardiovascular risk factors. Growth Hormone Deficiency (GHD) is the inadequate secretion of endogenous growth hormone. GHD may be idiopathic or organic and may occur in childhood or adulthood. Pathophysiology differs between childhood or adulthood onsets. GHD is diagnosed through a combination of clinical and biochemical examination, testing and analysis. Page 1 of 30

2 Generally results from conditions affecting the hypothalamus or pituitary gland including surgery and radiation therapy. Adults frequently report symptoms such as unintentional weight gain or difficult losing weight, low energy, reduced physical performance, decreased libido, impaired psychological well-being and a feeling that things are not right. Physical findings may include increased fat mass, decreased lean body and muscle mass, decreased bone density as well as reduced muscle strength and exercise capacity. There is however no single symptom or sign that is pathognomonic for GHD in adults. In addition, some adults with GHD may be entirely asymptomatic. Growth hormone treatment is not authorized for treatment of short stature in the absence of a growth hormone deficiency or for the majority of other conditions in which growth hormone has not been shown to provide clinical benefits or improvements in functional impairment or long-term health outcomes. Molina Healthcare authorize rhgh therapy if there is a significant physical functional impairment and treatment with rhgh treatment can be reasonably expected to improve the physical functional impairment of the member as a result of an illness, disease or injury. EQUIVALENCE OF PRODUCTS Growth hormone products are equally safe and effective, although they differ in how the medication is prepared and injected. No clinical trials have been conducted to evaluate the comparative efficacy or safety of available synthetic growth hormone products. There is a lack of reliable evidence that any one brand of GH is superior to other brands for medically necessary indications. Omnitrope brand of GH is the PREFERRED brand of GH for Molina Healthcare since other brands (e.g., Genotropin, Humatrope, Norditropin, Nutropin, Nutropin AQ, Saizen) of GH are not as cost-effective brand of growth hormone and highly expected to produce equivalent therapeutic results for the treatment of the member's disease. Other brands of GH will be considered NON-PREFERRED and not authorized unless the member has a documented contraindication or intolerance PREFERRED brand of GH (Omnitrope). If the PREFERRED brand (Omnitrope) does not have the labeled indication for member s diagnosis, Molina Healthcare will select the most cost-effective brand of GH that has the required labeling indication. PREFERRED AGENT: OMNITROPE may be authorized when ALL of the following criteria for member s specific diagnosis are met. Omnitrope vial: Medicaid Omnitrope pen: Marketplace NON-PREFERRED products: ALL of the following criteria for member s specific diagnosis are met AND when a preferred growth hormone product is contraindicated or not tolerated. CLASSIFICATION: Hormones and Hormone Modifiers; Pituitary Hormones; Growth hormone modifiers Page 2 of 30

3 FDA INDICATIONS FDA-approved indication does not, in itself, dictate coverage. Molina coverage Policy may not recommend coverage for all FDA-approved indications. Please review this policy in its entirety for indications covered by Molina Healthcare. The covered FDA-approved indications are conditions that are considered medically necessary; however it is not inclusive of all conditions which may be approved by the Medical Reviewer. At the discretion of the Medical Director and on a case-by-case basis, Molina Healthcare may consider authorization of the biologic therapy addressed in this Policy for members with exceptional circumstances and for members with severe disease who may fall outside of the defined criteria. Molina Healthcare reserves the right to update this Policy and revise coverage criteria to include or omit any offlabel condition(s) as necessary based on medical literature and clinical studies that may become available. The PREFERRED agent of Molina Healthcare brand of GH, OMNITROPE, is indicated in bold-faced type. Available as: Omnitrope: Cartridge 5, 10 mg; Vial 5.8mg The indications highlighted below are addressed in this policy. FDA-Approved Indication Growth failure in children due to inadequate secretion of endogenous growth hormone REFER TO: MCP-004-A Growth failure associated with Noonan syndrome (NS) REFER TO: MCP-004-B Growth failure associated with Prader-Willi syndrome (PWS) REFER TO: MCP-004-B Brands Genotropin, Humatrope, Norditropin, Nutropin, Nutropin AQ, Omnitrope, Saizen, Zomacton Norditropin Genotropin, Omnitrope Growth failure associated with Turner syndrome (TS) REFER TO: MCP-004-B Genotropin, Humatrope, Norditropin, Nutropin, Nutropin AQ, Omnitrope Short stature homeobox containing (SHOX) gene deficiency REFER TO: MCP-004-B Growth failure associated with CRI/CKD REFER TO: MCP-004-C Children born small for gestational age (SGA) who fail to manifest catch-up growth REFER TO: MCP-004-C Idiopathic Short Stature (ISS) **REFER TO EXCLUSIONS SECTION** Growth hormone deficiency in adults REFER TO: MCP-004-D Short bowel syndrome (SBS) REFER TO: MCP-004-D Wasting or cachexia associated with HIV HIV: human immunodeficiency virus **ADRESSED IN THIS POLICY** Humatrope Nutropin, Nutropin AQ Genotropin, Humatrope, Norditropin, Omnitrope Genotropin, Humatrope, Nutropin, Nutropin AQ Genotropin, Humatrope, Norditropin, Nutropin, Nutropin AQ, Omnitrope, Saizen Zorbtive Serostim CLASSIFICATION: Hormones and Hormone Modifiers; Pituitary Hormones; Growth Hormone Modifiers Page 3 of 30

4 RECOMMENDATIONS/COVERAGE CRITERIA Members authorized for GH therapy under previous Molina Healthcare GH policy (MCP) may be authorized for continuation of therapy in accordance with MCP continuation of therapy criteria Members receiving GH therapy without previous authorization by Molina Healthcare GH policy may be considered for continuation of therapy in accordance with MCP initiation criteria (per member s clinical data prior to initiation of therapy) and MCP continuation criteria (per member s current clinical data) Members previously treated with GH therapy but who have had treatment subsequently discontinued may be considered for re-initiation of therapy in accordance with MCP initial treatment criteria and continuation criteria except growth velocity TRANSITION FROM AFTER CHILDHOOD TO ADULT GROWTH HORMONE THERAPY Continuation of Therapy After Completion of Linear Growth Transition is required for childhood onset growth hormone deficiency (GHD), hypopituitarism, and Prader- Will syndrome (PWS) only. [NOTE: These indications are not addressed in this MCP] Chronic renal insufficiency (CRI/CKD) and Small for Gestational Age (SGA) treatment may continue until epiphyseal closure OR Continuation of Therapy criteria are not met for member s respective condition. The transition period is the time from late puberty to establishment of adult muscle and bone composition, and encompasses attainment of adult height. As attainment of adult or near-adult height is an easily measurable variable, reevaluation of the somatotropic axis is most conveniently performed when growth has slowed to the point when pediatric GH dosing will be discontinued, as detailed above. Since all children with GHD will not require continued treatment into adulthood, the transition period is significant. The transition period can be defined as beginning in late puberty the time when near adult height has been attained, and ending with full adult maturation (6-7 years after achievement of adult height). During this period ongoing growth hormone therapy may be necessary to attain somatic maturation, normal intermediary metabolism and appropriate quality of life. Once adult height has been achieved, subjects should be retested for GH deficiency to determine if continuing replacement therapy is necessary. The level of GH considered normal for an adult is much lower than that for a child, especially one undergoing the pubertal growth spurt. The American Association of Clinical Endocrinologists published guidelines in 2009 that stressed the need for and use of GH for continued treatment of persistently GH-deficient transition and adult patients. The metabolic improvements and long-term benefit with continuation of GH treatment in GH-deficient adolescents transitioning to adulthood Mauras N et al. remains uncertain. COVERAGE CRITERIA Recombinant GH therapy (rhgh, somatotropin) may be authorized for the treatment of adolescents and young adults with childhood onset GHD, who have completed linear growth as defined by growth rate less than 2 cm per year and meets ALL of the following criteria below: [ALL] 1. Member has completed linear growth as defined by growth rate less than 2 cm per year [GHRS, J] 2. GH treatment has been discontinued for at least THREE (3) months after completion of linear growth Page 4 of 30

5 3. Member meets ONE (1) of following sets of criteria are met: [A OR B] A. GH treatment has been stopped for at least THREE (3) months AND the diagnosis of GHD has been reconfirmed as follows: [ONE] Idiopathic isolated GHD [ONE: 1 OR 2] 1) Subnormal response to TWO (2) provocative GH stimulation tests: [TWO] [ng/ml = mcg/l] ITT [5.1mcg/L] Arginine: [4.1mcg/L] Glucagon [2.5-3 mcg/l, 1 mcg/l for obese patients and 3mcg/L in normal weight J ] Arginine/GHRH [4.1mcg/L OR cutoff value varies by waist circumference, body mass index (BMI), and age: peak GH values 11 ng/ml if body mass index [BMI] < 25 kg/m 2 ; 8 ng/ml if BMI 25 and < 30 kg/m 2 ; 4 ng/l if BMI 30 kg/m 2 ] Arginine/L-Dopa [peak GH < 1.5 ng/ml] EXCEPTION to GH provocation tests: NOT required for members where it would not be expected to produce a clinical response (in absence of all pituitary hormones): [ANY] o Surgical removal of the pituitary o Panhypopituitarism (criteria below) 2) Subnormal response to ONE (1) provocative test (similar to the stimulation tests and values above criterion) AND low IGF-1/IGFBP-3 level based on specific laboratory reference range Multiple Pituitary Hormone Deficiencies: Subnormal response (similar to the stimulation tests and values above criterion) to ONE (1) provocative GH test AND/OR low IGF-1/IGFBP-3 level based on specific laboratory reference range B. Documented presence of ANY of the following conditions [ANY] GH reassessment through stimulation testing is not required for the following members: [ANY] Severe GHD in childhood due to a genetic cause: Genetic mutations associated with deficient GH production or secretion (e.g.gh-1 or GHRH-R) Structural hypothalamic-pituitary disease Central nervous system tumors Severe GHD and the receipt of high-dose cranial radiation therapy Panhypopituitarism: defined by at least 3 pituitary hormone deficiencies (ACTH, TSH, FSH, LH, prolactin) AND IGF-1 level below the normal range for age and gender, based on specific lab reference values (IGF-1 while not receiving growth hormone therapy) NOTE: Peak GH level must be adjusted if monoclonal-based assay or recombinant human GH reference preparations are used, based upon specific lab reference values Informational Note: Due to the irreversible nature of the cause of the GHD in children with structural lesions with multiple hormone deficiencies and those with proven genetic causes, a low insulin-like growth factor I (IGF-I) level at least one month off GH therapy is sufficient documentation of persistent GHD without additional provocative testing (level of evidence, moderate). Page 5 of 30

6 4. Contraindications/Exclusions Authorization to continue GH therapy will not be authorized if ANY of the following has occurred: [ANY] Hypersensitivity to somatropin or any component of the formulation Growth promotion in pediatric patients with closed epiphyses Progression or recurrence of any underlying intracranial lesion or actively growing intracranial tumor Acute critical illness caused by complications following open-heart or abdominal surgery, multiple accidental trauma or acute respiratory failure Active proliferative or severe non-proliferative diabetic retinopathy Active malignancy Due to the potent anabolic effects, GH therapy is contraindicated in children with active malignancies and is generally withheld until after completion of successful therapy for a malignancy. ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD Consult the manufacturer's labeling for more detailed information on dosage and administration of this drug, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. Recommended Dosing Regimen [ALL] After linear growth is complete, member is transitioned to adult dosing if ALL criteria in this section are met for ongoing GH treatment: Omnitrope: GHD (adults): Initially, not more than 0.04 mg/kg SC per week divided into 7 equal daily injections, preferably administered in the evening. Increase dose as needed at 4-8 week intervals to a maximum of 0.08 mg/kg per week as 7 equal daily injections. Gradually increase the dose by 0.1 to 0.2 mg/day every 1 to 2 months as needed. NOTE: For continuation, yearly reassessment of serum levels of IGF-I is required with appropriate dosage adjustments as GH requirements in adults will decrease with age. To optimize the GH dose for an adolescent during the transition period, initiate with the adult dose and then titrate to a serum IGF-I level in the upper portion of the normal range for age and gender Authorization Limit [ALL] Authorization period: May authorize up to 12 months Maximum dose: up to 0.3 mg/week Quantity limitation sufficient for a 30-day supply per fill based on FDA-approved dosages Total vials of GH required calculated by dividing total milligrams (mg) of GH for 12 months by size of vials (mg/vial) Calculation: Multiply number of mg per dose by number of doses per week = mg/week. Multiply mgs/week by 52 weeks = total mgs/year. Divide mgs/year by number of mg per vial = number of vials for 12 month period. Route of Administration [ALL] GH therapy is considered a self-administered medication and is deemed appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility will not be authorized. NOTE: The status of an individual member, such as the ability to administer the medication, is not a consideration in determining whether a medication is defined as self-administered. If member meets all criteria and approval for therapy is authorized, medication will be dispensed by a specialty pharmacy vendor at the discretion of Molina Healthcare. Self-administered medications may not be dispensed for self-administration and billed through the medical benefit by a provider. These agents must be dispensed through a participating pharmacy. Page 6 of 30

7 ADULT GROWTH HORMONE DEFICIENCY (GHD) Growth Hormone Deficiency for Individuals 18 Years of Age and Older Recombinant human growth hormone (rhgh, somatotropin) is not a covered benefit for treatment of short stature in the absence of a growth hormone deficiency or for conditions in which growth hormone has not been shown to provide clinical benefits or improvements in functional impairment or long-term health outcomes. Patients with childhood-onset GHD who are appropriate candidates for GH therapy should be re-tested for GHD as adults unless they have known mutations, embryopathic lesions, or irreversible structural lesions/damage (level of evidence, high). A stimulation test is needed to confirm the diagnosis of GHD in adults. Numerous tests are available. (AACE 2009) Complicating the issue is a lack of universal agreement on cutoff points for GH levels. Most experts suggest a peak value of less than 5 nanograms per milliliter after stimulation as an indication of GHD. The insulin tolerance test (ITT) is currently considered the gold standard of the tests available and is preferred. The ITT is contraindicated in patients with a history of seizures or coronary artery disease. Other pharmacological stimuli include arginine, levodopa, and glucagon. A test using arginine and the hypothalamic releasing hormone for GH (GHRH) has been used and is considered a more accurate predictor of GHD than arginine alone or levodopa alone. Regardless of the stimulation test and GH assay used, 5 ng/ml is the cutoff point for all provocative tests. There are too many variables to consider in the various GH assays to specify different cutoff points for different assays. Cutoff values do not vary with patient age. This MCP addresses rhgh therapy for individuals whose epiphyses have closed. REFER TO: MCP-004-A for growth failure in children due to inadequate secretion of endogenous growth hormone. COVERAGE CRITERIA Recombinant GH therapy (rhgh, somatotropin) may be authorized for members who meet ALL of the following criteria [ALL] 1. Prescriber specialty [ONE] Prescribed and managed by a board-certified endocrinologist 2. Age/Gender/Restrictions 18 years of age or older or has closed/fused epiphyses (If member is younger than 18 years, reference Pediatric criteria) 3. Diagnosis/Indication [ALL] Member meets ALL of the following criteria require documentation [ALL] Significant clinical symptoms related to GHD [i.e. increased body fat, increased abdominal fat mass, insulin resistance (although hyperglycemia does not usually develop), decreased lean body mass, decreased muscle mass and strength, decreased exercise capacity, impaired sense of well-being, excessive fatigue, poor sense of well-being persist despite maximizing treatment of other hormonal disorders, mood disorders, and medical illness), decreased bone density, and cardiovascular risk factors (such as increased clotting factors, decreased cardiac function, increase LDL, decrease HDL)] Page 7 of 30

8 Diagnosis of ONE (1) of the following [ONE: A, B, OR C] A. CHILDHOOD OR ADOLESCENT ONSET GHD GH replacement is considered medically necessary for adults with childhood-onset GHD who meet ALL of the following criteria: [ALL] Diagnosis of childhood-onset GHD supported by member s clinical documentation TRANSITION FROM AFTER CHILDHOOD TO ADULT GROWTH HORMONE THERAPY criteria has been met: GH treatment has been discontinued for at least THREE (3) months after completion of linear growth AND member has persistent GH deficiency documented by at least ONE (1) failed GH stimulation test NOTE: TRANSITION FROM AFTER CHILDHOOD TO ADULT GROWTH HORMONE THERAPY is required for GHD, hypopituitarism, and Prader-Will syndrome (PWS) only GH reassessment through stimulation testing is not required for members with a high likelihood of GHD, as defined as having a serum IGF-I level < 84µg/L while not receiving GH therapy AND at least ONE (1) of the following: [ONE] Severe GHD in childhood due to a genetic cause Structural hypothalamic-pituitary disease Central nervous system tumors Severe GHD and the receipt of high-dose cranial radiation therapy Panhypopituitarism: defined by at least 3 pituitary hormone deficiencies (ACTH, TSH, FSH, LH, prolactin) AND IGF-1 level below the normal range for age and gender, based on specific lab reference values (IGF-1 while not receiving growth hormone therapy) NOTE: Peak GH level must be adjusted if monoclonal-based assay or recombinant human GH reference preparations are used, based upon specific lab reference values. B. IDIOPATHIC GHD: ADULT OR CHILDHOOD ONSET For members with a low IGF-1 (a marker of GH response) concentrations (SDS less than -2): Failure to respond to only ONE (1) standard GH stimulation test is required An abnormal response to TWO (2) provocative stimulation test: [TWO] [ng/ml = mcg/l] ITT [5.1mcg/L] Arginine: [4.1mcg/L] Glucagon [2.5-3 mcg/l, 1 mcg/l for obese patients and 3mcg/L in normal weight J ] Arginine/GHRH [4.1mcg/L OR cutoff value varies by waist circumference, body mass index (BMI), and age: peak GH values 11 ng/ml if body mass index [BMI] < 25 kg/m 2 ; 8 ng/ml if BMI 25 and < 30 kg/m 2 ; 4 ng/l if BMI 30 kg/m 2 ] Arginine/L-Dopa [peak GH < 1.5 ng/ml] EXCEPTION to GH provocation tests: NOT required for members where it would not be expected to produce a clinical response (in absence of all pituitary hormones): [ANY] o Surgical removal of the pituitary o Panhypopituitarism (criteria below) Page 8 of 30

9 Informational note: Refer to Appendix 1 for additional information on GH stimulation tests Stimulation tests used to diagnose growth hormone deficiency in adults include insulin tolerance (ITT), arginine, growth hormone releasing hormone (GHRH), and glucagon. The ITT is the best indicator of GHD. This test is contraindicated in patients with a history of seizures or coronary artery disease. A provocation test using arginine and GHRH (ARG + GHRH) is also acceptable and is considered more stringent than tests using arginine alone or levodopa alone. Twenty-four hour continuous measurements of GH, serum levels of IGF-I, or serum of levels IGFBP [insulin-like growth factor-binding protein] are considered inadequate to document GHD. C. PITUITARY OR HYPOTHALAMIC DISEASE Members who meet ALL of the following criteria may be authorized for the following: [ALL] Adult GHD is due to or the result of ONE (1) of the following: [ONE] Pituitary-hypothalamic disease (e.g., Sheehan s syndrome, autoimmune hypophysitis, or hypophysitis associated with other inflammatory conditions, such as sarcoidosis) Cranial surgery Cranial radiation therapy Head trauma Idiopathic adult-onset growth hormone deficiency An abnormal response to ONE (1) provocative stimulation test: [ONE] [ng/ml = mcg/l] ITT [5.1mcg/L] Arginine: [4.1mcg/L] Glucagon [2.5-3 mcg/l, 1 mcg/l for obese patients and 3mcg/L in normal weight J ] Arginine/GHRH [4.1mcg/L OR cutoff value varies by waist circumference, body mass index (BMI), and age: peak GH values 11 ng/ml if body mass index [BMI] < 25 kg/m 2 ; 8 ng/ml if BMI 25 and < 30 kg/m 2 ; 4 ng/l if BMI 30 kg/m 2 ] Arginine/L-Dopa [peak GH < 1.5 ng/ml] EXCEPTION to GH provocation tests: NOT required for members where it would not be expected to produce a clinical response (in absence of all pituitary hormones): [ANY] o Surgical removal of the pituitary o Panhypopituitarism (criteria below) D. PANHYPOPITUITARISM Diagnosis of panhypopituitarism defined by at least 3 pituitary hormone deficiencies (ACTH, TSH, FSH, LH, prolactin). Documentation required. IGF-1 level below the normal range for age and gender, based on specific lab reference values (IGF-1 while not receiving growth hormone therapy) NOTE: Peak GH level must be adjusted if monoclonal-based assay or recombinant human GH reference preparations are used, based upon specific lab reference values. NOTE: Growth hormone stimulation testing is not required for panhypopituitarism. AACE (2009) does not recommend GH stimulation testing in patients with three or more pituitary hormone deficiencies and low IGF1. Page 9 of 30

10 4. Labs/Reports/Documentation required [ALL] All of the following documentation requested for the criteria below must be submitted for review Thyroid function tests are within normal range (TSH miu/l) NOTE: Documentation of normal thyroid function (TSH) is needed at the time of GH stimulation testing NOTE: If TSH level is not within normal range, TSH deficiency should be corrected before performing GH stimulation tests since GH secretion may be subnormal as a result of the hypothyroidism. Hypothyroidism is indicated by an elevated serum TSH, which is defined as a TSH concentration above the upper limit of the normal TSH reference range, which is usually 4 to 5 mu/l in most laboratories. Untreated/undiagnosed hypothyroidism may decrease response to therapy; monitor thyroid function test periodically and initiate/adjust thyroid replacement therapy as needed. Other causes of GHD or secondary medical illnesses that affect GH have been ruled out [including but not limited to: liver/kidney disease, chronic systemic disease, intracranial malignancy or tumor, growthinhibiting medication(s), endocrine disorders, cranial tumors, cranial irradiation, chronic systemic disease, infections of the central nervous system, genetic syndromes, skeletal disorders, or other organic causes] Other pituitary hormone deficiencies have been ruled out and/or corrected prior to time of testing [e.g. adrenocorticotropin hormone (ACTH), thyroid stimulating hormone (TSH), gonadotropin deficiency (leutinizing hormone [LH] and/or follicle stimulating hormone [FSH] are counted as 1 deficiency), prolactin, or arginine vasopressin (VAP) deficiency] Nutritional status has been optimized, metabolic abnormalities have been corrected, and steroid usage has been reduced to a minimum History of malignancy: Anti-malignancy treatment must be completed AND evidence of complete remission for at least 12 months free of recurrence J Imaging Studies [RECOMMENDED but NOT REQUIRED. SUBMIT IF AVAILABLE] Magnetic Resonance Imaging (MRI) of the hypothalamic-pituitary area to rule out tumors, investigate for structural causes of GHD, and to evaluate the severity and prognosis of the deficiency. Criterion is not required for authorization; however is recommended and Prescriber is requested to submit if available for documentation. MRI without contrast is sufficient; MRI contrast helpful if anatomy is not normal on regular MRI. The Endocrine Society guidelines do not specifically state MRI testing is required, however most AMR Reviewer2017 endocrinologists order imaging as standard practice. 5. Contraindications/Exclusions Authorization to continue GH therapy will not be authorized if ANY of the following has occurred: [ANY] Hypersensitivity to somatropin or any component of the formulation Growth promotion in pediatric patients with closed epiphyses Progression or recurrence of any underlying intracranial lesion or actively growing intracranial tumor Acute critical illness caused by complications following open-heart or abdominal surgery, multiple accidental trauma or acute respiratory failure Active malignancy Due to the potent anabolic effects, GH therapy is contraindicated in children with active malignancies and is generally withheld for at least one year after completion of successful therapy for a malignancy. Active proliferative or severe non-proliferative diabetic retinopathy Page 10 of 30

11 CONTINUATION of Therapy for GHD in ADULTS [over 18 years of age] Recombinant GH therapy (rhgh, somatotropin) may be authorized for continuation of therapy if meet ALL of the following criteria are met: [ALL] 1. Member meets the Initial Therapy criteria Continuation of therapy criteria must be met for ALL conditions defined in the previous section (except panhypopituitarism) for reauthorization every 12 months 2. Compliance with GH therapy as verified by Prescriber and member s medication fill history NOTE: GH therapy should be discontinued and will not be authorized when there is poor adherence to the treatment regimen for any reason. 3. Labs/Reports/Documentation required [ALL] All of the following documentation requested for the criteria below must be submitted for review IGF-1 is in normal range for age and gender based on specific lab reference values. (If above normal, dose reduction required) Serum IGF-1 levels are the main determinant for adjusting the dose of GH. No studies are available to guide this decision. Thyroid function tests are within normal range (TSH miu/l) Clinical improvement since previous authorization of therapy, including: [ALL APPLICABLE] Improvement in body composition, weight loss Cardiovascular health Body mineral density, increase bone mass Improvement on lipid profile, serum cholesterol Increase in physical or muscle strength Increase of IGF-1 into the normal range Improvement in 'Quality of Life Assessment of Growth Hormone Deficiency in Adults' (QoL- AGHDA) score NOTE: Children on GH therapy who transitions into GH therapy into adulthood OR adults with hypopituitarism of recent onset will not exhibit the manifestations of adult GHD and will not show the improvements listed above. 4. Contraindications/Exclusions Authorization to continue GH therapy will not be authorized if ANY of the following has occurred: [ANY] Hypersensitivity to somatropin or any component of the formulation Growth promotion in pediatric patients with closed epiphyses Progression or recurrence of any underlying intracranial lesion or actively growing intracranial tumor Acute critical illness caused by complications following open-heart or abdominal surgery, multiple accidental trauma or acute respiratory failure Active malignancy Due to the potent anabolic effects, GH therapy is contraindicated in children with active malignancies and is generally withheld for at least one year after completion of successful therapy for a malignancy. Active proliferative or severe non-proliferative diabetic retinopathy Page 11 of 30

12 5. Discontinuation of Treatment Discontinue treatment if ANY of the following conditions applies: [ANY] Intolerable adverse effects or drug toxicity Persistent and uncorrectable problems with adherence to treatment Poor response to treatment as evidenced by physical findings and/or clinical symptoms Contraindications/Exclusions to therapy o Hypersensitivity to somatropin or any component of the formulation o Growth promotion in pediatric patients with closed epiphyses o Progression or recurrence of any underlying intracranial lesion or actively growing intracranial tumor o Acute critical illness caused by complications following open-heart or abdominal surgery, multiple accidental trauma or acute respiratory failure o Active malignancy o Active proliferative or severe non-proliferative diabetic retinopathy ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD Consult the manufacturer's labeling for more detailed information on dosage and administration of this drug, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. Recommended Dosing Regimen [ALL] Omnitrope: GHD (adult): Adults: Initially, not more than 0.04 mg/kg SC per week divided into 7 equal daily injections, preferably administered in the evening. Increase dose as needed at 4-8 week intervals to a maximum of 0.08 mg/kg per week as 7 equal daily injections. Gradually increase the dose by 0.1 to 0.2 mg/day every 1 to 2 months as needed. For continuation, yearly reassessment of serum levels of IGF-I is required with appropriate dosage adjustments as GH requirements in adults will decrease with age. Authorization Limit [ALL APPLICABLE] Initial therapy authorization period: 6 months Continuation of therapy authorization period: 12 months NOTE: For continuation, yearly reassessment of serum levels of IGF-I is required with appropriate dosage adjustments as GH requirements in adults will decrease with age. Quantity limitation sufficient for a 30-day supply per fill based on FDA-approved dosages Total vials of GH required calculated by dividing total milligrams (mg) of GH for 12 months by size of vials (mg/vial) Calculation: Multiply number of mg per dose by number of doses per week = mg/week. Multiply mgs/week by 52 weeks = total mgs/year. Divide mgs/year by number of mg per vial = number of vials for 12 month period. Route of Administration [ALL] GH therapy is considered a self-administered medication and is deemed appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility will not be authorized. NOTE: The status of an individual member, such as the ability to administer the medication, is not a consideration in determining whether a medication is defined as self-administered. If member meets all criteria and approval for therapy is authorized, medication will be dispensed by a specialty pharmacy vendor at the discretion of Molina Healthcare. Self-administered medications may not be dispensed for self-administration and billed through the medical benefit by a provider. These agents must be dispensed through a participating pharmacy. Page 12 of 30

13 HUMAN IMMUNODEFICIENCY VIRUS (HIV)-ASSOCIATED CACHEXIA HIV/AIDS-associated wasting and cachexia is defined as unintentional and progressive weight loss (cachexia) often accompanied by weakness, fever, nutritional deficiencies and diarrhea. The wasting can be caused by opportunistic infections that interfere with the gut s ability to absorb nutrients, altered metabolism of nutrients or by inadequate food intake due to nausea and vomiting. The syndrome reduces the quality of life, exacerbates the illness and increases the risk of death for people with HIV. The goal of therapy is to increase the person s body weight and promote an increase in lean body mass (muscle). Stimulation testing requirements not applicable for diagnosis of HIV/AIDS-associated wasting and cachexia Serostim is a purified recombinant growth hormone prepared by using either Escherichia coli or mammalian cells. Serostim (somatropin) for injection is indicated for the treatment of wasting or cachexia in HIV Members to increase lean body mass and body weight, and to improve physical endurance. Only Serostim is FDA approved and can be used for this indication. Initial authorization is limited to 12 weeks duration in order to determine effectiveness. Therapy with somatropin for AIDS related wasting should be limited to 48 weeks. COVERAGE CRITERIA Serostim for the treatment of adults with HIV/AIDS-associated wasting and cachexia may be authorized for an initial 4-week trial course with documentation of ALL of the following: 1. Prescriber specialty Prescribed and managed by a board-certified endocrinologist or infectious disease specialist 2. Age/Gender/Restrictions 18 years of age or older Safety and effectiveness in pediatric patients with HIV have not been established. Available evidence suggests that somatropin clearance is similar in adults and children, but no pharmacokinetic studies have been conducted in children with HIV. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. 3. Diagnosis [ALL] Clinical documented diagnosis of (includes clinical notes from the member s medical records including any applicable labs and/or tests, supporting the diagnosis) Diagnosis of HIV/AIDS-associated wasting and cachexia, defined by ONE (1) of the following, not attributable to other concurrent illness(es) or medical condition(s): [ONE] Unintentional weight loss of at least 10% of baseline weight within the past 12 months BMI < 20 kg/m 2, not attributable to other concurrent illness(es) or medical condition(s), OR Weighs less than 90% Ideal Body Weight, OR Baseline bioelectrical impedance analysis (BIA) or total body DEXA showing body cell mass (BCM) below 40% in males and 35% in females Page 13 of 30

14 Other underlying treatable conditions that may potentially cause weight loss have been ruled out, including: [ALL] Inadequate nutritional intake evidenced by written evaluation by a Registered Dietician (RD) Presence of significant anxiety and/or depression affecting food intake Growth inhibiting medication, chronic disease or chronic infectious diarrhea or endocrine disorders Opportunistic infections (i.e. Mycobacterium avium, Pneumocystis carinii, esophageal candidiasis, cryptosporidiosis, microsporidiosis, Salmonella, Shigella, cytomegalovirus, tuberculosis) Evidence of other causes of wasting and cachexia have been ruled out, such as: hypothyroidism, chronic systemic disease, nutritional/emotional deprivation, intracranial malignancy or tumor, growth-inhibiting medication(s), and endocrine disorders Members with history of malignancy: At least the past twelve (12) months should be free of recurrence prior to initiating GH therapy. Anti-malignancy treatment must be completed with evidence of remission. Members with thyroid deficiency: Results of GH secretion tests will only be accepted after thyroid deficiency has been adequately treated because GH secretion may be subnormal merely as a result of hypothyroidism. 4. Labs/Reports/Documentation required ALL of the following documentation requested for the criteria below must be submitted for review [ALL] Currently receiving optimal antiretroviral therapy for > 30 days prior to beginning somatropin therapy and will continue antiretroviral therapy throughout the course of somatropin treatment Maintain patients with HIV infection on antiretroviral therapy to prevent the potential increase in viral replication. Male members only: Normal testosterone blood levels (lab result within the past 2 months). If serum testosterone level is low, a documented trial of testosterone replacement therapy is required. A trial of androgen for HIV-associated wasting. If a trial of androgen is omitted, a statement documenting the clinical decision to advance directly to Serostim therapy is required. Continued weight loss despite adequate nutrition and other measures including the following: [ALL] Inadequate response, intolerance or contraindication to appetite stimulants, anabolic medications (Oxandrin, Winstrol, Nandrolone) and appetite stimulants (Marinol or Megace) Nutritional evaluation by a registered dietician (RD): RD has assessed, intervened, and monitored the Member according to the American Dietetic Association (ADA) Nutrition Therapy Protocol for HIV/AIDS. Documentation required. Baseline measurements of the following: [ALL] Height, weight, ideal body weight, body mass index (BMI) Body cell mass (BCM) by bioelectrical impedance analysis (BIA) Serial measurements, weekly Page 14 of 30

15 5. Contraindications/Exclusions Authorization to continue GH therapy will not be authorized if ANY of the following has occurred: [ANY] Hypersensitivity to somatropin or any component of the formulation Growth promotion in pediatric patients with closed epiphyses Progression or recurrence of any underlying intracranial lesion or actively growing intracranial tumor Acute critical illness caused by complications following open-heart or abdominal surgery, multiple accidental trauma or acute respiratory failure Active malignancy Active proliferative or severe non-proliferative diabetic retinopathy CONTINUATION of Therapy for HIV/AIDS-RELATED WASTING SYNDROME May be authorized after an initial 4-week course of somatropin for HIV infection with wasting or cachexia for the following members: [ALL] 1. Member meets the Initial Therapy criteria AND Diagnosis of HIV cachexia or wasting syndrome, defined by unintentional weight loss of at least 10% of baseline weight, or BMI < 20 kg/m 2, not attributable to other concurrent illness(es) or medical condition(s) (such as AIDSassociated diarrhea, infection, malignancy or depression) NOTE: Therapy may be continued until this definition is no longer met OR until duration of therapy is reached. 2. Compliance with previous GH therapy as verified by Prescriber and member s medication fill history NOTE: GH therapy should be discontinued and will not be authorized when there is poor adherence to the treatment regimen for any reason. There is no safety and efficacy data from controlled trials in patients treated with somatropin for patients who start, stop, and then restart treatment. 3. Labs/Reports/Documentation required [ALL] All of the following documentation requested for the criteria below must be submitted for review [ALL] Member received a 3-month (12-week) course of somatropin for HIV infection with wasting or cachexia AND have been off somatropin for at least ONE (1) month NOTE: Therapy with somatropin for AIDS related wasting should be limited to 24 weeks total. Positive clinical response to therapy from ONE of the following baseline measures: [ONE] Body mass index (BMI) Body cell mass (BCM) by bioelectrical impedance analysis (BIA) For members who experienced weight loss after the initial four (4) weeks of therapy ONLY: Continuation of treatment will be considered after re-evaluation and documentation of the following [ALL] Intervention of a clinical event (e.g., opportunistic infection) and resolution/treatment of this clinical event Current clinical status Measured BMI and BCM Page 15 of 30

16 Discontinuation of Treatment [ANY] Discontinue treatment if ANY of the following conditions applies: [ANY] Intolerable adverse effects or drug toxicity Persistent and uncorrectable problems with adherence to treatment Poor response to treatment as evidenced by physical findings and/or clinical symptoms Contraindications/Exclusions to therapy o Hypersensitivity to somatropin or any component of the formulation o Growth promotion in pediatric patients with closed epiphyses o Progression or recurrence of any underlying intracranial lesion or actively growing intracranial tumor o Acute critical illness caused by complications following open-heart or abdominal surgery, multiple accidental trauma or acute respiratory failure o Active malignancy o Active proliferative or severe non-proliferative diabetic retinopathy ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD Consult the manufacturer's labeling for more detailed information on dosage and administration of this drug, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. Recommended Dosing Regimen Serostim Dosing Recommendations g Weight range Dose > 55 kg 6 mg subcutaneously at bedtime 45 to 55 kg 5 mg subcutaneously at bedtime 35 to 45 kg 4 mg subcutaneously at bedtime < 35 kg 0.1 mg/kg subcutaneously at bedtime a Based on an approximate daily dose of 0.1 mg/kg. Authorization Limit [ALL] Initial therapy authorization period: Limited to 4 weeks duration in order to determine effectiveness Continuation of Therapy or Repeat Courses: May be authorized for an additional 3 months (12 weeks) Duration of therapy: 24 weeks total Per FDA-approved labeling: Most of the effect on work output and lean body mass was apparent after 12 weeks of treatment. The effect was maintained during an additional 12 weeks of therapy. There is no safety or efficacy data available from controlled studies in which patients were treated continuously for more than 48 weeks. There are no safety or efficacy data available from trials in which patients were treated intermittently. g Maximum dosage: up to 6mg/day Route of Administration [ALL] GH therapy is considered a self-administered medication and is deemed appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility will not be authorized. NOTE: The status of an individual member, such as the ability to administer the medication, is not a consideration in determining whether a medication is defined as self-administered. If member meets all criteria and approval for therapy is granted, medication will be dispensed by a specialty pharmacy vendor at the discretion of Molina Healthcare. Self-administered medications may not be dispensed for self-administration and billed through the medical benefit by a provider. These agents must be dispensed through a participating pharmacy. Page 16 of 30

17 SHORT BOWEL SYNDROME (SBS) Short Bowel Syndrome (SBS) is a result of extensive surgical resection of the bowel resulting in various degrees of malabsorption depending on the area and site of resection and persistence of damage to the remaining bowel. (Seguy D et al.) Stimulation testing requirements not applicable for diagnosis of SBS. Only Zorbtive is FDA-approved and can be used for this indication. Authorization is limited to one 4-week course of therapy (28 days) for SBS as there are currently no studies showing that additional benefit is conferred by further treatment beyond four weeks. COVERAGE CRITERIA 1. Prescriber specialty [ONE] Prescribed and managed by a board-certified endocrinologist 2. Age/Gender/Restrictions 18 years of age or older NOTE: Members under the age of 18 with a confirmed diagnosis of short bowel syndrome are considered on a case-by-case basis in consultation with a Pharmacy/Medical Director. 3. Diagnosis [ALL] Member has not previously received 4 weeks of treatment with growth hormone Diagnosis of SBS by a gastroenterologist 4. Labs/Reports/Documentation required [ALL] All of the following documentation requested for the criteria below must be submitted for review [ALL] Concurrent specialized nutritional support, including enteral feedings, fluid and micronutrient supplements AND dependent on intravenous parenteral nutrition (IPN) for nutritional support Specialized nutritional support may consist of a high carbohydrate, low-fat diet, adjusted for individual patient requirements and preferences. Nutritional supplements may be added at the discretion of the treating physician. Optimal management of SBS may include dietary adjustments, enteral feedings, parenteral nutrition, fluids, and micronutrient supplements as needed. 5. Contraindications/Exclusions Authorization to continue GH therapy will not be authorized if ANY of the following has occurred: [ANY] Hypersensitivity to somatropin or any component of the formulation Growth promotion in pediatric patients with closed epiphyses Progression or recurrence of any underlying intracranial lesion or actively growing intracranial tumor Acute critical illness caused by complications following open-heart or abdominal surgery, multiple accidental trauma or acute respiratory failure Active malignancy Active proliferative or severe non-proliferative diabetic retinopathy Page 17 of 30

18 CONTINUATION of Therapy for SBS Continuation of therapy not applicable for SBS. Zorbtive may only be authorized one 4-week course. Growth hormone treatment of SBS for more than 4 weeks is will NOT be authorized since administration of GH for more than 4 weeks duration has not been adequately studied for short bowel syndrome. h ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD Consult the manufacturer's labeling for more detailed information on dosage and administration of this drug, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. Recommended Dosing Regimen Zorbtive: 8 mg/day Authorization Limit [AS APPLICABLE] Initial therapy authorization period: 4 weeks of therapy for quantity limitation sufficient for a 30-day supply per fill based on FDA-approved dosages Continuation of therapy authorization period: Authorization is limited to 4 weeks duration as administration for longer periods has not been adequately proven or studied. h Route of Administration [ALL] GH therapy is considered a self-administered medication and is deemed appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility will not be authorized. NOTE: The status of an individual member, such as the ability to administer the medication, is not a consideration in determining whether a medication is defined as self-administered. If member meets all criteria and approval for therapy is granted, medication will be dispensed by a specialty pharmacy vendor at the discretion of Molina Healthcare. Self-administered medications may not be dispensed for self-administration and billed through the medical benefit by a provider. These agents must be dispensed through a participating pharmacy. Page 18 of 30