subject: recombinant human growth hormone original effective … · 2019. 6. 8. · • human...

Subject: Recombinant Human Growth Hormone

(somatropin)_ADULT Growth Hormone Deficiency

° GHD

° HIV/AIDS-associated wasting and cachexia

° Short Bowel Syndrome (SBS)

Original Effective Date: 7/5/2007

Policy Number:

MCP-004-D

Revision Date(s): 4/28/2010, 4/27/2011,

3/14/2017

Review Dates: 4/28/2010, 4/27/2011, 3/14/2017, 7/10/2018

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.

of 30

‹ 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

of 30

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 off-

label 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 Brands

Growth failure in children due to inadequate secretion of

endogenous growth hormone

REFER TO: MCP-004-A

Genotropin, Humatrope, Norditropin, Nutropin,

Nutropin AQ, Omnitrope, Saizen, Zomacton

Growth failure associated with Noonan syndrome (NS)

REFER TO: MCP-004-B Norditropin

Growth failure associated with Prader-Willi syndrome (PWS)

REFER TO: MCP-004-B 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 Humatrope

Growth failure associated with CRI/CKD

REFER TO: MCP-004-C Nutropin, Nutropin AQ

Children born small for gestational age (SGA) who fail to

manifest catch-up growth

REFER TO: MCP-004-C

Genotropin, Humatrope, Norditropin, Omnitrope

Idiopathic Short Stature (ISS)

**REFER TO ‘EXCLUSIONS’ SECTION** Genotropin, Humatrope, Nutropin, Nutropin AQ

Growth hormone deficiency in adults

REFER TO: MCP-004-D

Genotropin, Humatrope, Norditropin, Nutropin,

Nutropin AQ, Omnitrope, Saizen

Short bowel syndrome (SBS)

REFER TO: MCP-004-D Zorbtive

Wasting or cachexia associated with HIV HIV: human immunodeficiency virus

**ADRESSED IN THIS POLICY** Serostim

CLASSIFICATION: Hormones and Hormone Modifiers; Pituitary Hormones; Growth Hormone Modifiers

of 30

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, re-

evaluation 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

remains uncertain. Mauras N et al.

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

2. GH treatment has been discontinued for at least THREE (3) months after completion of linear growth[GHRS, J]

of 30

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]

û ITT [5.1mcg/L]

û Arginine: [4.1mcg/L]

û Glucagon [2.5-3 mcg/L, 1 mcg/L for obese patients and 3mcg/L in normal weightJ]

û 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/m2; ≤ 8 ng/mL if BMI ≥ 25 and < 30 kg/m2; ≤ 4 ng/L if BMI ≥ 30 kg/m2]

û Arginine/L-Dopa [peak GH < 1.5 ng/mL]

û 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

ß 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]

ß 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)

ß Structural hypothalamic-pituitary disease

ß Central nervous system tumors

ß Severe GHD and the receipt of high-dose cranial radiation therapy

ß 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).

of 30

4.� Contraindications/Exclusions

¶ Authorization to continue GH therapy will not be authorized if ANY of the following has occurred: [ANY]

û Hypersensitivity to somatropin or any component of the formulation

û Growth promotion in pediatric patients with closed epiphyses

û Progression or recurrence of any underlying intracranial lesion or actively growing intracranial tumor

û Acute critical illness caused by complications following open-heart or abdominal surgery, multiple

accidental trauma or acute respiratory failure

û Active proliferative or severe non-proliferative diabetic retinopathy

û 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:�

ß 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.

of 30

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]

ß 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)]

of 30

ß 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]

ß Diagnosis of childhood-onset GHD supported by member’s clinical documentation

ß ‘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

ß 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]

û Severe GHD in childhood due to a genetic cause

û Structural hypothalamic-pituitary disease

û Central nervous system tumors

û Severe GHD and the receipt of high-dose cranial radiation therapy

û 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

ß 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

ß An abnormal response to TWO (2) provocative stimulation test: [TWO]�[ng/mL = mcg/L]�

û ITT [5.1mcg/L]



û 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/m2;

≤ 8 ng/mL if BMI ≥ 25 and < 30 kg/m2; ≤ 4 ng/L if BMI ≥ 30 kg/m2]


û 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]



of 30

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]

ß Adult GHD is due to or the result of ONE (1) of the following: [ONE]

û Pituitary-hypothalamic disease (e.g., Sheehan’s syndrome, autoimmune hypophysitis, or

hypophysitis associated with other inflammatory conditions, such as sarcoidosis)

û Cranial surgery

û Cranial radiation therapy

û Head trauma

û Idiopathic adult-onset growth hormone deficiency

ß An abnormal response to ONE (1) provocative stimulation test: [ONE]

[ng/mL = mcg/L]

û ITT [5.1mcg/L]



û 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/m2;

≤ 8 ng/mL if BMI ≥ 25 and < 30 kg/m2; ≤ 4 ng/L if BMI ≥ 30 kg/m2]


û 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]



D.� PANHYPOPITUITARISM

ß Diagnosis of panhypopituitarism defined by at least 3 pituitary hormone deficiencies (ACTH, TSH,

FSH, LH, prolactin). Documentation required.

ß 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.

of 30

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 0.4 - 4.0 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, growth-

inhibiting 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]

û 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]

û Nutritional status has been optimized, metabolic abnormalities have been corrected, and steroid

usage has been reduced to a minimum

û History of malignancy: Anti-malignancy treatment must be completed AND evidence of complete

remission for at least 12 months free of recurrenceJ

û 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

endocrinologists order imaging as standard practice.AMR Reviewer2017









and is generally withheld for at least one year after completion of successful therapy for a malignancy.


of 30

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

ß 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.


All of the following documentation requested for the criteria below must be submitted for review

ß 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.

ß Thyroid function tests are within normal range (TSH 0.4 - 4.0 mIU/L)

ß Clinical improvement since previous authorization of therapy, including: [ALL APPLICABLE]

û Improvement in body composition, weight loss

û Cardiovascular health

û Body mineral density, increase bone mass

û Improvement on lipid profile, serum cholesterol

û Increase in physical or muscle strength

û Increase of IGF-1 into the normal range

û 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.









and is generally withheld for at least one year after completion of successful therapy for a malignancy.


of 30

5.� Discontinuation of Treatment

¶ Discontinue treatment if ANY of the following conditions applies: [ANY]

û Intolerable adverse effects or drug toxicity

û Persistent and uncorrectable problems with adherence to treatment

û Poor response to treatment as evidenced by physical findings and/or clinical symptoms

û 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


o Active malignancy

o Active proliferative or severe non-proliferative diabetic retinopathy



Recommended Dosing Regimen [ALL]

ß 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.

ß 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]

ß Initial therapy authorization period: 6 months

ß 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.

ß 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.


ß GH therapy is considered a self-administered medication and is deemed appropriate for self-administration or





ß If member meets all criteria and approval for therapy is authorized, medication will be dispensed by a specialty




of 30

-

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


¶ 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]

û Unintentional weight loss of at least 10% of baseline weight within the past 12 months

û BMI < 20 kg/m2, not attributable to other concurrent illness(es) or medical condition(s), OR

û Weighs less than 90% Ideal Body Weight, OR

û Baseline bioelectrical impedance analysis (BIA) or total body DEXA showing body cell mass

(BCM) below 40% in males and 35% in females

of 30�

¶ Other underlying treatable conditions that may potentially cause weight loss have been ruled out, including:

[ALL]

û Inadequate nutritional intake evidenced by written evaluation by a Registered Dietician (RD)

û Presence of significant anxiety and/or depression affecting food intake

û Growth inhibiting medication, chronic disease or chronic infectious diarrhea or endocrine disorders

û Opportunistic infections (i.e. Mycobacterium avium, Pneumocystis carinii, esophageal candidiasis,

cryptosporidiosis, microsporidiosis, Salmonella, Shigella, cytomegalovirus, tuberculosis)

û 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

û 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.

û 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.

ß 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.

ß 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]

û Inadequate response, intolerance or contraindication to appetite stimulants, anabolic medications

(Oxandrin, Winstrol, Nandrolone) and appetite stimulants (Marinol or Megace)

û 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.

ß Baseline measurements of the following: [ALL]

û Height, weight, ideal body weight, body mass index (BMI)

û Body cell mass (BCM) by bioelectrical impedance analysis (BIA)

û Serial measurements, weekly

of 30








û Active malignancy


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/m2, not attributable to other concurrent illness(es) or medical condition(s) (such as AIDS-associated 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.


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]

û Body mass index (BMI)

û Body cell mass (BCM) by bioelectrical impedance analysis (BIA)

ß 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]

û Intervention of a clinical event (e.g., opportunistic infection) and resolution/treatment of this clinical

event

û Current clinical status

û Measured BMI and BCM

of 30

ß Discontinuation of Treatment [ANY]�Discontinue treatment if ANY of the following conditions applies: [ANY]�

û Intolerable adverse effects or drug toxicity

û Persistent and uncorrectable problems with adherence to treatment

û Poor response to treatment as evidenced by physical findings and/or clinical symptoms

û 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



Recommended Dosing Regimen

Serostim Dosing Recommendationsg

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 aBased on an approximate daily dose of 0.1 mg/kg.

Authorization Limit [ALL]

ß Initial therapy authorization period: Limited to 4 weeks duration in order to determine effectiveness

ß 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

ß Maximum dosage: up to 6mg/day







ß If member meets all criteria and approval for therapy is granted, medication will be dispensed by a specialty




of 30

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


¶ 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]

ß Member has not previously received 4 weeks of treatment with growth hormone

ß 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







û Active malignancy


of 30�

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



Recommended Dosing Regimen

¶ Zorbtive: 8 mg/day

Authorization Limit [AS APPLICABLE]

ß Initial therapy authorization period: 4 weeks of therapy for quantity limitation sufficient for a 30-day supply per fill

based on FDA-approved dosages

ß 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







ß If member meets all criteria and approval for therapy is granted, medication will be dispensed by a specialty




of 30

-

PREFERRED/NON PREFERRED

PREFERRED

OMNITROPE may be authorized when ALL of the criteria for member’s diagnosis has been met: [APPLICABLE]

¶ Omnitrope vial: Medicaid�

¶ Omnitrope pen: Marketplace�

NON-PREFERRED

A NON-PREFERRED product may be authorized when ALL criteria for member’s diagnosis has been met in addition to:

¶ Failure or inadequate clinical response to the PREFERRED agent documented to ANY of the following: [ANY]�

û Inadequate clinical response from previous trial of PREFERRED product. Documentation of trial and

failure of the preferred GH product required either through previous claims history or by member’s medical

records.

û Member’s diagnosis is not an FDA-labeled indication of the PREFERRED product (Omnitrope)�

û Allergy, *labeled contraindication, or clinical intolerance of the PREFERRED product (Omnitrope)�*Contraindications/Exclusions to Omnitrope includes the following: [ANY]

o Documented sensitivity to benzyl alcohol (a preservative in Omnitrope 5 Pen and Omnitrope

5.8mg/vial) and to phenol (a preservative in Omnitrope 10 Pen)

NOTE: Genotropin or Humatrope contains a different preservative

o Children under the age of 3: Benzyl alcohol should not be used in children under the age of 3.

Omnitrope 5 & 5.8mg which contains benzyl alcohol as a preservative is contraindicated in

children under the age of 3. Omnitrope 10 should be used in children under the age of 3 as it does

not contain benzyl alcohol.

of 30

COVERAGE EXCLUSIONS

This policy only addresses the indication of growth hormone in the treatment of PEDIATRIC members for Growth

Hormone Deficiency as stated in the Coverage Criteria section when all appropriate criteria are met.

All other uses of growth hormone that are not an FDA-approved indication or not included in the ‘Coverage Criteria’

section of this policy are considered experimental/investigational or not a covered benefit of this policy. This subject to

change based on research and medical literature, or at the discretion of Molina Healthcare.

Growth hormone is not authorized for all other indications, including (but not limited to) the following indications due

to a lack of medical literature to establish efficacy for these indications: [ANY]

• Amyotrophic lateral sclerosis

• Anabolic therapy to enhance body mass or strength for professional, recreational or social reasons

• Anti-aging

• Burn injuries

• Cerebral palsy

• CHARGE (Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia,

Ear anomalies/deafness) syndrome

• Chondrodystrophy

• Chronic catabolic states, including inflammatory bowel disease, pharmacologic glucocorticoid administration,

and respiratory failure

• Chronic fatigue syndrome

• Congestive heart failure

• Constitutional delay* defined as lower than expected height percentiles compared with their target height

percentiles and delayed skeletal maturation when growth velocities and rates of bone age advancement are

normal (i.e., delayed skeletal maturation with normal growth velocities and rates of bone age advancement,

members who are at the lowest 5% of the growth curve at age three)

• Corticosteroid-induced pituitary ablation

• Crohn's disease

• Cystic fibrosis

• Depression

• Down syndrome and other syndromes associated with short stature and increased susceptibility to neoplasms

(e.g., Bloom syndrome, Fanconi syndrome)

• Fibromyalgia

• Fracture healing

• Glucocorticoid-induced growth failure

• Growth hormone insensitivity (partial or complete)

• Growth retardation due to amphetamines (e.g., Adderall, Ritalin)

• Hypochondroplasia

• Hypophosphatemia (e.g., hypophosphatemic rickets)

• Infertility/in-vitro fertilization

• HIV-associated adipose redistribution syndrome (HARS) ‹ Serostim has been studied in the treatment of HARS. There is limited short-term data that indicate Serostim

decreases visceral adipose tissue; however, the clinical significance with respect to cardiovascular risk profile is

unknown.

• HIV lipodystrophy

• Hypertension

• Idiopathic Short Stature (ISS) **Further information below**

• Intra-Uterine Growth Restriction (IUGR)/Small for Gestational Age (SGA) **Further information

below**

of 30

• Ischemic heart disease

• Isochromosome Yp defect

• Juvenile rheumatoid arthritis

• Kabuki syndrome

• Muscular dystrophy

• Neurosecretory growth hormone dysfunction

• Non-classic congenital adrenal hyperplasia

• Obesity/morbid obesity

• Osteogenesis imperfect

• Osteoporosis

• Post bariatric surgery

• Post-traumatic stress disorder

• Precocious puberty

• Pseudohypoparathyroidism

• Russell-Silver syndrome (that does not result in small for gestational age)

• Skeletal dysplasias (e.g., achondroplasia, kyphomelic dysplasia)

• “Somatopause” in older adults

• Spina bifida

• Stem cell mobilization

• Wound healing

Idiopathic Short Stature (ISS) ISS is also referred to as non-GHD short stature in children.

∑ ISS is a clinical description rather than a disease. ISS is defined as short stature in an otherwise healthy child,

exclusion of other causes of short stature (endocrine, metabolic, or other disease), bone age within 2 standard

deviations (SD) of chronological age, a height below the 3rd percentile for that age and gender in the same ethnic

group, or normal growth hormone response on provocative testing (Lee, 2006; Manmohan, 2005). Cohen 2008

∑ ISS is not associated with a definable physical functional impairment (e.g., limiting ability to drive), is not due to

growth hormone deficiency, and is not the result of accidental injury, disease, trauma, or treatment of a disease and is

not a congenital defect. Even though the child may be below the 3rd percentile on the growth chart, he/she may only

be on the low side of a scale. They are not considered as having a disease or disability by most standards.

∑ There are no well-designed trials to support that gains in adult height from growth hormone treatment significantly

improve functional status or long-term health outcomes for these children. Although GH therapy has been around for

decades, the safety and efficacy of long-term use of rhGH in children with ISS (non-GH deficient short stature) is

unknown at this time. There are some concerns that long-term administration of growth hormone therapy in

supraphysiological doses may lead to malignancy, slipped capital femoral epiphysis, carbohydrate metabolism and

irreversible joint disturbances years after treatment therapy (Holden, 2000; Kemp et al., 2005; Quigley et al., 2005)

∑ A Cochrane review by Bryant et al. (2009) evaluated GH therapy for idiopathic short stature in children and

adolescents. A total of 10 RCTs met eligibility criteria, which included being conducted in children who had normal

GH secretion, normal size for gestational age at birth, and no evidence of chronic organic disease. In addition, studies

needed to compare GH treatment with placebo or no treatment and provide GH treatment for at least 6 months. Three

studies were placebo- controlled, and the other 7 compared GH therapy with no treatment. Unlike the Deodati and

Cianfarani review previously described, studies were not required to report final adult height. Nine of 10 studies in the

Cochrane review were short term and reported intermediate outcomes. A pooled analysis of 3 studies reporting

growth velocity at 1 year found a statistically significantly greater growth velocity in treated than in untreated

children. The WMD was 2.84 (95% CI, 2.06 to 2.90). Five studies reported height SDSs, but there was heterogeneity

among studies and the findings were not pooled. These data suggest that GH has an effect on height in children with

idiopathic short stature in the short term but that evidence on GH’s effects on adult height is extremely limited.

of 30

∑ There is a lack of medical consensus within the pediatric endocrinology community, and the approved use of GH to N, et al 2012 increase height in ISS remains controversial.Maheshwari Although GH therapy initially causes growth

acceleration, it also accelerates pubertal development and advances bone age so that the duration of growth during

puberty is shortened.

∑ Molina Healthcare does not consider ISS a disease as coverage of treatment extends to disease or injury. This

basis of this policy is coverage of growth hormone therapy as a replacement for endogenous growth hormone in

patients with evidence of a deficiency. Therefore, growth hormone treatment is not authorized when used 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.

Small for Gestational Age (SGA)/Intrauterine Growth Retardation (IUGR)

∑ SGA with IUGR may or may not be associated with a growth hormone deficiency and occurs from a pathophysiologic

process in utero that adversely affects fetal growth.A SGA has been defined as a birth weight < 2500 grams (g) at

gestational age > 37 weeks or birth weight or length below the 3rd percentile for gestational age (AACE, 2003).A

∑ IUGR is diagnosed during pregnancy and is linked to an increase of 6 to 10 times in perinatal mortality (Creasy and

Resnik, 1994; Bernstein and Gabbe, 1996). Children born SGA but with no comorbidities are often not diagnosed

until they fail to achieve catch-up height by the age of 2 to 4 years or when they start school (Lee et al., 2003). Severe

short stature may be physically debilitating in untreated children (Munns et al., 2003), with children being at greater

risk of bullying at school and social isolation (Voss and Mulligan, 2000). Some children with short stature may also

have difficulties with emotionally immature behavior, anxiety, and poor school performance (Tanaka et al., 2002).

However, not all children who are shorter than their peers will experience problems. For example, the Royal College

of Obstetricians and Gynecologists states that the majority of children born SGA do not have any appreciable

morbidity or mortality (RCOG, 2002). However, others indicate that children born SGA who remain short may suffer

from alienation, low self-esteem, impaired social dynamics, behavioral problems, lower educational achievement and

professional success (Lee et al., 2003).

∑ Clinical trials show that growth hormone treatment results in a significant height gains compared to pre-treatment

predictions and final adult height that is closer to their mid-parental target height. • Wilton P et al. Growth hormone treatment induces a dose-dependent catch-up growth in short children born small for

gestational age: A summary of four clinical trials. Horm Res 1997;48(suppl1):67-71.

• Ranke MB et al. Growth hormone treatment of short children born small for gestational age or with Silver-Russell

syndrome: results from KIGS (Kabi International Growth Study), including the first report on final height. Acta Paediatr

1996;47(suppl):18-26.

• Coutant R et al. Response to growth hormone treatment and final height in children with short stature secondary to

intrauterine growth retardation. J Clin Endocrinol Metab 1998;83:1070-74

• Arends NJ et al. Growth Hormone treatment and its effect on bone mineral density, bone maturation and growth in short

children born small for gestational age: 3-year results of a randomized, controlled Growth Hormone trial. Clin

Endocrinol (Oxf). 2003;59:779-87.

• Hokken-Koelega AC et al. Final height data, body composition and glucose metabolism in growth hormone treated short

children born small for gestational age. Horm Res. 2003;60 (Suppl 3):113-4.

• Boonstra V et al. Puberty in growth hormone treated children born small for gestational age (SGA). J Clin Endocrinol

Metab. 2003 Dec;88:5753-8.

• Bryant J et al. Recombinant growth hormone in idiopathic short stature in children and adolescents (Cochrane Review).

In: The Cochrane Library, Issue 4, 2004. Chichester, UK: John Wiley & Sons, Ltd.

• Carel JC et al. Improvement in adult height after growth hormone treatment in adolescents with short stature born small

for gestational age: results of a randomized controlled study. J Clin Endocrinol Metab. 2003;88:1587-93.

∑ Many studies have noted an association between intrauterine growth restriction and long-term health risks, including

type 2 diabetes, the metabolic syndrome, and cardiovascular disease. However, the mechanisms underlying this

of 30

association have not been established. It is still unclear whether growth hormone treatment exacerbates or improves

these long-term risks. Reference: Rogol, Alan D. Growth hormone treatment for children born small for gestational age. In: UpToDate, Geffner,

Mitchell E (Ed), UpToDate, Waltham, MA. Literature review current through: Jan 2017. (Accessed on February 2017) 2013.)

∑ Hayes assigned a *D2 rating ‘for rhGH treatment for preterm infants with intrauterine growth retardation/restriction.

This Rating reflects the very limited negative evidence (1 study) available for this population.’

*D2: Insufficient evidence. There is insufficient published evidence to assess the safety and/or impact on health

outcomes or patient management.

Reference: A Hayes assessment addressing “Recombinant Human Growth Hormone Treatment in Children Under 2

Years of Age” (reviewed April 6, 2016) is available via a Medical Technology Directory.

∑ Similar to ISS, there is inadequate data to support gains in final adult height in children with SGA/IUGR with

growth hormone therapy make a substantial clinical difference in functional status or long-term outcomes.

Drug Safety Communication

∑ In December 2010, the FDA issued a Drug Safety Communication to inform the public that it was reviewing the

results from a study conducted in France, the Santé Adulte GH Enfant (SAGhE) study, and other available

information of a possible increased risk of death of children treated with rhGH (Drug Safety Commumication). The

study found that persons with certain kinds of short stature (idiopathic GHD, ISS, SGA), who were treated with rhGH

during childhood and who were followed over a long period of time, were at a small increased risk of death when

compared with individuals in the general population of France.

∑ In August 2011, the FDA issued another Drug Safety Communication updating the public about its ongoing safety

review of rhGH, or somatropin, and the reported potential risk and recommended that patients continue their rhGH

treatment as prescribed by their healthcare provider (Safety Review Update of Recombinant Human Growth

Hormone). The FDA identified a number of study design weaknesses that limit the interpretability of the study results.

Also, the FDA’s review of the medical literature, as well as reports from the Agency's Adverse Event Reporting

System, did not provide evidence suggestive of a link between rhGH and an increased risk of death. The FDA

determined that the evidence regarding rhGH and increased risk of death was inconclusive and that healthcare

professionals and patients should continue to prescribe and use rhGH according to the labeled recommendations.

*Pharmaceutical samples: The use of pharmaceutical samples (from the prescriber or manufacturer assistance program)

will not be considered when evaluating the medical condition, prior prescription history, or as continuation of therapy.

of 30

SUMMARY OF EVIDENCE/POSITION

CLINICAL PRACTICE GUIDELINES

American Association of Clinical Endocrinologists (AACE)

AACE issued updated guidelines (2009) on growth hormone (GH) use in growth hormone-deficient adults and

transition patients include the following: F

• GH should only be prescribed to patients with clinical features suggestive of adult GHD and biochemically

proven evidence of adult GHD.

• For childhood GH treatment of conditions other than GHD, such as Turner’s syndrome and idiopathic short

stature, there is no proven benefit to continuing GH treatment in adulthood; hence, there is no indication to

retest these patients when final height is achieved.

• On restarting GH therapy, the starting dose of GH in transition patients should be approximately 50% of the

dose between the pediatric doses required for growth and the adult dose.

• 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).

• Adult patients with evidence of structural hypothalamic/pituitary disease, surgery or irradiation to these areas,

or other pituitary hormone deficiencies should be considered for evaluation for acquired GHD (level of

evidence, high).

• The insulin tolerance test (ITT) or the growth hormone releasing hormone (GHRH)-arginine test is the

preferred test for establishing the diagnosis of GHD. However, in those with clearly established recent

hypothalamic causes of suspected GHD (e.g. irradiation) testing with GHRH-arginine may be misleading (level

of evidence, high).

• Because of 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).

• No data are available to suggest that GH has beneficial effects in treating aging and age-related conditions and

the enhancement of sporting performance; therefore, we do not recommend the prescription of GH to patients

for any reason other than the well-defined approved uses of the drug.

• There is no evidence that one GH product is more advantageous over the other, apart from differences in pen

devices, dose increments and decrements, and whether or not the product requires refrigeration; therefore, we

do not recommend the use of one commercial GH preparation over another.

GH STIMULATION (PROVOCATIVE) TESTS

GH stimulation (provocative) tests serve a significant role in the diagnosis of GHD. The most frequently used tests

include the insulin tolerance test (ITT); arginine; growth hormone releasing hormone (GHRH), with or without

arginine; levodopa (L-dopa); glucagon, with or without a beta blocker, such as propranolol; and clonidine.

Endocrinologists generally use a cutoff serum growth hormone concentration of more than 10 mcg/L in children and of

more than 3 mcg/L (some authorities use 5 mcg/L) in adults to define normal response on provocative tests. The

following are the most recent guidelines regarding stimulation testing (2009 and 2011) and not up-to-date with current

clinical practice.11,12,AACE 2009

• The Growth Hormone Research Society has recommended the ITT as the standard test for the diagnosis of

GHD in adults.

• In an ITT, insulin is administered intravenously to produce a nadir in the plasma glucose level of less than 40

mg/dL (2.2 mmol/L); serum (or blood) glucose and serum growth hormone levels are measured at times 0, 15,

30, 60, 90, and 120 minutes after administering insulin. An experienced staff under the direct supervision of a

of 30

physician should perform the test. GHD is diagnosed when the growth hormone level is less than 5 mcg/L.

• An ITT is contraindicated in patients with cardiovascular disease, cerebrovascular disease, or seizure disorders,

or in patients older than 65 years.

• The GHRH-arginine test was used by many centers as an alternative to the ITT. When the GHRH-arginine test

was employed, a GHD was diagnosed when the growth hormone level was < 4.1 mcg/L. However, manufacture

of Geref (GHRH) was indefinitely discontinued in 2008 and unavailability of recombinant GHRH in the United

States has created a need for a reliable alternative to this test. To establish the diagnosis of adult GHD in

patients with child-onset GHD, the ITT is the preferred test. The glucagon test, and rarely the ARG test, are

acceptable alternatives.

• In patients with a GHD of hypothalamic origin (as a result, for example, of irradiation), GHRH can give falsely

normal testing. In such patients, ITT or glucagon should be used. (AACE 2009)

• In patients where the ITT is not desirable and when recombinant GHRH is not available, the glucagon test is a

reliable alternative, but not the levodopa and clonidine tests. (AACE 2009)

• Some clinicians require that these criteria occur on 2 provocative tests because of the high frequency of false-

negative results for each single test.11

GROWTH HORMONE THERAPY IN ADULTS In adults, the syndrome of GHD characteristically manifests as: deficiencies in bone mineral density; reduced muscle

strength and exercise capacity; abnormal body composition with reduced lean body mass and increased body fat; higher

lipid concentration; impaired psychological well-being; anxiety; and increased social isolation. Literature shows that

over 90% of adults with GHD have overt pituitary disease, which is usually caused by a pituitary adenoma, or by

surgery or radiation therapy for a pituitary adenoma.

Adults with idiopathic, isolated childhood-onset GHD must be re-tested before long-term replacement therapy is

initiated as childhood GHD frequently does not persist into the adult years.

Decreased growth hormone in otherwise normal aging adults who are not congenitally GH deficient and who have no

evidence of organic pituitary disease is referred to as "age-related GH deficiency" (AR-GHD). Older adults tend to

have reduced GH secretion compared to younger adults and by age 70 it is estimated that GH levels are 20% of those

seen at age 30. A number of age-associated changes, including an increase in body fat, loss of muscle mass, decrease in

bone mineral density, and reduced cardiac performance, resemble those seen in younger adults with biochemically

verified GHD. The controversy lies in whether decreased GH levels in older adults are "normal" or a sign of a deficient

hormonal state. The administration of GH to AR-GHD individuals has resulted in improvements in some intermediate

outcomes such as bone mineral density and body composition but results are not consistent across trials and the

relationship of these intermediate outcomes to long term health outcomes has not been established. The limited results

do not suggest marked improvement with GH therapy and are insufficient to permit conclusions regarding the

effectiveness of GH in improving quality of life for adults with AR-GHD.

∑ In adults with GHD, there is evidence from RCTs that treatment leads to increases in lean body mass and decreases

in body fat.5 Meta-analyses of RCTs have shown evidence for increases in muscle strength and exercise capacity,

although this was not a robust finding across all studies.6,7 There is also evidence from meta-analyses that GH

therapy is associated with increased bone mineral density (BMD) in adults with GHD.8,9 For example, a 2014 meta-

analysis by Barake et al identified 9 placebo- controlled RCTs with at least 1-year follow-up on the effect of daily

GH therapy on BMD. Analysis of RCT data found a statistically significant increase in BMD of the lumbar spine

and femoral neck in patients with GHD who received GH therapy for more than 2 months. Change in BMD ranged

from 1% to 5% at the spine and 0.6% to 4% at the femoral neck. A limitation of the Barake analysis is that data

were not available on fracture rates, a clinically important outcome. The evidence on other outcomes such as

quality of life, lipid profiles, cardiovascular disease, and total mortality is not consistent and is insufficient to

determine whether these outcomes are improved with treatment.10-13

of 30

-

HUMAN IMMUNODEFICIENCY VIRUS (HIV) ASSOCIATED CACHEXIA Growth hormone for treatment of wasting or cachexia in individuals with acquired immunodeficiency syndrome

(AIDS) was FDA approved in 1996. This approval was based on evidence that growth hormone increased lean body

mass and decreased fat mass in individuals with AIDS, although no survival benefit was observed. This drug must be

used in conjunction with antiretroviral therapy. The recommended duration of treatment is 12 weeks. No significant

additional treatment benefit was observed in individuals receiving therapy beyond 12 weeks. There are no data

available from studies for individuals who start, stop and restart treatment.

The use of growth hormone has also been studied in small numbers of adults with other catabolic illnesses, including

those associated with respiratory failure, recovery from surgery, congestive cardiomyopathy, liver transplantation, and

renal failure. No consistent benefit has yet been demonstrated. Growth hormone has been given to individuals with

obesity, osteoporosis, muscular dystrophy, and infertility, but with no consistent benefit.

SHORT BOWEL SYNDROME (SBS)

Short bowel syndrome (SBS) is experienced by individuals who have had half or more of the small intestine removed

with resulting malnourishment because the remaining small intestine is unable to absorb enough water, vitamins, and

other nutrients from food. The FDA label for Zorbtive indicates growth hormone has been shown in human clinical

trials to enhance the transmucosal transport of water, electrolytes, and nutrients.

Recommendations for the use of recombinant human GH in adult SBS patients dependent on parenteral nutrition:

(Steiger E, et al.)

• Patients considered for GH treatment should be well nourished to maximize mucosal absorptive function and

diet and medications optimized before initiation of treatment and subsequent weaning of PN.

• Appropriate patients should have intestinal failure and be dependent on PN but must also be able to ingest an

adequate amount of enteral nutrients and fluids.

• Even if patients cannot be completely weaned, a reduction in PN use may improve quality of life and reduce

costs and risks associated with PN use.

• Patients with remnant colon are more likely to be weaned than those without, although treatment with GH has

been shown to be beneficial for patients without a colon also.

• There is currently insufficient evidence to determine the optimal timing of initiating GH treatment after the

onset of SBS.

Zorbtive received FDA approval based on the results of a randomized, controlled, phase III clinical trial in which

subjects dependent on intravenous parenteral nutrition who received Zorbtive (either with or without glutamine) over a

4-week period had significantly greater reductions in the weekly total volume of intravenous parenteral nutrition

required for nutritional support. However, the effects beyond 4 weeks were not evaluated nor were the treatment

location (inpatient vs. outpatient) identified. Several published studies have also demonstrated improved intestinal

absorption in short bowel syndrome subjects receiving parenteral nutrition (Scolapio, 1999; Wu, 2003). However,

studies have noted the effects of increased intestinal absorption are limited to the treatment period (Seguy, 2003;

Szkudlarek, 2000; Wu, 2003). Specialized clinics may offer intestinal rehabilitation for individuals with short bowel

syndrome; GH may be one component of this therapy.

of 30

DEFINITIONS

∑ Insulin-Like Growth Factor 1 (IGF-1): A hormone created mainly by the liver that mediates most of the effects of

growth hormone. IGF-1 blood tests may be used in the diagnosis of growth hormone deficiency.

∑ Insulin-Like Growth Factor Binding Protein (IGFBP-3): The transport protein for IGF-1 and IGF-2 in the circulation.

It modulates IGF activity and inhibits cell growth. Its levels increase in the presence of IGF-I, insulin and other

growth-stimulating factors such as growth hormone. IGFBP-3 blood tests may be used in the diagnosis of growth

hormone deficiency.

∑ Hypopituitarism: Pituitary gland produces a number of hormones, which are released into the blood to control other

glands in the body (thyroid, adrenal, ovary or testicles). If the pituitary is not producing one or more of these

hormones, the condition. If all the hormones produced by the anterior pituitary are decreased, the condition is called

panhypopituitarism.

∑ Panhypopituitarism: defined by at least 3 pituitary hormone deficiencies: Luteinizing Hormone (LH), Follicle

Stimulating Hormone (FSH), Thyroid Stimulating Hormone (TSH), Adrenocorticotropic Hormone (ACTH), prolactin

APPENDIX

APPENDIX 1: Growth Hormone (GH) Provocative Stimulation Test

Current published guidelines recommend that evaluation of adult GHD be based on clinical findings, medical history and

using the appropriate GH stimulation test for biochemical confirmation.

GH Stimulation Tests

• A provocative agent is used to stimulate the pituitary gland to secrete GH. All GH stimulation tests are based on the

concept that a pharmacological agent stimulates pituitary GH secretion, with peak GH levels detectable by timed

frequent serum sampling after administration of the stimulus.

• A stimulation test is needed to confirm the diagnosis of GHD in adults. Numerous tests are available; none perfectly

predict GHD.A

• The intent is to determine the maximum peak GH response from the provocative agent. This peak is the value used to

determine whether the response is considered normal or abnormal for the purpose of supporting the diagnosis of

GHD. Most experts suggest a peak value of less than 5 nanograms per milliliter after stimulation as an indication of

GHD. A

• Serum levels may be measured by radioimmunoassay (RIA) or immunoradiometric assay (IRMA). Baseline testing is

performed prior to administration of the provocative agent and frequent blood sampling is done thereafter. Sampling

occurs approximately 30, 60, 90, 120 and 180 minutes after provocative agent administration. Sampling defines the

“curve” of the response (going from a lower GH value prior to provocation to the highest, or peak, GH value after

provocation and then a drop from peak) and must provide sufficient information to determine a peak value.

• The insulin tolerance test (ITT) is currently considered the gold standard of the tests available and is preferred.A The

ITT is contraindicated in patients with a history of seizures or coronary artery disease.1 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.A 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.

of 30

-

Accepted GH cut points (µg/L) for GH stimulation tests used in the United States by

different consensus guidelines for diagnosis of adult GHD

GRS 2007 AACE 2009 Endocrine Society 2011

ITT < 3.0 ≤ 5.0 < 3.0 to 5.0

GHRH-arginine

- BMI < 25 kg/m2

- BMI 25-30 kg/m2

- BMI ≥ 30 kg/m2

< 11.0

< 8.0

< 4.0

≤ 11.0

≤ 8.0

≤ 4.0

< 11.0

< 8.0

< 4.0

Glucagon < 3.0 ≤ 3.0 < 3.0

Arginine No data described ≤ 0.4 No data described

Abbreviations: ITT, insulin tolerance test; GHRH, growth hormone releasing hormone; BMI, body mass index; AACE, American

Association of Clinical Endocrinologists; GRS, Growth Hormone Research Society.

Units: ng/mL = mcg/L

Reference: Yuen KCJ. Growth Hormone Stimulation Tests in Assessing Adult Growth Hormone Deficiency. [Updated 2016 Aug 1].

In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.

Available from: https://www.ncbi.nlm.nih.gov/books/NBK395585/

CODING INFORMATION: THE CODES LISTED IN THIS CLINICAL POLICY ARE FOR INFORMATIONAL PURPOSES ONLY. LISTING OF A

SERVICE OR DEVICE CODE IN THIS POLICY DOES NOT IMPLY THAT THE SERVICE DESCRIBED BY THIS CODE IS A COVERED OR NON-

COVERED. COVERAGE IS DETERMINED BY THE BENEFIT DOCUMENT. THIS LIST OF CODES MAY NOT BE ALL INCLUSIVE AND INCLUSION OR

EXCLUSION OF ANY CODES DOES NOT GUARANTEE COVERAGE. PROVIDERS SHOULD REFERENCE THE MOST UP-TO-DATE SOURCES OF

PROFESSIONAL CODING GUIDANCE PRIOR TO THE SUBMISSION OF CLAIMS FOR REIMBURSEMENT OF COVERED SERVICES.

CPT Description NA

HCPCS Description J2941 Injection, somatropin, 1 mg

S9558

Home injectable therapy; growth hormone, including administrative services, professional pharmacy

services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded

separately), per diem

REFERENCES

Package Insert, FDA, Drug Compendia�a. Genotropin (somatropin) [prescribing information]. New York, NY: Pharmacia & Upjohn; September 2016.

b. Humatrope (somatropin) [prescribing information]. Indianapolis, IN: Lilly USA LLC; July 2014.

c. Norditropin (somatropin) [prescribing information]. Plainsboro, NJ: Novo Nordisk; January 2015.

d. Nutropin® Nutropin® AQ prescribing information, Genentech, South San Francisco, CA. March 2014..

e. Omnitrope (somatropin) package insert. Princeton, NJ: Sandoz, Inc.; 2016 Dec.

f. Saizen (somatropin) [prescribing information]. Rockland, MA: Serono Inc; June 2014.

g. Serostim (somatropin) [prescribing information]. Rockland, MA: Serono Inc; April 2012.

h. Zorbtive (somatropin) [prescribing information]. Rockland, MA: Serono Inc; January 2012.

i. Drug Facts and Comparisons. Facts and Comparisons eAnswers [online]. Clinical Drug Information LLC, 2017.

Available from Wolters Kluwer Health, Inc. [via subscription only] Accessed February 2017.

j. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2017. URL:

http://www.clinicalpharmacology.com. [via subscription only] Accessed February 2017.

of 30

https://www.ncbi.nlm.nih.gov/books/NBK395585

k.� American Hospital Formulary Service (AHFS). Drug Information 2017. [STAT!Ref Web site]. 05/02/14. Available

at: http://online.statref.com. [via subscription only].

l.� Micromedex Healthcare Series. DrugDex. [Micromedex Web site]. Available at:

http://www.thomsonhc.com/micromedex2/librarian [via subscription only].

m.�Lexi-Drugs Compendium. Sebelipase alfa. [Lexicomp Online Web site via UpToDate subscription]. 2017. Available

at: https://www.uptodate.com/contents/sebelipase-alfa-drug-

information?source=search_result&search=kanuma&selectedTitle=1%7E4. Accessed February 2017.

n.� DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. 908510, Growth hormone

deficiency in children; [updated 2016 Feb 02, cited place cited date here]; [about 11 screens]. Available from

http://search.ebscohost.com/login.aspx?direct=true&db=dnh&AN=908510&site=dynamed-live&scope=site.

Registration and login required.

Clinical Trials, Definitions, Peer-Reviewed Publications

1.� CDC. 2005 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among

adolescents and adults. MMWR 2007; 56:634.

2.� Nemechek PM, Polsky B, and Gottlieb MS. Treatment guidelines for HIV-associated wasting. Mayo Clin Proc. 2000

Apr;75(4):386-94. Richmond, Erick J, et al. Diagnosis of growth hormone deficiency in children. UpToDate

https://www.uptodate.com/contents/diagnosis-of-growth-hormone-deficiency-in-children#H10

3.� Nieschlag E, Swerdloff R, Behre HM, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in

males: ISA, ISSAM, and EAU recommendations. J Androl. 2006 Mar-Apr;27(2):135-7.

4.� Polsky B, Kotler D, and Steinhart C. Treatment guidelines for HIV-associated wasting. HIV Clin Trials. 2004 Jan-

Feb;5(1):50-61.

5.� Beauregard C, Utz AL, Schaub AE, et al. Growth hormone decreases visceral fat and improves cardiovascular risk

markers in women with hypopituitarism: a randomized, placebo-controlled study. J Clin Endocrinol Metab. Jun

2008;93(6):2063-2071. PMID 18381581

6.� Widdowson WM, Gibney J. The effect of growth hormone replacement on exercise capacity in patients with GH

deficiency: a metaanalysis. J Clin Endocrinol Metab. Nov 2008;93(11):4413-4417. PMID 18697875

7.� Widdowson WM, Gibney J. The effect of growth hormone (GH) replacement on muscle strength in patients with GH-

deficiency: a meta-analysis. Clin Endocrinol (Oxf). Jun 2010;72(6):787-792. PMID 19769614

8.� Xue P, Wang Y, Yang J, et al. Effects of growth hormone replacement therapy on bone mineral density in growth

hormone deficient adults: a meta-analysis. Int J Endocrinol. 2013;2013:216107. PMID 23690770

9.� Barake M, Klibanski A, Tritos NA. Effects of recombinant human growth hormone therapy on bone mineral density

in adults with growth hormone deficiency: a meta-analysis. J Clin Endocrinol Metab. Mar 2014;99(3):852-860. PMID

24423364

10.�Hoffman AR, Kuntze JE, Baptista J, et al. Growth hormone (GH) replacement therapy in adult-onset gh deficiency:

effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial. J Clin

Endocrinol Metab. May 2004;89(5):2048-2056. PMID 15126520

11.�Bidlingmaier M, Strasburger CJ. What endocrinologists should know about growth hormone measurements.

Endocrinol Metab Clin North Am. Mar 2007;36(1):101-108.

12.�Biller BM, Samuels MH, Zagar A, et al. Sensitivity and specificity of six tests for the diagnosis of adult GH

deficiency. J Clin Endocrinol Metab. May 2002;87(5):2067-2079.

Idiopathic Short Stature (ISS)

• Cohen P, Rogol AD, Deal CL, et al; 2007 ISS Consensus Workshop participants. Consensus statement on the

diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research

Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology

Workshop. J Clin Endocrinol Metab. 2008;93(11):4210-4217.

• Maheshwari N, Uli NK, Narasimhan S, Cuttler L. Idiopathic short stature: decision making in growth hormone use.

Indian J Pediatr. 2012;79(2):238-243.

• Bryant J, Baxter L, Cave CB. Recombinant growth hormone for idiopathic short stature in children and adolescents.

Cochrane Database Syst Rev. 2009(1):CD004440.

of 30

https://www.uptodate.com/contents/diagnosis-of-growth-hormone-deficiency-in-children#H10

http://search.ebscohost.com/login.aspx?direct=true&db=dnh&AN=908510&site=dynamed-live&scope=site

https://www.uptodate.com/contents/sebelipase-alfa-drug

http://www.thomsonhc.com/micromedex2/librarian

http://online.statref.com

Transition of GHD patients from adolescence to adulthood

• Mauras N, Pescovitz OH, Allada V, Messig M, Wajnrajch, Lippe B. Limited efficacy of growth hormone (GH) during

transition of gh-deficient patients from adolescence to adulthood: a phase III multicenter, double-blind, randomized

two-year trial. J Clin Endocrinol Metab. 2005 Jul;90(7):3946-55.

Short Bowel Syndrome

• Seguy D, Vahedi K, Kapel N Souberbielle J, Messing B. Low-dose growth hormone in adult home parenteral

nutrition-dependent Short Bowel Syndrome patients: A positive study. Gastroenterology 2003;124:293-302.

• Steiger E, DiBaise JK, Messing B, Matarese LE, Blethen S. Indications and recommendations for the use of

recombinant human growth hormone in adult short bowel syndrome patients dependent on parenteral nutrition. J Clin

Gastrenterol 2006;40:S99-S106.

Government Agencies, Professional Societies, and Other Authoritative Publications

A.� American Association of Clinical Endocrinologists (AACE). Medical Guidelines for Clinical Practice for growth

hormone Use in Adult and Children--2003 Update. Endocrine Practice 2003;9:64-76.

B.� Raman S, Grimberg A, Waguespack SG, et al. Risk of neoplasia in pediatric patients receiving growth hormone

therapy--a report from the Pediatric Endocrine Society Drug and Therapeutics Committee. J Clin Endocrinol

Metab. Jun 2015;100(6):2192-2203. PMID 25839904

C.� Deal CL, Tony M, Hoybye C, et al. Growth Hormone Research Society workshop summary: consensus guidelines

for recombinant human growth hormone therapy in Prader-Willi syndrome. J Clin Endocrinol Metab. Jun

2013;98(6):E1072-1087. PMID 23543664

D.� Molitch ME, Clemmons DR, Malozowski S, et al. Evaluation and Treatment of Adult Growth Hormone Deficiency:

An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 2011, 96(6)1587-1609. Available at:

http://www.guideline.gov/content.aspx?id=34450. Accessed February 2017.

E.� National Institute for Health and Clinical Excellence (2010). Human growth hormone (somatropin) for growth

failure in children [TA188]. 2010. London: National Institute for Health and Clinical Excellence. Available at:

https://www.nice.org.uk/guidance/ta188. Accessed February 2017.

F.� American Association of Clinical Endocrinologists (2009) American Association of Clinical Endocrinologists

medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition

patients – 2009 update. Available at: http://www.aace.com/pub/pdf/guidelines/GrowthHormoneGuidelines.pdf

G.� Deal CL, Tony M, Hoybye C, et al. Growth Hormone Research Society workshop summary: consensus guidelines

for recombinant human growth hormone therapy in Prader-Willi syndrome. J Clin Endocrinol Metab. Jun

2013;98(6):E1072-1087. PMID 23543664

H.� National Kidney Foundation. Kidney Disease Outcomes Quality Initiative (2000) Clinical practice guidelines for

nutrition in chronic renal failure. National Kidney Foundation. Accessed February 2017.

I.� Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH)

deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society. J

Clin Endocrinol Metab 2000; 85:3990. Available at: http://www.ghresearchsociety.org/files/Eilat.pdf Accessed

February 2017.

J.� Yuen KC, Tritos NA, Samson SL, Hoffman AR, Katznelson L. A. American Association of Clinical

Endocrinologists (AACE) AND American College of Endocrinology Disease State Clinical Review: Update on

Growth Hormone Stimulation Testing and Proposed Revised Cut-Point for the Glucagon Stimulation Test in the

Diagnosis of ADULT GROWTH HORMONE DEFICIENCY. Endocr Pract. 2016 Oct;22(10):1235-1244.

of 30

http://www.ghresearchsociety.org/files/Eilat.pdf

https://www.aace.com/

https://www.nice.org.uk/guidance/ta188

http://www.guideline.gov/content.aspx?id=34450

subject: recombinant human growth hormone original effective … · 2019. 6. 8. · • human...

Documents