Download Non-preferred transdermal testosterone replacement products

Medication Policy Manual
Policy No: dru415
Topic: Non-preferred transdermal testosterone
replacement therapy products (Androderm®,
Axiron®, Fortesta®, Testim Gel®, Vogelxo™,
compounded transdermal testosterone products)
Date of Origin: August 14, 2015
Committee Approval Date: February 12, 2016
Next Review Date: April 2016
Effective Date: March 1, 2016
IMPORTANT REMINDER
This Medication Policy has been developed through consideration of medical necessity, generally
accepted standards of medical practice, and review of medical literature and government approval
status.
Benefit determinations should be based in all cases on the applicable contract language. To the
extent there are any conflicts between these guidelines and the contract language, the contract
language will control.
The purpose of medication policy is to provide a guide to coverage. Medication Policy is not
intended to dictate to providers how to practice medicine. Providers are expected to exercise their
medical judgment in providing the most appropriate care.
Description
Testosterone replacement therapy (TRT) products are used in the treatment of hypogonadism
(testosterone deficiency). The effectiveness of TRT is monitored by assessing serum testosterone
levels, as well as improvement in sexual function, mood, fatigue, bone mineral density, and wellbeing.
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Policy/Criteria
I.
Most contracts require prior authorization approval of non-preferred transdermal
testosterone replacement therapy (TRT) products, as listed in Appendix 1, prior to
coverage. Products listed in Appendix 1 may be considered medically necessary when
criteria A, B, and C below are met.
A.
Injectable testosterone cypionate or testosterone enanthate has been ineffective,
contraindicated, or not tolerated.
AND
B.
AndroGel has been ineffective, contraindicated, or not tolerated.
AND
C.
For coverage of initiation of transdermal testosterone replacement therapy, one
of the following two conditions is met:
1.
A diagnosis of primary (Testicular) hypogonadism or secondary
(Pituitary-Hypothalamic) hypogonadism caused by a specific medical
condition associated with a deficiency or absence of endogenous
testosterone including, but not limited to, those listed in Appendix 3,
when documentation of at least two low testosterone levels (less than 300
ng/dL for total testosterone, or less than 9 ng/dL for free testosterone)
drawn prior to 10 AM on two separate days is provided. This criterion is
not met by primary (Testicular) hypogonadism not caused by a specific
medical condition.
OR
2.
Gender dysphoria when all of the following criteria are met:
a.
Clinical records document that the patient has the capacity to
make fully informed decisions and consent for treatment.
AND
b.
A licensed behavioral health practitioner has diagnosed gender
dysphoria as defined by the DSM-5 criteria.
AND
c.
II.
At least one of the following criteria must be met for a period of 3
or more months prior to the initiation of hormone therapy
i.
Documentation of living as the desired gender; and/or
ii.
Psychotherapy with a licensed behavioral practitioner.
Administration, Quantity Limitations, and Authorization Period
A.
OmedaRx considers transdermal testosterone replacement therapy (TRT)
products to be self-administered medications.
B.
When prior authorization is approved, non-preferred transdermal TRT products
may be authorized as follows:
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TRT Products
testosterone topical solution (Axiron®); 30 mg
per actuation
testosterone topical gel 2% (Fortesta®); 10 mg
per actuation
testosterone topical gel 1% (Testim Gel® 50
mg/5 gm tubes)
testosterone topical gel 1% (Vogelxo™ 50 mg
/5 gm tube or packet)
testosterone topical gel 1% (Vogelxo™ pump
bottle); 12.5 mg per actuation
testosterone transdermal patch 2-4 mg/24
hours (Androderm®)
Quantity Level Limitation
(per Month, unless noted)
2 pump bottles (60
actuations/bottle)
2 pump bottles (120
actuations/bottle)
60 tubes
60 tubes or packets
4 pump bottles (60 actuations
per bottle)
2-mg/24 hour: 60 patches
4-mg/24 hour: 30 patches
C.
Quantities above the listed quantity limits are considered not medically
necessary.
D.
Authorization shall be reviewed in the timeframes defined below:
1.
Primary (Testicular) hypogonadism/secondary (PituitaryHypothalamic) hypogonadism: Authorization shall be reviewed after 6
months, and then at least annually to assure that both of the following
are met:
a.
The member has a specific medical condition associated with a
deficiency or absence of endogenous testosterone.
AND
The testosterone level does not exceed 700 ng/dL. (See Appendix 2,
Lab Monitoring Guidelines for TRT Products). For patients with a
testosterone level exceeding 700 ng/dL, ongoing coverage of
testosterone replacement therapy will be authorized only when
there is clinical documentation that the TRT dose will be adjusted
for a goal level of less than 700 ng/dL.
2.
Gender reassignment therapy: authorization may be reviewed at least
annually to confirm that current medical necessity criteria are met and
that the medication is effective.
Non-preferred transdermal TRT products, as listed in Appendix 1, are considered not
medically necessary for the following non-specific conditions:
A.
Primary (testicular) hypogonadism, not otherwise specified, including age-related
hypogonadism
b.
III.
B.
Testicular hypofunction, not otherwise specified
C.
Low libido in men without hypogonadism or women
D.
Use in women for infertility; sexual dysfunction, cognitive dysfunction,
cardiovascular dysfunction, metabolic dysfunction, bone health, or well-being.
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IV.
Non-preferred transdermal TRT products, as listed in Appendix 1, are considered
investigational for the following conditions:
A.
Weight gain in HIV-infected men
Position Statement
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Testosterone replacement therapy (TRT) is commonly used for treatment of
hypogonadism in men and as part of gender reassignment therapy. All products are
considered effective for increasing serum testosterone levels.
There is no evidence demonstrating that any one TRT product is safer or more effective
than less costly generic injectable options. There are no studies that directly compare
the clinical effects of different TRT products.
Hypogonadism may be caused either by failure of the testicles to produce testosterone
(primary), or by central defects in the hypothalamus or pituitary gland which lead to
secondary testicular failure. [1]
A diagnosis of hypogonadism is confirmed by measuring serum testosterone levels. [1]
Testosterone levels vary throughout the day and are highest in the morning. Normal
ranges for serum testosterone levels are usually established using morning blood
samples. [1]
Threshold testosterone levels below which adverse health symptoms occur are not
known. Likewise, optimal levels of testosterone at which TRT improves outcomes are not
known. For most symptoms in younger men, the average testosterone threshold
corresponds to the lower limit of the normal range. [1]
Because testosterone levels vary significantly due to body rhythms, episodic secretion,
and measurement variations, at least two levels should be obtained to confirm a
diagnosis of hypogonadism. [1]
Normal ranges for testosterone vary among laboratories and assays. The Endocrine
Society recommends that a lower limit for normal testosterone levels is 300 ng/dL for
total testosterone and 9.0 ng/dL for free testosterone. [1]
The Endocrine Society Clinical Guideline recommends evaluating patients 3 to 6 months
after initiating treatment to evaluate patients for side effects and to make sure total
testosterone levels are between 400 ng/dL and 700 ng/dL. [1]
Overall, TRT products are well tolerated.
In March 2015, the FDA released a drug safety communication clarifying that the benefits
and safety of TRT have not been established for the treatment of low testosterone levels
due to aging, even if a man’s symptoms seem related to low testosterone. The
communication also stated that there is a possible increased cardiovascular risk
associated with testosterone use. [2]
Since the initial drug safety communication, a limitation of use has been added to the
prescribing information for multiple testosterone replacement products. The updated
labeling states that safety and efficacy has not been established for age-related
hypogonadism (also referred to as late-onset hypogonadism).
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Age-related hypogonadism does not have a unique ICD-10 code, and therefore may be
billed under a more general code, such as testicular hypofunction or testicular
hypogonadism, not otherwise specified (NOS).
Primary hypogonadism NOS or testicular hypofunction NOS, including age-related
hypogonadism, is not a covered indication. For hypogonadism, testosterone
replacement may be considered medically necessary when low testosterone levels are
due to a documented medical cause, such as those listed in Appendix 3.
Low-dose testosterone therapy is a standard treatment option for the management of
delayed puberty in boys. Goals of therapy include the induction of secondary sexual
characteristics or growth and the mitigation of psychosocial difficulties. [3]
Testosterone enanthate may be used secondarily in women with advancing inoperable
metastatic breast cancer who are one to five years postmenopausal. Although several
testosterone products are FDA-approved for this indication, newer, targeted therapies
have largely replaced its use in this setting.[4]
While branded TRT products are comparable in price, testosterone cypionate and
testosterone enanthate offer members the best value and they are available at preferred
copayments.
Due to serious adverse events, such as pulmonary oil microembolism (POME) reactions
and anaphylaxis, that are not present with other products, the use of testosterone
undecanoate (Aveed) is considered not medically necessary. [5]
TRT should not be started in men who are at high risk for, or who have, prostate cancer.
While there is limited evidence that testosterone may have some benefit in for sexual
dysfunction in post-menopausal women there is insufficient evidence to establish the
safety and efficacy of testosterone in this indication. Additionally, the Endocrine Society
recommends against the general use of testosterone for the indications of infertility,
sexual dysfunction (other than hypoactive sexual desire disorder), cognitive health,
cardiovascular health, bone health, or general well-being in women due to limited
evidence of efficacy and safety. [6]
Small increases in lean body mass and body weight have been reported in HIV-infected
men with weight loss; however, it is uncertain whether the change was clinically
meaningful or whether it correlated with clinically relevant endpoints (increased muscle
strength and physical functioning, overall quality of life, or improved survival).
Due to the availability of many testosterone formulations, quantities above the quantity
limits listed criterion II.B. are considered not medically necessary. The quantity limits
listed correspond with the manufacturer’s prescribing information for each medication.
There is a lack of literature showing improved health outcomes and safety when the
maximum dosing is exceeded.
Clinical Efficacy
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No single testosterone replacement therapy (TRT) product has been proven in reliable
clinical studies to be more effective than another TRT product.
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All TRT products appear to be similarly effective based on pharmacokinetic data. There
is pharmacokinetic evidence that all topical testosterone products replete testosterone
levels in men with hypogonadism. [7]
The FDA accepts open-label, non-comparative trials of new TRT formulations as
sufficient to provide evidence of safety and efficacy. More clinically relevant endpoints
would be trials with validated disease outcome measures, showing meaningful
improvements in symptoms, such as low mood, sexual function, lean muscle mass, and
energy levels. [2]
There are no trials comparing any branded TRT formulation, therefore there is no
evidence that one branded TRT product is superior to another.
Long-term health outcomes of TRT, such as decreased incidence of fracture or
cardiovascular risk, are uncertain. [2,8]
Clinical guidelines recognize TRT as standard of care and effective for treatment of
hypogonadism in men. All products are considered effective in raising testosterone
levels. Choice of TRT product is based on pharmacokinetics, patient preference, and cost.
However, oral TRT is not recommended due to poor absorption and liver toxicity. [9,10]
The efficacy of TRT has not been established in men with age-related hypogonadism.
There are no valid, reliable, clinically relevant endpoints for studies assessing the effect
of testosterone on desire, frequency of sexual activity, erectile function, mood, energy,
overall quality of life, body composition (lean and fat body mass), and bone mineral
density in men with age-related hypogonadism.
Safety [7]
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Overall, testosterone topical replacement (TRT) is well tolerated. Common adverse
effects (≥ 3%) include acne, gynecomastia, oral irritation (buccal formulation), headache,
and enlarged prostate. The most commonly reported adverse event with topical TRT is
application site reactions. However, testosterone transdermal patch (Androderm®) is
associated with a significantly higher rate of skin reactions, including blistering of the
skin.
TRT may be associated with increased risk of adverse cardiovascular outcomes
(increased mortality, myocardial infarction, and stroke). Although findings in several
large observational studies and meta-analyses are inconsistent, the FDA’s Bone,
Reproductive and Urologic Drugs Advisory Committee concluded that there is a small
signal of risk. Based on conclusions reached in the advisory committee, the FDA
subsequently released a drug safety communication related to the CV risk and will
require labeling changes for all prescription testosterone products. [2,8-11]
TRT is contraindicated in men with known or suspected prostate cancer.
Testosterone undecanoate (Aveed) has boxed warnings for pulmonary oil microembolism
(POME) reactions and anaphylaxis. POME reactions may be life threatening; symptoms
include cough, dyspnea, throat tightening, chest pain, dizziness, and syncope. Patients
who received testosterone undecanoate (Aveed) must be monitored in a healthcare
setting for 30 minute post-dose in case of serious POME reactions or anaphylaxis.
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In 2009, the FDA issued a MedWatch safety alert of inadvertent (secondary)
testosterone exposure with topical testosterone gel (Testim and AndroGel), based on
eight case reports of exposure in children, age nine months to five years old. Signs of
virilization (development of male secondary sexual characteristics) and bone aging were
observed. Black box warnings are now required on all topical gel and solution
formulations of testosterone, as well as educational REMS programs to reduce secondary
exposure. [12]
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Appendix 1: Non-Preferred Transdermal Testosterone Replacement Therapy (TRT)
Products
testosterone topical solution 2% (Axiron®)
testosterone topical gel 2% (Fortesta®)
testosterone topical gel 1% (Testim Gel®)
testosterone topical gel 1% (Vogelxo™)
testosterone transdermal patch 2-4 mg/24 hours (Androderm®)
Appendix 2: Lab Monitoring Guidelines for TRT Products
Transdermal patches
Androderm®
Measure morning testosterone (following
application of the patch the previous evening)
Transdermal gels and solutions
AndroGel®, AndroGel Pump®, Testim®
Measure pre-dose morning testosterone level
Fortesta®
Measure testosterone 2 hours after application
Axiron®
Measure testosterone 2 to 8 hours after application
Vogelxo™
Measure testosterone 4 to 8 hours after application
Subcutaneous pellet
Testopel®
Measure pre-dose level and periodically during
therapy
Buccal tablet
Striant®
Measure pre-dose morning testosterone level
Nasal gel
Natesto™
Measure pre-dose level
Injectable
testosterone cypionate (generics)
Measure pre-dose level and periodically during
therapy
testosterone enanthate (generics)
Measure pre-dose level and periodically during
therapy
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Appendix 3: Causes of Primary (Testicular) and Secondary (Pituitary-Hypothalamic)
hypogonadism [13,14]
Primary (Testicular) Hypogonadism due to testicular dysfunction, including but not
limited to, the following conditions: a
Bilateral Torsion
Cryptorchidism
Disorders of androgen biosynthesis
Klinefelter’s syndrome or other chromosomal abnormalities
Myotonic dystrophy
Orchitis
Toxic damage from chemotherapy, alcohol, or heavy metals
Trauma to the testicles
Vanishing testis syndrome
Varicocele
Secondary (Pituitary-Hypothalamic) hypogonadism due to pituitary-hypothalamic
dysfunction, including but not limited to, the following conditions:
Congenital GnRH deficiency
Hyperprolactinemia
Idiopathic gonadotropic or luteinizing hormone-releasing hormone deficiency
Kallman Syndrome
Pituitary-hypothalamic dysfunction (not otherwise specified)
Pituitary-hypothalamic injury from tumors, trauma, or radiation
a
Primary (Testicular) Hypogonadism (not otherwise specified, including age-related) and
testicular hypofunction (not otherwise specified, including age-related) are not covered
indications.
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Cross References
Testosterone Replacement Therapies, BlueCross BlueShield Association Medical Policy, 5.01.23,
Issue 12:2014
Transgender Services, Medical Policy. Medicine, Policy No. 153.
Testosterone cypionate, testosterone enanthate, Medication Policy Manual, Policy No. dru395
Preferred transdermal testosterone replacement therapy products (AndroGel®, AndroGel
Pump®), Medication Policy Manual, Policy No. dru411
Non-preferred non-transdermal testosterone replacement therapy products, Medication Policy
Manual, Policy No. dru297
References
1.
Bhasin, S, Cunningham, GR, Hayes, FJ, et al. Testosterone therapy in men with androgen
deficiency syndromes: an Endocrine Society clinical practice guideline. The Journal of
clinical endocrinology and metabolism. 2010;95:2536-59. PMID: 20525905
2.
U.S. Food and Drug Administration. Summary Minutes of the Joint Meeting of the Bone,
Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk
Management Advisory Committee. [cited 11/7/2014]; Available from:
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drug
s/ReproductiveHealthDrugsAdvisoryCommittee/UCM418144.pdf.
3.
Palmert, MR, Dunkel, L. Clinical practice. Delayed puberty. The New England journal of
medicine. 2012 Feb 2;366(5):443-53. PMID: 22296078
4.
Ellis, M, Naughton, MJ, Ma, CX. Treatment approach to metastatic hormone receptorpositive breast cancer: Endocrine therapy. In: UpToDate, Basow, DS (Ed). UpToDate,
Waltham, MA, 2015.
5.
Aveed [package insert]. Malvern, PA: Endo Pharmaceuticals; September 2014
6.
Wierman, ME, Arlt, W, Basson, R, et al. Androgen therapy in women: a reappraisal: an
Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and
metabolism. 2014 Oct;99(10):3489-510. PMID: 25279570
7.
Micromedex® Healthcare Series [internet database]. Greenwood Village, Colo: Thomson
Reuters (Healthcare) Inc. Updated periodically.
8.
U.S. Food and Drug Administration. FDA Briefing Information for the September 17,
2014 Joint Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee
and the Drug Safety and Risk Management Advisory Committee Meeting. [cited
11/7/2014]; Available from:
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drug
s/ReproductiveHealthDrugsAdvisoryCommittee/UCM412536.pdf.
9.
Vigen, R, O'Donnell, CI, Baron, AE, et al. Association of testosterone therapy with
mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA :
the journal of the American Medical Association. 2013;310:1829-36. PMID: 24193080
© 2016 OmedaRx. All rights reserved.
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10.
Xu, L, Freeman, G, Cowling, BJ, Schooling, CM. Testosterone therapy and
cardiovascular events among men: a systematic review and meta-analysis of placebocontrolled randomized trials. BMC Med. 2013;11:108. PMID: 23597181
11.
Finkle, WD, Greenland, S, Ridgeway, GK, et al. Increased risk of non-fatal myocardial
infarction following testosterone therapy prescription in men. PLoS One. 2014;9:e85805.
PMID: 24489673
12.
MedWatch. FDA news release: Testosterone Gel Safety Concerns Prompt FDA to
Require Label Changes, Medication Guide. 7May2009. [cited 2/16/2011]; Available
from:
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm149580.htm.
13.
Snyder, PJ. Causes of secondary hypogonadism in males. In: UpToDate, Martin, K.A.
(Ed). UpToDate, Waltham, MA, 2015.
14.
Snyder, PJ. Causes of primary hypogonadism in males. In: UpToDate, Martin, K.A. (Ed).
UpToDate, Waltham, MA, 2015.
Revision
Date
Revision Summary
2/12/2016
• Removed generic testosterone 1% gel from step therapy
• Clarified that primary (testicular) hypogonadism and testicular
hypofunction not otherwise specified (NOS), including age-related are
considered not medically necessary
• Clarified that Appendix 3 is not an exhaustive list of potential
causes of primary (testicular) and secondary (pituitaryhypothalamic) hypogonadism.
• Updated not medically necessary uses
12/11/2015
• Rearranged policy criteria
• Clarified that the cause of hypogonadism must be caused by a
condition listed in appendix 3
• Updated appendix 3 with additional causes of hypogonadism
• Allowed for reauthorization if testosterone levels exceed 700 ng/ml.
Reauthorization requires a documented plan to address the high
level or adjust the dose.
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