UTAH MEDICAID DUR REPORT
JUNE 2015
ANDROGENIC AGENTS: TESTOSTERONE
(UPDATE)
AVEED® (testosterone undecanoate) intramuscular injection CIII
Natesto (testosterone) nasal gel CIII
VOGELXO ™ (testosterone) topical gel CIII
Drug Regimen Review Center
Joanita Lake B.Pharm, MSc EBHC (Oxon), Clinical Pharmacist
Melissa Archer, PharmD, Clinical Pharmacist
Gary M. Oderda Pharm D, M.P.H, Professor
Bryan S. Larson, Pharm D, BCPS, Clinical Pharmacist
Devin H. Stock Pharm D student
University of Utah College of Pharmacy
Copyright © 2015 by University of Utah College of Pharmacy
Salt Lake City, Utah. All rights reserved
Contents
Introduction ... 3
Background ... 3
Methodology ... 5
Testosterone products ... 5
Indications ... 6
Diagnosing hypogonadism ... 7
Guidelines for Hypogonadism in Men ... 8
Guideline(s) for androgen therapy in women ... 13
Use in special populations ... 13
Clinical Efficacy ... 15
FDA update ... 15
Safety ... 16
Place in therapy / Factors to consider for potential criteria ... 18
Utah Medicaid Utilization Data ... 22
Conclusions ... 27
Potential clinical criteria ... 27
Appendix 1 – Drug information ... 28
Appendix 2 – Systematic Reviews ... 32
Appendix 3 – FDA data summary ... 55
Appendix 4 - Utilization Data ... 56
Introduction
In September 2011, the P&T Committee reviewed the Androgenic agents (fluoxymesterone,
methyltestosterone, oxandrolone, and testosterone), followed by a DUR Board review in
October/November 2012. Indications for androgens include male hypogonadism, delayed puberty, an
adjunct to promote weight gain or offset protein catabolism, and in the palliative treatment of
metastatic breast cancer. During the P&T meeting, “utilization data was also examined and questions
entertained about how the drug is monitored.”
3It was reported that blood draws are not routinely done
and that it is mostly monitored through symptoms. In the previous DUR review and report, the
guidelines were reviewed, and it is recommended to obtain serum testosterone concentrations for
diagnosis of hypogonadism and throughout testosterone therapy, to monitor for safety and efficacy.”
3,4According to the 2012 DUR review, utilization increased dramatically over the previous two years,
testosterone blood levels were not done as recommended, and several safety and monitoring issues
were identified including misuse, abuse, screening for conditions, monitoring of testosterone levels,
adverse effects, risk of virilization in children and safety in specific populations.
In November 2012 the DUR Board decided to accept the prior authorization criteria recommended by
the University of Utah. The topical/transdermal products’ criteria require that the patient be male, >18
years old, diagnosis codes for primary or secondary hypogonadism (ICD-9 257.2 or 253.4), and evidence
of low testosterone symptoms and signs (two morning total testosterone levels below the reference
range). The injectable testosterone products’ criteria require a valid diagnosis code for breast cancer
submitted by an oncologist for women.
The American Urological Association (AUA) states in their 2014 position statement that the “increased
awareness about hypogonadism has been stimulated by an increase in availability and diversity of
patient-acceptable forms of testosterone replacement options in recent years.”
5The purpose of this DUR review is to examine the appropriateness of testosterone use in the Utah
Medicaid population. That is when testosterone is used for approved indications and not being misused
or abused. This report contains updated information and includes information on the three new
products that have been approved recently; AVEED® (testosterone undecanoate) intramuscular
injection CIII, Natesto (testosterone) nasal gel CIII, and VOGELXO ™ (testosterone) topical gel CIII.
Background
Testosterone is known as the male sex hormone and synthetic variants of it are often referred to as
“anabolic steroids”.
6Endogenous testosterone is secreted in the testicles of males and the ovaries of
females and small amounts are also secreted by the adrenal glands. Endogenous androgens are needed
for normal growth, development and maintenance of male organs and characteristics such as deepening
of the voice, male hair distribution (beard, axillary, etc.), growth of the Adam’s apple, increased libido,
increased muscle strength and mass, and alterations in fat distribution.
7,8It causes the growth spurts in adolescents, but also the fusion of the epiphyseal growth center
responsible for the termination of linear growth. If exogenous androgens are used for long periods in
children, it may result in fusion of the epiphyseal growth centers and termination of the growth
process.
7The condition where the body does not produce enough testosterone is called male hypogonadism
which may be congenital or acquired (e.g. injury, infection or aging).
9Andropause (male menopause) is
the period when hormones naturally start declining (by about 1-2% yearly) usually during men’s late
forties or early fifties.
10According to the American Association of Clinical Endocrinologists as many as 30
percent of men over 75 have a testosterone level that's below normal.
9Endogenous testosterone levels are maintained through a hypothalamus pituitary testicles axis which
involves stimulating and inhibitory effects. The hypothalamus secretes gonadotrophin-releasing
hormone (GnRH) which controls the release of follicle-stimulating hormone (FSH) and luteinizing
hormone (LH) by the anterior pituitary. LH regulates testosterone production by the testicles (by Leydig
cells) and FSH stimulates spermatogenesis. When exogenous androgens are used, the elevated blood
levels inhibit production of pituitary luteinizing hormone (LH) which blocks production of endogenous
androgens
by Leydig cells.
7Figure 1. Hypothalamus pituitary testicles axis (excerpt)
8Primary hypogonadism refers to a problem with the testicles (low testosterone production & elevated
gonadotrophins). Causes include Klinefelter syndrome (chromosome abnormality), injury to the testes
(including radiation or chemotherapy) and undescended testes. Secondary hypogonadism indicates a
problem in the hypothalamus or the pituitary gland (failure to produce enough LH and FSH, low
testosterone). This can be caused by aging, obesity, drug use (prescription and recreational use),
tumors, trauma, or radiation. This condition can occur during fetal development, before puberty or
during adulthood (e.g. with aging) and the signs and symptoms will therefore depend on the person’s
physiological age. It is also possible to have a combination of primary and secondary hypogonadism for
example with aging. This may also be seen in patients with certain conditions such as cirrhosis or sickle
cell disease.
9,10Signs and symptoms of hypogonadism may include underdeveloped genitals/female genitals (fetal);
decreased development of muscle, impaired growth in beard/body hair and male organs, excessive
growth of arms and legs compared to trunk, gynecomastia (puberty), erectile dysfunction or decreased
sex drive, infertility, decrease in muscle mass, osteoporosis, hot flashes, and emotional and mental
effects such as fatigue or difficulty concentrating (adulthood).
9It has been estimated that 1% of the entire US population use androgens.
11A US survey found that
about 4 out of 5 users were recreational athletes and body builders.
12Pharmaceutical marketing on the potential benefits of testosterone may have attributed to the increase
in testosterone use. Commercials often use the term “low T” for low testosterone levels. People are
lured toward testosterone use for physical and psychological wants such as big muscles and improved
sexual function and/or mood.
13However, the FDA recently issued drug safety communication that they
have become aware that “testosterone is being used extensively in attempts to relieve symptoms in
men who have low testosterone for no apparent reason other than aging”, and that “the benefit and
safety of these medications 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”.
14On 01/31/2014, the FDA issued a Drug Safety Communication that they were investigating the risk of
cardiovascular events associated with testosterone products.
15The FDA announced on
03/03/2015 that
they are requiring labels to be revised to clarify the approved uses of these medications (“prescription
testosterone products are approved only for men who have low testosterone levels caused by certain
medical conditions”) and to include information about a possible increased risk of heart attacks and
strokes in patients taking testosterone.
14Methodology
A Cochrane Library literature search for systematic reviews was conducted. Medline (PubMed), Up to
Date, the Agency for Healthcare Research and Quality (AHRQ), relevant society websites, the FDA
website (including product labeled information), Micromedex and Lexicomp were searched for safety
information, systematic reviews, clinical trials, and guidelines. As per the hierarchy of evidence, high
quality systematic reviews and evidence based guidelines were searched first.
Testosterone products
Table 1 (Appendix 1) contains a summary of the products. Testosterone products include injectables
(enanthate, cypionate, or undecanoate), a buccal patch, the nonscrotal transdermal patch, implantable
pellets, transdermal gels/solutions, and the recently approved nasal gel (Natesto approved by FDA in
May 2014
16).
17The scrotal patch (Testoderm TTS) was marketed until 2002 and has been discontinued.
18Testosterone undecanoate (Aveed) was not approved in the United States at the time of the previous
report, but was approved by the FDA in March 2014.
19Vogelxo topical gel was approved in June 2014.
20Oral capsules/tablets (methyltestosterone) is not available in the US.
17Oral alkylated androgens are not
recommended due to rapid first-pass metabolism so that sufficient blood levels cannot be achieved.
They are also not recommended because of adverse effects including lipid changes and hepatic effects
such as hemorrhagic liver cysts, cholestasis, and hepatocellular adenoma.
4,21,22The FDA marketing status
information for testosterone propionate injections states “discontinued”.
23Indications
“Aveed (testosterone undecanoate) injection is an androgen indicated for testosterone replacement
therapy in adult males for conditions associated with a deficiency or absence of endogenous
testosterone:
o Primary hypogonadism (congenital or acquired)
o Hypogonadotropic hypogonadism (congenital or acquired)
Aveed should only be used in patients who require testosterone replacement therapy and in whom the
benefits of the product outweigh the serious risks of pulmonary oil microembolism and anaphylaxis.
Limitations of use:
• Safety and efficacy of Aveed in males less than 18 years old have not been established.”
24“Natesto is an androgen indicated for replacement therapy in males for conditions associated with a
deficiency or absence of endogenous testosterone:
•
Primary hypogonadism (congenital or acquired)
•
Hypogonadotropic hypogonadism (congenital or acquired)
Limitations of use:
•
Safety and efficacy of Natesto in males less than 18 years old have not been established.”
25“Vogelxo is an androgen indicated for testosterone replacement therapy in males for conditions
associated with a deficiency or absence of endogenous testosterone:
•
Primary hypogonadism (congenital or acquired).
•
Hypogonadotropic hypogonadism (congenital or acquired).
Limitations of Use:
•
Safety and efficacy of Vogelxo in males less than 18 years old have not been established
•
Topical testosterone products may have different doses, strengths, or application instructions
that may result in different systemic exposure.”
1Indications of different dosage forms† (adapted from information in Lexicomp
17):
Labelled indications Androgen replacement therapy in the treatment of delayed puberty Male hypogonadism (primary or hypogonadotropic) Inoperable metastatic female breast cancer
Injection Enanthate only ✓ Enanthate only
Pellet ✓ ✓ x Buccal system x ✓ x Intranasal gel x ✓ x Topical gel x ✓ x Topical solution x ✓ x Transdermal system x ✓ x
†Capsule (not available in US): Conditions associated with a deficiency or absence of endogenous testosterone.
Diagnosing hypogonadism
Hypogonadism was defined by the Endocrine Society’s Clinical Practice Guideline for Testosterone as “a
clinical syndrome that results from failure of the testis to produce physiological levels of testosterone
(androgen deficiency) and a normal number of spermatozoa due to disruption of one or more levels of
the hypothalamic-pituitary-gonadal (HPG) axis”.
27Diagnosis of testosterone deficiency is based on the patient’s history (e.g. injury), symptoms and signs
(physical examination) as well as morning serum testosterone levels.
27Measuring testosterone levels:
Testosterone levels vary throughout the day and the Endocrine Society
therefore recommend an initial morning total testosterone level and recommend repeating the total
testosterone measurement.
13,27Transient testosterone levels could be caused by acute illness,
medications and other factors and up to 30% of patients have a normal level upon repeat
measurement.
27The “normal” testosterone level varies for different people and at different ages. The
threshold for hypogonadism has not been established, but in general a level below 280-300ng/dL is
considered low (300-1,000 ng/dL is considered normal).
27The Endocrine Society advises against making a diagnosis during acute or subacute illness and the use of
questionnaires such as the “Aging Male Symptom Score”.
27Possible reversible causes of hypogonadism should be ruled out, such as environmental toxins,
medications, eating disorders, excessive exercise, and recreational drug use.
28Some examples of drugs
that may cause hypogonadism have been included in the table below.
Potential drug causes of hypogonadism
Spironolactone Chronic opiate use
Estrogen and progesterone Anabolic steroids
Glucocorticoid Marijuana
Ketoconazole (high dose use) Heroin
Guidelines for Hypogonadism in Men
North America
American Urological Association: AUA Position Statement on Testosterone Therapy (2014)5
Contradictory evidence: Cardiovascular risk in men with hypogonadism vs. beneficial influence on cardiovascular risk.
Concerned about the potential for misuse of testosterone for non-medical indications (i.e. body building or performance enhancement).
“Hypogonadism is defined as biochemically low testosterone levels in the setting of a cluster of symptoms which may include reduced sexual desire (libido) and activity, decreased spontaneous erections, decreased energy and depressed mood. Men with hypogonadism may also experience reduced muscle mass and strength and increased body fat. Hypogonadism may also contribute to reduced bone mineral density and anemia. Testosterone therapy is an appropriate treatment for hypogonadism after full discussion of potential adverse effects. Treatment requires follow-up and medical monitoring. Testosterone therapy in the absence of hypogonadism is not appropriate.”
“Management of hypogonadism should start with careful evaluation by a physician experienced in diagnosing hypogonadism. Many of the symptoms are non-specific and may be multifactorial in origin. Hence, symptoms may not be necessarily linked to hypogonadism alone. This fact needs to be considered in the overall evaluation. The diagnosis and management of testosterone deficiency should be made by a physician with training in the
condition and its treatments. The diagnosis should be made only after taking detailed medical history, physical examination, and obtaining appropriate blood tests. Testosterone therapy should not be offered to men with normal testosterone levels. Testosterone therapy is never a treatment for infertility.
The potential adverse effects of testosterone therapy should be discussed prior to treatment. These include acne, breast swelling or tenderness, increased red blood cell count, swelling of the feet or ankles, reduced testicular size and infertility. Current evidence does not provide any definitive answers regarding the risks of testosterone therapy on prostate cancer and cardiovascular disease, and patients should be so informed.
The optimal follow-up of men on testosterone therapy has not been defined, but should include measurement of testosterone level, PSA and hematocrit. Other patient-specific measures may be appropriate.
The AUA recognizes and encourages the need for increased educational awareness of the benefits and risks of testosterone therapy among both patients and health care providers.”5
American Urological Association: Prostate specific antigen best practice statement (2009)29,30
TRT USE/BENEFIT:
Testosterone is not indicated for the treatment of erectile dysfunction in men with normal serum testosterone concentrations
CONTRAINDICATIONS/SCREENING:
Age 40:
Evaluation of a prostate specific antigen (PSA) level and a digital rectal examination of the prostate PSA>0.6ng/dl should be monitored annually (less frequent otherwise)
American Geriatric Society (AGS): American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults / The American Geriatrics Society 2012 Beers Criteria Update Expert Panel.31
TRT USE/BENEFIT & CONTRAINDICATIONS/SCREENING:
The AGS guidelines recommend that testosterone and methyltestosterone be avoided in patients aged 65 and over (due to the potential for cardiac problems as well as its contraindication in men with prostate cancer) unless it is indicated for moderate to severe hypogonadism.
The Endocrine Society’s Clinical Practice Guideline: Testosterone Therapy in Adult Men With Androgen Deficiency Syndromes (2010)27
TESTOSTERONE LEVEL AND MONITORING:
Measurement of morning total testosterone level as initial diagnostic test and confirmation by repeating the measurement of morning total testosterone
Men in whom total testosterone is near the lower limit of normal or in whom sex hormone binding globulin (SHBG) abnormality is suspected => measure free or bioavailable testosterone level
The lower limit of the normal range for healthy young men should be used. This is 280-300ng/dL in some laboratories.
Aim for testosterone levels in the mid-normal range
Evaluating patient 3-6 months after treatment initiation and then annually to assess response to treatment, potential adverse effects and compliance
Monitoring testosterone levels 3-6 months after initiation of testosterone treatment
Refer to guidelines summary for monitoring of hematocrit, bone mineral density, PSA, and formulation-specific adverse effects
TRT USE/BENEFIT:
Androgen deficiency diagnosis: only in men with consistent symptoms and signs and unequivocally low serum testosterone levels.
Testosterone therapy for men with symptomatic androgen deficiency to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density.
Adjunctive therapy in HIV-infected men with low testosterone levels and weight loss
Men receiving high doses of glucocorticoids who have low testosterone levels
Against a general policy of testosterone treatment in older men. Should be an individualized basis and include explicit discussions of the uncertainty about the risks and benefits.
FORMULATIONS:
Chosen on the basis of the patient’s preference, consideration of pharmacokinetics, treatment burden, and cost.
CONTRAINDICATIONS/SCREENING:
Not in patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen greater than 4 ng/ml or greater than 3 ng/ml in men at high risk for prostate cancer such as African Americans or men with first-degree relatives with prostate cancer without further urological evaluation, hematocrit >50%, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms with International Prostate Symptom Score (IPSS) > 19, or uncontrolled or poorly controlled heart failure.
Against screening for androgen deficiency in the general population
RECOMMENDATIONS FOR INITIATION OF TESTOSTERONE THERAPY:
IM testosterone enanthate or cypionate 75-100mg weekly or 150-200mg every 2 weeks, one or two 5 mg patches applied to skin nightly, 1% testosterone gel 5-10g applied daily, buccal testosterone 30mg every 12 hours, implantable testosterone pellets every 3-6 months.
The American College of Physicians: Hormonal testing and pharmacologic treatment of erectile dysfunction: a clinical practice guideline from the American College of Physicians (2009)32
TESTOSTERONE LEVEL AND MONITORING:
No recommendations against or for routine use of hormonal blood tests
Decisions to measure hormone levels should be based on the basis of clinical presentation and physical findings that suggest hormonal abnormality
TRT USE/BENEFIT:
No recommendations against or for hormonal treatment (inconclusive evidence)
Erectile dysfunction: Phosphodiesterase-5 (PDE-5) inhibitor (if no contraindication)
Clinical benefit of PDE-5 inhibitors was demonstrated regardless of the cause (e.g. diabetes, depression, or prostate cancer)or baseline severity of ED
The American Society of Andrology (ASA) (2006)19 TESTOSTERONE LEVEL AND MONITORING:
Hypogonadal below 300 ng/dL measured in the morning
Periodic monitoring: 3 to 6 months after initiation of therapy and then yearly
Physical examination: At 3, 6, and 12 months and then annually - including digital rectal examination of the prostate, a prostate-related symptom, assessment, prostate-specific antigen (PSA) level, and hematocrit (alter or discontinue testosterone if > 52%).
TRT USE/BENEFIT:
TRT in aging men: when both clinical symptoms and signs suggestive of androgen deficiency and decreased testosterone levels are present.
TRT” may also be warranted in older men with markedly decreased testosterone levels regardless of symptoms, but signs of androgen deficiency should be present.”19
CONTRAINDICATIONS/SCREENING: Pretreatment screening in older men
1) Medical history:
a. Potential sleep apnea, congestive heart failure, symptoms consistent with lower urinary tract obstruction, and personal or family history of prostate or breast carcinoma.
b. Patients counseling: testosterone therapy will affect spermatogenesis and their fertility potential during treatment and for some time following cessation of therapy.
2) Physical examination, including a digital rectal examination of the prostate. 3) Laboratory tests, including hematocrit and PSA level.
Abnormal digital rectal examinations and/or consistently elevated PSA level: a urological evaluation including trans-rectal ultrasound and biopsy of the prostate should be performed prior to initiation of testosterone therapy.
AmericanAssociation of Clinical Endocrinologists:
Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hypogonadism in Adult Male Patients (2002)21
TESTOSTERONE LEVEL AND MONITORING:
TRT should maintain testosterone levels within the physiological range (280-800 ng/dL)
Testosterone dosing should follow recommended dosing from manufacturers and the FDA.
Monitoring and follow-up should be conducted every 3-4 months to assess response and side effects. TRT USE/BENEFIT:
Male patients with hypogonadism who is not interested in fertility or not able to achieve fertility
o Increased sexual interest and number of spontaneous erections
o Improved secondary sex characteristics (i.e. increased muscle mass, beard growth, growth of
pubic and axillary hair, and phallus growth)
Adolescent male patients with hypogonadotropic hypogonadism: Increased bone mineral density(pre-pubertal hypogonadotropic hypogonadism: diminished bone mass my only improve marginally)
Normalization of growth hormone in elderly men: No recommendations (research is needed to clarify the potential risks and benefits)
Delayed puberty (late teenage male patients):
o Short-term, low-dose testosterone therapy should be withdrawn to determine whether spontaneous
puberty is occurring.
Cardiovascular risk: effect (increases, decreases or no effect) remains uncertain
FORMULATIONS:
Oral testosterone not recommended (metabolized quickly and cannot achieve sufficient levels; adverse effects: lipid and hepatic)
International
European Association of Urology:
Guidelines on Male Hypogonadism (2015)
TRT USE/BENEFIT:
To restore physiologic testosterone levels in men with hypogonadism.
Indications for initiation of testosterone treatment included: delayed puberty, Klinefelter syndrome with hypogonadism, low testosterone accompanied by sexual dysfunction, low testosterone accompanied by low bone mass, men with consistent unresolved symptoms of hypogonadism after treatment for obesity and comorbidities, hypopituitarism, testicular dysgenesis with hypogonadism, or type 2 diabetes with hypogonadism.
FORMULATIONS:
The use of short acting agents over long acting agents is preferred in initial treatment of men with hypogonadism
RECOMMENDATIONS FOR INITIATION OF TESTOSTERONE THERAPY:
Initiation doses of therapies are similar to U.S. guidelines in frequency, however some dosage amounts and routes differ due to differences in approved drugs in the U.S. vs. Europe.
International Society for the Study of Aging Male (ISSAM), International Society of Andrology (ISA), European Association of Urology (EAU), European Academy of Andrology (EAA), and American Society of Andrology (ASA):
Investigation, treatment and monitoring of late-onset hypogonadism in males(2009)33
TESTOSTERONE LEVEL AND MONITORING:
Optimum serum testosterone level: Inadequate data. No evidence for or against the need to maintain the physiological circadian rhythm of serum testosterone levels. Mid-to-lower young adult male serum level seems appropriate.
Response to TRT should be assessed and TRT withdrawn if no improvement within a reasonable time-frame
o Libido, sexual function, muscle function, improved body fat: 3-6 months, but if the testosterone level is
borderline (not low), a short (i.e. 3 months) trial may be justified
o Bone mineral density: longer interval required TRT USE/BENEFIT:
Late-onset hypogonadism:
o Characterized by symptoms and a deficiency in serum testosterone levels o May result in significant loss in quality of life and affect multiple organ systems For men with hypogonadal testosterone values TRT:
o Improves body composition (i.e. decrease of fat mass and increase of lean body mass)
o Increases bone density; fracture data is not yet available (osteopenia, osteoporosis and fracture
prevalence rates are greater in hypogonadal younger and older men)
o Erectile dysfunction and/or diminished libido AND documented testosterone deficiency are candidates
Some evidence (but additional studies needed) for combining TRT with phosphodiesterase-5 (PDE-5) inhibitor in hypogonadal or borderline eugonadal men
Combination for hypogonadal men with ED should be considered when failing to either treatment alone. It is unclear whether men should be treated with testosterone, PDE-5 inhibitors, or the combination initially.
FORMULATIONS:
Selection of the preparation should be a joint decision of an informed patient and physician (pharmacokinetics, advantages and disadvantages)
Patients with late-onset hypogonadism: short-acting may be preferred because of the possible development of an adverse event that may require rapid discontinuation
The 17-α-alkylated preparations such as methyltestosterone are obsolete because of their potential liver toxicity and should no longer be prescribed
CONTRAINDICATIONS/SCREENING:
Men with prostate or breast cancer
Men with significant erythrocytosis, untreated obstructive sleep apnea, and untreated severe congestive heart failure should not be started on TRT without prior resolution of the comorbid condition
Age is not a contraindication. Risk versus benefits and individual assessments should be considered
Summary
Testosterone replacement therapy is medically necessary/appropriate in hypogonadism and evidence of
this is a total testosterone level below the limit used by the laboratory AND symptoms of malaise,
fatigue, lethargy, muscle loss, depression, or decreased libido.
19,27,34The threshold for hypogonadism
has not been established, but in general a level below 280-300ng/dL is considered low (300-1,000 ng/dL
is considered normal).
27Andropause without evidence of hypogonadism is not considered a legitimate medical diagnosis for use
of testosterone treatment in the United States because there is insufficient safety information to
support such use.
7,19Canada however covers the treatment of partial androgen deficiency of aging men
(PADAM) on their insurance program.
35According to the guidelines and prior authorization criteria used
by others, testosterone replacement is considered not medically necessary
if the only symptom is
Erectile Dysfunction or Impotence
.
34For use in men with sexual dysfunction and low serum testosterone,
underlying causes of erectile dysfunction (ED) should be evaluated and other established therapies for
ED should be considered before starting testosterone.
36Short-term testosterone use can be considered
in men with HIV who have low testosterone levels and weight loss to support weight gain and support
muscle strength.
36Men with low testosterone who take high dose glucocorticoids should be considered
for testosterone therapy to preserve bone mineral density and lean body mass.
36The guidelines include
conditions that are contraindications for androgen therapy and makes recommendations regarding
monitoring strategies (and schedule).
36Guideline(s) for androgen therapy in women
North America
The Endocrine Society’s Clinical Practice Guideline:
Androgen therapy in women: a reappraisal: an endocrine society clinical practice guideline.37
“PARTICIPANTS:
A Task Force appointed by the Endocrine Society, American Congress of Obestricians and Gynecologists (ACOG), American Society for Reproductive Medicine (ASRM), European Society of Endocrinology (ESE), and International Menopause Society (IMS) consisting of six experts, a methodologist, and a medical writer.
EVIDENCE:
The Task Force commissioned two systematic reviews of published data and considered several other existing meta-analyses and trials. The GRADE methodology was used; the strength of a recommendation is indicated by a number "1" (strong recommendation, we recommend) or "2" (weak recommendation, we suggest).
CONSENSUS PROCESS:
Multiple e-mail communications and conference calls determined consensus. Committees of the Endocrine Society, ASRM, ACOG, ESE, and IMS reviewed and commented on the drafts of the guidelines.
CONCLUSIONS:
We continue to recommend against making a diagnosis of androgen deficiency syndrome in healthy women because there is a lack of a well-defined syndrome, and data correlating androgen levels with specific signs or symptoms are unavailable. We recommend against the general use of T for the following indications: infertility; sexual dysfunction other than hypoactive sexual desire disorder; cognitive, cardiovascular, metabolic, or bone health; or general well-being. We recommend against the routine use of dehydroepiandrosterone due to limited data concerning its effectiveness and safety in normal women or those with adrenal insufficiency. We recommend against the routine prescription of T or dehydroepiandrosterone for the treatment of women with low androgen levels due to
hypopituitarism, adrenal insufficiency, surgical menopause, pharmacological glucocorticoid administration, or other conditions associated with low androgen levels because there are limited data supporting improvement in signs and symptoms with therapy and no long-term studies of risk. Evidence supports the short-term efficacy and safety of high physiological doses of T treatment of postmenopausal women with sexual dysfunction due to hypoactive sexual desire disorder. Importantly, endogenous T levels did not predict response to therapy. At present, physiological T preparations for use in women are not available in many countries including the United States, and long-term safety data are lacking. We recommend that any woman receiving T therapy be monitored for signs and symptoms of androgen excess. We outline areas for future research. Ongoing improvement in androgen assays will allow a redefinition of normal ranges across the lifespan; this may help to clarify the impact of varying concentrations of plasma androgens on the biology, physiology, and psychology in women and lead to indications for therapeutic interventions.”37
Use in special populations
Hypogonadism is a known problem in aging men, but it is also commonly seen in people with conditions
such as HIV and type 2 diabetes.
13,27,38,39The FDA information states that testosterone products are only
FDA-approved for use in men who lack or have low testosterone levels in conjunction with an associated
medical condition.
14a.
Women
Testosterone levels also decline in women as they age.
40This is associated with postmenopausal
symptoms like diminished libido.
41However, there is insufficient data to support the use of
testosterone for this indication and the Endocrine society advises against generalized use of
testosterone in women.
13,27Testosterone enanthate is indicated for use in inoperable metastatic female breast cancer, but the
product label states that “judgment concerning androgen therapy should be made by an oncologist
with expertise in this field”.
42Injectable testosterone (Delatestryl) “may be used secondarily in
women with advancing metastatic (skeletal) mammary cancer who are one to five years
postmenopausal.”
7In premenopausal women, it has been used for breast cancer in patients who
have benefited from oophorectomy (removal of ovaries) and who have a hormone-responsive
tumor.
7It is recommended to monitor for virilization (developing male sex characteristics) and to
discontinue if mild virilization is present to prevent irreversible symptoms.
17Symptoms of
virilization include excess facial and body hair, baldness, acne, deepening of the voice, increased
muscularity, and an increased sex drive.
43The other testosterone products are not indicated for use in women because they have not been
evaluated in women.
44-49Apart from the lack of data for this indication, safety is another important
concern. Testosterone may cause fetal harm.
b.
Males under 18 years
Only testosterone enanthate (Intramuscular solution), testosterone cypionate (Intramuscular
solution), and Testopel (pellet subcutaneous implantation) are indicated for use in adolescent
males (safety and efficacy have not been evaluated in males <12 years of age).
17,42Safety and
efficacy of all the other currently available testosterone products (including Natesto, Vogelxo, and
Aveed) in males under 18 have not been established.
17The DELATESTRYL
®(Testosterone Enanthate Injection, USP) product label states that it may be used
to stimulate puberty in carefully selected males with clearly delayed puberty. “These patients
usually have a familial pattern of delayed puberty that is not secondary to a pathological disorder;
puberty is expected to occur spontaneously at a relatively late date. Brief treatment with
conservative doses may occasionally be justified in these patients if they do not respond to
psychological support. The potential adverse effect on bone maturation should be discussed with
the patient and parents prior to androgen administration. An X-ray of the hand and wrist to
determine bone age should be obtained every six months to assess the effect of treatment on the
epiphyseal centers.”
42c.
Geriatric patients
The BEERS Criteria recommend avoiding use in older adults except in moderate to severe
hypogonadism.
17It is important to consider that there is a potential increased risk for
cardiovascular disease, and elderly patients may be at greater risk for fluid retention and
transaminase elevations.
17Also, testosterone use is contraindicated in men with prostate cancer
and the elderly may be at greater risk for prostatic hyperplasia and prostate cancer.
17d.
HIV disease
Hypogonadism often occurs in HIV-infected men.
48The Endocrine Society Guidelines recommend
that clinicians consider short-term testosterone therapy as adjunctive therapy in HIV patients with
low testosterone levels and weight loss. The aim is to improve weight maintenance and increase
lean body mass and muscle strength.
27e.
Glucocorticoid-Treated Men
Patients receiving long-term corticosteroid treatment may develop hypogonadism, which is
associated with bone loss.
48The Endocrine Society Guidelines recommend that clinicians offer
testosterone therapy to men receiving high doses of glucocorticoids who have low testosterone
levels to promote preservation of lean body mass and bone mineral density.
27f.
Other conditions
Conditions that may increase the risk of hypogonadism include type 2 diabetes, obesity, metabolic
syndrome and hypertension.
50The authors of a recent review of the metabolic effects of
testosterone replacement therapy (TRT) in hypogonadal type 2 diabetic men found that TRT can
improve glycemic control and decrease triglyceride levels, but that additional evidence is needed
(large, well-conducted RCTs).
51Clinical Efficacy
Appendix 2 contains abstracts of systematic reviews for FDA-approved and off-label indications.
FDA update
“Testosterone Products: Drug Safety Communication - FDA Cautions About Using Testosterone
Products for Low Testosterone Due to Aging; Requires Labeling Change to Inform of Possible Increased
Risk of Heart Attack And Stroke
UPDATE 04/15/2015. The
testosterone product labels ha
ve been updated. The revised labels clarify the
approved uses of these medications and include information about a possible increased risk of heart
attacks and strokes in patients taking testosterone.
[This information is an update to the FDA Drug Safety Communication: FDA Evaluating Risk of Stroke,
Heart Attack, and Death with FDA-Approved Testosterone Products issued on January 31, 2014.]
[Posted 03/03/2015]
AUDIENCE: Health Professional, Endocrinology, Urology, Family Practice, Patient
ISSUE: FDA is requiring that the manufacturers of all approved prescription testosterone products change
their labeling to clarify the approved uses of these medications. FDA is also requiring these
manufacturers to add information to the labeling about a possible increased risk of heart attacks and
strokes in patients taking testosterone. FDA cautions that prescription testosterone products are
approved only for men who have low testosterone levels caused by certain medical conditions. The
benefit and safety of these medications 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.
Based on the available evidence from studies and expert input from an
FDA Advisory Committee
meeting, FDA has concluded that there is a possible increased cardiovascular risk associated with
testosterone use. These studies included aging men treated with testosterone. Some studies reported an
increased risk of heart attack, stroke, or death associated with testosterone treatment, while others did
not. See the Data Summary section of the FDA Drug Safety Communication for additional details.
BACKGROUND: Testosterone is FDA-approved as replacement therapy only for men who have low
testosterone levels due to disorders of the testicles, pituitary gland, or brain that cause hypogonadism.
However, FDA has become aware that testosterone is being used extensively in attempts to relieve
symptoms in men who have low testosterone for no apparent reason other than aging. The benefits and
safety of this use have not been established.
RECOMMENDATION: Health care professionals should prescribe testosterone therapy only for men with
low testosterone levels caused by certain medical conditions and confirmed by laboratory tests. Health
care professionals should make patients aware of the possible increased cardiovascular risk when
deciding whether to start or continue a patient on testosterone therapy. Patients using testosterone
should seek medical attention immediately if symptoms of a heart attack or stroke are present, such as
chest pain, shortness of breath or trouble breathing, weakness in one part or one side of the body, or
slurred speech.”
14“
More Info for Health Care Professionals
•
Testosterone replacement therapy is approved for use only in men with primary or secondary
hypogonadism resulting from certain medical conditions.
•
The safety and efficacy of testosterone replacement therapy for age-related hypogonadism have
not been established.
•
Before initiating testosterone replacement therapy, ensure that the diagnosis of hypogonadism
has been confirmed with laboratory testing. Verify that serum testosterone concentrations have
been measured on at least two separate mornings and are consistently below the normal range.
Avoid measuring testosterone concentrations later in the day, when measurements can be low
even in men who do not have hypogonadism.
•
For each patient, weigh the potential increased risk of major adverse cardiovascular outcomes
and other risks of testosterone replacement therapy against the potential benefits of treating
hypogonadism.
•
Inform patients of the potential increased cardiovascular risk associated with testosterone
replacement therapy.
•
Encourage patients to read the patient
Medication Guide
or patient information leaflet they
receive with their testosterone prescriptions.
•
Report adverse events involving testosterone treatment to the FDA MedWatch program, using
the information in the “Contact FDA” box at the bottom of the page.”
14The FDA data summary has been included in appendix 3.
Safety
Appendix 2 contains abstracts of systematic reviews regarding safety of testosterone.
Safety issues are also discussed on page 21 (e) Screening. Monitoring requirements have been included
in the drug table in appendix 1.
Black boxed Warnings in the U.S.
17
Transdermal gel and transdermal solution testosterone preparations (including Vogelxo) carry a
black boxed warning for secondary exposure risks; inadvertent transfer of the medication to
other people especially children.
20,49,52“Reported signs and symptoms have included enlargement of the penis or clitoris, premature
development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone
age.”
49The Institute for Safe Medication Practices (ISMP) has reported that they have observed a signal for
adverse events resulting from the use of the topical testosterone products, Androgel and Testim. In the
first three quarters of 2009, there were 210 adverse effect reports associated with testosterone
products, 155 in women (70%) and 22 in children (10%), even though it is only licensed for use in men
with hypogonadism. “Despite an FDA warning, it appears accidental exposure and inappropriate
off-label use continues to cause injuries.”
53
Testosterone undecanoate (Aveed) carries a black boxed warning for serious pulmonary oil
microembolism reactions and patients must be observed for 30 minutes following injection in a
health care facility that can provide appropriate medical treatment in the case of a serious
reaction or anaphylaxis.
“WARNING: SECONDARY EXPOSURE TO TESTOSTERONE
•
Virilization has been reported in children who were secondarily
exposed to testosterone gel
•
Children should avoid contact with unwashed or unclothed
application sites in men using testosterone gel
•
Healthcare providers should advise patients to strictly adhere to
recommended instructions for use”
1“Pulmonary oil microembolism (testosterone undecanoate):
Serious pulmonary oil microembolism (POME) reactions, involving urge to cough,
dyspnea, throat tightening, chest pain, dizziness, and syncope; and episodes of
anaphylaxis, including life-threatening reactions, have been reported to occur
during or immediately after the administration of testosterone undecanoate
injection. These reactions can occur after any injection of testosterone
undecanoate during the course of therapy, including after the first dose.
Following each injection, observe patients in the health care setting for 30 minutes in
order to provide appropriate medical treatment in the event of serious POME
reactions or anaphylaxis.
Because of the risks of serious POME reactions and anaphylaxis, testosterone
undecanoate is available only through a restricted program under a risk
evaluation and mitigation strategy (REMS) called the Aveed REMS Program.”
2Serious hepatic adverse effects (Cholestatic jaundice syndrome, liver carcinoma, neoplasm of liver,
Peliosis hepatis) can result from prolonged use of high doses of orally active 17-alpha-alkyl
androgens (e.g., methyltestosterone) or long-term therapy with testosterone enanthate.
47,54Kidney
impairment and cardiovascular problems (including risks of stroke and heart attack) have been
associated with steroid misuse and abuse.
6In general, side effects of androgens include
6,7,19Males
Females
General
•
gynecomastia,
•
excessive frequency or
persistent penile
erections
•
shrinkage of testicles
•
reduced sperm count or
infertility
•
baldness
•
menstrual irregularities
•
clitoral enlargement
•
hoarseness
•
acne
•
more facial hair (hirsutism)
•
male-pattern baldness
•
GI including nausea &vomiting
•
alterations in liver function tests
•
cholestatic jaundice (changes in skin color)
•
pelosis hepatitis
•
fluid and electrolyte disturbances (e.g.
ankle swelling)
•
hematologic (suppression of clotting
factors, polycythemia, increased hematocrit
and hemoglobin)
•
exacerbations of sleep apnea
•
uropathy (related to BPH)
•
male pattern baldness.
Place in therapy / Factors to consider for potential criteria
Factors and limitations to consider:
a.
Misuse
Misuse of androgens is over-prescribing for conditions without sufficient evidence, or regular medical
prescribing of androgens without the patient having a valid clinical indication.
As mentioned earlier,
the FDA information states that testosterone products are only FDA-approved for use in men who
lack or have low testosterone levels in conjunction with an associated medical condition.
14Misuse
and off-label (non-FDA labeled) indications include
14,55o
Testosterone for sexual dysfunction without proven androgen deficiency
oAnti-aging uses
o
Cognitive function
o
Female-to-male transsexual - Gender identity disorder
oMale infertility
o
Osteoporosis, Male (to relieve osteoporosis-related bone pain)
oMuscle injury or repair
o
Weight gain (after weight loss following extensive surgery, chronic infections, severe
trauma, AIDS-associated wasting syndrome without hypogonadism or in patients who
without definite pathological reasons fail to gain or maintain weight)
Systematic reviews identified in the Cochrane Library (abstracts included in appendix 2) include
off-label/empirical/experiential uses of testosterone such as use in postmenopausal women
56,57, poor
responders undergoing in vitro fertilization (IVF)
58-60, contraception in men
61, schizophrenia
62,
depression
63, lower limb atherosclerosis
64,
treatment in HIV for weight loss without low
testosterone levels
14,65, treatment in HIV of decreased bone mineral density without low
testosterone levels
14,66, genital lichen sclerosis
67, for rehabilitation after hip fracture in older
people
68, its effect on bone health,
69use in COPD
70, and hypospadias surgery
71. Some of these
reviews state that it might be beneficial for these conditions in men with hypogonadism. Use in
these conditions when there is evidence of hypogonadism (as recommended by the guidelines) may
be appropriate.
There has been increasing advocacy of testosterone treatment for male sexual dysfunction and
whether treatment is necessary for andropause is a matter of opinion.
9,72It needs to be considered whether testosterone treatment is medically necessary vs. not medically
necessary for a particular condition, and whether sufficient evidence exists for such use.
Guidelines state that men with erectile dysfunction and/or diminished libido and documented
testosterone deficiency are candidates for TRT.
21Most plans do not cover testosterone for use in
sexual dysfunction and require prior authorization to ensure the drugs are only being used where
medically necessary.
73The authors of a recent review concluded that “testosterone
supplementation plays positive effects on male sexual function in hypogonadal subjects. The role of
TS is uncertain in men who are not clearly hypogonadal.”
74Sufficient evidence supports the use of TRT in males with diseases of the
hypothalamic-pituitary-gonadal axis and in boys who have not initiated puberty by the age of 14. However, TRT in aging
men or in men with chronic diseases is much more controversial.
30It is often difficult to distinguish
between real testosterone deficiency and other chronic conditions such as depression and fatigue or
sometimes just the desires of patients due to environmental pressure or psychological factors. Also,
there is not sufficient evidence regarding the risks associated with treatment in these patients.
30The
FDA cautions against use in men with “age-related hypogonadism” and the product labels state that
safety and efficacy have not been established for this use.
14The authors of a recent review
concluded that “testosterone may be used as monotherapy in dysthymia and minor depression or as
an augmentation therapy in major depression in middle-aged hypogonadal men.”
75The transdermal testosterone products have not been tested in women and the FDA said it believed
that in 2007 there were 27,000 prescriptions off label for women.
53The “Use in special populations”
section contains more information on use in specific populations (e.g. women) or conditions (e.g.
HIV).
b.
Abuse
Abuse is the illicit or inappropriate use of androgens without a prescription for non-clinical purposes
(i.e. body building or cosmetic reasons in sport, recreational and occupational settings). The most
common use of androgens in an abusive manner is for body building/ cosmetic enhancement for
males and athletic performance enhancement. Androgen abuse usually consists of taking 10-100
times the recommended doses of a product. Androgen “stacking” is common, this is using multiple
agents at a time. Abuse among athletes is typically in the elite athletic field, but has been seen in
collegiate and high school sports arenas.
55,76Testosterone-containing products are classified as controlled substances under the Anabolic
Steroids Control Act of 1990 and are Schedule III substances.
7,77Androgens and anabolic steroids have been
misused and abused
by athletes, bodybuilders, weight
lifters, and others such as security professionals (police, security guards and bouncers) to increase
muscle size and strength to enhance athletic performance or physique and to enhance
occupationally useful intimidating muscularity.
6,12,76This is also a problem in high school students.
According to the Centers for Disease Control (CDC), 3.6% of high school students had used these
steroids without a prescription at least once.
78Using androgens and anabolic steroids to increase muscle size and strength to enhance athletic
performance or physique is not considered to be the treatment of a disease or injury and therefore
not medically necessary.
6The FDA recommends against this practice.
4,79,80The illicit
self-administration of androgens for non-medical purposes pose health hazards to users and the
community through hazardous injection techniques
12(such as sharing of needles) and non-intended
exposure of other people.
Most policies exclude coverage of steroids for performance enhancement
and require Prior Authorization to prevent abuse.
73,81According to the National Institute on Drug Abuse (NIDA), anabolic steroids are reinforcing and can
lead to addiction. It does not cause the same rapid “high” as other drugs of abuse, but long-term use
may affect similar pathways and it has a huge impact on mood and behavior. It is also associated
with withdrawal symptoms such as depression, mood swings, restlessness, loss of appetite, steroid
cravings and just like with other drugs, people therefore continue using it. NIDA report that
evidence of addiction has been seen in studies where even animals self-administer steroids. Oral,
injectable and transdermal (cream or gel) anabolic steroids are abused and often used intermittently
so that it is used for periods of months or weeks followed by a break in steroid use after which it is
restarted again. This “cycling” prevents a decrease in the body’s response to the steroids and by
doing this users are also hoping to reduce unwanted side effects. However, steroid abuse could
cause serious and irreversible adverse effects and it involves a risk of HIV/AIDS or hepatitis. Another
problem reported by NIDA is “stacking” whereby users combine different types of steroids and may
include non-steroidal supplements in an attempt to maximize their effectiveness. Negative behavior
of steroid abusers include using other drugs (e.g. opioids), spending large amounts of time and
money on their addiction, violence associated with anger, impaired judgment, paranoid jealousy,
and impaired social relationships.
6Regulating this use through a PA (prior authorization) may be difficult as users may obtain drugs
from other sources. However, some users may be taking more than the prescribed dose or may use
drugs prescribed to others. Unusual utilization patterns may assist in identifying potential abuse.
c.
Adverse effects
d.
Duration of therapy
The duration of treatment depend on the diagnosis and patient’s response to treatment as well as
age, sex, and adverse effects.
7There are no large placebo controlled studies evaluating the
long-term effects of testosterone.
13Oral testosterone is not recommended for long-term treatment (liver problems, raised cholesterol
levels and increased risk of cardiac disease).
4,21,22e.
Screening and monitoring
Table 1 (Appendix 1) contains information on how doses should be titrated/adjusted based on
serum concentrations. In general, the product labels recommend monitoring the following
periodically: serum testosterone, PSA, hemoglobin, hematocrit, liver function test, calcium, and lipid
panels. Please refer to product label information for product specific information.
Some conditions could be exacerbated by testosterone and it is therefore important to screen
patients and to continue monitoring patients during treatment.
28•
Risk of benign prostatic hyperplasia and prostate cancer:
Patients must have a baseline PSA
test performed with a digital rectal exam.
•
History of breast cancer:
Avoid testosterone therapy (risk of recurrence).
•
Testosterone (excessive levels) could cause erythrocytosis:
Monitor complete blood count
(CBC) at baseline and periodically thereafter.
Androgens cause retention of sodium, chloride, water, potassium, phosphorus, nitrogen, and
decrease urinary excretion of calcium. This could cause edema with or without congestive heart
failure in patients with cardiac disease, renal or hepatic dysfunction. It may also alter cholesterol
concentrations and patients with a history of myocardial infarction or coronary artery disease would
be at increased risk of complications.
7Please refer to the FDA update section on the potential
increased cardiovascular risk.
Utah Medicaid Utilization Data
Utilization data have been included in appendix 4 (September 1
st2012 to April 30
th2015). It includes
products for which there was no utilization whereas the charts and tables presented in the section
below only includes the products which were filled. In November 2012 the DUR Board decided to accept
the prior authorization criteria recommended by the University of Utah. The number of prescriptions,
patients and cost decreased since then (shown below). There were also fewer unique patients in the
first year below compared to the previous report. The current claims data for the last period (only 8
months) indicates a potential slight increase in the number of patients compared to year 2.
9/1/2012 - 8/31/2013 9/1/2013 - 8/31/2014 9/1/2014 - 4/30/2015 RX PT COST RX PT COST RX PT COST 1645 418 $471,885.00 1226 295 $377,368.00 760 209 $210,329.00
Estimated for 12 months
1140 313 $315,494.00
From the previous report: 9/1/2011-8/31/2012: 457 unique patients
To date there has been no utilization of the three new products; Natesto (nasal gel), Vogelxo (gel), or
Aveed (injection).
A.
Oral
Utilization of the oral methyltestosterone capsules or tablets is very limited.
9/1/2012 - 8/31/2013 9/1/2013 - 8/31/2014 9/1/2014 - 4/30/2015
Rx Patients Rx Patients Rx Patients
Methyltestosterone ANDROID Capsule 5 3 2 1 1 1
Methyltestosterone METHITEST Tablet 1 1 0 0 0 0
B.
Injectable
9/1/2012 -
8/31/2013 9/1/2013 - 8/31/2014 9/1/2014 - 4/30/2015
Rx Patients Rx Patients Rx Patients
DEPO-TESTOST INJ Oil 96 34 95 26 31 11
TESTOST CYP INJ Oil 348 122 297 110 292 109
C.
Transdermal/topical
Please note that the third time-frame below is not a full year.
Utilization for these products were lower in year 2 compared to year 1 apart from Fortesta and
testosterone gel where utilization increased.
ANDRODERM ANDROGEL AXIRON FORTESTA TESTIM TESTOSTERONE 9/1/2012 - 8/31/2013 16 203 48 9 28 0 9/1/2013 - 8/31/2014 8 114 14 16 20 6 9/1/2014 - 4/30/2015 4 61 4 4 11 11 0 50 100 150 200 250
Number of patients
ANDRODERM ANDROGEL AXIRON FORTESTA TESTIM TESTOSTERONE 9/1/2012 - 8/31/2013 75 827 120 29 113 0 9/1/2013 - 8/31/2014 41 549 50 68 97 10 9/1/2014 - 4/30/2015 26 289 13 13 42 47 0 100 200 300 400 500 600 700 800 900
Number of prescriptions
Utilization in specific populations
A.
Pediatrics (<18 years old)
The previous review showed limited, but an increase in utilization in the pediatric population including
the topical/transdermal products which are not indicated for use in patients under 18 years old. No oral
or transdermal/topical products were filled for pediatric patients during this timeframe.
9/1/2012 -
8/31/2013 9/1/2013 - 8/31/2014 9/1/2014 - 4/30/2015
Rx Patients Rx Patients Rx Patients
Testosterone Cypionate DEPO-TESTOST INJ Oil 0 0 0 0 1 1
Testosterone Cypionate TESTOST CYP INJ Oil 3 3 6 2 2 2
Testosterone Enanthate TESTOST ENAN INJ Oil 0 0 1 1 1 1
B.
Geriatrics (>65 years old)
9/1/2012 -
8/31/2013 9/1/2013 - 8/31/2014 9/1/2014 - 4/30/2015
Rx Patients Rx Patients Rx Patients
Testosterone ANDROGEL Gel 9 4 3 2 5 1
Testosterone AXIRON Solution 3 1 1 1 0 0
Testosterone TESTIM Gel 3 1 0 0 0 0
Testosterone Cypionate DEPO-TESTOST INJ Oil 7 2 5 3 0 0
Testosterone Cypionate TESTOST CYP INJ Oil 10 4 12 7 8 3
Testosterone Enanthate TESTOST ENAN INJ Oil 2 1 2 1 0 0
The previous review showed broader use of these agents in the elderly (more products) which could
indicate a potential for increased use. During this timeframe utilization in the geriatric population
appears to be decreasing.
C.
Females
Utilization is limited in females. In the previous review there was some utilization of the
transdermal/topical products which are not indicated in women. The prior authorization appears to
have taken care of this issue (none in this time period).
Methyltestosterone ANDROID Capsule 4 2 2 1 1 1
Patients with diagnosis codes submitted within 60 days of filling a prescription for an oral,
transdermal, or injectable androgen product
The diagnosis codes that were defined for inclusion included the licensed indications as well as some
conditions that could have caused hypogonadism. Indications outside of guidelines were also included
to identify potential misuse. It is possible that diagnosis codes may have been submitted for the
approved conditions without evidence of low testosterone levels (as recommended by current
guidelines).
279/1/2014 - 4/30/2015
TESTOSTERONE THERAPY AND DIAGNOSIS * ICD All Dosing Routes Products Oral Transdermal Products Injection Products
Hypogonadism – Testicular Hypofunction 257.2 126 0 61 67
Hypogonadism – Hypogonadotropic, Pituitary 253.4 10 0 1 9
Other Hypopituitarism and Related Disorders 253.2, 253.7, 253.8 7 0 2 5
Malignant Neoplasm of Breast 174.0 - 175.9 0 0 0 0
Delayed Puberty 259 0 0 0 0
Congenital Anomalies of Genital Organs 752.5* - 752.9* 2 0 0 2
Lack of Expected Normal Physiological
Development in Childhood 783.4* 4 0 0 4 Klinefelter’s Syndrome 758.7 2 0 1 1 Cachexia 783.2 1 0 0 1 HIV Disease 042 11† 0 10 1 Anemia 284*, 285.21, 285.22 2 0 0 2 Trans-Sexualism 302.5* 0 0 0 0
Decreased Libido without Hypogonadism 799.81 and 257.2 or 253.4 NOT 3 0 2 2
Erectile Dysfunction without Hypogonadism 307.72 and 257.2 or 253.4 NOT 0 0 0 0
Psychosexual Dysfunction without Hypogonadism 302.7* and 257.2 or 253.4 NOT 0 0 0 0
TOTAL UNIQUE PATIENTS WITH DIAGNOSIS 142 0 65 80 TOTAL UNIQUE PATIENTS ON TESTOSTERONE THERAPY 209 1 91 121 Percentage of patients on testosterone therapy with a diagnosis code
submitted (as defined above) 68% 0% 71% 66%
Previous report (time period was for 12 months, but comparing %) 45% 25% 41% 44%
* Diagnosis date within 60 days before or 60 days after receiving testosterone product.