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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

(2)

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

(3)

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.”

3

It 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.”

3,4

According 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.”

5

The 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”.

6

Endogenous 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.

7,8

It 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.

7

(4)

The 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).

9

Andropause (male menopause) is

the period when hormones naturally start declining (by about 1-2% yearly) usually during men’s late

forties or early fifties.

10

According to the American Association of Clinical Endocrinologists as many as 30

percent of men over 75 have a testosterone level that's below normal.

9

Endogenous 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.

7

Figure 1. Hypothalamus pituitary testicles axis (excerpt)

8

Primary 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.

9,10

Signs 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

(5)

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).

9

It has been estimated that 1% of the entire US population use androgens.

11

A US survey found that

about 4 out of 5 users were recreational athletes and body builders.

12

Pharmaceutical 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.

13

However, 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”.

14

On 01/31/2014, the FDA issued a Drug Safety Communication that they were investigating the risk of

cardiovascular events associated with testosterone products.

15

The 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.

14

Methodology

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

).

17

The scrotal patch (Testoderm TTS) was marketed until 2002 and has been discontinued.

18

Testosterone 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.

19

Vogelxo topical gel was approved in June 2014.

20

Oral capsules/tablets (methyltestosterone) is not available in the US.

17

Oral 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.

4,21,22

The FDA marketing status

information for testosterone propionate injections states “discontinued”.

23

(6)

Indications

“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.”

1

Indications 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.

(7)

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”.

27

Diagnosis 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.

27

Measuring 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.

13,27

Transient 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.

27

The “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).

27

The Endocrine Society advises against making a diagnosis during acute or subacute illness and the use of

questionnaires such as the “Aging Male Symptom Score”.

27

Possible reversible causes of hypogonadism should be ruled out, such as environmental toxins,

medications, eating disorders, excessive exercise, and recreational drug use.

28

Some 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

(8)

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.

(9)

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

(10)

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):

(11)

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

(12)

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.

19,27,34

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).

27

Andropause 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.

7,19

Canada however covers the treatment of partial androgen deficiency of aging men

(PADAM) on their insurance program.

35

According 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

.

34

For 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.

36

Short-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.

36

Men with low testosterone who take high dose glucocorticoids should be considered

for testosterone therapy to preserve bone mineral density and lean body mass.

36

The guidelines include

conditions that are contraindications for androgen therapy and makes recommendations regarding

monitoring strategies (and schedule).

36

(13)

Guideline(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.

13,27,38,39

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.

14

(14)

a.

Women

Testosterone levels also decline in women as they age.

40

This is associated with postmenopausal

symptoms like diminished libido.

41

However, 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.

13,27

Testosterone 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”.

42

Injectable testosterone (Delatestryl) “may be used secondarily in

women with advancing metastatic (skeletal) mammary cancer who are one to five years

postmenopausal.”

7

In 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.

7

It is recommended to monitor for virilization (developing male sex characteristics) and to

discontinue if mild virilization is present to prevent irreversible symptoms.

17

Symptoms of

virilization include excess facial and body hair, baldness, acne, deepening of the voice, increased

muscularity, and an increased sex drive.

43

The other testosterone products are not indicated for use in women because they have not been

evaluated in women.

44-49

Apart 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).

17,42

Safety and

efficacy of all the other currently available testosterone products (including Natesto, Vogelxo, and

Aveed) in males under 18 have not been established.

17

The 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.”

42

c.

Geriatric patients

The BEERS Criteria recommend avoiding use in older adults except in moderate to severe

hypogonadism.

17

It 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.

17

Also, testosterone use is contraindicated in men with prostate cancer

and the elderly may be at greater risk for prostatic hyperplasia and prostate cancer.

17

(15)

d.

HIV disease

Hypogonadism often occurs in HIV-infected men.

48

The 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.

27

e.

Glucocorticoid-Treated Men

Patients receiving long-term corticosteroid treatment may develop hypogonadism, which is

associated with bone loss.

48

The 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.

27

f.

Other conditions

Conditions that may increase the risk of hypogonadism include type 2 diabetes, obesity, metabolic

syndrome and hypertension.

50

The 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).

51

Clinical 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.

(16)

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.”

14

The 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.

(17)

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.”

49

The 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.”

2

(18)

Serious 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.

47,54

Kidney

impairment and cardiovascular problems (including risks of stroke and heart attack) have been

associated with steroid misuse and abuse.

6

In general, side effects of androgens include

6,7,19

Males

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.

14

Misuse

and off-label (non-FDA labeled) indications include

14,55

o

Testosterone for sexual dysfunction without proven androgen deficiency

o

Anti-aging uses

o

Cognitive function

o

Female-to-male transsexual - Gender identity disorder

o

Male infertility

o

Osteoporosis, Male (to relieve osteoporosis-related bone pain)

o

Muscle 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)

(19)

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,

69

use 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.

9,72

It 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.

21

Most 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.

73

The 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.”

74

Sufficient 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.

30

It 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.

30

The

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.

14

The 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.”

75

The 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.

53

The “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

(20)

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.

55,76

Testosterone-containing products are classified as controlled substances under the Anabolic

Steroids Control Act of 1990 and are Schedule III substances.

7,77

Androgens 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.

6,12,76

This 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.

78

Using 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.

6

The FDA recommends against this practice.

4,79,80

The 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.

73,81

According 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.

6

Regulating 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

(21)

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.

7

There are no large placebo controlled studies evaluating the

long-term effects of testosterone.

13

Oral testosterone is not recommended for long-term treatment (liver problems, raised cholesterol

levels and increased risk of cardiac disease).

4,21,22

e.

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.

7

Please refer to the FDA update section on the potential

increased cardiovascular risk.

(22)

Utah Medicaid Utilization Data

Utilization data have been included in appendix 4 (September 1

st

2012 to April 30

th

2015). 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

(23)

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

(24)

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

(25)

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).

27

9/1/2014 - 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.

† 9 patients have diagnoses for HIV disease and TESTICULAR HYPOFUNC NEC (ICD 257.2.), but 2 patients

(both using transdermal products) did not have a diagnosis code for hypogonadism.

During the last review it was decided to require diagnosis code submission for these products so that

utilization could be monitored. The percentage has improved but diagnosis codes (as defined above)

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