111 TRT Environmental Scan Final Dec 01

Testosterone Replacement Therapy
Environmental Scan and Local/Historical Context
December 1, 2014
30 Bond Street, Toronto ON, M5B 1W8 www.odprn.ca info@odprn.ca

2
Executive Summary
Part A: Pharmacy Benefit Programs in Ontario, across Canada and internationally
In Canada, testosterone is available as a long-acting injectable (testosterone cypionate and testosterone
enanthate), oral product (testosterone undecanoate) or topical product [testosterone transdermal
patch (Androderm), testosterone 1% topical gel (Testim), testosterone 1% gel foil packet and pump
(Androgel) and testosterone 2% axillary topical solution (Axiron)]. The long-acting injectable
testosterone cypionate and oral testosterone are available as generic products. The cost of a one-
month supply for the oral generic product is $17-51, for the injectable products $29-51 and for the
topical products $60-200.
In Ontario, commercially available testosterone products (including oral, long-acting injectable,

Androgel, Testim and Androderm) are listed as “limited use” products. Restriction criteria limit the use
of these testosterone products for male patients with confirmed serum testosterone levels associated
with documented and symptomatic hypothalamic, pituitary or testicular disease, or in HIV-infected
patients. Across Canada, special authorization is required for selected topical products in 5 jurisdictions;
five jurisdictions do not provide coverage for these products. Although restriction criteria vary among
the public drug plans, most state that the testosterone products are indicated for treatment of
congenital and acquired primary or secondary hypogonadism in males.
Part B: Guidelines for the management of patients with hypogonadism

Five consensus recommendations and/or guidelines were reviewed for the management of men with
hypogonadism: Endocrine Society (2010), European Association of Urology (2012), British Society for
Sexual Medicine (2010), International Society of Andrology/International Society for the Study of the
Aging Male, European Association of Urology/European Academy of Andrology/American Society of
Andrology (2009), Canadian panel (2010). There are no formal Canadian guidelines available for the
management of hypogonadism.
All guidelines suggest that choice of testosterone formulation should be based on numerous factors
including patient’s preference, treatment burden and cost, and should be made as a joint decision
between patient and physician. Although four of the five guidelines/consensus recommendations
suggest that diagnosis of hypogonadism should be based on consistent signs and symptoms as well as
low serum testosterone levels, there is no consensus regarding the number of signs/symptoms that
must be present before making a diagnosis, nor is there consensus regarding the definition of a low
serum testosterone level.
Part C: Impact of different drug reimbursement schemes for testosterone replacement products
Despite these agents, in particular the topical products, being restricted through the use of prior
authorization in both Canada and international jurisdictions, there is a paucity of literature assessing
these reimbursement schemes for adherence or usage patterns. One study showed that a restriction
policy (using Limited Use codes) in Ontario resulted in a temporary decrease in testosterone prescribing;
Ontario Drug Policy Research Network

3
however, testosterone use rose over 450% in the six years after implementation of the restriction policy
suggesting that such a policy has minimal long-term effect testosterone use.
Part D: Rapid Review of Selected Topics

Choice of treatment for testosterone replacement therapies: In Canada, testosterone is available as an
oral formulation, as an intramuscular injectable agent and in various topical preparations including gels,
patch and topical axillary solution. Selection of a product is based on the patient’s preference,
pharmacokinetics of the testosterone formulation, treatment burden, cost and safety profile.
Adherence to testosterone replacement therapies: Information on adherence and/or persistence with

testosterone replacement therapy has been inconsistent, with some studies showing poor adherence
(i.e., 15% by 12 months) and other showing high adherence patterns (e.g., 91% after 12 months). In one
study, TRT was used in a cyclic fashion (i.e., patients used TRT for a few months, stopped treatment for
2-3 months and then restarted TRT with the same dose and medication.)
Testosterone levels: Controversy still exists regarding reference ranges for normal levels of
testosterone. Most guidelines suggest that total testosterone level above 12 nmol/L does not require
replacement; patients with serum levels below 8nmol/L will usually benefit from treatment. As well, it
is recommended that testosterone levels be measured prior to commencement of treatment.

4
Table of Contents
List of Exhibits ............................................................................................................................................... 6

Acknowledgments......................................................................................................................................... 7
Introduction .................................................................................................................................................. 8
Part A: Pharmacy Benefit Programs in Ontario, across Canada and internationally ................................. 10
Availability and Costs of Testosterone Replacement Therapy (TRT) in Canada ..................................... 10
Common Drug Review ............................................................................................................................ 12
TRT product listing in Ontario ................................................................................................................. 12
Public Plan Listings in Canada ................................................................................................................. 13
Restriction Criteria .............................................................................................................................. 14
Selected International Jurisdictions ........................................................................................................ 16
Part B: Guidelines for the management of men with hypogonadism ....................................................... 21
Part C: Impact of different drug reimbursement schemes for testosterone replacement therapies ....... 23
Methods .................................................................................................................................................. 23
Results ..................................................................................................................................................... 23
Part D: Rapid Review of Selected Topics.................................................................................................... 24
Choice of Treatment for Testosterone Replacement Therapy ............................................................... 24
Adherence to Testosterone Products ..................................................................................................... 25
Testosterone Levels ................................................................................................................................ 26
Health Canada and Food and Drug Administration (FDA) Alerts and Warnings .................................... 27
Discussion.................................................................................................................................................... 27
Part A: Pharmacy Benefit Programs in Ontario, across Canada and internationally ............................. 27
Availability in Canada .......................................................................................................................... 27
Public Plan Listing in Ontario .............................................................................................................. 28
Public Plan Listing in Canada ............................................................................................................... 28
Selected International Jurisdictions .................................................................................................... 28
Part B: Guidelines for the management of patients with hypogonadism ............................................. 28
Part C: Impact of different drug reimbursement schemes for testosterone replacement therapy....... 29

5
Part D: Rapid Reviews of Selected Topics .............................................................................................. 29

Health Equity............................................................................................................................................... 29
Conclusion ................................................................................................................................................... 29
Reference List.............................................................................................................................................. 31
Appendix 1: Restriction Criteria for Testosterone Products in Canada ..................................................... 35
Appendix 2: Webpages for Provincial Drug Formularies ........................................................................... 37
Appendix 3: Interview Questions ............................................................................................................... 38
Appendix 4: Tiered cost-sharing options ................................................................................................... 39

6
List of Exhibits
Exhibit 1: Testosterone replacement therapy available in Canada ........................................................... 11

Exhibit 2: Public plan listings in Canada for testosterone products .......................................................... 14
Exhibit 3: Summary of Provincial Criteria for Testosterone Products ....................................................... 14
Exhibit 4: Summary of interviews with representative from public drug program ................................... 15
Exhibit 5: Listing of testosterone products for select plans in the United States* .................................... 17
Exhibit 6: Testosterone Replacement Therapies (Australia)...................................................................... 19
Exhibit 7: TRT products (Scotland) ............................................................................................................. 20
Exhibit 8: Comparison of guidelines for management of men with hypogonadism ................................. 21
Exhibit 9: Choice of Treatment for Testosterone Replacement Therapy .................................................. 25

7
Acknowledgments
This review was funded by grants from the Ontario Ministry of Health and Long-Term Care (MOHLTC)
Health System Research Fund and Drug Innovation Fund. The opinions, results and conclusions reported
in this paper are those of the authors and are independent from the funding sources. No
endorsement by ICES, CIHI, or the Ontario MOHLTC is intended or should be inferred.
A special thank you to all of the provincial and territorial representatives in Canada from the respective
Ministries of Health as well as the representative from the Non-Insured Health Benefits for First Nations
and Inuit (NIHB) who participated in the telephone survey.

8
Introduction
Testosterone replacement therapy (TRT) has been available since the 1950’s in Canada for the
treatment of hypogonadism. Hypogonadism results from testicular failure (e.g., Klinefelter syndrome,
testicular tumors)(referred to as primary hypogonadism), or is due to hypothalamic-pituitary
dysfunction (e.g., hyperprolactinemia, Kallmann syndrome)(referred to as secondary hypogonadism), or
both (e.g., late-onset hypogonadism).1-3 Medications can also result in hypogonadism, in particular
glucocorticoids in supraphysiological doses and opioid analgesics .3 Testosterone level increases until
the age of 17 years, when it stabilizes until the ages of 35-40 years; thereafter, levels decline at 1.2-2%
per year. Approximately 20% of men over the age of 60 years and about 50% of men older than 80
years have serum testosterone levels that are subnormal compared with younger men.1
Clinical symptoms vary with age of onset, duration and severity of the deficiency. In infants and
pubertal males, hypogonadism is often recognized due to an anatomic abnormality (e.g., failure of
testicular descent) or delayed or absent testicular growth or puberty. In late-onset hypogonadism,
symptoms such as decreased muscle mass, loss of libido and impotence, and poor concentration and
decreased energy may be mistaken for signs of aging.1
Although the use of TRT for the treatment of primary and secondary hypogonadism (“classical
hypogonadism”) is considered standard of care, controversy still exists regarding treatment of aging
men with testosterone.4 Different terms have been used to describe hypogonadism in the aging male
including androgen deficiency syndrome, andropause, age-related androgen deficiency, male
menopause, late-onset hypogonadism, androgen deficiency in the aging male (ADAM).5 Male
hypogonadism may increase the risk for cardiovascular disease, type 2 diabetes mellitus, metabolic
syndrome and Alzheimer’s disease.1;2
Primary hypogonadism is uncommon. Klinefelter syndrome, the most frequent form of primary
hypogonadism, affects approximately 0.2% (about 1 in 600 live births) of the male population.3
Testicular tumors occur in about 12 per 100,000 males; approximately 25% of patients have
testosterone deficiency after treatment.2 Forms of secondary hypogonadism include Kallmann
syndrome (prevalence 1 in 10,000), Prader-Willi syndrome (prevalence 1 in 10,000), congenital adrenal
hypoplasia with hypogonadotropic hypogonadism (prevalence 1 in 12,500 individuals),
hyperprolactinemia (caused by prolactin-secreting pituitary adenomas or drug-induced), non-
functioning pituitary adenomas and post-pituitary surgery.2 The prevalence of unequivocal
hypogonadism (testosterone less than 6 nmol/L) is reported as 6.3% in a survey conducted in the UK.6
The prevalence of late-onset hypogonadism is not well defined, and has varied from 2 to 40%7-9,
depending on various factors including the population studied and the definition of hypogonadism. In
one study, the overall prevalence of late-onset hypogonadism was 2.1%. For men aged 40 to 49 years of
age, the prevalence was 0.1%, and increased to 5.1% for those 70 to 79 years of age.8 Prevalence is
higher among those with specific comorbidities, including HIV, diabetes mellitus and obesity.3
The diagnosis of late-onset hypogonadism is not consistent among the various guidelines or consensus
recommendations. In the aging male, there is on average a 1-2% decline of total testosterone per year

9
with a more rapid decline in free testosterone levels.10 The authors of one study suggest requirement
of the presence of at least three sexual symptoms with a total testosterone level of less than 11 nmol/L
and a free testosterone level of less than 220 pmol/L.8 Guidelines from the European Association of
Urology2 and the Endocrine Society11 recommend a diagnosis of hypogonadism based on persistent
signs and symptoms and consistently low testosterone levels, measured on more than one occasion. It
should be noted that not all men with low testosterone levels are symptomatic.7;9 For example, in one
study, presence of one or more symptoms occurred in 66% of patients with testosterone levels less than
300 ng/dL (<10.1 nmol/L).7 Another study showed that 37-47% of subjects with total testosterone levels
less than 200 ng/dL (<6.9 nmol/L) failed to have three or more symptoms.9
Testosterone replacement therapy is used in men with a confirmed diagnosis of hypogonadism. TRT is
used to establish and maintain secondary sexual characteristics, sexual function, body composition and
quality of life.3 The target testosterone concentration is individualized, but the goal is to achieve levels
in the mid-normal range. Various testosterone products and formulations are available in Canada. All
testosterone products, regardless of formulation, are federally designated controlled substances. Under
Ontario’s Narcotics Safety and Awareness Act 2010, the Ministry of Health Long-Term Care requires the
collection and disclosure of personal health information to monitor prescribing, dispensing and to
ensure the appropriate use of testosterone and other controlled substances.12 Intramuscular
testosterone esters (testosterone enanthate and cypionate) are long-acting preparations that are
administered every 2-3 weeks, with peak concentrations occurring shortly after injection and gradual
decline after 7-15 days. 1 Oral testosterone (testosterone undecanoate) requires multiple, high daily
doses due to low bioavailability.1 There are four topical/transdermal testosterone products available in
Canada that are applied once daily: testosterone transdermal patch (Androderm), testosterone 1%
topical gel (Testim), testosterone 1% gel foil packet (Androgel) and testosterone 2% topical solution
(Axiron).
The objectives of this report are:
• Part A: To summarize coverage of testosterone replacement therapy through public drug programs
in Ontario and across Canada, as well as in select international jurisdictions
• Part B:To summarize the guidelines for management of patients with hypogonadism
• Part C:To review the evidence relating to the impact of different drug reimbursement schemes for
testosterone replacement therapy (e.g. cost sharing options) on patient access and/or utilization
and costs
• Part D: To provide rapid reviews on selected topics, including choice of treatment for testosterone
replacement therapy and adherence to testosterone therapy

10
Part A: Pharmacy Benefit Programs in Ontario, across Canada and

internationally
Availability and Costs of Testosterone Replacement Therapy (TRT) in Canada
In Canada, testosterone is available as a long-acting injectable, oral product or topical product. There
are two long-acting testosterone injectable products: testosterone cypionate and testosterone
enanthate. Only one product is available as an oral product: testosterone undecanoate. Four topical
products are commercially available: testosterone transdermal patch (Androderm), testosterone 1%
topical gel (Testim), testosterone 1% gel foil packet (Androgel) and testosterone 2% topical solution
(Axiron). The long-acting injectable products (testosterone cypionate and testosterone enanthate) and
the oral testosterone (testosterone undecanoate) are available as generic products. Exhibit 1 outlines
the dosage forms and costs (based on wholesale costs) for TRT products.

Exhibit 1: Testosterone replacement therapy available in Canada
Drug Name Brand name Manufacturer Availability DIN # Recommended dose Monthly Date available
cost*
Oral
†
Testosterone Andriol Merck 40mg capsule 00782327 Maintenance: 40- 28.2-84.60 Dec 1992
undecanoate 120mg/day (divided
doses)
†
PMS- PMS 40mg capsule 02322498 Maintenance: 40- 16.92-50.76 Oct 2009
Testosterone 120mg/day (divided
doses)
Long-acting injectable
†
Testosterone Depo- Pfizer 100mg/mL 00030783 200 mg every 2 weeks 28.59 Dec 1953
cypionate Testosterone (x10mL)
Testosterone Sandoz 100mg/mL 02246063 200 mg every 2 weeks 23.58 Aug 2002
Cypionate
Injection USP
†
Testosterone Delatestryl Valeant 200mg/mL (x5mL) 00029246 100-400 mg every 4 50.57 Dec 1955
enanthate weeks
Topical
†
Testosterone Androderm Watson 12.2mg/patch 02239653 2.5-7.5mg/day (usual 62.79-188.35 Dec 2000
(2.5mg/day) 02245972 dose 5mg/day)
24.3mg/patch
(5mg/day)
†
Testosterone Androgel Abbott 2.5g/packet (1%) 02245346 5-10g/day 66.90-118.30 May 2002
5g/packet (1%) 02249499
1.25g/actuation 02382369 Sep 2004
(pump)
††
Testosterone Axiron Eli Lilly 30mg/actuation 02382369 60mg once daily 141.35 May 2013
(metered dose
pump-60 doses)
†
Testosterone Testim Auxilium 1% 5g tubes (unit 02280248 5-10g daily 108.09-216.18 April 2007
dose) x 30
*Based on recommended dosages in product monographs
†
Based on costs obtained from the Ontario Drug Benefit Formulary (Accessed: May 23, 2014)
††
Based on costs obtained from McKesson (Accessed: May 23, 2014)
Summary
• Testosterone is available as an oral formulation, long-acting injectable and topical products.
• The monthly cost ranges from $23/month (for generic long-acting testosterone cypionate) to
$216/month (for highest dose of Testim).
12
Common Drug Review

The Common Drug Review (CDR) is a single process for reviewing new drugs and providing listing
recommendations to participating publicly funded federal, provincial and territorial drug benefit plans in
Canada; it was established in September 2003. None of the testosterone products (including the
recently introduce topical products) underwent review through CDR.
TRT product listing in Ontario

Limited Use (LU)
Limited use (LU) drugs are drugs that have been deemed to have value in certain circumstances,
although they may not be appropriate for general listing in the Formulary. Testosterone products
(namely: Androgel, Testim, Androderm, Depo-Testosterone, Delatestryl and testosterone undecanoate
capsules) are available as Limited Use products in Ontario since 2005. Prior to that date, they were
available as general benefit on the ODB formulary.
The Limited Use criteria are as follows:

Code 397: For male patients with confirmed low morning serum testosterone levels associated
with documented, symptomatic hypothalamic, pituitary or testicular disease, or in HIV-infected
patients.
Note: Older males with nonspecific symptoms of fatigue, malaise, depression who have a low
normal random testosterone level do not satisfy these criteria.
LU Authorization Period: 1 year.
Committee to Evaluate Drugs:

The Committee to Evaluate Drugs (CED) is the Ministry of Health and Long-term care’s independent
expert advisory committee on drug-related issues. In 2003-04, the CED reviewed and recommended
Limited Use listing for oral testosterone, injectable testosterone, Androderm (12.2mg) and Androgel foil
packets (but not the pump). Subsequently Testim was added as a limited use product in 2009.
The manufacturer of Axiron submitted a request for review to CED in 2013; the review is currently
deferred until completion of the Drug Class Review.
Summary
• In Ontario, oral testosterone and injectable testosterone were available as general benefits until
2005. Thereafter, all listed testosterone products were available through the Limited Use
program.

13
Public Plan Listings in Canada

Part 1: Listing Status
In order to determine the listing of testosterone products across Canada, the relevant webpages of the
provincial drug formularies were searched (See Appendix 2). In Canada, all public plans provide
coverage for at least one testosterone product for eligible patients. These products are available either
as a general benefit or as a restricted benefit. The restricted benefit is enforced (e.g., prescriber is
required to provide information, often in writing, regarding justification for use of testosterone
products).
A summary of the various listings (see Exhibit 1) is as follows:
Long-acting injectable products

• General benefits without restrictions: Alberta, Saskatchewan, Manitoba, Quebec, New
Brunswick, Nova Scotia, PEI (only testosterone enanthate), Newfoundland, Yukon, NIHB/NT/NU
• Restricted (enforced): British Columbia
• Restricted (passive): Ontario
Oral products
• General benefits without restrictions: Saskatchewan, Manitoba, Quebec, Nova Scotia, Yukon,
NIHB/NU/NW
• Restricted (enforced): Alberta, New Brunswick, PEI, Newfoundland
• Not listed: British Columbia
Topical products
Androderm
• General benefits without restrictions: Quebec
• Restricted (enforced): Alberta, New Brunswick, Nova Scotia, Newfoundland
• Not listed: British Columbia, Saskatchewan, Manitoba, Prince Edward Island, NIHB/NU/NT,
Yukon
Testim
• Restricted (enforced): PEI, New Brunswick, Nova Scotia, Newfoundland
• Not listed: British Columbia, Alberta, Saskatchewan, Manitoba, NIHB/NU/NT, Yukon
Androgel
• Restricted (enforced): PEI, New Brunswick, Nova Scotia, Newfoundland
• Not listed: British Columbia, Saskatchewan, Manitoba, Prince Edward Island, NIHB/NU/NT,
Yukon
Axiron

14
• Not listed: all other jurisdictions in Canada
Exhibit 2: Public plan listings in Canada for testosterone products

Drug BC AB SK MB ON QC NB NS PEI NL YK NIHB/
NU/
NW
Oral
testosterone undecanoate No Res Ben Ben Pas Ben Res Ben Res Res Ben Ben
Long-acting injectable
testosterone cypionate Res Ben Ben Ben Pas Ben Ben Ben No Ben Ben Ben
testosterone enanthate Res Ben Ben Ben Pas Ben Ben Ben Ben Ben Ben Ben
Topical
testosterone transdermal patch No Res No No Pas Ben Res Res No Res No No
(Androderm)
testosterone 1% topical gel (Testim) No No No No Pas Ben Res Res Res Res No No
testosterone 1% gel foil packet No No No No Pas Ben Res Res Res Res No No
(Androgel)
testosterone 2% topical solution No No No No No Ben No No No No No No
(Axiron)
No=not listed;
Res=restricted listing - enforced
Ben=unrestricted listing
Pas= restricting listing – passive
Restriction Criteria
In order for patients to be eligible for publically funded TRTs, various jurisdictions use restriction criteria
(see Appendix 1). Summary of the restriction criteria is found in Exhibit 3.
Exhibit 3: Summary of Provincial Criteria for Testosterone Products

Criteria AB BC ON NB, PEI, NS
NF
Treatment of congenital and acquired primary or
secondary hypogonadism in males
√ √ √
Not considered for use for treatment of androgen decline
in the aging male (ADAM)
√ √ √
Hypogonadism or orchiectomy or undescended testes or
Klinefelter’s syndrome or female-to-male transformation
√ √ √
or pituitary tumour or removal of pituitary gland
Surgery of pituitary gland and low testosterone levels
√ √ √
AIDS-wasting syndrome and low testosterone levels
√ √
Confirmed low morning serum testosterone levels
associated with documented, symptomatic hypothalamic,
√
pituitary or testicular disease
Clinical features and confirmed by two separate free
testosterone measurements
√ √

15
Part 2: Telephone Interview with Public Drug Program Representatives
A representative from each public drug program (except Quebec) was contacted to participate in a 30
minute telephone interview to gather further information about formulary listing of testosterone
replacement therapies (see Appendix 3 for interview questions). Exhibit 4 summarizes the information
obtained in the interviews.
Exhibit 4: Summary of interviews with representative from public drug program

Province Listing Was there ever a change in listing? What was the basis for listing/change
in listing?
British Restricted No Topicals were reviewed in 2002/2003;
Columbia (injectable); not at that time a decision was made not
listed (oral, to fund based on cost of products
topicals)
Saskatchewan General benefit No Internal review in 2002 of topical
(oral, injectable); products determined that no
no listing significant benefit over incremental
(topicals) cost.
Manitoba General benefit No Topical products are not listed in the
(oral, injectable); formulary, due to pricing concerns.
no listing
(topicals)
Ontario Limited Use Oral and injectable testosterone Review of testosterone replacement in
were available as general benefits 2003/04, with changes to listing in
prior to 2005 2005, based on clinical knowledge,
efficacy, safety and cost-effectiveness
New Restricted Topical testosterone products, Atlantic Common Drug Review (2008)
Brunswick (enforced) (oral, including Androgel, Testim and
PEI topical), Androderm (not added in PEI), were
added to the formulary as special
Newfoundland general listing
authorization products in 2008.
(injectable)
Andriol was added in 2009.
Nova Scotia Restricted
(enforced)
(topical), general
listing (oral,
injectable)
NIHB Oral, injectable No recent change in listing status Topical testosterone products can be
(general accessed on a case-by-case basis
benefit); no
listing for
topicals
Yukon Injectable oral, Topical products (Androderm and An environmental scan showed that
topicals (general Testim) will be removed from the testosterone topical products were
benefit) formulary in August 2014 either not listed or listed as restricted
products in other Canadian
jurisdictions
NA: not applicable

16
Summary
• Oral product: Six of the 12 (50%) public drug programs in Canada list oral testosterone
undecanoate as a general benefit. In five jurisdictions, the oral product is available on
a restricted basis, requiring special authorization. In Ontario it is listed as a Limited
Use Product. One province (BC) does not list this product.
• Long-acting injectable: These products are available as a general benefit in 10

jurisdictions (83%) and restricted in two. In Ontario, these products are listed as
Limited Use Products
• Topical products: No topical treatment is listed on the formulary of five (42%)

jurisdictions. It is a restricted listing (enforced or passive) in six (50%), and a general
benefit in one jurisdiction. Topical testosterone products are listed as Limited Use
products in Ontario.
• Although restriction criteria vary among the public drug plans, most state that the
testosterone products are indicated for treatment of congenital and acquired primary
or secondary hypogonadism in males. Five jurisdictions state that these products are
not considered for use in the treatment of androgen decline in the aging male.
Selected International Jurisdictions

United States
As a measure to control ever-increasing costs associated with healthcare, the use of a preferred drug list
(“formulary”) has been implemented in some jurisdictions. For example a preferred drug list is a list of
medications that the provider will cover the cost for without the need to request a prior authorization.
The preferred drugs are usually medications that are available generically or are the result of price
negotiations between the pharmaceutical company and the provider. For example, in Oregon
(Medicaid), the preferred topical testosterone product is Androgel (requiring prior authorization);
Testim, Androderm and Axiron are considered non-preferred.
A tiered co-payment system is a combination of cost-sharing and a preferred drug list.13 Three-tier
structures commonly assign generic medications the lowest copay, formulary brand medications a
somewhat higher copay, and non-formulary brand medications the highest copay. Three-tier copays
provide consumers with more choice than in a closed formulary (where tier three drugs would not be
covered at all) and attempt to reduce the number of prior authorizations that are needed for drug
approval.14 In a five-tier system, tier 1 includes preferred generic drugs, tier 2 non-preferred generic
drugs, tier 3 preferred brand drugs, tier 4 non-preferred brand drugs and tier 5 specialty drugs (e.g.,
injectables) (see Appendix 4 for examples of copayments with tiered formulary systems). See Exhibit 5
for some sample listings of testosterone replacement therapies in the United States. Note:
testosterone undecanoate (oral) is not commercially available in the United States.

17
Exhibit 5: Listing of testosterone products for select plans in the United States*
Drug Plan Testim Androderm Androgel Axiron Injectable
products
AETNA Preferred List (Chronic Preferred Non-preferred Preferred Non-preferred Not listed
Medications: Asthma) (3-Tier system)
(www.aetna.com)
Amerigroup Medication Formulary Non-preferred Preferred (prior Preferred (prior Non-preferred Non-preferred
(Medicaid markets in Florida, Louisiana, authorization authorization
Maryland, Nevada, New Jersey and required) required)
Washington) (www. providers.amerigroup.com)
Blue Cross Blue Shield of South Carolina Tier 3 (non- Tier 2 (preferred) Tier 3 (non- Tier 2 (preferred) Tier 3 (non-
Preferred Drug List preferred) preferred) preferred)
(www.southcarolinablues.com)
Blue Cross Blue Shield of Texas Standard Non-preferred Preferred Non-preferred Non-preferred Not listed
Preferred Drug List (January 2014)
(www.bcbstx.com)
Connecticut Medicaid Preferred Drug List Preferred Non-preferred Preferred Non-preferred Non-preferred
(www.ctdssmap.com)
Idaho Medicaid Preferred Drug List Preferred Non-preferred Preferred Non-preferred Not listed
(www.healthandwelfare.idaho.gov)
Illinois Medicaid Preferred Drug List Prior Prior authorization Prior authorization Prior Prior
http://www2.illinois.gov/hfs/sitecollectiondocument authorization required required authorization authorization
s/pdl.pdf
required required required
Kaiser Permanente 2014 Medicare Part D Tier 4 Tier 3 Tier 4 Tier 4 Tier 2
Comprehensive Formulary (5-tier system)
(www.healthy.kaiserpermanente.org)
Kentucky Preferred Drug List 2014 (www. Non-preferred Preferred Preferred Non-preferred Not listed
kentucky.magellanmedicaid.com)
Oregon Fee-for-Service Enforceable Non-preferred Non-preferred Preferred (prior Non-preferred Preferred
Physical Health Preferred Drug List 2014 authorization)
(http://www.oregon.gov/oha/healthplan/pages/tool
s_prov/pdl.aspx)
Texas Medicaid Preferred Drug List Non-preferred Non-preferred Preferred Non-preferred Not listed
(http://www.txvendordrug.com/pdl/) (prior (prior authorization
authorization required)
required)

18
WellCare Comprehensive Formulary Tier 3 Nonformulary Nonformulary Nonformulary Tier 3

(Medicare Advantage Plans) (covers New
York, Connecticut, Florida, Georgia, Hawaii
and others) (5-tier system)
(https://www.wellcare.com/medicare_formulary/ne
w_york)
Wellmark Prior authorization/Step therapy Tier 4 Tier 4 Tier 2 Tier 4 Tier 1
(http://www.wellmark.com/HealthAndWellness/Dru
gInformation/PharmacyHome.aspx)
*NOTE: Oral testosterone undecanoate is not available in the United States
Prior Authorization
Testim Transdermal (Tier 3) https://www.wellcare.com/medicare_formulary/new_york)
Covered Use: All FDA-approved indications not otherwise excluded from Part D.
Exclusion Criteria: Pregnancy Category X
Required Medical Information: Statement indicating diagnosis of hypogonadism in men with pretreatment total testosterone level below normal
physiological value of 300 ng/dl or below normal reference level provided by the laboratory required.

19
Other Countries
Australia:
In Australia, the Pharmaceutical Benefits Scheme (PBS) restricts testosterone replacement therapies to
specific populations.15 See Exhibit 6 for TRT products available under PBS.
A surveillance of testosterone prescribing in Australia was undertaken to compare use of these products
between January 1992 to December 2010.16 Over the two decades, total annual expenditure increased
ninefold, according to PBS data. However, despite the increase, there has been no change in the
approved indications for use of testosterone or the frequency of these conditions. The authors suggest
that the increase in use of testosterone products is driven by indications such as “andropause” and male
sexual dysfunction.
Exhibit 6: Testosterone Replacement Therapies (Australia)
Product Dosage form Listing

Axiron Testosterone Authority required:
2% • Androgen deficiency in males with established
transdermal pituitary or testicular disorders
Androderm Testosterone • Androgen deficiency in males 40 years and older
2.5 mg/24 hr who do not have established pituitary or testicular
patch disorders other than aging, confirmed by at least 2
5 mg/24 hr morning blood samples taken on different
patch mornings. Androgen deficiency is confirmed by
Testogel* Testosterone testosterone less than 8 nmol per L, or 8-15 nmol
1% gel per L with high LH (greater than 1.5 times the
Testosterone implant* 100mg, 200mg upper limit of the eugonadal reference range for
implant young men.
Testosterone enanthate 250 mg/mL • Micropenis, pubertal induction, or constitutional
injection delay of growth or puberty, in males under 18
Testosterone 40 mg capsule years of age
undecanoate 1g/4mL
injection*
*Not available in Canada
New Zealand:
There are limited products listed on the New Zealand formulary as fully subsidized: testosterone
transdermal patch 2.5 mg/24 hrs (Androderm), testosterone cypionate 100mg/mL, testosterone esters
250 mg/mL, testosterone undecanoate 40mg capsules and 250mg/mL injection.17 Note that no special
authority is needed for these medications for eligible beneficiaries.

20
Scotland:
In Scotland, various testosterone products have been evaluated for use within NHS Scotland.18 See
Exhibit 7 for advice for testosterone replacement products in Scotland.
Exhibit 7: TRT products (Scotland)
Product Advice/criteria
Testosterone 2% gel (Tostran) Replacement therapy with testosterone for male hypogonadism
(2007) when testosterone deficiency has been confirmed by clinical
symptoms and laboratory analyses. It is an alternative to other
formulations of testosterone gel, with similar costs for equivalent
doses. It is restricted to use as an alternative to testosterone patches
for those patients requiring a transdermal delivery system.
Testosterone gel is at least as effective as testosterone patches and
costs less.
Testosterone 50mg/5g gel (Testim) Replacement therapy for adult male hypogonadism when
(2006) testosterone deficiency has been confirmed by clinical features and
biochemical tests. It is an alternative to another formulation of
testosterone gel, of the same strength and cost, and is restricted to
use as an alternative to testosterone gel patches for those patients
requiring a transdermal delivery system. Testosterone is at least as
effective as testosterone patches and costs less.
Testosterone gel (Testogel) (2003) Replacement therapy for adult male hypogonadism is accepted for
restricted use within NHS Scotland. It offers an alternative to
testosterone patches for those patients requiring a transdermal
delivery system. Testosterone gel is at least as effective as
testosterone patches and costs less, so is a cost effective
transdermal treatment for this condition
Testosterone undecanoate (Nebido) As testosterone replacement therapy for male hypogonadism when
(2009) testosterone deficiency has been confirmed by clinical features and
biochemical tests. Compared with alternative intramuscular
preparations it offers the advantage of reduced frequency of dosing
with less inter-dose fluctuation of testosterone levels
Summary
• In the United States, many health plans restrict the use of testosterone products through
a prior authorization process.
• In Australia, testosterone products (including topical, injectable, oral) are available
through a Special Authorization process. In contrast, New Zealand funds testosterone
patch (Androderm), testosterone injectable products and oral testosterone as a general
listing.

21
Part B: Guidelines for the management of men with hypogonadism

Various consensus recommendations and guidelines are available for the management of men with hypogonadism. There are no formal Canadian guidelines
available for the management of hypogonadism. A summary of these guidelines is below in Exhibit 8.
Exhibit 8: Comparison of guidelines for management of men with hypogonadism

11 21
Endocrine Society ISA/ISSAM/ British Society for Sexual Canadian panel European Association of
19 20 2
EAU/EAA/ASA Medicine Urology
Diagnosis
Blood levels obtained in ✔ ✔ ✔ ✔ Not stated
am between 7-11am
Normal Testosterone Use lower limit of No generally accepted Total testosterone level above Not defined due to Lower normal range (8-12
levels normal established in lower limits of normal; 12 nmol/L does not require difficulties with equipment nmol/L)
laboratory (lower limit however total replacement; patients with standardization and
in some laboratories is testosterone level above serum levels below 8nmol/L interlaboratory variability
9.8-10.4 nmol/L) 12 nmol/L does not will usually benefit from
require substitution, and treatment
levels below 8 nmol/L will
usually benefit from
treatment
Repeat testosterone ✔ Not explicitly stated Abnormal (low or borderline) Abnormal (low or ✔
levels require confirmation with borderline) require
repeat T plus SHBG and LH, confirmation with repeat T
FSH and prolactin plus SHBG and LH, FSH and
prolactin
Type of testosterone test Total testosterone level Total testosterone Total testosterone Bioavailable testosterone Total testosterone (free
recommended (free or bioavailable testosterone if total close to
testosterone if total lower normal range)
near lower limit of
normal)
Based on consistent ✔ ✔ ✔ Not explicitly stated ✔
symptoms and signs and
low serum testosterone
levels
Measurement of BMD in ✔ Assessment of bone Not stated Not stated Adult men with severe
men with severe density at 2-yr intervals in hypogonadism should be
androgen deficiency or hypogonadal men screened for concomitant
low trauma fracture osteoporosis

22
Screening
Population Sellar mass, treatment Not stated Not stated Men with diabetes Sellar mass, end-stage renal
recommended for with medications that disease, treatment with
screening affect testosterone medications that affect
product/metabolism, testosterone, moderate to severe
HIV-associated weight COPD, osteoporosis or low
loss, end-stage renal trauma fractures, HIV infection
disease, with sarcopenia, type 2 DM,
moderate/severe COPD, infertility, adult men with
infertility, osteoporosis consistent and multiple signs and
or low trauma fracture, symptoms associated with late-
type 2 DM onset hypogonadism
Treatment
Choice of formulation Based on patient’s Selection based on joint Selection based on joint Based on physician and Selection based on joint decision
preference, decision between patient decision between patient and patient discussions by patient and physician
consideration of and physician physician
pharmacokinetics,
treatment burden and
cost
Indications Symptomatic men with Focus of Men with erectile dysfunction Focus of consensus was Delayed puberty (idiopathic,
classical androgen recommendations was and/or diminished libido and management of patients Kallmann syndrome)
deficiency syndromes late-onset hypogonadism documented testosterone with testosterone deficiency Klinefelter syndrome with
deficiency syndrome (also known as hypogonadism
andropause, or late-onset Sexual dysfunction and low
hypogonadism) testosterone
Low bone mass in hypogonadism
Adult men with consistent and
preferably multiple signs and
symptoms of hypogonadism
Hypopituitarism
Testicular dysgenesis and
hypogonadism
Summary
• Guidelines/consensus recommendations vary in the definition of normal testosterone levels. Three of the five reviews suggest that
the lower normal range as 8-12 nmol/L (using total testosterone levels).
• Although four of the five guidelines/consensus recommendations suggest that diagnosis of hypogonadism is based on consistent
symptoms and signs and low serum testosterone levels, there is no consensus regarding the number of signs/symptoms that must be
present before making a diagnosis.
• All guidelines suggest that choice of testosterone formulation should be based on numerous factors including patient’s preference,
treatment burden and cost, and should be made as a joint decision between patient and physician.
23
Part C: Impact of different drug reimbursement schemes for

testosterone replacement therapies
Methods
A literature search was conducted in Pubmed using the terms: testosterone AND (healthcare
accessibility OR insurance coverage OR insurance pharmaceutical services OR health policy OR
reimbursement incentive OR national health programs OR cost sharing). Bibliographies of identified
articles were scanned for additional relevant articles.
Results
Despite testosterone replacement therapies being restricted in many jurisdictions, there is a lack of
information in the literature detailing the impact of different drug reimbursement schemes. In one
small retrospective study, 23 male HIV-1 infected patients who received at least one dose of IM
testosterone were switched to topical therapy.22 Assessment of the clinical outcomes and estimated
cost savings for patients switched were evaluated. After a median of 21.63 months (SD=12.9 months),
22 patients remained on topical testosterone and one patient returned to IM therapy after recurrence
of symptoms. No adverse effects were reported in any of the patients. Utilization of the topically
applied testosterone relative to the injectable formulations resulted in approximately $81,000 fewer
dollars spent (included drug acquisition cost, as well as cost of administration of IM testosterone).
In another recent time series analysis conducted in Ontario, a temporary decrease in testosterone
prescribing was observed when a restriction policy (Limited Use code) was introduced in 2005 for all
testosterone products, including the topical formulations.23 Testosterone prescribing declined 27.9% in
the 6 months following implementation of the restriction policy. However, by the end of the study
period in 2010, the rate of testosterone use exceeded pre-policy levels; this increase was largely driven
by the use of topical testosterone products which rose 464% between 2006 and 2012.
Summary
• There is a dearth of literature detailing the impact of different drug reimbursement options for
testosterone replacement therapies.
• Data from Ontario have shown that a restriction policy (using Limited Use codes) may result in a
temporary decrease in testosterone prescribing. However, testosterone use rose over 450% in
the six years after implementation of the restriction policy suggesting that such a policy has
minimal long-term effect on testosterone use.

24
Part D: Rapid Review of Selected Topics

Choice of Treatment for Testosterone Replacement Therapy
The objective of testosterone replacement therapy is to restore physiological testosterone levels in
hypogonadal men.2 Several products are available in Canada, and differ in their route of administration
and pharmacokinetics. Selection of a product is based on the patient’s preference, pharmacokinetics of
the testosterone formulation, treatment burden, cost and adverse effects (see Exhibit 9).
Intramuscular testosterone esters (testosterone enanthate and cypionate) are long-acting preparations
that are administered every 2-3 weeks, with peak concentrations occurring shortly after injection and
gradual decline after 7-15 days. After IM injection of the testosterone ester, testosterone
concentrations in serum rise into the supraphysiological range within 24-48 hours and gradually decline
into the low-normal range over 2 weeks.3 However, resulting wide peak-to-trough fluctuations in
serum testosterone levels may lead to instability in mood, libido and sexual function.1;2 As well,
intramuscular testosterone may cause discomfort on injection. However, cost of the injection may be
an important driver in the choice of an injectable product over a topical/transdermal preparation for
some patients. For example, in one study cost was a statistically significant reason for a patient’s
preference for injectable therapy (34.5%) over gel (21.3%, p=0.023).24
Oral testosterone is available as testosterone undecanoate. This product is absorbed into the systemic
circulation through the lymphatic system and bypasses first-pass hepatic metabolism. In order to
facilitate lymphatic absorption, oral testosterone undecanoate must be taken soon after meals.3 It is
recommended that it be taken with at least 20 mg of fat.25 It requires multiple, high daily doses due to
low bioavailability; it often results in an irregular serum testosterone pattern during the course of the
day.25 As well, it can cause gastrointestinal upset; approximately 40% of patients report nausea and/or
other GI complaints.1;26 In contrast to other oral forms of testosterone, such as methyltestosterone and
fluoxymesterone, testosterone undecanoate does not appear to have appreciable hepatotoxicity.26;27 A
10-year safety study found that liver function test results were normal in 33 men receiving oral
testosterone undecanoate 80-200mg.28
Topical/transdermal preparations are available as skin patches, gel or underarm spray. They provide a
uniform testosterone level for 24 hours (hence dosing once daily). Adverse effects include skin irritation
at the site of application and possible risk of interpersonal transfer if appropriate precautions are not
taken, in particular with the gel formulations.2 3 Accidental transference can lead to virilization of
contacts, especially in children.29 Although there are two gel preparations available (Androgel and
Testim), these products are not considered interchangeable. One report highlighted that patients who
may not have responded to one gel preparation, may derive benefit from the alternative preparation.30
In this study, 75/370 (20%) hypogonadal men on testosterone gel replacement therapy underwent a
brand substitution, due to suboptimal clinical or biochemical response to initial product selection.

25
Exhibit 9: Choice of Treatment for Testosterone Replacement Therapy
Formulation Route of Interval for Advantages Disadvantages

administration administration
Testosterone Oral Twice daily Absorbed through Variable levels of
undecanoate lymphatic system testosterone
Convenient route of Need for several doses per
administration day with intake of fatty food
Flexible dosage and self-
administered; immediate
decrease in testosterone
levels after interruption of
treatment
Testosterone Intramuscular Every 2-3 weeks Administered every 2-3 Discomfort on injection
cypionate, weeks (convenient); Possible fluctuation of
testosterone patients can self-inject testosterone levels
enanthate Often administered by
health care professional
Testosterone Topical/ Once daily Reliable steady-state Skin irritation at site of
transdermal testosterone levels application (patch: 19-66%,
Convenience of gel: 7-10%, axillary solution:
3
application 5-7%)
Risk of interpersonal transfer
Adapted from Dohle et al 2
Summary
In Canada, testosterone is available as an oral formulation, as an intramuscular injectable agent and in
various topical preparations including gels, patch and topical axillary solution. Selection of a product is
based on the patient’s preference, pharmacokinetics of the testosterone formulation, treatment
burden, cost and safety profile.
Adherence to Testosterone Products

Adherence is defined as the extent to which patients take medications as prescribed by their healthcare
providers.31 Overall, lack of adherence has been linked to potentially negative clinical outcomes and
higher costs.32 Adherence to topical testosterone replacement therapy (specifically Androgel and
Testim) was assessed using data from Thomas Reuters MarketScan database, containing record of
commercially insured and Medicare-insured US patients.31 A total of 15,435 men with hypogonadism
were included in the study. Overall, adherence to either Androgel or Testim was low; only 35% of
patients had continued on medication by 6 months, and by 12 months, only 15.4%. Patients with
specific and nonspecific hypogonadal diagnosis had low adherence rates (32.7% vs. 29.4%, respectively).
However, approximately 50% of men reinitiated therapy, usually on the same dose and dosage form;
only 5% of men were switched to the other topical therapy. Another study used the same Truven
MarketScan Database and same cohort of 15,435 men who received topical TRT prescription. An
additional 517 men were identified who received short-lasting TRT injection. All men were followed for
up to 30 months after treatment initiation.33 By 3 months, 54% of patients receiving topical TRT and
37% of patients prescribed short-lasting TRT injections were still receiving treatment. After one year

26
after initiation of therapy, only 18% of topical TRT users and 5% of short-lasting TRT injection users were
still continuing treatment. However, almost 60% of patients received TRT in a cyclic fashion. In general,
these patients used TRT for a few months, stopped treatment for 2-3 months and then restarted TRT
with the same dose and medication.
Other studies have found higher rates of adherence with testosterone products. For example, a chart
review evaluated the subjective response rates and characteristics of 125 men treated with TRT. Initial
mode of TRT was injectable in 55% of patients (n=70) and transdermal gel (Androgel).27 Approximately
60% of men (n=80) completed 12 months of therapy. Treatment was discontinued in 34 patients
(26.8%) who reported no major benefit and 13 (10%) were lost to followup. 27 Adherence to TRT
(specifically Testim) at 12 months was found to be 91% in another study.34 No difference was observed
in patients 65 years and older and those younger than 65 years of age. However, it should be noted
that only 33% of men completed the follow-up period.
Summary
Information on adherence and/or persistence with testosterone replacement therapy has been
inconsistent, with some studies showing poor adherence (i.e., 15% by 12 months) and other showing
high adherence patterns (e.g., 91% after 12 months).
Testosterone Levels
Reference ranges for lower normal level of testosterone (percentile 2.5) have been compiled from three
large community-based samples, suggesting a cut-off of 12.1 nmol/L for total serum testosterone and
calculated free testosterone 243 pmol/L. 35 Levels should be taken in the morning, when levels are
highest and best reproducible. In men aged 40-79 years, the threshold for total testosterone was 8
nmol/L for decreased frequency of sexual thoughts, 8.5 nmol/L for erectile dysfunction, 11 nmol/L for
decreased frequency of morning erections and 13 nmol/L for diminished vigour.2 Other studies have
suggested that 10.4 nmol/L (300 ng/dL) is a threshold that can be used for the treatment of
symptomatic men.3 In one study, the use of a 300 ng/dL threshold for total testosterone captured most
symptoms identified as related to androgen deficiency.36 Although total testosterone in serum is a
suitable screening test for the diagnosis of hypogonadism is many men, if abnormalities in
concentrations of sex-hormone-binding globulin are suspected, measurement of free or bioavailable
testosterone is indicated.3 Lower thresholds for free testosterone range from 0.17 to 0.31 nmol/L, and
depend on the method of measurement of free testosterone. Free testosterone measurements by
analog methods (used in most laboratories in Ontario) are affected by alterations in sex hormone
binding globulin (SHBG) and their use is not recommended.37 It should be noted, that a decrease in
testosterone levels is observed with age that is unrelated to illness. Levels begin to decline between the
ages of 35 and 40 years, when there is on average, a 1-2% decline of total testosterone levels per
year.1;10
Most clinical guidelines recommend testosterone supplementation in patients with symptomatic,

unequivocally low testosterone levels confirmed by repeated laboratory tests.2;11 Although there are
few long-term RCTs of testosterone use in patients with classic hypogonadism, agreement exists that

27
men with these conditions should be treated.38 However, controversy exists regarding the treatment of
older men with lower testosterone levels, who may not fully meet diagnostic or symptomatic criteria for
hypogonadism. In one study, 54% of patients in the UK who were initiated on testosterone did not have
a total testosterone measurement in the 180 days before initiation, 33% had one test and the remaining
had more than one test.39 Men in the US had more testosterone tests immediately before initiation:
40% did not have a baseline test, 50% had one test, and the remaining had more than one test.
Another study found that almost 25% of men prescribed testosterone in the US had not previously had a
blood test to determine if their testosterone was low.40
Summary
Controversy still exists regarding reference ranges for normal levels of testosterone. Most guidelines
suggest that total testosterone level above 12 nmol/L does not require replacement; patients with
serum levels below 8nmol/L will usually benefit from treatment.11;19 As well, it is recommended that
testosterone levels be measured prior to commencement of treatment.
Health Canada and Food and Drug Administration (FDA) Alerts and Warnings
• Health Canada issued an information update on July 15, 2014 advising the community of new safety
information regarding testosterone hormone replacement products and risk of serious and possible
life-threatening cardiovascular problems.41 Health Canada completed a safety review and found
evidence for serious and possible life-threatening cardiovascular problems. They noted that
testosterone products:
o Should not be used in men for non-specific symptoms if laboratory tests have not been done
to confirm a low testosterone level and other possible causes for the symptoms have not
been excluded
o Should not be used in children under the age of 18 as safety and effectiveness has not been
established in these patients
o Should not be used by women
• FDA has added a general warning in the drug labeling of all approved testosterone products about
the risk of blood clots in the veins.42 In addition, the FDA is investigating the risk of stroke, heart
attack and death in men taking testosterone products. 43
Discussion
Part A: Pharmacy Benefit Programs in Ontario, across Canada and
internationally
Availability in Canada
• In Canada, testosterone is available as a long-acting injectable, oral product or topical product.
There are two long-acting testosterone injectable products: testosterone cypionate and
testosterone enanthate. Only one product is available as an oral product: testosterone
undecanoate. Four topical products are commercially available: testosterone transdermal patch

28
(Androderm), testosterone 1% topical gel (Testim), testosterone 1% gel foil packet and pump
(Androgel) and testosterone 2% topical solution (Axiron).
• The long-acting injectable testosterone cypionate and the oral testosterone (testosterone
undecanoate) are available as generic products.
• The cost of a one-month supply for the oral generic product is $17-51, for the injectable product
$29-51 and for the topical products $60-200.
Public Plan Listing in Ontario

• In Ontario, available testosterone products (including oral, injectables, Androgel, Testim and
Androderm) are listed as “limited use” products. Restriction criteria limit the use of the
testosterone products for male patients with confirmed serum testosterone levels associated with
documented, symptomatic hypothalamic, pituitary or testicular disease, or in HIV-infected patients.
Public Plan Listing in Canada

• Oral product: Six of the 12 (50%) public drug programs in Canada list oral testosterone undecanoate
as a general benefit. In five jurisdictions, the oral product is available on a restricted basis, requiring
special authorization. In Ontario it is listed as a Limited Use Product. One province (BC) does not list
this product.
• Long-acting injectable: These products are available as a general benefit in 10 jurisdictions and
restricted in two. In Ontario, these products are listed as Limited Use Products
• Topical products: No topical treatment is listed on the formulary of five (42%) jurisdictions. It is a
restricted listing (enforced or passive) in six (50%), and a general benefit in one jurisdiction. Topical
testosterone products are listed as Limited Use products in Ontario.
• Although restriction criteria vary among the public drug plans, most state that the testosterone
products are indicated for treatment of congenital and acquired primary or secondary
hypogonadism in males. Five jurisdictions state that these products are not considered for use in
the treatment of androgen decline in the aging male.
Selected International Jurisdictions

• In the United States, many health plans restrict the use of testosterone products through a prior
authorization process.
• In Australia, testosterone products (including topical, injectable, oral) are available through a
Special Authorization process. In contrast, New Zealand funds testosterone patch (Androderm),
testosterone injectable products and oral testosterone as a general listing.
Part B: Guidelines for the management of patients with hypogonadism

• Guidelines/consensus recommendations vary in the definition of normal testosterone levels. Three
of the five reviews suggest that the lower normal range is 8-12 nmol/L (using total testosterone
levels).
• Although four of the five guidelines/consensus recommendations suggest that diagnosis of
hypogonadism is based on consistent symptoms and signs and low serum testosterone levels, there
is no consensus regarding the number of signs/symptoms that must be present before making a

29
diagnosis.
• All guidelines suggest that choice of testosterone formulation should be based on numerous factors
including patient’s preference, treatment burden and cost, and should be made as a joint decision
between patient and physician.
Part C: Impact of different drug reimbursement schemes for testosterone

replacement therapy
• There is a lack of information detailing the impact of different drug reimbursement options for
testosterone replacement therapies.
• A restriction policy (using Limited Use codes) in Ontario resulted in a temporary decrease in
testosterone prescribing; however, testosterone use rose over 450% in the six years after
implementation of the restriction policy suggesting that such a policy has minimal long-term effect
testosterone use.
Part D: Rapid Reviews of Selected Topics

• Choice of treatment for testosterone replacement therapies: In Canada, testosterone is available as
an oral formulation, as an intramuscular injectable agent and in various topical preparations
including gels, patch and topical axillary solution. Selection of a product is based on the patient’s
preference, pharmacokinetics of the testosterone formulation, treatment burden, cost and safety
profile.
• Adherence to testosterone replacement therapies: Information on adherence and/or persistence
with testosterone replacement therapy has been inconsistent, with some studies showing poor
adherence (i.e., 15% by 12 months) and other showing high adherence patterns (e.g., 91% after 12
months). In one study, TRT was used in a cyclic fashion (i.e., patients used TRT for a few months,
stopped treatment for 2-3 months and then restarted TRT with the same dose and medication.)
• Testosterone levels: Controversy still exists regarding reference ranges for normal levels of
testosterone. Most guidelines suggest that total testosterone level above 12 nmol/L does not
require replacement; patients with serum levels below 8nmol/L will usually benefit from treatment.
As well, it is recommended that testosterone levels be measured prior to commencement of
treatment.
Health Equity
In Ontario, all testosterone formulations (with the exception of testosterone axillary topical solution) are
available on the formulary as Limited Use products. No health equity issue was identified for patients
with a diagnosis of classical hypogonadism .
Conclusion
Testosterone (injectable, oral, topical preparations with the exception of the axillary topical solution) is
available on the ODB formulary as a Limited Use product for the treatment of patients with documented

30
and symptomatic hypothalamic, pituitary or testicular disease, or in HIV-infected patients.
Most public drug plans in Canada require special authorization prior to funding testosterone
preparations. All jurisdictions in Canada fund the injectable product, most the oral product and two-
thirds one or more of the topical products. Some international jurisdictions (e.g., Australia) restrict the
use of these products via a special authorization process. However, there is a lack of literature assessing
these more restrictive reimbursement strategies for adherence or outcome measures.

31
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analysis. The journal of sexual medicine 2013; 10(5):1401-1409.
(32) Ho P, Bryson C, Rumsfeld J. Medication adherence: its importance in cardiovascular outcomes.

Circulation 119, 3028-3035. 2009.
(33) Donatucci C, Cui Z, Fang Y, Muram D. Long-term treatment patterns of testosterone

replacement medications. The journal of sexual medicine 2014; 11(8):2092-2099.
(34) Bhattacharya RK, Khera M, Blick G, Kushner H, Miner MM. Testosterone replacement therapy
among elderly males: the Testim Registry in the US (TRiUS). Clin Interv Aging 2012; 7:321-330.
(35) Bhasin S, Pencina M, Jasuja G, et al. Reference ranges for testosterone in men generated using
liquid chromatography tandem mass spectrometry in a community-based sample of healthy
nonobsese young men in the Framingham Heart Study and applied to three geographically
distinct cohorts. The Journal of clinical endocrinology and metabolism 2011; 96:2430-2439.
(36) Hall S, Esche G, Araujo A, et al. Correlates of low testosterone and symptomatic androgen
deficiency in a population-based sample. The Journal of clinical endocrinology and metabolism
2008; 93:3870-3877.
(37) Bhasin S, Cunningham G, Hayes F, et al. Testosterone therapy in men with androgen deficiency
syndromes: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology
and metabolism 2010; 95:2536-2359.
(38) Spitzer M, Huang G, Basaria S, Travison TG, Bhasin S. Risks and benefits of testosterone therapy
in older men. Nature reviews Endocrinology 2013; 9:414-424.
(39) Layton JB, Li D, Meier CR, Sharpless JL, Sturmer T, Jick SS et al. Testosterone lab testing and
initiation in the United Kingdom and the United States, 2000 to 2011. The Journal of clinical
endocrinology and metabolism 2014; 99(3):835-842.
(40) Baillargeon J, Urban R, Ottenbacher K, et al. Trends in androgen prescribing in the United States,

34
2001 to 2011. JAMA Intern Med 173, 1465-1466. 2013.
(41) Health Canada. Information update: possible cardiovascular problems associated with
testosterone products. http://www healthycanadians gc ca/recall-alert-rappel-avis/hc-
sc/2014/40587a-eng php. 2014
(42) US Food and Drug Administration. FDA adding general warning to testosterone products about
potential for venous blood clots. http://www fda gov/drugs/drugsafety/ucm401746 htm. 2014
(43) US Food and Drug Administration. FDA evaluating risk of stroke, heart attack and death with
FDA-approved testosterone products. http://www fda
gov/downloads/Drugs/DrugSafety/UCM383909 pdf 2014
(44) New Brunswick Department of Health. New Brunswick Prescription Drug Program Formulary.
http://www gnb ca/0212/nbpdpformulary-e asp 2013
(45) Nova Scotia Pharmacare. Nova Scotia Formulary. http://novascotia

ca/dhw/pharmacare/formulary asp 2013
(46) PEI Pharmacare. Formulary. http://healthpei ca/formulary 2013
(47) Newfoundland and Labrador Department of Health and Community Services. Newfoundland
and Labrador Interchangeable Drug Products Formulary. http://www health gov nl
ca/health/nlpdp/fmlsearch asp 2013

35
Appendix 1: Restriction Criteria for Testosterone Products in Canada

Province Criteria
Alberta Androderm, testosterone undecanoate (Andriol)
For use in males for the treatment of congenital and acquired primary and secondary
hypogonadism. Coverage cannot be considered when used for the treatment of androgen
decline in the aging male (ADAM).
Special authorization may be granted for 6 months.
British Columbia For the treatment of testosterone deficiency in one of the following diagnoses:
Hypogonadism OR Orchiectomy OR Undescended testes OR Klinefelter's syndrome OR
Female-to-male (gender) transformation OR Pituitary tumour OR Removal of pituitary gland
OR
For the indication of:
Surgery of pituitary gland AND where low testosterone levels have been documented OR
AIDS-wasting syndrome AND where low testosterone levels have been documented.
Ontario LU Code 397: For male patients with confirmed low morning serum testosterone levels
associated with documented, symptomatic hypothalamic, pituitary or testicular disease, or in
HIV-infected patients.
Note: Older males with nonspecific symptoms of fatigue, malaise, depression who have a low
normal random testosterone level do not satisfy these criteria.
LU Authorization Period: 1 year
44
New Brunswick TESTOSTERONE (ANDRODERM, ANDROGEL, TESTIM) 12.2mg and 24.3mg patches, 2.5g and 5g
packets, 1% gel TESTOSTERONE UNDECANDOATE (ANDRIOL and generic brand) 40 mg
capsules
For the treatment of congenital and acquired primary or secondary hypogonadism in males
with a specific diagnosis of:
• Primary: cryptorchidism, Klinefelter’s, orchiectomy, and other established causes
• Secondary: Pituitary-hypothalamic injury due to tumors, trauma, radiation
Testosterone deficiency should be clearly demonstrated by clinical features and
confirmed by two separate free testosterone measurements before initiating any
replacement therapy
Note: Older males with non-specific symptoms of fatigue, malaise, or depression who have
low testosterone levels do not satisfy these criteria.
45
Nova Scotia TESTOSTERONE, TOPICAL (Androderm Patch, Androgel Gel Packet & Testim Gel)
• Primary: cryptorchidism, Klinefelter's, orchidectomy, and other established causes ·
• Secondary: pituitary-hypothalamic injury due to tumors, trauma, radiation
• deficiency should be clearly demonstrated by clinical features and confirmed by two
separate biochemical tests before initiating any therapy
NOTE: Maximum dose approved is 5g per day or a 5mg patch per day.
by limiting the quantity payable each quarter (e.g. Jan-Mar) to: 120 Androderm Patches
(2.5mg or 5mg Patch); · 300g of Androgel 2.5g gel (packet);
or ·600g of Testim G el.

36
46
PEI Testosterone, transdermal gel, 25mg/2.5gm packet, 50mg/5gm packet (AndroGel-ABB);
50mg/5gm tube (Testim-PAL)
Note: Not interchangeable.
with a specific diagnosis of;
• Primary - Cryptorchidism, Klinefelter's, orichidectomy, and other established causes.
• Secondary - Pituitary-hypothalamic injury due to tumors, trauma, radiation.
Testosterone deficiency should be clearly demonstrated by clinical features and
confirmed by two separate biochemical tests before initiating any testosterone
therapy. Limited to 5 g/day gel.
Older males with non-specific symptoms of fatigue, malaise or depression who have low
testosterone (T) levels do not satisfy these criteria.
Testosterone Undecanoate, capsule, 40mg (Andriol-MSD)

For patients with a documented deficiency in whom treatment with depo-testosterone
products have been unsuccessful, intolerable or are medically contraindicated.
Yukon Coverage for hormonal replacement required for an approved chronic condition (e.g. primary
hypogonadism, pituitary disorders). Cases reviewed individually.
47
Newfoundland Testosterone Undecanoate (Andriol 40mg capsule and generics) Testosterone topical
(Androgel 2.5mg & 5mg sachets, Testim 1% gel, Androderm 25mg/24hr, 50mg/24hr patch)
• Primary: Cryptorchidism, Klinefelter’s, orichidectomy, and other established causes.
• Secondary: Pituitary-hypothalamic injury due to tumors, trauma, radiation.
Testosterone deficiency should be clearly demonstrated by clinical features and confirmed by
two separate biochemical tests before initiating any T therapy.
Older males with non-specific symptoms of fatigue, malaise or depression who have low
testosterone (T) levels do not satisfy these criteria.
Limited to 5 g/day gel or 5 mg patch. (for topical products)

37
Appendix 2: Webpages for Provincial Drug Formularies
Province Webpage for Drug Formulary

British Columbia http://www.health.gov.bc.ca/pharmacare/benefitslookup/faces/Search.jsp
Alberta https://idbl.ab.bluecross.ca/
Saskatchewan http://formulary.drugplan.health.gov.sk.ca/
Manitoba http://web6.gov.mb.ca/eFormulary/
Ontario https://www.healthinfo.moh.gov.on.ca/formulary/index.jsp
Quebec http://www.ramq.gouv.qc.ca/en/regie/legal-publications/Pages/list-
medications.aspx
New Brunswick http://www.gnb.ca/0212/nbpdpformulary-e.asp
Nova Scotia http://novascotia.ca/dhw/pharmacare/formulary.asp
Prince Edward Island http://healthpei.ca/formulary
Newfoundland http://www.health.gov.nl.ca/health/nlpdp/fmlsearch.asp
Yukon Territories https://apps.gov.yk.ca/pls/apex40p/f?p=161:9000:4324580815029961:::::
NIHB (Non-insured http://www.hc-sc.gc.ca/fniah-spnia/nihb-ssna/provide-fournir/pharma-prod/med-
Health Benefits) list/index-eng.php
Program

38
Appendix 3: Interview Questions
How long have you listed testosterone products on your provincial formulary? How are they listed
(e.g., restricted, general benefit)?
Why did you decide to list TRTs this way?
What was the basis for this listing (e.g., quantity limits, general listing)?
Do you have any studies comparing usage/costs before and after implementation of this listing?
Why are certain TRTs NOT funded?
Do you restrict prescribing to certain specialties (or are certain specialties exempt from restrictions)?

39
Appendix 4: Tiered cost-sharing options
Prescription Tier 1 Tier 2 Tier 3 Tier 4

Drug Plan (generic) (preferred brand) (non-preferred brand) (specialty)
Plan A $5 $28 $55 25%
Plan B $2 $20 $40 N/A
Plan C $10 $25 50% 25%
Plan D $4 $17 75% 25%
Adapted from:
http://www.cancer.org/treatment/findingandpayingfortreatment/managinginsuranceissues/medicare/
medicarepartd/medicare-part-d-formularies-and-drug-coverage

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Testosterone Replacement Therapy

Environmental Scan and Local/Historical Context

30 Bond Street, Toronto ON, M5B 1W8 www.odprn.ca info@odprn.ca

In Ontario, commercially available testosterone products (including oral, long-acting injectable,

Part B: Guidelines for the management of patients with hypogonadism

Ontario Drug Policy Research Network

Part D: Rapid Review of Selected Topics

Adherence to testosterone replacement therapies: Information on adherence and/or persistence with

Ontario Drug Policy Research Network

List of Exhibits ............................................................................................................................................... 6

Ontario Drug Policy Research Network

Part D: Rapid Reviews of Selected Topics .............................................................................................. 29

Ontario Drug Policy Research Network

Exhibit 1: Testosterone replacement therapy available in Canada ........................................................... 11

Ontario Drug Policy Research Network

Ontario Drug Policy Research Network

Ontario Drug Policy Research Network

The objectives of this report are:

Ontario Drug Policy Research Network

Part A: Pharmacy Benefit Programs in Ontario, across Canada and

Ontario Drug Policy Research Network

Common Drug Review

TRT product listing in Ontario

The Limited Use criteria are as follows:

Committee to Evaluate Drugs:

Ontario Drug Policy Research Network

Public Plan Listings in Canada

A summary of the various listings (see Exhibit 1) is as follows:

Long-acting injectable products

Ontario Drug Policy Research Network

• Not listed: all other jurisdictions in Canada

Exhibit 2: Public plan listings in Canada for testosterone products

Exhibit 3: Summary of Provincial Criteria for Testosterone Products

Ontario Drug Policy Research Network

Part 2: Telephone Interview with Public Drug Program Representatives

Exhibit 4: Summary of interviews with representative from public drug program

Ontario Drug Policy Research Network

• Long-acting injectable: These products are available as a general benefit in 10

• Topical products: No topical treatment is listed on the formulary of five (42%)

Selected International Jurisdictions

Ontario Drug Policy Research Network

Ontario Drug Policy Research Network

WellCare Comprehensive Formulary Tier 3 Nonformulary Nonformulary Nonformulary Tier 3

Ontario Drug Policy Research Network

Exhibit 6: Testosterone Replacement Therapies (Australia)

Product Dosage form Listing

Ontario Drug Policy Research Network

Exhibit 7: TRT products (Scotland)

Ontario Drug Policy Research Network

Part B: Guidelines for the management of men with hypogonadism

Exhibit 8: Comparison of guidelines for management of men with hypogonadism

Ontario Drug Policy Research Network

Part C: Impact of different drug reimbursement schemes for

Ontario Drug Policy Research Network

Part D: Rapid Review of Selected Topics

Ontario Drug Policy Research Network

Exhibit 9: Choice of Treatment for Testosterone Replacement Therapy

Formulation Route of Interval for Advantages Disadvantages

Adherence to Testosterone Products

Ontario Drug Policy Research Network