Hypogonadismand Testosterone Replacement Practical ... · 9/19/2000 1 Hypogonadismand Testosterone...

9/19/2000

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Hypogonadism and Testosterone Replacement Therapy: Practical Insights for thePractical Insights for the

Pharmacist

Roger G. Hefflinger, PharmDg g

Associate Professor of Pharmacy

Practice and Administrative Services

Idaho State University, College of Pharmacy

Pocatello, Idaho

Faculty Information

Presenter:Roger G. Hefflinger, PharmD




Pocatello, Idaho

Moderator:Jeff D. Prescott, PharmD, RPh

Vice President, Clinical Affairs

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Pharmacy Times

This activity is supported by an educational grant from Abbott Laboratories.

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DisclosuresRoger G. Hefflinger, PharmD, has no relevant financial relationships to disclose.

The planning staff from the Pharmacy Times Office of Continuing Professional Education have no relevant financial relationships to disclose.

The contents of this webinar may include information regarding the use of products that may be inconsistent with or outside

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p ythe approved labeling for these products in the United States. Physicians should note that the use of these products outside current approved labeling is considered experimental and are advised to consult prescribing information for these products.

Educational Objectives

At the conclusion of this program, participants should be able to:

• Review the prevalence, epidemiology, and pathophysiology of testosterone deficiency

• Recognize the signs and symptoms related to hypogonadism, as well as causative factors, including medications

• Evaluate the available and emerging testosterone replacement therapies and examine their risks and benefits

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p p

• Counsel patients on the correct usage of the various testosterone dosage forms in order to improve patient adherence and outcomes

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Pharmacy Accreditation

Pharmacy Times Office of Continuing Professional Education is accredited by the A dit ti C il f PhAccreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This program is approved for 1 contact hour (0.1 CEU) under the ACPE universal program number 0290‐0000‐11‐039‐H01‐P. This program is available for CE credit through

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program is available for CE credit through September 15, 2013.

Type of Activity: Knowledge‐based.

Hypogonadism and Testosterone Replacement Therapy: Practical Insights for the

Pharmacist

Roger G. Hefflinger, PharmD




Pocatello, Idaho

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Origination of Testicular Dysfunction

• Male hypogonadism– Fetal hypogonadism

– Pubertal hypogonadism

– Adult hypogonadism

7http://www.mayoclinic.com/health/male‐hypogonadism/DS00300

Signs and Symptoms of Hypogonadism

• Birth and infancy: early signs– Failure of the testes to descendN ll f d h t hi i– Normally formed hypotrophic penis

• Adolescent males– Delayed, arrested, or absent testicular growth– Delayed secondary sex characteristics

H i

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• Hair• Acne• Muscle mass• Vocal cord development – voice changes

http://www.mayoclinic.com/health/male‐hypogonadism/DS00300

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Signs and Symptoms of Hypogonadism

• In adult males:– Psychological symptoms

• Sad, down, loss of energy, tired, fatigued?

– Physical symptoms• Health‐limited vigorous activity, walking <1 km, limited bending, kneeling, stooping?

– Sexual symptoms

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• Awaken with morning erection, erection sufficient for sexual activity, frequency of thoughts of sex?

1. http://www.mayoclinic.com/health/male‐hypogonadism/DS00300; 2. Wu et al. N Engl J Med. 2010;363(2):123‐135; 3. Trinick TR et al. Aging Male. 2011;14(1):10‐15; 4. http://issam.ch/AMS_English.pdf.

Incidence• Estimated that there is a decline in net testosterone of

0.4% to 0.7% a year above age 40– Total T

– Free T

– Albumin bound T

– Sex Hormone Binding Globulin (SHBG)

• 20% of men >60 years old

• 30% to 40% of men >80 years old

S l l l h d l

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• Serum testosterone levels lower than younger adult males

1. Feldman HA et al. J Clin Endo Metab. 2002;87:589‐598; 2. Faiman C. Male hypogonadism. In: Cleveland Clinic Current Clinical Medicine 2nd ed. 397‐401.

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Incidence/Prevalence

• Difficult for clinicians and researchers to come to consensus– Survey of 3369 males, 40 to 79 years of age

– Questionnaires; measurement of morning total testosterone, free testosterone

– International Web survey shows high prevalence of symptomatic testosterone deficiency in men

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of symptomatic testosterone deficiency in men

1. Wu et al. N Engl J Med. 2010;363(2):123‐135; 2. Trinick TR et al. Aging Male. 2011;14(1):10‐15.

Nomenclature

Primary• Primary testicular failure

– Undescended testicles

Secondary• Problem originates in the

hypothalamus or theUndescended testicles– Mumps– Injury– Hemachromatosis– Klinefelter syndrome

hypothalamus or the pituitary gland– Pituitary tumors– Obesity– HIV/AIDS– Medications– Inflammatory diseases

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y– Kallmann syndrome– Normal aging

UpToDate® Causes of Primary Hypogonadism.

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Late‐Onset Hypogonadism

• Androgen Decline in the Aging Male (ADAM)

• Partial Androgen Deficiency of the Aging Male (PADAM)

• Andropause

• Male Climacteric

• Testosterone Deficiency Syndrome

ll f h

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• All are representative names for the symptoms that correlate with declining testosterone levels

ISSAM Standards and Guidelines. Aging Male. 2002;5:74‐86.

Testosterone Levels Throughout Life• In utero: first trimester

– Fetal testes secrete T

– Stimulated by placental y pgonadotropins

• Second trimester– Same as mid‐puberty

– Falls and then rises at birth

• InfancyF ll i f ll

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– Falls, rises, falls

– Significance unknown

• Puberty– Peaks 500 to 700 ng/dl

Brunton LL et al. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. http://www.accessmedicine.com.

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Puberty/Control of Testicular Function

• Hypothalamus synthesizes:– Gonadotropin releasing hormone

(GnRH)

GnRH pulses every 30 to 120 minutes– GnRH pulses every 30 to 120 minutes

• Anterior pituitary– Responds to GnRH and releases

leutinizing hormone (LH) and follicle‐stimulating hormone

• Leydig cells of the testes– Testosterone 95%

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– Dihydrotestosterone <20%

– Estradiol <20%

– Estrone <2%

– DHEA <10%


Actions of TestosteroneTestosterone

EstradiolDihydrotestosterone

Androgen Receptor

Estrogen Receptor

Androgen Receptor

Internal genitalia:‐Wolffiandevelopment during gestation

Skeletal muscle:

External genitalia:‐ Differentiation during gestation

‐Maturation during puberty

Bone:‐ Epiphyseal closure and increased density

Libido?

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Skeletal muscle:‐ Increase mass and strength during puberty

Erythropoiesis Bone?

puberty‐ Adulthood prostatic diseases

Hair follicles:‐ Increased growth during puberty


Libido?

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Effects of Androgens on Tissues

• Skeletal muscles

• Skin

• Bone marrow

• Testes

• Hair– Male pattern baldness

• CNS– Mood

– Energy

• Libido

• Prostate tissue

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– Motivation

– Aggression

1. Brunton LL et al. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 1th ed. http://www.accessmedicine.com. 2. UpToDate® Causes of Primary Hypogonadism.

Correlations of Low Testosterone

• Obesity• OsteoporosisM t b li d

• Fatigue

• Erectile dysfunction• Metabolic syndrome• Diabetes• Cardiovascular disease• Alzheimer’s disease• Depression

• Decreased sex drive

• Difficulty concentrating

• Hot flushes

• Muscle weakness

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• Frailty• Premature Death

1. Trinick TR et al. Aging Male. 2011;14(1):10‐15; 2. UpToDate® Causes of Primary Hypogonadism; 3. http://www.mayoclinic.com/health/male‐hypogonadism/DS0030.

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Data to Show Beneficial Outcomes

• Reduced cardiovascular risk?

• Increased cardiovascular risk?

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Patients to be Considered for Replacement Therapy

• Positive questionnaire • Low to lower – Aging Males’ Symptom Scale AMS

– 36‐Item Short‐Form Health Survey (SF‐36)

testosterone levels

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International Society for the Study of Aging

Males

Aging Males’ Symptoms(AMS) Scale

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http://issam.ch/AMS_English.pdf.

The International Society for the Study of the Aging Male

• Easily recognized features of diminished sexual desire and

• Decrease in body hair and skin alterations

erectile quality, particularly nocturnal erections

• Changes in mood with concomitant decreases in intellectual activity, spatial orientation ability, fatigue,

• Decrease in bone mineral density resulting in osteopenia and osteoporosis

• Increased visceral fat

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depressed mood, and irritability

• Decrease in lean body mass with associated decreased muscle mass and strength

Morales A et al. Aging Male. 2002;5:74‐86.

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Other Related Factors

• Recent weight gain (29%)

• Alcohol (17 3%)

• Medications:– Methadone– Opiates• Alcohol (17.3%)

• Testicular problems and orchitis (11.4%)

• Prostate operations and infections (5.6%)

• Urinary Infections

– Opiates– Buprenorphine– Glucocorticoids– Ketoconazole– Chemotherapy

• Alkylating agents• Cisplatin

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Urinary Infections (5.2%)

• Diabetes (5.7%)

• Cisplatin

1. Trinick TR et al. Aging Male. 2011;14(1):10‐15; 2. UpToDate® Causes of Primary Hypogonadism; 3. http://www.mayoclinic.com/health/male‐hypogonadism/DS00300.

Androgen Replacement Therapy (ART)

• Testosterone– Rapid first pass

• 17α‐alkylated androgens– Methytestosterone

– Winstrol (stanozolol)

• Testosterone esters– Testosterone enanthate

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– Testosterone cypionate

Adapted from Brunton LL et al. Good & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. http://wwww.accessmedicine.com.

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ART (cont.)

• Transdermal patches– Serum level fluctuates;

peaks 6 to 9 hours; drops

• Testosterone cream• Testosterone ointment• IM enanthate oruntil next patch

• Testosterone gels– Mean testosterone levels

relatively constant between each application

• Testosterone buccall

• IM enanthate or cypionate– Administered every 2 to 4

weeks–may be supratherapeutic and then drop

– Blood level at the mid i j ti i t l h ld b

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• Testosterone implant• Testosterone solution

injection interval should be normal and dosage and interval adjusted accordingly

Adverse Effects of Androgens

• “Hypogonadal men who undergo replacement may experience similar effects to testosterone may experience similar effects to testosteronesurges in puberty”– Acne– Gynecomastia– More aggressive sexual behavior

• Mineral Corticoid EffectsSodium and water retention CHF HTN CAD

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– Sodium and water retention – CHF, HTN, CAD• Erythropoesis Stimulation

– Increase hemoglobin, hematocrit (sudden death in abuse?)

Adapted from Brunton LL et al. Good & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. http://wwww.accessmedicine.com.

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ART Adverse Drug Reactions Monitoring Parameters

• Prostate– Enlargement

• Hemoglobin

• Hematocrit– Enlargement

– Alterations urine

– Increase risk CA

– PSA• Baseline

• Periodically

• Hematocrit– “Periodically”

• Lipids– “Periodically”

• Transaminitis/

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– 18% of patients had increase over 42 months

– Most within first year

– AST/ALT

– “Periodically”

AndroGel (testosterone gel) 1% [prescribing information]; Fortesta (testosterone) Gel [prescribing information]; Testim 1% (testosterone gel) [prescribing information].

Boxed Warnings

• Virilization has been reported in children who have been secondarily exposed to topical have been secondarily exposed to topicaltestosterone products

• Children should avoid contact with unwashed or unclothed application sites of patients using topical testosterone

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• Health care providers should advise patients to strictly adhere to instructions for use


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Contraindications to Testosterone

• Men with carcinoma of the breast or known or suspected prostate cancerknown or suspected prostate cancer

• Pregnant or breast‐feeding women. Testosterone may cause fetal harm

29AndroGel (testosterone gel) 1% [prescribing information]; Fortesta (testosterone) Gel [prescribing information]; Testim 1% (testosterone gel) [prescribing information].

Cautions

• Patients with benign prostatic hyperplasia (BPH) treated with androgens are at an increased risk for worsening of signs andincreased risk for worsening of signs and symptoms of BPH

• Secondary exposure to testosterone in children and women can occur with use of testosterone gel. Cases of secondary exposure

lti i i ili ti f hild h b

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resulting in virilization of children have been reported


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Cautions (cont.)

• Exogenous testosterone administration may lead to azospermia

• Edema with or without congestive heart failure may be a complication in patients with preexisting heart, renal, or hepatic disease

• Exacerbation of sleep apnea may occur, especially in patients with obesity and chronic

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especially in patients with obesity and chronic lung disease


General Application Education

• Children and women should avoid contact with unwashed or unclothed application site(s) in men using testosterone gel

• To minimize the potential for transfer to others, patients using topical testosterone h ld l h d d d d

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should apply the product as directed and strictly adhere to the following:


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Topical Education (cont.)

– Wash hands with soap and water after application

– Cover the application site with clothing after the gel has dried

– Wash the application site thoroughly with soap and water prior to any situation where skin‐to‐skin contact of the application site with another

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person is anticipated

AndroGel [prescribing information]; Fortesta [prescribing information]; Testim [prescribing information].

Common Sense Counseling

• Avoid fire, flames, or smoking until the gel has dried, since alcohol‐based products are flammable

34AndroGel (testosterone gel) 1% [prescribing information]; Fortesta (testosterone) Gel [prescribing information]; Testim 1% (testosterone gel) [prescribing information].

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Transdermal Testosterone Gels

• AndroGel (testosterone gel) 1%– 25 mg/2.5 g– 50 mg/5 g

• AndroGel (testosterone gel)

• Fortesta (testosterone) Gel– 10 mg/actuation– 4 actuations, 40 mg

• Testim 1% (testosterone gel)• AndroGel (testosterone gel) Pump– 1.25 g/pump– 2 to 4 pumps per day

• AndroGel (testosterone gel) 1.62%– 20.25 mg/actuation 40.5 mg– 2 pumps to start

• Testim 1% (testosterone gel)– 50 mg/5 g tube

35AndroGel (testosterone gel) 1% [prescribing information]; Fortesta [prescribing information]; Testim [prescribing information].

Dosage Adjustment: “Older” 1% Gels

AndroGel• Serum testosterone levels

h ld b d

Testim• Morning serum

d 14should be measured at intervals

• If the levels are below normal, the dose may be increased to 5 to 7.5 g, 7.5 to 10 gf h l l i

testosterone measured 14 days after starting

• Increase if below normal ranges; to 10 g (2 tubes)

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• If the serum level is consistently above normal at a dose of 5 g, should discontinue

AndroGel® (testosterone gel) 1%)[prescribing information].

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Dosage Adjustment: AndroGel 1.62%

• 20.25 mg/actuation

• 2 pumps to start

• Around days 14 and 35

• Pre‐dose morning blood T level

Pre‐Dose Monitoring Total Serum Testosterone Concentration

Dose Titration

>750 ng/dLDecrease daily dose by 20.25 mg

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>750 ng/dL(1 pump actutation)

≥350 and ≤750 ng/dL No change; continue on current dose

<350 ng/dLIncrease daily dose by 20.25 mg

(1 pump actutation)

AndroGel (testosterone gel) 1.62%) [prescribing information].

Dosage Adjustment: Fortesta

• Normal starting dose: 4 pumps (40 mg)

• 2 hours after application:pp– On days 14, 35

Total Serum Testosterone Concentration 2 hours Post Fortesta Application

Dose Titration

>2500 ng/dLDecrease daily dose by 20 mg

(2 pump actuations)

Decrease daily dose by 10 mg

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≥1250 and <2500 ng/dLDecrease daily dose by 10 mg

(1 pump actuation)

≥500 and <1250 ng/dL No change; continue on current dose

<350 ng/dLIncrease daily dose by 10 mg

(1 pump actuation)

Fortesta (testosterone) Gel [prescribing information].

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Transdermal Testosterone Solution• Axiron

• Underarm applicator

• Blood level T 14 days after

• 2 to 8 hours after application

• Dosage adjustment: 300 to 1050initiation 1050

• Application instructions

Daily Prescribed Dose

# of Pump Actuations

Application

30 mg 1 (once daily) Apply once to 1 axilla only (left or right)

60 mg 2 (once daily)Apply once to the left axilla and then apply once to right axilla

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g

90 mg 3 (once daily)Apply once to the left and once to the right axilla, wait for the product to dry, and then apply once again to the left OR right axilla

120 mg 4 (once daily)Apply once to the left and once to the right axilla, wait for the product to dry, and then apply once again to the left AND right axilla

Axiron (testosterone topical solution) 1% [prescribing information].

Transdermal Testosterone Cream/Ointment

Cream

Fi t T t t MC

Ointment

Fi t T t t• First‐Testosterone MC– 48 g moisturizing cream

– 12 ml T (100 mg/ml)

– When mixed, 2% cream

– Stable at room temperature for 6

• First‐Testosterone– 48 g petrolatum

– 12 ml T (100 mg/ml)

– When mixed, 2% ointment

– Stable at room

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temperature for 6 months

– 5 ml rubbed onto shoulders once daily

Stable at room temperature for 6 months

– 5 ml rubbed onto shoulders once daily

First‐Testosterone MC 2% [prescribing information].

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Transmucosal Buccal

Striant

• 30 mg buccal systemg y

• Twice daily dosing

• Serum concentrations rise for 10 hours

Study 1 Study 2

12 weeks (N = 82) 7 days (N = 29)

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12 weeks (N 82) 7 days (N 29)

Cavg(0‐24) (ng/dL) 520 (± 205) 550 (± 169)

Cmax(0‐24) (ng/dL) 970 (± 442) 910 (± 319)

Cmin(0‐24) (ng/dL) 290 (± 130) 320 (± 131)

Striant (testosterone buccal system) [prescribing information].

Intramuscular Testosterone

Cypionate

• Depo‐Testosterone

Enanthate

• Delatestryl

• 100, 200 mg/ml

• In oil base

• Normal for discoloration

• 100 to 400 mg IM every

• 200 mg/ml

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g y2 to 4 weeks

www.drugs.com. Accessed August 8, 2011.

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Transdermal Testosterone Patchs

• Androderm– 2.5 mg/24 hours

– 5 mg/24 hours

Mean steady state levels d h

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• 29 men used 2.5 mg patches• 27 used 2 systems (5 mg) • 2 used 3 systems (7.5 mg)

Androderm (testosterone transdermal system) [prescribing information].

Role of the Pharmacist

• Patient advocacy for candidate males– Depression medications– Increased appearance of obesity– Flat affect at consultation– Prescriptions/samples for ED medications

• Physician education for the symptoms– Diabetes

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– CAD– HTN– Depression

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• Monitoring for interacting medications• Drug‐induced hypogonadism

– ethanol, opiates, methadone, ketoconazole

• Drug interactions with testosterone replacement– We induced a problem prostate

• Alpha 1 antagonists– Selective, Not

• 5‐alpha reductase inhibitors

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5 alpha reductase inhibitors

– We induced a problem with hairline– Corticosteroid coadministration


• Cost coverage issues– AndroGel “Restoration Program”g

– Axiron “Promise Program”– Testim “Savings Voucher Program”

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• CounselingAvoiding secondary exposure– Avoiding secondary exposure

• Apply to upper chest and shoulders, cover with shirt

– Appropriate application

– Daily adherence

– Do not self‐escalate dosage

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Hypogonadism and Testosterone Replacement Therapy:

Practical Insights for the Pharmacistg

THANK YOU!THANK YOU!

For any questions regarding this activity, contact: [email protected]

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