Hypogonadism and Testosterone Replacement Therapy: Practical Insights for the Pharmacist Roger G. Hefflinger, PharmD Associate Professor of Pharmacy Practice and Administrative Services Idaho State University, College of Pharmacy Pocatello, Idaho Faculty Information Presenter: Roger G. Hefflinger, PharmD Associate Professor of Pharmacy Practice and Administrative Services Idaho State University, College of Pharmacy Pocatello, Idaho Moderator: Jeff D. Prescott, PharmD, RPh Vice President, Clinical Affairs Pharmacy Times This activity is supported by an educational grant from Abbott Laboratories. 2 1
Disclosures Roger 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 the 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. 3 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 Counsel patients on the correct usage of the various testosterone dosage forms in order to improve patient adherence and outcomes 4 2
Pharmacy Accreditation Pharmacy Times Office of Continuing Professional Education is accredited by the Accreditation ti Council ilfor 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 September 15, 2013. Type of Activity: Knowledge based. 5 Hypogonadism and Testosterone Replacement Therapy: Practical Insights for the Pharmacist Roger G. Hefflinger, PharmD Associate Professor of Pharmacy Practice and Administrative Services Idaho State University, College of Pharmacy Pocatello, Idaho 3
Origination of Testicular Dysfunction Male hypogonadism Fetal hypogonadism Pubertal hypogonadism Adult hypogonadism http://www.mayoclinic.com/health/male hypogonadism/ds00300 7 Signs and Symptoms of Hypogonadism Birth and infancy: early signs Failure of the testes to descend Normally formed dhypotrophic hi penis Adolescent males Delayed, arrested, or absent testicular growth Delayed secondary sex characteristics Hi Hair Acne Muscle mass Vocal cord development voice changes http://www.mayoclinic.com/health/male hypogonadism/ds00300 8 4
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 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. 9 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 Serum testosterone levels l 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. 10 5
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 ofsymptomatic 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. 11 Nomenclature Primary Primary testicular failure Undescended testicles Mumps Injury Hemachromatosis Klinefelter syndrome Secondary Problem originates in the hypothalamus or the pituitary gland Pituitary tumors Obesity HIV/AIDS Medications Inflammatory diseases Kallmann syndrome Normal aging UpToDate Causes of Primary Hypogonadism. 12 6
Late Onset Hypogonadism Androgen Decline in the Aging Male (ADAM) Partial Androgen Deficiency of the Aging Male (PADAM) Andropause Male Climacteric Testosterone Deficiency Syndrome All are representative names for the symptoms that correlate with declining testosterone levels ISSAM Standards and Guidelines. Aging Male. 2002;5:74 86. 13 Testosterone Levels Throughout Life In utero: first trimester Fetal testes secrete T Stimulated by placental gonadotropins Second trimester Same as mid puberty Falls and then rises at birth Infancy Fll Falls, rises, falls fll 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. 14 7
Puberty/Control of Testicular Function Hypothalamus synthesizes: Gonadotropin releasing hormone (GnRH) GnRH pulses every 30 to 120 minutes Anterior pituitary Responds to GnRH and releases leutinizing hormone (LH) and folliclestimulating hormone Leydig cells of the testes Testosterone 95% Dihydrotestosterone <20% Estradiol <20% Estrone <2% DHEA <10% Brunton LL et al. Goodman & Gilman s The Pharmacological Basis of Therapeutics. 11th ed. http://www.accessmedicine.com. 15 Actions of Testosterone Testosterone Dihydrotestosterone Estradiol Androgen Receptor Androgen Receptor Estrogen Receptor External genitalia: Differentiation during gestation Maturation during puberty Adulthood prostatic diseases Hair follicles: Increased growth during puberty Internal genitalia: Wolffian development during gestation Skeletal muscle: Increase mass and strength during puberty Erythropoiesis Bone? Bone: Epiphyseal closure and increased density Libido? Brunton LL et al. Goodman & Gilman s The Pharmacological Basis of Therapeutics. 11th ed. http://www.accessmedicine.com. 16 8
Effects of Androgens on Tissues Skeletal muscles Skin Hair Male pattern baldness CNS Mood Energy Motivation Aggression Bone marrow Testes Libido Prostate tissue 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. 17 Correlations of Low Testosterone Obesity Osteoporosis Mtbli Metabolic syndrome Diabetes Cardiovascular disease Alzheimer s disease Depression Frailty Premature Death Fatigue Erectile dysfunction Decreased sex drive Difficulty concentrating Hot flushes Muscle weakness 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. 18 9
Data to Show Beneficial Outcomes Reduced cardiovascular risk? Increased cardiovascular risk? 19 Patients to be Considered for Replacement Therapy Positive questionnaire Aging Males Symptom Scale AMS 36 Item Short Form Health Survey (SF 36) Low to lower testosterone levels 20 10
International Society for the Study of Aging Males Aging Males Symptoms (AMS) Scale http://issam.ch/ams_english.pdf. 21 The International Society for the Study of the Aging Male Easily recognized features of diminished sexual desire and erectile quality, particularly nocturnal erections Changes in mood with concomitant decreases in intellectual activity, spatial orientation ability, fatigue, depressed mood, and irritability Decrease in lean body mass with associated decreased muscle mass and strength Decrease in body hair and skin alterations Decrease in bone mineral density resulting in osteopenia and osteoporosis Increased visceral fat Morales A et al. Aging Male. 2002;5:74 86. 22 11
Other Related Factors Recent weight gain (29%) Alcohol (17.3%) Testicular problems and orchitis (11.4%) Prostate operations and infections (5.6%) Urinary Infections (5.2%) Diabetes (5.7%) Medications: Methadone Opiates Buprenorphine Glucocorticoids Ketoconazole Chemotherapy Alkylating agents 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. 23 Androgen Replacement Therapy (ART) Testosterone Rapid first pass 17α alkylated androgens Methytestosterone Winstrol (stanozolol) Testosterone esters Testosterone enanthate Testosterone cypionate Adapted from Brunton LL et al. Good & Gilman s The Pharmacological Basis of Therapeutics. 11th ed. http://wwww.accessmedicine.com. 24 12
ART (cont.) Transdermal patches Serum level fluctuates; peaks 6 to 9 hours; drops until next patch Testosterone gels Mean testosterone levels relatively constant between each application Testosterone buccal Testosterone implant Testosterone solution Testosterone cream Testosterone ointment IM enanthate or cypionate Administered every 2 to 4 weeks may be supratherapeutic and then drop Blood level at the mid injection interval should ldbe normal and dosage and interval adjusted accordingly 25 Adverse Effects of Androgens Hypogonadal men who undergo replacement may experience similar effects to testosterone surges in puberty Acne Gynecomastia More aggressive sexual behavior Mineral Corticoid Effects 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. 26 13
ART Adverse Drug Reactions Monitoring Parameters Prostate Enlargement Alterations urine Increase risk CA PSA Baseline Periodically 18% of patients had increase over 42 months Most within first year Hemoglobin Hematocrit Periodically Lipids Periodically Transaminitis AST/ALT Periodically AndroGel (testosterone gel) 1% [prescribing information]; Fortesta (testosterone) Gel [prescribing information]; Testim 1% (testosterone gel) [prescribing information]. 27 Boxed Warnings Virilization has been reported in children who have been secondarily exposed to topical testosterone products Children should avoid contact with unwashed or unclothed application sites of patients using topical testosterone Health care providers should advise patients to strictly adhere to instructions for use AndroGel (testosterone gel) 1% [prescribing information]; Fortesta (testosterone) Gel [prescribing information]; Testim 1% (testosterone gel) [prescribing information]. 28 14
Contraindications to Testosterone Men with carcinoma of the breast or known orsuspected prostate cancer Pregnant or breast feeding women. Testosterone may cause fetal harm AndroGel (testosterone gel) 1% [prescribing information]; Fortesta (testosterone) Gel [prescribing information]; Testim 1% (testosterone gel) [prescribing information]. 29 Cautions Patients with benign prostatic hyperplasia (BPH) treated with androgens are at an increased 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 resulting in virilization ili of children have been reported AndroGel (testosterone gel) 1% [prescribing information]; Fortesta (testosterone) Gel [prescribing information]; Testim 1% (testosterone gel) [prescribing information]. 30 15
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 lung disease AndroGel (testosterone gel) 1% [prescribing information]; Fortesta (testosterone) Gel [prescribing information]; Testim 1% (testosterone gel) [prescribing information]. 31 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 should apply the product as directed dand strictly adhere to the following: AndroGel (testosterone gel) 1% [prescribing information]; Fortesta (testosterone) Gel [prescribing information]; Testim 1% (testosterone gel) [prescribing information]. 32 16
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 toskin contact of the application site with another person is anticipated AndroGel [prescribing information]; Fortesta [prescribing information]; Testim [prescribing information]. 33 Common Sense Counseling Avoid fire, flames, or smoking until the gel has dried, since alcohol based products are flammable AndroGel (testosterone gel) 1% [prescribing information]; Fortesta (testosterone) Gel [prescribing information]; Testim 1% (testosterone gel) [prescribing information]. 34 17
Transdermal Testosterone Gels AndroGel (testosterone gel) 1% 25 mg/2.5 g 50 mg/5 g 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 Fortesta (testosterone) Gel 10 mg/actuation 4 actuations, 40 mg Testim 1% (testosterone gel) 50 mg/5 g tube AndroGel (testosterone gel) 1% [prescribing information]; Fortesta [prescribing information]; Testim [prescribing information]. 35 Dosage Adjustment: Older 1% Gels AndroGel Serum testosterone levels should ldbe measured at intervals If the levels are below normal, the dose may be increased to 5 to 7.5 g, 7.5 to 10 g If the serum level lis consistently above normal at a dose of 5 g, should discontinue Testim Morning serum testosterone measured 14 days after starting Increase if below normal ranges; to 10 g (2 tubes) AndroGel (testosterone gel) 1%)[prescribing information]. 36 18
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 >750 ng/dl 350 and 750 ng/dl <350 ng/dl Dose Titration Decrease daily dose by 20.25 mg (1 pump actutation) No change; continue on current dose Increase daily dose by 20.25 mg (1 pump actutation) AndroGel (testosterone gel) 1.62%) [prescribing information]. 37 Dosage Adjustment: Fortesta Normal starting dose: 4 pumps (40 mg) 2 hours after application: On days 14, 35 Total Serum Testosterone Concentration 2 hours Post Fortesta Application >2500 ng/dl 1250 and <2500 ng/dl 500 and <1250 ng/dl <350 ng/dl Dose Titration Decrease daily dose by 20 mg (2 pump actuations) Decrease daily dose by 10 mg (1 pump actuation) No change; continue on current dose Increase daily dose by 10 mg (1 pump actuation) Fortesta (testosterone) Gel [prescribing information]. 38 19
Transdermal Testosterone Solution Axiron Underarm applicator Blood level T 14 days after initiation 1050 Daily Prescribed Dose # of Pump Actuations 2 to 8 hours after application Dosage adjustment: 300 to 1050 Application instructions Application 30 mg 1 (once daily) Apply once to 1 axilla only (left or right) 60 mg 2 (once daily) 90 mg 3 (once daily) 120 mg 4 (once daily) Apply once to the left axilla and then apply once to right axilla 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 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]. 39 Transdermal Testosterone Cream/Ointment Cream First Testosterone t t MC 48 g moisturizing cream 12 ml T (100 mg/ml) When mixed, 2% cream Stable at room temperature for 6 months 5 ml rubbed onto shoulders once daily Ointment First Testosterone t t 48 g petrolatum 12 ml T (100 mg/ml) When mixed, 2% ointment Stable at room temperature for 6 months 5 ml rubbed onto shoulders once daily First Testosterone MC 2% [prescribing information]. 40 20
Striant Transmucosal Buccal 30 mg buccal system Twice daily dosing Serum concentrations rise for 10 hours Study 1 Study 2 12 weeks (N = 82) 7 days (N = 29) C avg(0 24) (ng/dl) 520 (± 205) 550 (± 169) C max(0 24) (ng/dl) 970 (± 442) 910 (± 319) C min(0 24) (ng/dl) 290 (± 130) 320 (± 131) Striant (testosterone buccal system) [prescribing information]. 41 Intramuscular Testosterone Cypionate Depo Testosterone 100, 200 mg/ml In oil base Normal for discoloration 100 to 400 mg IM every 2 to 4 weeks Enanthate Delatestryl 200 mg/ml www.drugs.com. Accessed August 8, 2011. 42 21
Transdermal Testosterone Patchs Androderm 2.5 mg/24 hours 5 mg/24 hours Mean steady state levels 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]. 43 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 CAD HTN Depression 44 22
Role of the Pharmacist 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 We induced a problem with hairline Corticosteroid coadministration 45 Role of the Pharmacist Cost coverage issues AndroGel Restoration Program Axiron Promise Program Testim Savings Voucher Program 46 23
Role of the Pharmacist Counseling Avoiding secondary exposure Apply to upper chest and shoulders, cover with shirt Appropriate application Daily adherence Do not self escalate dosage 47 Hypogonadism and Testosterone Replacement Therapy: Practical Insights for the Pharmacist THANK YOU! For any questions regarding this activity, contact: CEINFO@pharmacytimes.com 24