Stakeholder Perspectives in Men's Health October 2014

STAKEHOLDER PERSPECTIVES IN

en’s Health OCTOBER 2014 • PART 2 IN A SERIES

The Central Role of the Urology Practice in Managing Patients with Erectile Dysfunction and Low Testosterone

By Loretta Fala, Medical Writer

B

etween 2012 and 2050, the aging of the baby boomer generation will generate a dramatic increase in the number of people in the United States who are ≥65 years of age.1 More than 20% of the US population will be in this age group by 2020, and the number of people in this age group is projected to nearly double from 43.1 million in 2012 to 83.7 million by 2050.1 Fortunately, life expectancy for men and women in all age groups, including older Americans, is also projected to improve between 2012 and 2050. By 2030, men will account for approximately 45% of the population aged 65 years and older, and women will account for 55% of this age group.1 This steady increase in the number of aging Americans will have a substantial impact on healthcare delivery, resources, and policy in the coming decades.

As the healthcare system continues to evolve in response to far-reaching changes at the national, state, and local levels, there is an increasing demand for payers, providers, and patients to consider both the clinical and economic implications of healthcare decisions—with emphasis on quality, value, and accountability. The aging of the population and major healthcare changes are having a profound impact on urology practices, from business as well as clinical perspectives.

Men’s Health: The Increasing Importance of the Urology Practice Men’s health issues, particularly those more common in aging men—erectile dysfunction (ED) and low testosterone (Low T)—warrant greater clinical focus. Often underrecognized and underestimated as clinical entities, both ED and Low T are associated with such serious co-

Editor’s Note

Urology Practice Management™ is publishing a series of newsletters about selected men’s health topics that are of interest to the urology community. The newsletters provide relevant, up-to-date, evidence-based information on current topics of interest in a straightforward, concise manner. The series is specifically designed to raise awareness about new treatment approaches that may interest urologists and urology practice administrators from a business as well as a clinical perspective.

The second issue of the newsletter series focuses on erectile dysfunction and low testosterone (see the article on this page). Both disorders continue to be underrecognized and underestimated as clinical entities, yet are associated with serious comorbidities such as cardiovascular disease, hypertension, diabetes, and depression. Early detection is especially vital, as it may reveal the existence of life-threatening underlying conditions affecting the patient’s overall health.

Urology practices face many challenges and opportunities in today’s healthcare environment, and, based on their training, urologists are well-equipped to play a key role in the care of patients with erectile dysfunction, low testosterone, and other men’s health issues.

This second issue in our newsletter series explores both of these disorders, including etiologies and comorbidities, evaluation and treatment, as well as considerations for the patient and practice.

IMPORTANT SAFETY INFORMATION • There is a potential for cardiac risk during sexual activity in patients with preexisting cardiovascular disease. Patients should therefore not use STENDRA if sexual activity is inadvisable due to cardiovascular status or any other reason.

• Patients with the following characteristics (recent serious cardiovascular events, resting hypotension or uncontrolled hypertension, unstable angina, angina with sexual intercourse, New York Heart Association Class 2 or greater congestive heart failure, or hereditary degenerative retinal disorders, including retinitis pigmentosa) were not included in the clinical safety and efficacy trials. STENDRA is therefore not recommended for those patients.

• As with other PDE5 inhibitors STENDRA has systemic vasodilatory properties and may augment the blood pressurelowering effect of other antihypertensive medications. Physicians should carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity.

• STENDRA metabolism is principally mediated by the CYP450 isoform 3A4 (CYP3A4). Inhibitors of CYP3A4 may reduce STENDRA clearance and increase plasma concentrations of avanafil. Do not use STENDRA in patients taking concomitant strong CYP3A4 inhibitors. For patients taking concomitant moderate CYP3A4 inhibitors, the maximum recommended dose of STENDRA is 50 mg, not to exceed once every 24 hours.

• Prolonged erections greater than 4 hours in duration and priapism (painful erections greater than 6 hours in duration) have been reported with other PDE5 inhibitors. Patients should seek emergency treatment for an erection that lasts longer than 4 hours. If not treated immediately, penile tissue damage and permanent loss of potency could result. Use with caution in patients with anatomical deformation of the penis or in patients with conditions that may predispose them to priapism.

• Physicians should advise patients to stop use of all PDE5 inhibitors, including STENDRA, and seek medical attention in the event of a sudden loss of vision in one or both eyes. This may be a sign of nonarteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision. STENDRA should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION. • Use of PDE5 inhibitors has been associated with sudden decrease or loss of hearing, which may be accompanied by tinnitus or dizziness. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Patients experiencing these symptoms should be advised to stop taking STENDRA and seek prompt medical attention.

• Physicians should discuss with patients the potential for STENDRA to augment the blood pressure-lowering effect of alpha-blockers and other antihypertensive medications.

• Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors. Patients should be stable on alpha-blocker therapy prior to initiating treatment with a PDE5 inhibitor. In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose (STENDRA 50 mg). In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dosage may be associated with further lowering of blood pressure when taking a PDE5 inhibitor.

• Both alcohol and PDE5 inhibitors including STENDRA act as vasodilators. When vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Physicians should therefore inform patients that substantial consumption of alcohol (ie, greater than 3 units) in combination with STENDRA may increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.

• The safety and efficacy of combinations of STENDRA with other treatments for ED have not been studied. The use of such combinations is therefore not recommended.

• The safety of STENDRA is unknown in patients with bleeding disorders and patients with active peptic ulceration.

In vitro studies with human platelets indicate that STENDRA potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide [NO] donor).

• The use of STENDRA offers no protection against sexually transmitted diseases. Counseling patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV), should be considered.

• The most common adverse reactions (greater than or equal to 2%) include headache, flushing, nasal congestion, nasopharyngitis, and back pain.

• Drug interactions: STENDRA can potentiate the hypotensive effect of nitrates, alpha-blockers, antihypertensives, and alcohol. CYP3A4 inhibitors (eg, ketoconazole, ritonavir, erythromycin) increase STENDRA exposure.

References: 1. STENDRA [package insert]. VIVUS, Inc.; 2014. 2. Viagra® [package insert]. Pfizer Inc; 2014. 3. Levitra® [package insert].

Bayer Healthcare Pharmaceuticals Inc.; 2014. 4. Staxyn® [package insert]. Bayer Healthcare Pharmaceuticals Inc.; 2014.

5. Cialis® [package insert]. Eli Lilly and Company; 2014.

Please see Brief Summary of Prescribing Information on adjacent pages.

THIS TIME HE WAS READY

BEFORE datE night EvEn staRtEd

stEndRa—thE FiRst and Only Fda-appROvEd pdE5i that can BE 1-5 takEn as EaRly as ~15 minutEs BEFORE sExual activity * INDICATION STENDRA is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction.

IMPORTANT SAFETY INFORMATION • Administration of STENDRA with any form of organic nitrates, either regularly and/or intermittently, is contraindicated. STENDRA has been shown to potentiate the hypotensive effects of nitrates.

• STENDRA is contraindicated in patients with a known hypersensitivity to any component of the tablet.

*STENDRA 100 and 200 mg dosage strengths.

STENDRATM (avanafil) Tablets Brief Summary of Prescribing Information Please see the full Prescribing Information for STENDRA available at Stendra.com INDICATIONS AND USAGE STENDRA is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction.

CONTRAINDICATIONS Nitrates Administration of STENDRA with any form of organic nitrates, either regularly and/or intermittently, is contraindicated. Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway, STENDRA has been shown to potentiate the hypotensive effects of nitrates.

In a patient who has taken STENDRA, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of STENDRA before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring [see Dosage and Administration (2.3), and Clinical Pharmacology (12.2) in full Prescribing Information].

Hypersensitivity Reactions STENDRA is contraindicated in patients with a known hypersensitivity to any component of the tablet. Hypersensitivity reactions have been reported, including pruritis and eyelid swelling.

WARNINGS AND PRECAUTIONS Evaluation of erectile dysfunction (ED) should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options.

Before prescribing STENDRA, it is important to note the following: Cardiovascular Risks There is a potential for cardiac risk during sexual activity in patients with pre-existing cardiovascular disease. Therefore, treatments for ED, including STENDRA, should not be used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. Patients with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure can be particularly sensitive to the actions of vasodilators, including STENDRA. The following groups of patients were not included in clinical safety and efficacy trials for STENDRA, and therefore until further information is available, STENDRA is not recommended for the following groups: • Patients who have suffered a myocardial infarction, stroke, life-threatening arrhythmia, or coronary revascularization within the last 6 months; • Patients with resting hypotension (blood pressure less than 90/50 mmHg) or hypertension (blood pressure greater than 170/100 mmHg); • Patients with unstable angina, angina with sexual intercourse, or New York Heart Association Class 2 or greater congestive heart failure. As with other PDE5 inhibitors STENDRA has systemic vasodilatory properties and may augment the blood pressure-lowering effect of other anti-hypertensive medications. STENDRA 200 mg resulted in transient decreases in sitting blood pressure in healthy volunteers of 8.0 mmHg systolic and 3.3 mmHg diastolic [see Clinical Pharmacology (12.2) in full Prescribing Information], with the maximum decrease observed at 1 hour after dosing. While this normally would be expected to be of little consequence in most patients, prior to prescribing STENDRA, physicians should carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity.

Concomitant Use of CYP3A4 Inhibitors STENDRA metabolism is principally mediated by the CYP 450 isoform 3A4 (CYP 3A4). Inhibitors of CYP 3A4 may reduce STENDRA clearance and increase plasma concentrations of avanafil.

For patients taking concomitant strong CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir and telithromycin), do not use STENDRA [see Drug Interactions]. For patients taking concomitant moderate CYP3A4 inhibitors (including erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the maximum recommended dose of STENDRA is 50 mg, not to exceed once every 24 hours [see Drug Interactions].

Prolonged Erection Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported with other PDE5 inhibitors. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If not treated immediately, penile tissue damage and permanent loss of potency could result. STENDRA should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

Effects on Eye Physicians should advise patients to stop use of all PDE5 inhibitors, including STENDRA and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision including permanent loss of vision that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged ≥ 50. An observational study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION. The results suggest an approximate 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. From this information, it is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors (see Adverse Reactions) Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including STENDRA, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with “crowded” optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including STENDRA, for this uncommon condition.

Sudden Hearing Loss Use of PDE5 inhibitors has been associated with sudden decrease or loss of hearing, which may be accompanied by tinnitus or dizziness. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions]. Patients experiencing these symptoms should be advised to stop taking STENDRA and seek prompt medical attention.

Alpha-Blockers and Other Antihypertensives Physicians should discuss with patients the potential for STENDRA to augment the blood pressure-lowering effect of alpha-blockers and other antihypertensive medications [see Drug Interactions and Clinical Pharmacology (12.2) in full Prescribing Information]. Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. Phosphodiesterase type 5 inhibitors, including STENDRA, and

alpha-adrenergic blocking agents are both vasodilators with blood pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting). Consideration should be given to the following: • Patients should be stable on alpha-blocker therapy prior to initiating treatment with a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.

• In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose (STENDRA 50 mg).

• In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor. Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs [see Dosage and Administration in full Prescribing Information and Drug Interactions].

Alcohol Patients should be made aware that both alcohol and PDE5 inhibitors including STENDRA act as vasodilators.

When vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., greater than 3 units) in combination with STENDRA may increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache [see Drug Interactions and Clinical Pharmacology (12.2) in full Prescribing Information].

Combination with Other PDE5 Inhibitors or Erectile Dysfunction Therapies The safety and efficacy of combinations of STENDRA with other treatments for ED has not been studied. Therefore, the use of such combinations is not recommended.

Effects on Bleeding The safety of STENDRA is unknown in patients with bleeding disorders and patients with active peptic ulceration. In vitro studies with human platelets indicate that STENDRA potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide [NO] donor).

Counseling Patients about Sexually Transmitted Diseases The use of STENDRA offers no protection against sexually transmitted diseases. Counseling patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV), should be considered.

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. STENDRA was administered to 1923 men during clinical trials. In trials of STENDRA for use as needed, a total of 493 patients were exposed for greater than or equal to 6 months, and 153 patients were treated for greater than or equal to 12 months. In three randomized, double-blind, placebo-controlled trials lasting up to 3 months in duration, the mean age of patients was 56.4 years (range from 23 to 88 years). 83.9 % of patients were White (83.9%), 13.8% were Black, 1.4% Asian, and < 1% Hispanic. 41.1% were current or previous smokers. 30.6% had diabetes mellitus. The discontinuation rate due to adverse reactions for patients treated with STENDRA 50 mg, 100 mg, or 200 mg was 1.4%, 2.0%, and 2.0%, respectively, compared to 1.7% for placebo-treated patients.

Table 1: Adverse Reactions Reported by Greater Than or Equal to 2% of Patients Treated with STENDRA From 3 Placebo-Controlled Clinical Trials Lasting 3 Months for STENDRA Use as Needed Adverse Reaction

Placebo (N = 349)

STENDRA 50 mg (N = 217)

STENDRA 100 mg (N = 349)

STENDRA 200 mg (N = 352)

Headache Flushing Nasal congestion Nasopharyngitis Back pain

1.7% 0.0% 1.1% 2.9% 1.1%

5.1% 3.2% 1.8% 0.9% 3.2%

6.9% 4.3% 2.9% 2.6% 2.0%

10.5% 4.0% 2.0% 3.4% 1.1%

Adverse reactions reported by greater than or equal to 1%, but less than 2% of patients in any STENDRA dose group, and greater than placebo included: upper respiratory infection (URI), bronchitis, influenza, sinusitis, sinus congestion, hypertension, dyspepsia, nausea, constipation, and rash. In an, open-label, long-term extension study of two of these randomized, double-blind, placebo-controlled trials, the total duration of treatment was up to 52 weeks.

Among the 712 patients who participated in this open-label extension study, the mean age of the population was 56.4 years (range from 23 to 88 years). The discontinuation rate due to adverse reactions for patients treated with STENDRA (50 mg, 100 mg, or 200 mg) was 2.8%. In this extension trial, all eligible patients were initially assigned to STENDRA 100 mg. At any point during the trial, patients could request to have their dose of STENDRA increased to 200 mg or decreased to 50 mg based on their individual response to treatment. In total, 536 (approximately 75%) patients increased their dose to 200 mg and 5 (less than 1%) patients reduced their dose to 50 mg.

Table 2: Adverse Reactions Reported by Greater Than or Equal to 2% of Patients Treated With STENDRA in an Open-Label Extension Trial Adverse Reaction Headache Flushing Nasopharyngitis Nasal congestion

STENDRA (N = 711) 5.6% 3.5% 3.4% 2.1%

Adverse reactions reported by greater than or equal to 1%, but less than 2% of patients in the open-label extension study included: upper respiratory infection (URI), influenza, sinusitis, bronchitis, dizziness, back pain, arthralgia, hypertension, and diarrhea. In an additional, randomized, double-blind, placebo-controlled study lasting up to 3 months in men who had undergone bilateral nerve-sparing radical prostatectomy for prostate cancer, the mean age of patients was 58.4 years (range 40 – 70).

Table 3: Adverse Reactions Reported by Greater than or Equal to 2% of Patients Treated with STENDRA in a Placebo-Controlled Clinical Trial Lasting 3 Months in Patients Who Underwent Bilateral Nerve-Sparing Radical Prostatectomy Adverse Reaction Headache Flushing Nasopharyngitis Upper respiratory infection Nasal congestion Back pain Electrocardiogram abnormal Dizziness

Placebo (N = 100) 1.0% 0.0% 0.0% 0.0% 1.0% 1.0% 0.0% 0.0%

STENDRA 100 mg (N = 99) 8.1% 5.1% 3.0% 2.0% 3.0% 3.0% 1.0% 1.0%

STENDRA 200 mg (N = 99) 12.1% 10.1% 5.1% 3.0% 1.0% 2.0% 3.0% 2.0%

A randomized, double-blind, placebo-controlled 2 months study was conducted in 435 subjects with a mean age of 58.2 years (range 24 to 86 years) to determine the time to onset of effect of STENDRA, defined as the time to the first occurrence of an erection sufficient for sexual intercourse .

Table 4: Adverse Reactions Reported by ≥ 2% of Patients Treated with STENDRA in a PlaceboControlled Clinical Trial Lasting 2 Months to Determine the Time to Onset of Effect Adverse Reaction Headache Flushing Nasopharyngitis

Placebo (N = 143) 0.7% 0.0% 0.0%

STENDRA 100 mg (N = 146) 1.4% 0.7% 0.0%

STENDRA 200 mg (N = 146) 89% 4.1% 2.1%

Across all trials with any STENDRA dose, 1 patient reported a change in color vision.

The following events occurred in less than 1% of patients in the three placebo-controlled 3-month clinical trials and/or the open-label, long-term extension study lasting 12 months: edema peripheral, fatigue, angina, unstable angina, deep vein thrombosis, palpitations, gastritis, gastroesophageal reflux disease, hypoglycemia, blood glucose increased, alanine aminotransferase increased, oropharyngeal pain, stomach discomfort, vomiting, muscle spasms, musculoskeletal pain, myalgia, pain in extremity, depression, insomnia, somnolence, vertigo, cough, dyspnea exertional, epistaxis, wheezing, pruritus, balanitis, erection increased, hematuria, nephrolithiasis, pollakiuria and urinary tract infection. A causal relationship to STENDRA is uncertain. Excluded from this list are those events that were minor, those with no plausible relation to drug use and reports too imprecise to be meaningful.

POSTMARkETING ExPERIENCE Ophthalmologic Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors [see Warnings and Precautions and Patient Counseling Information (17.6) in full Prescribing Information].

DRUG INTERACTIONS Nitrates Administration of STENDRA to patients who are using any form of organic nitrate, is contraindicated. In a clinical pharmacology trial, STENDRA was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken STENDRA, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of STENDRA before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring [see Contraindications, Dosage and Administration (2.3), and Clinical Pharmacology (12.2) in full Prescribing Information].

Alpha-Blockers Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including STENDRA, and alpha-adrenergic blocking agents are both vasodilators with blood pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting) [see Warnings and Precautions, Dosage and Administration (2.3), and Clinical Pharmacology (12.2) in full Prescribing Information] Antihypertensives PDE5 inhibitors, including STENDRA, are mild systemic vasodilators. A clinical pharmacology trial was conducted to assess the effect of STENDRA on the potentiation of the blood pressure-lowering effects of selected antihypertensive medications (amlodipine and enalapril). Additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single 200 mg dose STENDRA with these agents compared with placebo [see Warnings and Precautions and Clinical Pharmacology (12.2) in full Prescribing Information].

Alcohol Both alcohol and PDE5 inhibitors, including STENDRA, act as vasodilators. When vasodilators are taken in combination, blood pressure-lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., greater than 3 units) in combination with STENDRA can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache [see Drug Interactions and Clinical Pharmacology (12.2) in full Prescribing Information].

Potential for Other Drugs to Affect STENDRA STENDRA is a substrate of and predominantly metabolized by CYP3A4.

STENDRA is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure.

Strong CYP3A4 Inhibitors Ketoconazole (400 mg daily), a selective and strong inhibitor of CYP3A4, increased STENDRA 50 mg single-dose systemic exposure (AUC) and maximum concentration (Cmax) equal to 13-fold and 3-fold, respectively and prolonged the half-life of avanafil to approximately 9 hours. Other potent inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir and telithromycin) would be expected to have similar effects. Do not use STENDRA in patients taking strong CYP3A4 inhibitors [see Warnings and Precautions and Dosage and Administration (2.3) in full Prescribing Information].

HIV Protease inhibitor — Ritonavir (600 mg twice daily), a strong CYP3A4 inhibitor, which also inhibits CYP2C9, increased STENDRA 50 mg single-dose Cmax and AUC equal to approximately 2-fold and 13-fold, and prolonged the half-life of avanafil to approximately 9 hours in healthy volunteers. Do not use STENDRA in patients taking ritonavir.

Moderate CYP 3A4 Inhibitors Erythromycin (500 mg twice daily) increased STENDRA 200 mg single-dose Cmax and AUC equal to approximately 2-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately Licensor: Mitsubishi Tanabe Pharma Corporation. ©2014 Auxilium Pharmaceuticals, Inc. STE-00475 October 2014

8 hours in healthy volunteers. Moderate CYP3A4 inhibitors (e.g., erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil) would be expected to have similar effects. Consequently, the maximum recommended dose of STENDRA is 50 mg, not to exceed once every 24 hours for patients taking concomitant moderate CYP3A4 inhibitors [see Warnings and Precautions and Drug Interactions].

Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice are likely to increase avanafil exposure.

Weak CYP3A4 Inhibitors No in vivo drug-drug interaction studies with weak CYP3A4 inhibitors were conducted.

CYP3A4 Substrate When administered with STENDRA 200 mg, amlodipine (5 mg daily) increased the Cmax and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of STENDRA was prolonged to approximately 10 hrs. The Cmax and AUC of amlodipine decreased by approximately 9% and 4%, respectively [see Dosage and Administration (2.3) in full Prescribing Information].

Cytochrome P450 Inducers The potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated. The concomitant use of STENDRA and CYP inducers is not recommended.

Potential for STENDRA to Affect Other Drugs In vitro studies Avanafil had no effect on CYP1A1/2, 2A6, 2B6 and 2E1 (IC50 greater than 100 micromolar) and weak inhibitory effects toward other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4). Major circulating metabolites of avanafil (M4 and M16) had no effect on CYPs 1A, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. Avanafil and its metabolites (M4 and M16) are unlikely to cause clinically significant inhibition of CYPs 1A, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4.

In vivo studies Warfarin —A single 200 mg dose of STENDRA did not alter the changes in PT or INR induced by warfarin, and did not affect collagen-induced platelet aggregation or the AUC or Cmax of R- or S-warfarin, a 2C9 substrate.

Desipramine — A single STENDRA 200 mg dose increased AUC and Cmax of a single 50 mg dose of desipramine, a CYP2D6 substrate, by 5.7% and 5.2%, respectively.

Omeprazole — A single STENDRA 200 mg dose increased AUC and Cmax of a single 40 mg dose of omeprazole, a CYP2C19 substrate, given once daily for 8 days by 5.9% and 8.6%, respectively.

Rosiglitazone — A single STENDRA 200 mg dose increased AUC by 2.0% and decreased Cmax by 14% of a single 8 mg dose of rosiglitazone, a CYP2C8 substrate.

Amlodipine— A single STENDRA 200 mg dose did not affect the pharmacokinetics of amlodipine (5 mg daily), a CYP3A4 substrate [see Dosage and Administration (2.3) in full Prescribing Information].

Alcohol — A single oral dose of STENDRA 200 mg did not affect alcohol (0.5 g ethanol/kg) plasma concentrations [see Warnings and Precautions].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C STENDRA is not indicated for use in women. There are no adequate and well-controlled studies of STENDRA in pregnant women.

Fetal Risk Summary Based on animal data, STENDRA is predicted to have a low risk for major developmental abnormalities in humans.

Animal Data In pregnant rats administered 100, 300, or 1000 mg/kg/day from gestation days 6 to 17, no evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed at exposures up to approximately 8 times the exposure at the Maximum Recommended Human Dose (MRHD) of 200 mg based on AUCs for total avanafil (protein bound plus free avanafil).

At the maternally toxic dose (1000 mg/kg/day), a dose producing exposures approximately 30 times the MRHD on an AUC basis, decreased fetal body weight occurred with no signs of teratogenicity. In pregnant rabbits administered 30, 60, 120, or 240 mg/kg/day from gestation days 6 to 18, no teratogenicity was observed at exposures up to approximately 6 times the human exposure at the MRHD based on AUC. At the high dose associated with maternally-reduced body weights, increased postimplantation loss was observed consistent with increased late resorptions. In a pre- and post-natal development study in rats given 100, 300, or 600 mg/kg/day on gestation days 6 through lactation day 20, offspring growth and maturation were reduced when maternal rats were given avanafil doses greater than or equal to 300 mg/kg/day resulting in exposures greater than or equal to 17 times the human exposure. There was no effect on reproductive performance of the maternal rats or offspring, or on the behavior of the offspring at up to the highest dose tested. The no observed adverse effect level (NOAEL) for developmental toxicity (100 mg/kg/day) was approximately 2-fold greater than the systemic exposure in humans at the MRHD. Pediatric Use STENDRA is not indicated for use in pediatric patients. Safety and efficacy in patients below the age of 18 years has not been established.

Geriatric Use Of the total number of subjects in clinical studies of avanafil, approximately 23% were 65 and over. No overall differences in efficacy and safety were observed between subjects over 65 years of age compared to younger subjects; therefore no dose adjustment is warranted based on age alone. However, a greater sensitivity to medication in some older individuals should be considered [see Clinical Pharmacology (12.3) in full Prescribing Information] Renal Impairment In a clinical pharmacology trial using single 200 mg doses of STENDRA, avanafil exposure (AUC or Cmax) in normal subjects was comparable to patients with mild (creatinine clearance greater than or equal to 60 to less than 90 mL/min) or moderate (creatinine clearance greater than or equal to 30 to less than 60 mL/min) renal impairment. No dose adjustment is necessary for patients with mild to moderate renal impairment (creatinine clearance greater than or equal to 30 to less than 90 mL/min). The pharmacokinetics of avanafil in patients with severe renal disease or on renal dialysis has not been studied; do not use STENDRA in such patients [see Clinical Pharmacology (12.3) in full Prescribing Information] Hepatic Impairment In a clinical pharmacology trial, avanafil AUC and Cmax in patients with mild hepatic impairment (Child-Pugh Class A) was comparable to that in healthy subjects when a dose of 200 mg was administered. Avanafil Cmax was approximately 51% lower and AUC was 11% higher in patients with moderate hepatic impairment (Child Pugh Class B) compared to subjects with normal hepatic function. No dose adjustment is necessary for patients with mild to moderate hepatic impairment (Child Pugh Class A or B). The pharmacokinetics of avanafil in patients with severe hepatic disease has not been studied; do not use STENDRA in such patients [see Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE Single doses up to 800 mg have been given to healthy subjects, and multiple doses up to 300 mg have been given to patients. In cases of overdose, standard supportive measures should be adopted as required.

Renal dialysis is not expected to accelerate clearance because avanafil is highly bound to plasma proteins and is not significantly eliminated in the urine.

This Brief Summary is based on PI version PH-04-002-06, Rev. September 2014

Moving Toward Individualized Care of Patients with Type 2 Diabetes

PUBLISHING STAFF Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Vice President, Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Editorial Directors Dalia Buffery dbuffery@the-lynx-group.com

FEATURES Editor’s Note...................................................................................................................1 The Central Role of the Urology Practice in Managing Patients with Erectile Dysfunction and Low Testosterone...............................1 Men’s health issues, particularly erectile dysfunction and low testosterone, warrant greater clinical focus. This article explores the prevalence, diagnosis, comorbidities, and treatment options for these conditions, as well as practice management concerns.

Anne M. Cooper acooper@the-lynx-group.com

Associate Editor Lara J. Lorton Copyeditor Jessica Cheng Editorial Assistant Cara Guglielmon Production Manager Marie RS Borrelli

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Neil Baum, MD Practicing Urologist New Orleans, LA Cheris Craig, MBA, CMPE Chief Administrative Officer Urology of Greater Atlanta, LLC Atlanta, GA Michael deWitt Clayton, MD, FACS Urology Associates of San Luis Obispo, CA Rick Janss, MBA, CMPE Practice Administrator Clinical Urology Associates Gadsden, AL

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MISSION STATEMENT Urology healthcare requires providers to focus attention on financial concerns and strategic decisions that affect the bottom line. To continue to provide the high-quality care urology patients deserve, providers must master the ever-changing business of urology. Urology Practice Management offers process solutions for members of the urology care team—medical, surgical, and radiation urologists, as well as executives, administrators, and coders/billers—to assist them in reimbursement, staffing, electronic health records, REMS, and compliance with state and federal regulations.

Urology Practice Management™, ISSN 2374-0752 (print); 2374-0760 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 1249 South River Road, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. Urology Practice Management™ is a trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

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POSTMASTER: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Urology Practice Management™, 1249 South River Road, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

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6 I October 2014

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morbidities as cardiovascular disease, hypertension, diabetes, and depression. Early detection is especially vital, because it may reveal the existence of a life-threatening underlying condition affecting the patient’s overall health.

ED and Low T have physical as well as psychosocial components. Effective treatment can improve the physical health and mental well-being of affected men and enhance their quality of life and personal relationship with partners.

Today, urology practices encounter numerous challenges and opportunities. In the current healthcare environment, urology practices are faced with many business-related pressures, and they are exploring strategies to help retain patients and sustain financial viability. Some practices are consolidating with other practices or expanding their cov-

KEY POINTS ➤

Both ED and Low T are associated with serious comorbidities, including cardiovascular disease, hypertension, diabetes, and depression.

Urologists are well equipped to play a key role in men’s health; they are in a position to improve the lives of men with ED and Low T.

➤

For most men affected with it, ED is a symptom of an underlying condition; it also imposes a physical and psychological burden.

➤

ED treatment has been transformed by the development of effective therapies; despite these advances, a recent study demonstrated that only one quarter of men with ED were treated during a 12-month period.

➤

Therapeutic decisions for men with ED involve consideration of the biological, psychological, social, and cultural factors that are most important to the ED patient and his partner.

➤

Low T occurs in men as a natural consequence of aging; a number of comorbid conditions are present in men with Low T.

➤

The diagnostic evaluation for Low T includes a medical history and physical examination, conducting a blood test, and assessing the patient’s symptoms.

➤

Low T is treated with testosterone replacement therapy; treatment selection is based on patient-specific factors, including age, needs, and preferences.

➤

erage area to attract more patients. They may need to maximize referrals from primary care physicians, increase patient volume (workload) by seeing more patents per day, or add evening hours to maximize revenue and better serve their patients. In the midst of sweeping changes in healthcare

Based on their specialized training in men’s health issues, urologists are well equipped to play a key role in men’s health. policy in recent years, notable technological and pharmaceutical innovations have improved outcomes for men with urologic conditions. Progressive urology practices seek to integrate therapeutic innovation and improve surgical techniques to maximize the breadth of service options they can offer their patients.

Based on their specialized training in men’s health issues, urologists are well equipped to play a key role in men’s health.

While addressing male health issues, the urologist may also detect comorbidities that are clinically relevant to a man’s overall health and well-being. In fact, in recent years, the urology community has assumed an increasingly active leadership role in men’s health.

The American Urological Association (AUA) created the Committee on Male Health in 2009 to address men’s health issues, including education, community outreach, research, integration with other specialties, and support of local and national initiatives.2 Moreover, in 2012, the AUA published a Men’s Health Checklist to strengthen the urologist’s role in caring for male patients and to improve the coordination of patient care among all physicians. This checklist captures urology-specific and general age-related symptoms and concerns, including androgen deficiency, ED, and Peyronie’s disease, a connective tissue disorder characterized by the formation of fibrous plaques that result in penile deformities during erection.3,4 The evaluation and management of men with ED and Low T has become an important aspect of the urologist’s practice.5 ED and Low T are underrecognized and undertreated, despite the association of these conditions with serious comorbidities.

According to Johns Hopkins urologist Kevin Billups, MD, chronic but preventable medical conditions account for more than 50% of premature male deaths in the United States.6 Dr Billups added, “Erectile dysfunction and low testosterone often are associated with chronic illness, but they also can Stakeholder Perspectives in Men’s Health I 7

Moving Toward Individualized Care of Patients with Type 2 Diabetes

precede a major medical event such as a heart attack or stroke by several years, offering an opportunity for early detection and prevention.”6 Urologists are in a position to improve the lives of men with ED and Low T and to uncover potentially life-threatening comorbidities. They also have a key role in coordinating care with other healthcare providers, particularly for men with ED and Low T who have underlying conditions.

Erectile Dysfunction ED is a common condition with potentially serious implications, including cardiovascular disease and vascular disease.

For most men affected with it, ED is a symptom of an underlying condition7; moreover, ED imposes a physical and psychological burden. ED is defined as the inability to achieve and maintain an erection suitable for sexual intercourse or other activity in the absence of an ejaculatory disorder, including premature ejaculation.8 ED affects an estimated 18 million men in the United States, with an overall prevalence of 18.4% in men ≥20 years of age, based on a study by researchers from the Johns Hopkins Bloomberg School of Public Health.9 Age was directly correlated with ED: 70% of men aged ≥70 years had ED versus 5% of men aged 20 to 39 years. Nearly 90% of men with ED had at least 1 cardiovascular disease risk factor, including hypertension, poor cholesterol levels, current smoking, or diabetes. In fact, 51.3% of the men with diabetes also had ED, and 50% of men with a history of cardiovascular disease had ED, based on crude and age-adjusted prevalence estimates from this study.9

ED is a common condition with potentially serious implications, including cardiovascular disease and vascular disease.

For most men affected with it, ED is a symptom of an underlying condition.

The study authors concluded as follows: “With the advent of highly effective and widely available pharmacotherapy for ED, physicians should be aggressive in screening for and managing their middle-aged and older patients with this important quality-of-life issue.” 9 The authors also acknowledged the importance of diet and exercise as strategies to improve car8 I October 2014

diovascular health and diabetes risk factors, thereby slowing the progression of ED.9 The impact of ED extends well beyond quality of life, particularly given its link to a number of other underlying medical conditions, a factor that underscores the importance of early diagnosis and management of ED. Etiology and Comorbidities The process of male sexual arousal is complex and involves multiple signals, including the brain, hormones, nerves, emotions, muscles, and blood flow/vessels. ED can result when there are problems in 1 or more of these signals (ie, a combination of physical and psychological issues, or anxiety from a physical problem that worsens ED).10 Psychological factors that interfere with libido may play a role in ED.11 In addition, a number of hormones contribute to ED, including prolactin, adrenocorticotropic hormone, oxytocin, and androgens, especially testosterone.11 Vascular issues that affect blood flow into or within the penis are another common cause of ED.11 Nitric oxide, considered to be the main vasoactive nonadrenergic, noncholinergic neurotransmitter and chemical mediator involved in erectile response, www.uropracticemanagement.com

is involved in many of the common etiologies and comorbidities of ED.11 A number of medical conditions are associated with ED (Table 1); obesity and a sedentary lifestyle are independent risk factors, as well.12 ED is an early, independent marker for cardiovascular disease, based on the common risk factors and endothelial dysfunction of these 2 conditions.12 In some cases, ED is a side effect of drugs prescribed to treat other conditions. Medications that can cause ED include antidepressants, antihistamines, diuretics, and antihypertensives, hormonal therapies, chemotherapy, and antiarrythmic agents.13 In addition, the abuse of other substances or drugs, including alcohol, nicotine, amphetamines, marijuana, cocaine, and opiates, can cause or lead to ED.13 Table 1. Medical Conditions Associated with Erectile Dysfunction Type of Disease

Specific Condition

Vascular7,10

Atherosclerosis

Diagnostic Evaluation According to AUA guidelines, the initial evaluation for ED is conducted in person to review the individual’s medical, sexual, and psychosocial histories.14 At that time, appropriate laboratory tests are performed to identify comorbid conditions that may contribute to ED or contraindicate specific treatments. The physician may also discuss with the patient any changes in sexual desire, ejaculation, and orgasm, the pres-

In some cases, ED is a side effect of drugs prescribed to treat other conditions. Medications that can cause ED include antidepressants, antihistamines, diuretics, antihypertensives, hormonal therapies, chemotherapy, and antiarrythmic agents.

Stroke Hypertension High cholesterol Other conditions that block blood supply to the penis as a result of vascular disease Cardiovascular10

Heart disease

Endocrine

Diabetes (particularly when it causes nerve damage)

Neurological10,36

Multiple sclerosis Parkinson’s disease Surgery with radical prostatectomy (resulting nerve damage) Stress

Psychological7

Depression Lack of stimulus from the brain Performance anxiety Injury

Trauma

7

Other conditions

7,10,11

Hypogonadism Metabolic syndromea Chronic illness Low testosterone Peyronie’s diseaseb

a A cluster of conditions, including high blood pressure, high insulin levels, high cholesterol, and excess body fat around the waist. b A condition characterized by the development of fibrous plaques that result in penile deformities during erection.3

ence of genital pain, a history of sexual function, and lifestyle factors, including sexual orientation and current relationship status with a spouse or partner. Other goals of the evaluation are to distinguish ED from ejaculation and/or orgasm issues, determine the chronology and symptom severity, and assess the patient/partner’s needs and therapeutic expectations.14 The AUA endorses the position statement of the Sexual Medicine Society of North America (SMSNA), which asserts that diagnostic studies used to evaluate the pathophysiology of ED should be based on the individual patient, and that a standard set of diagnostic tests for all patients is not an appropriate practice.15 Rather, tests should be limited to those that are needed to establish treatment options available to the patient, based on the individual patient’s clinical needs and therapeutic preferences.15 The evaluation generally includes a physical examination of the abdomen, penis, testicles, secondary sexual features, and lower extremity pulses. If the use of testosterone is being considered for the treatment of patients with ED, a prostate-specific antigen (PSA) measurement and rectal exam may be performed.14 Other tests, including testosterone level, blood tests, urinalysis, ultrasound, nocturnal erection monitoring, vascular assessment, or neurological assessment may also be warranted for some patients.10,14 ED Treatment Options Although ED is more common in older men, it need not be viewed as an acceptable consequence of aging, particularly Stakeholder Perspectives in Men’s Health I 9

Moving Toward Individualized Care of Patients with Type 2 Diabetes

given the availability of effective treatments. Over the past decade or so, the treatment of patients with ED has been transformed by the development of effective therapies.

Despite advances in ED therapies, a large-population study revealed that of more than 6.2 million men with ED, only 25.4% were treated during the 12-month study period—underscoring the fact that despite ED’s high prevalence with age and comorbidities, most men are not receiving treatment.16 Furthermore, although the stigma associated with ED has lessened somewhat in recent years, some men still avoid or delay seeking medical help. Generally, ED that occurs less than 20% of the time does not require treatment, whereas ED that occurs more than 50% of the time indicates that treatment is warranted.7

For ED that is caused by anxiety, stress, or depression, psychological counseling may be recommended. Maintaining a healthy diet and healthy weight, exercising regularly, and controlling cholesterol levels may also help prevent or mitigate the severity of ED. Treatment decisions for ED are based primarily on the cause and severity of the condition, underlying health issues, the risks and benefits of treatments, and the individual patient’s needs and preferences.10 Selection of a specific therapy is also based on the patient’s comorbid conditions and current medications.

Pharmacologic options for ED are listed in Table 2.

For 70% of men with ED, oral medications have been shown to be effective.17 Oral therapies include phosphodiesterase type 5 (PDE5) inhibitors: avanafil, sildenafil, tadalafil,

Table 2. Pharmacologic Therapies for Erectile Dysfunction Formulation

Generic

Brand

PDE5 inhibitors

Avanafil

Stendra, Spedra

Sildenafil

Viagra, Revatio

Tadalafil

Cialis, Adcirca

Vardenafil

Levitra, Staxyn

Intracavernosal injection

Alprostadil

Caverject, Edex

Intraurethral pellets

Alprostadil

Muse

PDE5 indicates phosphodiesterase type 5.

10 I October 2014

and vardenafil. These agents, which work by enhancing the effects of nitric oxide and increasing blood flow, vary in dosage, onset, duration of action, and side effect profiles. Some men may experience an adverse reaction with 1 of these agents but not with another.17 Although the PDE5 inhibitors have similar mechanisms of action, they have different pharmacologic properties, which can affect their labeling and usage. For example, unlike other oral ED agents, avanafil, a recently approved PDE5 inhibitor, can be taken as early as 15 minutes before sexual activity.18 The most common adverse reactions associated with the PDE5 inhibitor class of drugs include headache, flushing, nasal congestion, back pain, dyspepsia, and dizziness.18-21 Use of PDE5 inhibitors is contraindicated in patients taking organic nitrates in any form because the PDE5 inhibitors may potentiate the hypotensive effect of nitrates. Similarly, the labeling for these agents includes a warning about the concomitant use of PDE5 inhibitors with alpha-blockers, antihypertensives, or substantial amounts of alcohol, which may also lead to hypotension.18-21 Other medications for ED include alprostadil self-injection, alprostadil intraurethral suppository, and testosterone replacement therapy. 10 Alprostadil, a vasodilator, is a synthetic form of prostaglandin E1. Nonpharmacological therapies for ED include the vacuum erection device (penis pump), penile implants, and blood vessel surgery (if leaking or obstructed blood vessels are implicated in ED).10 For ED that is caused by anxiety, stress, or depression, psychological counseling may be recommended.10 Maintaining a healthy diet and healthy weight, exercising regularly, and controlling cholesterol levels may also help prevent or mitigate the severity of ED.7,22 Patient and Practice Management Considerations The patient has a key role in ED treatment decisions. Therapeutic decisions involve consideration of the biological, psychological, social, and cultural factors that are most important to the ED patient and his partner.23 Patient preferences often hinge on the individual’s age, duration of ED, and the frequency and nature of the sexual relationship, as well as the partner’s age, interest in sexual activity, and other factors.

Treatment-specific considerations for the patient include the drug’s rapid onset of action, duration of action, mode of administration, and side effects. Other considerations include convenience and cost.23 Cost is a concern for some patients with respect to the use of pharmacologic treatments.17 Patient cost-sharing for prescription drugs has increased steadily in recent years. In fact, www.uropracticemanagement.com

from 2000 to 2009, copayments for prescription drugs increased 25% for generic drugs, 80% for preferred drugs, and 59% for nonpreferred drugs.24 According to a major literature review (160 articles), 85% of the articles showed that increased patient cost for medications was associated with decreased treatment adherence; furthermore, most showed that increased treatment adherence was associated with improved outcomes.25 Other issues that may impact the use of ED drugs include prior authorizations and quantity limits imposed by payers.

Health plans generally require a prior authorization for pharmacologic ED treatments to ensure that these agents are being used safely and appropriately. Prior authorization involves consideration of several factors, including the health plan memberâ&#x20AC;&#x2122;s diagnosis, other conditions, and prescription drugs, FDA-approved labeling/prescribing information, and relevant clinical data. Prior authorization requirements for ED treatments may also include steps that are designed to establish medical/clinical justification that extends beyond quality-of-life issues. Moreover, quantity limits are often imposed by health plans to encourage utilization in accordance with product labeling.

Urology practice administrators often play a key role in helping patients gain access to prescribed ED therapies. By navigating prior authorization requirements and generating appropriate medical documentation, administrators and office Table 3. Most Common Symptoms and Signs of Low Testosterone Sexual Symptoms and Signs

Non-Sexual Symptoms and Signs

Poor erectile function

Decreased energy and fatigue

Diminished libido

Reduced muscle mass/strength

Reduced sexual activity

Depression; declining self-esteem

Weaker and fewer erections

6

Irritability Sweating; hot flashes Short-term memory problems Hair loss Reduction in HDL cholesterol Increase in total body fat Abdominal obesity Osteoporosis Reduction in proportion of red blood cells in plasma

HDL indicates high-density lipoprotein.

Source: Reference 27.

staff ensure that patients receive medications in a timely manner without undue cost burden.

Low Testosterone Low T, also known as androgen deficiency, occurs in men as a natural consequence of aging. Beginning in their 40s, men experience a decline in sex hormone levels, a process that gradually continues as they age.26 This process is sometimes referred to as andropause. Low T is also caused by hypogonadism or other conditions.

The early diagnosis of Low T is particularly important, even in young men, given its associated comorbidities and risk factors for serious health issues.

As many as 39% of men aged â&#x2030;Ľ45 years have Low T; in fact, Low T affects 20% of men aged >60 years, 30% of men aged >70 years, and 50% of men aged >80 years, according to the Urology Care Foundation of the AUA.27 One study showed that androgen deficiency occurred in 5.6% of a group of men aged 30 to 79 years and that its prevalence increased substantially with age.28 Another study estimated that 12.2% of men aged between 40 and 69 years may be androgen deficient, whereas 2.3% are definitely androgen deficient.26 As is the case with ED, a number of comorbid conditions are commonly present in men with Low T. In fact, Low T occurs in approximately 40% of men with hypertension, 40% with high cholesterol, 50% with diabetes, and 50% with obesity.27 A longitudinal study revealed that Low T is associated with an increased risk for developing metabolic syndrome.29 Another longitudinal study showed that men with Low T generally have a higher risk of cardiovascular morbidity and mortality, compared with men with higher T levels and women.30 Consequently, the early diagnosis of Low T is particularly important, even in young men, given its associated comorbidities and risk factors for serious health issues.5 The most common symptoms associated with Low T are listed in Table 3. Because the symptoms of Low T are sometimes subtle and vague, some men may downplay their symptoms or delay seeking medical help. Given that some of these symptoms may be caused by other disorders or are normal aspects of aging, the diagnosis of Low T is not made based on symptoms alone.26 Stakeholder Perspectives in Menâ&#x20AC;&#x2122;s Health I 11

Moving Toward Individualized Care of Patients with Type 2 Diabetes

Hypogonadism Hypogonadism, a condition in which the testicles are not functioning properly, is characterized by Low T and, in some cases, infertility.26 Primary hypogonadism occurs when the brain signals the testicle to produce testosterone and sperm, but the testicles fail to respond to the signaling. The causes of primary hypogonadism are congenital (Klinefelter syndrome, cryptorchidism, varicocele, myotonic dystrophy, some genetic mutations), acquired (infections [ie, orchitis from mumps], chemotherapy or radiation, environmental toxins, alkylating agents, autoimmune damage, glucocorticoids, and other medications), or idiopathic.31,32 Secondary hypogonadism occurs when the brain fails to signal the testicles properly. Men affected by secondary hypogonadism generally have extreme Low T levels and absence of sperm in the semen. Secondary hypogonadism is caused by congenital factors

The diagnosis of Low T presents a number of challenges: serum T levels are affected by time of day, season, age, illness, and some medications; total testosterone concentrations are affected by changes in sex-hormone binding globulin, which may also be affected by medications and comorbid conditions; and the assays for measuring T levels vary. (ie, Kallman syndrome, Prader–Willi syndrome), acquired conditions (hyperprolactinemia, diabetes, obesity, steroid treatment, critical illness), or damage to pi­tuitary function (benign tumors, malignancy, infections, trauma, radiation).31 Secondary hypogonadism can also be caused by hemochromatosis (excess iron in the blood) or certain inflammatory diseases, including sarcoidosis and tuberculosis.32 Moreover, older men may have lower testosterone levels because testosterone production gradually decreases with age.32 Adult men affected by hypogonadism are at a greater risk for complications, including ED, infertility, fatigue, diminished sex drive, muscle loss or weakness, gynecomastia, and osteoporosis.32 Diagnostic Evaluation for Low T Low T is diagnosed by assessing the patient’s symptoms and conducting a blood test. The diagnostic evaluation for Low T 12 I October 2014

includes the following: a medical history to determine contributing factors, onset, and severity of symptoms; a physical examination, including palpation of the testes to check for volume and consistency and assessment of body hair distri­ bution, musculature, and breast size; and for men ≥50 years of age, a digital rectal examination to check prostate size.26 Laboratory tests include a blood test to measure testosterone levels. Other hormones, including luteinizing hormone and follicle-stimulating hormone, may also be measured.26 In some cases, a PSA test is conducted to screen for prostate cancer, and a hematocrit level is measured because an increase in red blood cell count occurs in some men who receive testosterone treatment.27 If a blood test confirms a Low T level, further testing will follow to identify the cause.

These tests may include hormone testing, semen analysis, pituitary imaging, genetic studies, or testicular biopsy.

The diagnosis of Low T presents a number of challenges: serum T levels are affected by time of day, season, age, illness, and some medications; total testosterone (TT) concentrations are affected by changes in sex-hormone binding globulin, which may also be affected by medications and comorbid conditions; and the assays for measuring T levels vary. The correlation of TT with free testosterone relative to symptomatic androgen deficiency is still a subject of debate within the medical community.5 While efforts are under way to optimize assay platforms and standardize evidence-based normal assay ranges, there is currently no generally accepted T-concentration threshold to distinguish eugonadal men from hypogonadal men.

Consequently, laboratory results require interpretation within the appropriate clinical setting. The FDA uses a TT level of <300 ng/dL to define hypogonadism for the purpose of clinical trials.5 In a 2013 white paper, the AUA concluded that “the diagnosis of hypogonadism should be based as much on the presence of signs and symptoms as on serum T measurement.” 5 The position statement further states, “Based on overall poor quality of T testing in most clinical laboratories and age bias of published reference ranges, no patient should be denied coverage for treatment based solely on payer defined cut-off points if need for such treatment is established by a health professional.” 5 Treatment of Low T Low T is treated with testosterone replacement therapy in appropriate patients. Testosterone therapy is indicated in men with documented Low T in addition to the signs and symptoms of Low T.33 According to the SMSNA, “Treatment of T deficiency improves symptoms as well as several indicawww.uropracticemanagement.com

Table 4. Testosterone Replacement Therapies Formulation

Generic

Brand

Intramuscular injection

Testosterone enanthate

Delatestryl

Testosterone cypionate

Depo-Testosterone

(testosterone) Gel for topical use CIII

Fortesta

(testosterone) Gel for topical use CIII

AndroGel

(testosterone) Gel for topical use CIII

Testim

Subcutaneous implanted pellet

Testosterone pellets

Testopel

Buccal mucoadhesive

Testosterone buccal system

Striant

Transdermal patch

Testosterone transdermal system

Androderm

Testosterone transdermal system

Andropatch

Testosterone (transdermal)

Testoderm

Transdermal gels

Scrotal patch

tors of general health.â&#x20AC;?33 The therapeutic goals for Low T are to achieve but not exceed the normal testosterone range while minimizing adverse effects on cardiovascular function, the prostate, serum lipids, and liver and lung function. Treatment selection is based on patient-specific factors, including age, needs, and preferences.26 Other considerations include treatment preparation, side effects, convenience of administration, and cost.

Testosterone is an androgen (steroid), a class of drugs that develop and maintain male sex characteristics. Testosterone therapies are available in several formulations, as shown in Table 4: long-acting and short-acting intramuscular injections; a buccal mucoadhesive held between the cheek and the gums; transdermal gels; subcutaneously implanted pellets; and transdermal and scrotal patches. The gel preparation is the most widely used form of testosterone therapy.27 The use of oral methyltestosterone, a synthetic derivative of testosterone, is no longer prescribed or supported by relevant professional societies because of its substantial risk for liver toxicity.26 Generally, testosterone therapy is tried for up to 3 months, during which time testosterone levels and symptoms are monitored.26 If therapy is beneficial and continued, the patient should be monitored for symptoms at 3-month intervals, with testosterone levels checked, for the first year of treatment.26 Long-term use of oral hormone replacement is not recommended due to the risk of liver problems.32 Testosterone therapy may be associated with an increased risk for benign prostatic hyperplasia symptoms.27 Other risks associated with testosterone replacement include sleep apnea, gynecomastia (enlarged breasts), limited sperm production, erythrocytosis (increased production of red blood cells), for-

mation of blood clots in the veins, fluid retention, stimulation of noncancerous prostate growths, and stimulation of the growth of existing prostate cancer.33,34 Because many men aged >80 years may have subclinical (nonsymptomatic) prostate cancer, age is an important consideration when discussing testosterone therapy.26

Testosterone therapy may be associated with an increased risk for benign prostatic hyperplasia symptoms. Other risks associated with testosterone replacement include sleep apnea, gynecomastia (enlarged breasts), limited sperm production, erythrocytosis (increased production of red blood cells), formation of blood clots in the veins, fluid retention, stimulation of noncancerous prostate growths, and stimulation of the growth of existing prostate cancer.

Although further studies are warranted, testosterone therapy has also been linked to an increased risk for heart attack, according to recent studies. In January 2014, the FDA issued a safety announcement stating that the agency was investigating the risk of stroke, heart attack, and death in men taking FDA-approved testosterone medications.35 This alert was Stakeholder Perspectives in Menâ&#x20AC;&#x2122;s Health I 13

Moving Toward Individualized Care of Patients with Type 2 Diabetes

based on data from 2 observational studies. One study suggested a 30% increase in the risk of stroke, heart attack, and mortality in men receiving testosterone therapy (average age, 60 years; many had underlying cardiovascular disease). The other study reported a 2-fold to 3-fold increased risk of heart attack among men ≥65 years of age within the first 90 days following their first testosterone prescription.35 The FDA has not yet concluded that testosterone therapy increases these cardiovascular risks and has informed patients not to stop taking prescribed medication without discussing questions or concerns with their clinician. In the announcement, healthcare professionals are instructed to weigh the benefits and risks of treatment and to follow FDA-approved prescribing information.35 Conclusion Urology practices are evolving in order to stay competitive and keep pace with the changing healthcare landscape.

They must balance the clinical and business aspects of the practice in an era where quality, value, and accountability are increasingly scrutinized. Management of men’s health issues, including ED and Low T, are likely to become a larger focus for urology practices in the coming years, particularly as the number of aging men increases over the next few decades.

Urologists have an essential role in providing and coordinating appropriate care for men with ED, Low T, and other conditions that impact men’s health. Effective treatment of these conditions can improve outcomes for affected men, including quality of life and personal relations.

The health implications of ED and Low T often extend beyond quality of life. In recent years, strides have been made in the collective dialogue about men’s sexual health issues.

Nevertheless, further improvements are warranted in addressing the clinical significance of ED and Low T, particularly considering the medical significance of these underrecognized, undertreated conditions.

The symptoms of ED and Low T are often vague, and for some men, the stigma and embarrassment of seeking med14 I October 2014

ical help for these conditions persists. Given the potentially serious underlying conditions associated with ED and Low T and the challenges inherent in diagnosing and managing Low T, the specialized training and clinical expertise of urologists are vital. While a number of effective therapies are available to treat ED and Low T, treatment decisions involve a layered approach that considers patient-specific factors, including the patient’s comorbidities, medications, needs, and preferences, as well as the cost of a specific treatment/formulation.

Urologists have an essential role in providing and coordinating appropriate care for men with ED, Low T, and other conditions that impact men’s health. Effective treatment of these conditions can improve outcomes for affected men, including quality of life and personal relations. In addition, early diagnosis of ED and Low T may uncover associated chronic conditions and, in some cases, prevent the life-threatening consequences of these conditions. Urology practice administrators have a crucial role in supporting clinicians in the practice by facilitating timely access to treatments for patients without undue cost burden. Their role is likely to increase in importance as more patients seek medical attention for ED and Low T and more products enter the market in the future. ■ www.uropracticemanagement.com

References

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2. Elterman DS, Kaplan SA, Pelman RS, et al. How ‘male health’ fits into the field of urology. Nat Rev Urol. 2013;10:606-612.

3. Levine LA. The clinical and psychosocial impact of Peyronie’s disease. Am J Manag Care. 2013;19(suppl 4):S55-S61.

4. American Urological Association. AUA men’s health checklist. www.auanet.org/ common/pdf/education/clinical-guidance/Mens-Health-Checklist.pdf. Accessed October 9, 2014.

5. Paduch DA, Brannigan RE, Fuchs EF, et al; American Urological Association. The laboratory diagnosis of testosterone deficiency. www.auanet.org/common/pdf/education/ clinical-guidance/Testosterone-Deficiency-WhitePaper.pdf. Accessed October 9, 2014.

6. Grauer NA. Treating the whole man. Dome. 2013;64:7. www.hopkinsmedicine.org/ news/publications/dome/dome_january_2013/treating_the_whole_man. Accessed October 9, 2014.

7. Cleveland Clinic. Diseases & conditions. Erectile dysfunction. http://my.cleveland clinic.org/disorders/Erectile_Disorder_impotence/hic_Erectile_Dysfunction_Over view.aspx. Updated February 11, 2014. Accessed October 9, 2014.

8. Lakin M, Wood H; Cleveland Clinic Center for Continuing Education. Erectile dysfunction. www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/endo crinology/erectile-dysfunction/. Published November 2012. Accessed October 9, 2014.

9. Selvin E, Burnett AL, Platz EA. Prevalence and risk factors for erectile dysfunction in the US. Am J Med. 2007;120:151-157.

10. Mayo Clinic. Diseases and conditions. Erectile dysfunction. www.mayoclinic.org/ diseases-conditions/erectile-dysfunction/basics/definition/con-20034244?p=1. Published February 10, 2012. Accessed October 9, 2014.

11. Lasker GF, Maley JH, Kadowitz PJ. A review of the pathophysiology and novel treatments for erectile dysfunction. Adv Pharmacol Sci. 2010. www.hindawi.com/jour nals/aps/2010/730861/. Accessed October 9, 2014.

12. Jackson G, Rosen RC, Kloner RA, et al. The second Princeton consensus on sexual dysfunction and cardiac risk: new guidelines for sexual medicine. J Sex Med. 2006;3:28-36.

13. Cleveland Clinic. Diseases & conditions. Medications that may cause erectile dysfunction. http://my.clevelandclinic.org/disorders/Erectile_disorder_impotence/ hic_Medications_That_May_Cause_Erectile_Dysfunction.aspx. Updated April 7, 2011. Accessed October 9, 2014.

14. Montague DK, Jarow JP, Broderick GA, et al; for American Urological Association.

Erectile dysfunction. The management of erectile dysfunction (2005) [abridged]. www. auanet.org/education/guidelines/erectile-dysfunction.cfm. Accessed October 9, 2014.

15. American Urological Association. Diagnostic evaluation of erectile dysfunction. www.auanet.org/about/policy-statements/evaluation-of-erectile-dysfunction.cfm. Updated May 2012. Accessed October 9, 2014.

16. Frederick LR, Cakir OO, Arora H, et al. Undertreatment of erectile dysfunction: claims analysis of 6.2 million patients. J Sex Med. 2014;11:2546-2553.

17. Cost can limit choice of erectile function drug, from the June 2014 Harvard Men’s Health Watch [news release]. Boston, MA: Harvard Health Publications; 2014. www. health.harvard.edu/press_releases/cost-can-limit-choice-of-erectile-function-drug.

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23. Morales AM, Casillas M, Turbi C. Patients’ preference in the treatment of erectile dysfunction. A critical review of the literature. Int J Impot Res. 2011;23:1-8.

24. Kaiser Family Foundation. Prescription drug trends. http://kaiserfamilyfoundation.files. wordpress.com/2013/01/3057-08.pdf. Published May 2010. Accessed October 9, 2014.

25. Eaddy MT, Cook CL, O’Day K, et al. How patient cost-sharing trends affect adherence and outcomes: a literature review. P T. 2012;37:45-55.

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27. Urology Care Foundation. Low testosterone (hypogonadism). www.urologyhealth. org/urology/index.cfm?article=132. Updated June 2014. Accessed September 11, 2014.

28. Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007;92:4241-4247.

29. Haring R, Volzke H, Felix SB, et al. Prediction of metabolic syndrome by low serum testosterone levels in men: results from the study of health in Pomerania. Diabetes. 2009;58:2027-2031.

30. Haring R, John U, Volzke H, et al. Low testosterone concentrations in men contribute to the gender gap in cardiovascular morbidity and mortality. Gend Med. 2012;9(6):557-568.

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34. Nippoldt TB; for Mayo Clinic. What are the heart risks associated with testosterone therapy? www.mayoclinic.org/healthy-living/mens-health/expert-answers/testos terone-therapy-side-effects/faq-20090015. Published July 11, 2014. Accessed October 9, 2014.

35. US Food and Drug Administration. FDA drug safety communication: FDA evaluating risk of stroke, heart attack and death with FDA-approved testosterone products. www.fda.gov/drugs/drugsafety/ucm383904.htm. Published January 31, 2014.

Updated June 20, 2014. Accessed October 9, 2014.

36. Cleveland Clinic. Diseases & conditions. Sexual dysfunction and disease. http:// my.clevelandclinic.org/health/diseases_conditions/hic_An_Overview_of_Sexual_ Dysfunction/hic_Sexual_Dysfunction_and_Disease. Published January 10, 2007. Accessed October 9, 2014.

Stakeholder Perspectives in Men’s Health I 15

FOR UROLOGISTS, PRACTICE MANAGERS, FINANCIAL COUNSELORS, AND REIMBURSEMENT SPECIALISTS™

Call for Papers

Do you have a practice management story to share

?

In your background as a urology practice manager, it’s likely there’s one business experience—and maybe more—that practice managers across the nation would want to read about.

High-interest topics include: the solution you found to a practice management challenge, reimbursement, your experience with EMR, Medicare audits, a memorable encounter that shaped the way you now run your business and/or practice medicine, or how you successfully integrated ancillary products and services into your practice as a revenue generator.

Send us your ideas!

Submit a 600- to 1500-word original article to Urology Practice Management that your fellow practice managers will want to read.

Submit to: info@the-lynx-group.com UPM_73114