Slide 1 Pharmacologic Treatment of Erectile Dysfunction

Jeffrey Albaugh, PhD, APRN, CUCNS Director of Sexual Health NorthShore University Glenbrook Urology [email protected]

Slide 2 Disclosures/Conflict of Interest

• None

Slide 3 Erectile Dysfunction

• “The consistent or recurrent inability to attain and/or maintain a penile erection sufficient for sexual performance.” – WHO-ISIR. 1st International Consultation on ED, 1999

Slide 4 Male A&P

Slide 5 Endothelial Dysfunction

Slide 6 Oral Agents INTERVENTION: MEDICAL TREATMENTS - Oral Therapies PDE Type 5 inhibitors primary drug class - oral erectile dysfunction therapy Sildenafil (Viagra)-25-100mg Vardenafil (LeVitra) 5-20mg; Vardenafil (Staxyn) 10 mg Tadalafil (Cialis) 5-20mg, also 2.5-5 mg q day Avanafil (Stendra) 50-200mg Drugs are potent, selective inhibitors of type 5 phosphodiesterase - improve erectile function by inhibiting breakdown of cyclic GMP - smooth muscle relaxation enhanced Contraindicated with Nitrates, Teach Patient about Non-arteritic anterior ischemic optic neuropathy (NAION) Precautions with Alpha Blockers

Slide 7 Sildenafil (Viagra) • Dosage: 25-100mg, starting dose 50 mg • Onset 30-60 mins; peak 60-120 minutes; mostly gone in 8-12 hours; reduced clearance in elderly (start low, go slow); empty stomach most sensitive to food! • Contraindications: – Pt. On any nitrates – Patients with retinitis pigmentosa • Precautions: Start @ 25 w/ >65y/o, Caution w/ CHF or MI within last 6 months, resting hypotension, if on alpha blockers start low and titrate up as needed; >3 drinks of alcohol • Side Effects – Headache, flushing, indigestion, dyspepsia, stuffiness, visual disturbances

Slide 8 Sildenafil

• Stop & seek medical help if visual acuity or hearing changes • Hepatic impairment- start low, go slow • Renal Insufficiency: Volunteers with mild (CLcr=50-80 mL/min) and moderate (CLcr=30-49 mL/min) renal impairment, the pharmacokinetics of 1 oral dose of VIAGRA (50 mg) were not altered. With severe (CLcr=<30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of concentrations compared to age-matched volunteers with no renal impairment. • In addition, N-desmethyl metabolite AUC and Cmax values significantly increased 200% and 79% respectively in subjects with severe renal impairment compared to subjects with normal renal function. – From prescribing information @ http://www.pfizer.com/files/products/uspi_viagra.pdf

Slide 9 Vardenafil

• Dosage: 5-20mg, Starting dose 10 mg • Contraindicated: – Patients on nitrates or guanylate cyclase stimulators (riociguat) – Not for patients with QT prolongation – Do not use with patients on dialysis as no research done (prescribing info) • Precautions: Start @ 5 mg if >64; Adjust dose or don’t use w/ moderate-severe renal impairment; start low, go slow with hepatic impairment; hypotension with excessive alcohol • Drug Interactions • Adverse Reactions: – Headache, flushing, stuffy nose, dizzy • Instruction – High fat may effect absorption, others similar

Slide 10 Vardenafil Hcl

• Do not take with nitrates • Caution with alpha- blockers=may drop your blood pressure to an unsafe level, must start at lowest dose- start low, go slow. • Metabolism through CYP3A4- ritonavir and indinavir increase half LeVitra- use 2.5mg no more than every 72 hours for ritonavir and 2.5 mg in 24 hours with indinavir • Erthromyacin & Ketoconazole- increase Levitra- use 2.5-5 mg dose

Slide 11 Vardenafil Hcl

• Do not use LEVITRA in patients on renal dialysis as vardenafil has not been evaluated in such patients. • No dosage adjustment is necessary in patients with creatinine clearance (CLcr) of 30–80 mL/min. In male volunteers with CLcr = 50-80 ml/min, the pharmacokinetics of vardenafil were similar to those observed in a control group with CLcr >80 mL/min. In male volunteers with CLcr = 30-50 mL/min or CLcr<30 mL/min, the AUC of vardenafil was 20–30% higher compared to that observed in a control group with CLcr>80 mL/min. – From prescribing information at http://www.levitra.com/assets/pdf/PI.pdf

Slide 12 Tadalafil • Dosage: 5-20mg; Starting dose- 10mg; 36 hour duration • Onset 30-60 mins; peak effect- 60-120 mins • Contraindication: – Patients taking nitrates – Not recommended for men w/ MI last 90 days, stroke last 6 months, Class 2 or > heart failure; uncontrolled arrhythmias, hypotension <90/50 • Side Effects: – Headache, dyspepsia, dizziness, flushing, nasal stuffiness, back pain, myalgia – Teaching: Can take with foods, but high fat may delay absorption, same as others; no excessive alcohol (<5units) – Stop and seek medical help if visual acuity change or hearing loss

Slide 13 Tadalafil

• Renal Patients: • Patients with creatinine clearance 30 to 50 mL/min: Dosage adjustment may be needed. • Patients with creatinine clearance less than 30 mL/min or on hemodialysis: For use as needed: Dose should not exceed 5 mg every 72 hours. Once daily use is not recommended. – From prescribing info @ http://pi.lilly.com/us/cialis- pi.pdf

Slide 14 Avanafil

• Dosage: 50-200mg; starting dose 100mg • Onset 20 mins; peak effect 30-45 mins; Short 3 hour duration • Caution: alpha blockers- should be stable on them and then start with lowest dose and titrate as tolerated; if NAION • Can take with food, but delays absorption- empty stomach • Contraindication: – Patients taking nitrates- not within 12 hours • Side Effects: – Headache, flushing, nasal stuffiness, upper respiratory infection, back pain, dizziness – Teach to stop drug if changes in vision or hearing

Slide 15 Avanafil

• Not recommended in men with MI, stroke or life-threatening arrhythmia or coronary revascularization within last 6 months, Low BP < 90/50 or HTN >170/100; heart failure Class 2 or higher; angina with sex • No greater than 3 units of alcohol with avanafil • Start lower and may go to full dose in geriatric patients (caution depending on patient) • No data with severe renal or hepatic impairment

Slide 16 Avanafil

• Caution with alpha-blockers -may drop your blood pressure to an unsafe level, must start at lowest dose- start low, go slow. Caution with patients with left ventricular outflow obstruction or severely impaired autonomic BP control • Metabolism through CYP 450 isoform 3A4- Do not use stendra with drugs such as ketoconazole, clarithromyacin, ritonavir, atazanavir and indinavir, etc… • No higher than 50 mg maximum in 24 hours with erthromyacin, amprenavir, diltiazem, aprepitant, fluconazole, fosamprenavir and verapamil

Slide 17 Comparison of Medications

• No good head to head trials. • System review and network meta-analysis. 118 trials included (31,195 individuals). Tadalafil was most effective followed by vardenafil. Safety analysis did not reveal any differences amongst agents -Yuan, J et al. (2013). Comparative effectiveness and safety of oral phosphodiesterase type 5 inhibitors for erectile dysfunction: A systemic…European Urology, 63(2013), 902-912 • A trade-off network meta-analysis of PDE-5 inhibitors for ED. 82 trials for efficacy and 72 for adverse events. Sildenafil 50 mg was treatment of choice for efficacy and tadalafil 10mg for tolerability. – Chen, L. et al. (2015). Phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: A trade-off network meta-analysis. European Urology, 68(2015), 674-680.

Slide 18 Treatment: MUSE

Urethral suppository •Dosage: 125 to 1000 mcg •Onset: 5-10 mins; Duration 30-60mins •Contraindications: Hypersensitivity, Abnormally formed penis, conditions that can lead to priapism like sickle cell, multiple myeloma, leukemia, or if the patient has a penile implant •Caution if patient has low blood pressure or history of fainting •50% efficacy at best- may need to combine with orals •Adverse Reactions: penile pain, hypotension, prolonged erections, lightheadedness, or dizziness •http://www.muserx.com/pdf/muse-full-prescribing-information.pdf

Slide 19 MUSE

Always dose in the clinic and check vitals before and after medication Check applicator that medication present Keep penis upright during instillation process After administration, ensure that pellet delivered Roll penis for 10-30 seconds and watch tip to make sure pellet does come out of penis Walk to promote increased blood flow to penis Restrictive device placed at base of penis to decrease venous return from penis can not be on longer than 30 mins Lie down if dizzy, change positions slowly Do not give to patients with low blood pressure

Slide 20 MUSE & Oral Agents • Oral agent 1 hour before MUSE • Synergistic effect improves efficacy • 23 patients unsatisfied w/ Sildenafil (100mg) alone, added MUSE 500mcg. 83% reported improved penile rigidity and sexual function, erection sufficient for penetration 80% of the time -Raina, R., Nandipati, K.C., et al. (2005). Combination therapy: medicated urethral system for erection enhances sexual satisfaction in sildenafil citrate failure following nerve-sparing radical prostatectomy. Journal of Andrology, 26(6), 757-760. • 28 patients failed MUSE & Viagra as single agent- used MUSE 500mcg with sildenafil 100mg @ 30 months all 28 patients reported erections sufficient for penetration – Nebra, A. et al. (2002). Rationale for combination thereapy of intraurethral prostaglandin E1 & sildenafil in the salvage of erectile dysfunction patients desiring noninvasive therapy. International Journal of Impotence Research, 14 (Supp 1), S38-42. • 26 patients failed MUSE & Viagra as single agents- combo MUSE 500mcg & Sildenafil 100mg- Improved efficacy in combination -Nehra, A., Hakim, L.S., Barrett, D.M., Blute, M.L., & Moreland, R.B. (2000). Combination of sildenafil and intraurethral prostaglandin E1 salvaged a selected population of men with ED. Abstract submitted to the 95th Annual Meeting of the American Urological Association in Atlanta.

Slide 21 Treatment of ED: Injections

Intracavernosal Injection Therapy (PGE1 & Trimix): alprostadil sterile powder and alprostadil alfadex, both synthetic formulations of prostaglandin E1 Trimix (off-label/non-FDA approved)-PGE1, phentolamine, & papavarine •Dosage: alprostadil-5-40 mcg w/ PGE; Doses vary w/ trimix and bimix •Onset: 5-20 mins; duration: 30 mins-4hours •Contraindicated: drug hypersensitivity, risk for priapism (e.g. sickle cell disease, hypercoagulable states) & women/children •Adverse Reactions: prolonged erections or priapism, penile pain, and fibrosis with chronic use, ecchymosis, hematoma

Slide 22 Precautions Contraindications . Obese abdomen . Concurrent use of MAO . History vaso-vagal Inhibitors response . Penile prosthesis . Dexterity problems . Sexual activity is . Uncontrolled inadvisable or hypertension contraindicated . Severe Deformity of the . penis/Peyronie’s Predisposition to Disease priapism due to – www.caverject.com/prescribingInfo.a hematologic disorders spx – http://www.edex.com/filebin/pdf/Edex_ (e.g., sickle cell anemia, Full_Prescribing_Information.pdf multiple myeloma, leukemia) 22

Slide 23 Advantages Disadvantages . Invasiveness and . High efficacy rate anxiety of injecting . Reliable needle into penis . Suitable for travel but . Cost/insurance agents with PGE1 coverage requires refrigeration . Side effects: • Priapism • Bruising/bleeding • Hematoma

Albaugh (2010) Urological Nursing, 30, 167-177. • PGE1 pain 1Pierpaoli & Mulhall (1998). Journal of Urology, 159, 1299. . Papaverine may test (+) for opiates on urine screen1 23

Slide 24 Summary

• There are several treatment pharmacological options for erectile dysfunction including oral agents (pills), intraurethral agents and intracavernosal injections • Patients need to understand all treatment options to determine what they want to do • Instructions and teaching can make a big difference in success and continuation of medications