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The Consultant ImprovingR patient care through drug education September 2004 Volume XIII Number 8 Julio R. Lopez, Pharm.D.

OVERVIEW The medical management of male erectile dysfunction has The Bottom Line undergone significant changes in recent years. The introduction • Erectile dysfunction (ED) is a common of type 5 inhibitors (PDE5) such as condition. The cause is frequently physical, ® (Viagra ) changed the approach to treatment, making this the such as a medical condition, an injury or an preferred drug class for erectile dysfunction (ED). What was adverse effect from a , and may once a condition managed with surgical implants, vacuum also include psychological factors. pumps or penile injections is now typically approached with • Sildenafil, , and are oral therapy using drugs in the PDE5 class. Sildenafil, the first oral PDE5 inhibitors currently approved for PDE5 inhibitor approved by the FDA, was marketed in the use in ED. These drugs improve sexual United States in 1998. The new drug was quickly incorporated function in about 50-75% of men with ED. into practice, shifting utilization away from alprostadil • There is no evidence that one PDE5 drug or intraurethral suppository. The number of men seeking is more effective than another. The 3 drugs sildenafil prescriptions rose rapidly. By 2001 there had been an share similar precautions, but differ in onset 87% increase in prescriptions, to an estimated 145 million and duration of action. 1 annually. • PDE5 inhibitors can be effective in elderly Erectile dysfunction is a common problem. It is estimated men; those with cardiovascular disease, that most men 45 years of age or older experience the inability to or antidepressant-induced ED; and achieve an erection sufficient for sexual intercourse at least some in men who have undergone prostatectomy. of the time.2 The prevalence of ED increases with age so that by • PDE5 drugs can lower blood pressure. age 50, for example, about 50% of men have experienced erectile Cautious use is warranted in patients with dysfunction. Clearly, this is a large number of men and the cardiovascular disease. These drugs are potential use of drugs to treat ED is equally large. safe, however, in most men with controlled This article will review new data on the drugs used to treat or stable heart disease. erectile dysfunction. Information on sildenafil as well as the two • PDE5 drugs interact with many other new drugs, tadalafil (Cialis®) and vardenafil (Levitra®), will be drugs and all medication use should be presented. Issues surrounding the use of these drugs will be dis- carefully reviewed before these agents are used. Concurrent use of PDE5 drugs and or is contraindicated.

Continuing Education Objectives ACPE# 428-000-04-008-H01 CA BRN # 13118 • Describe the clinical efficacy of PDE5 drugs in the general cussed, including social issues such as market- population of men with ED and in men with medical condi- tions such as diabetes and heart disease. ing, the availability of ED drugs through non- conventional sources, and rationing via health • Discuss side effects of PDE5 drugs, and in particular how they relate to cardiovascular risks and benefits. care policy-making. Lastly, common questions regarding the off-label use of PDE5 drugs will be • Provide dosing information for PDE5 drugs and understand pharmacokinetic differences among the agents. answered, including uses other than sexual disorders. (See Insets, pages 3, 4, 6 and 7.) • List potentially dangerous drug interactions with PDE5 drugs.

1 Table 1. Commonly Used Drugs That May Cause Erectile Dysfunction Pathophysiology of Erectile Dysfunction Cardiovascular Drugs Beta blockers, centrally-acting sympatholytic ED is the inability to achieve sufficient penile engorge- drugs such as methyldopa and clonidine, thiazide ment to perform sexual intercourse. There are many rea- , spironolactone (high doses), digoxin sons why this happens.3 The physiology of normal pe- nile erection is complex and involves higher brain func- CNS Drugs tion, sympathetic and parasympathetic nervous system SSRI antidepressants, tricyclic antidepressants, pathways, and perhaps most importantly, a healthy pe- phenothiazines, atypical antipsychotics nile vascular system. With sexual stimulation, parasym- Endocrine Agents pathetic impulses via the cavernosal nervous system Drugs with estrogenic activity, antiandrogens used cause a release of , which in turn increases in , finasteride, dutasteride, intracellular cyclic guanosine monophosphate (cGMP) in anabolic steroids vascular within the corpus cavernosa. Miscellaneous This causes of the arteries and venules of alcohol, opioids the corpora cavernosa, allowing it to fill with blood. As the cavernosal sinusoids fill with blood, they compress the veins that drain these spaces, preventing outflow of blood. Elongation and rigidity of the penis occur. Once independent studies that compared each drug to pla- orgasm occurs, there is activation of the sympathetic ner- cebo. For example, patient selection criteria may have vous system leading to emptying of the corpus been different and the measurements of efficacy may cavernosum and penile detumescence. have used different self-reporting erectile dysfunction scales. In general, sildenafil is reported to have efficacy Any impairment of this system can lead to ED. This in- between 50% and 70% of the time when taken in doses cludes damage to the nervous system, as may occur with ranging from 25 to 200 mg. Indeed, in the pooled results diabetes or prostate surgery; vascular damage due to of 14 trials, 57% of intercourse attempts were successful atherosclerosis; or the effects of drugs and other agents among men taking sildenafil, compared to 21% among that impair both neural and vascular function such as men taking placebo.5 Vardenafil has been studied in overuse of alcohol. In particular, ED is commonly asso- doses ranging from 5 to 20 mg. Improvement in ED suf- ciated with cardiovascular disease and may be an early ficient to allow penetration was seen in 65% to 80% of 4 indicator of vascular disease. Many drugs are associ- patients, as compared to 52% with placebo.6 In the two ated with causing ED; some of the more commonly used U.S. studies used for the marketing approval of tadalafil, agents are listed in Table 1. If drug-related ED is sus- men taking tadalafil achieved erections sufficient for pected, other therapeutic options should be considered. penetration in 62% and 77% of attempts, compared to If the suspect drug is necessary, addition of a PDE5 drug 39% and 43% of attempts for men taking placebo.7 A may be appropriate. summary of five tadalafil studies conducted outside the U.S. reported a response rate of 75% based on ability to Phosphodiesterase Inhibitors complete intercourse.8 In summary, half to three quar- PDE5 drugs increase the normal response of the penile ters of patients with ED will get clinical benefit from vasculature to nitric oxide. They do so by inhibiting PDE5 drugs, with no apparent difference in efficacy rates phosphodiesterase, the that breaks down intrac- among the 3 drugs. As expected, the use of PDE5 drugs has been associated with improved well being and ellular cGMP. PDE5 drugs can overcome ED that results 9 from psychogenic causes (e.g., stress, anxiety) or neural sexual partner relationships. While there is no direct damage as long as the smooth muscle in the penile vas- comparative data among the PDE5 drugs, there is some culature is at least partially preserved. Sexual stimula- data comparing sildenafil to alprostadil and surgical im- tion is necessary to initiate an erection. plants. These data suggest that alprostadil and sildenafil are equivalent in efficacy but that penile implants are 10 Efficacy in the General Population superior for long term management of ED. The first commercially available drug in this class was Efficacy in Special Populations sildenafil. More recently, tadalafil and vardenafil have been marketed. Clinical trials directly comparing the Of particular interest is the use of PDE5 drugs in special three PDE5 agents have not been published. There are populations that are traditionally more difficult to treat many limitations when comparing the drugs by using or at higher risk of adverse events. Elderly patients are at higher risk of adverse events and drug interactions

2 Do sildenafil or similar drugs work in women with sexual dysfunction? because of an increased prevalence of heart disease and the concurrent use of other . A review of the Female sexual dysfunction appears to be elderly patients (defined as older than 65 years) included much more complex than male erectile dysfunc- in five clinical trials evaluating sildenafil shows that tion. Vascular events parallel to those that oc- sildenafil is effective in this age group, with an incidence cur in men lead to clitoral enlargement and of side effects similar to that seen in younger patients.16 vaginal lubrication. However, this plays a lim- Vardenafil and tadalafil are also equally effective in eld- ited role in female sexual dysfunction, as loss of erly men as compared to younger men.17,18 libido and anorgasmia are more prevalent. Treatment with PDE5 drugs, particularly Sildenafil has also been studied in patients with heart sildenafil, has resulted in reversal of failure and stable coronary artery disease who are not on anorgasmia in antidepressant induced sexual nitrates. In men with ED and NYHA class II or III heart dysfunction.11,12 However, evidence for the use failure, sildenafil improved ED scores and caused an as- of PDE5 drugs in treating general female sexual ymptomatic decrease in blood pressure of 6 mm Hg.19 dysfunction is very limited and conflicting, with ED is common in men with chronic stable coronary ar- most studies targeting sexual arousal disor- tery disease, with a reported prevalence of 75%.21 A re- der.13,14 These data do suggest improvement in cent 12 week study found that sildenafil was safe and sexual fulfillment in some women with arousal effective in this patient population. About 65% of the disorder, but there has been no improvement in men receiving sildenafil reported improved erections women with coexisting hypoactive sexual desire and improved intercourse, compared to 20% of those re- disorder. reported it will not apply for the ceiving placebo. The authors noted no adverse cardiac events.22 Similar results have been reported with approval of sildenafil for female sexual dysfunc- vardenafil in men with coronary artery disease. Men tion due to the disappointing study results to 15 received exercise tolerance testing following administra- date. tion of vardenafil. Heart rate and blood pressure were minimally affected and exercise tolerance remained the same as with a placebo.23 therapy was not al- post surgical ED is very high. Dysfunction occurs in lowed in these studies. PDE5 drugs should be used very about a third of patients, even with nerve sparing surgi- cautiously in men with CAD, since patients are at high cal techniques. Vardenafil improved ED scores in 60- 71% of patients after nerve sparing radical prostatec- risk for drug interactions if they need to use nitrates for 33 . Overall, therapy with PDE5 drugs is both safe tomy in one study. Sildenafil and tadalafil are also ef- and effective in most men with stable heart disease or fective for ED related to prostatectomy. However, unless 34 controlled hypertension. the surgery is nerve sparing, no response is seen. The incidence of ED in men with diabetes mellitus is Other specialized populations in whom sildenafil has been studied include patients on chronic dialysis35, men high, with as many as 46% of men with type 2 diabetes 36 37 reporting the problem.26 Studies of sildenafil, tadalafil with spina bifida , and men with spinal cord injuries . and vardenafil in patients with diabetes report efficacy In all these studies, sildenafil improved ED. Sildenafil is rates of about 54 to 72%, which is comparable to re- the most studied drug in the PDE5 class because it has sponses in patients without diabetes.27-29 Therapy with been on the market the longest. There is no reason to sildenafil is also effective and well tolerated in men with suspect other drugs in the PDE5 class would not work as type 1 diabetes.30 well. Antidepressant-induced ED is common. A study of 90 Combination Therapy men with major depression in remission who were Given the fact that the response to PDE5 drugs is not treated with serotonin reuptake inhibitors evaluated 100% or even close to that, investigators have explored 31 sildenafil in doses of 50-100 mg. Sexual function was combination therapy with alprostadil intracavernosal improved in 54% of patients with no effect on depres- injection or urethral suppository. While the data is very sion scores. Interestingly, in men with ED and mild de- limited, the combination of alprostadil and sildenafil ap- pression, treatment of ED with sildenafil is associated pears to result in successful intercourse in 47% to 100% with marked improvement in both erectile function and of men who do not respond to either agent alone.38 Ad- 32 depression scores, without the use of antidepressants. ditional studies are needed to validate these results. Radical prostatectomy is often used to treat patients with prostate cancer. The surgery often damages nerves in- Long Term Efficacy volved in normal erectile function and the frequency of Finally, there is the question of long term efficacy. Is

3 Are there uses for sildenafil, vardenafil and tadalafil other than erectile Of significance are the time to peak drug level and half- dysfunction? life, which predict the time of peak efficacy and the du- Several other uses of PDE5 drugs are under ration of action. All of the drugs may have a rapid onset investigation.24 These range from gastrointesti- of action, but their peak levels predict highest efficacy. nal disorders (esophageal dysmotility) to cardiac Vardenafil and sildenafil have the shortest time to peak diseases, as well as other sexual disorders such drug level. Tadalafil has the longest half-life, corre- as premature ejaculation. One of the most sponding to an estimated duration of action of 36 hours. promising and well studied indications is primary It has been effective 24 and 36 hours after administra- .25 The dosing for this tion.42 It is also possible that the effects of tadalafil last condition differs from that used in ED. For ex- long enough to have repeated intercourse within the 36 ample, a recent small study using sildenafil 50 hour estimated duration, but this has not been studied. mg every 8 hours on a continuous basis demon- strated a benefit. From a patient counseling perspective, the PDE5 drugs have to be taken well in advance of a sexual encounter – at least 1 hour and possibly two hours for tadalafil. This ensures peak drug levels and optimal efficacy at the time there tachyphylaxis to the effects of PDE5 drugs? In a of sexual intercourse. survey, 49% of patients who were given sildenafil con- tinued to use it two and a half years later.39 Patients with The recommended initial dose for each drug is listed in diabetes or prostate surgery were least likely to continue Table 2. A starting dose at the low end of the dose range use of sildenafil. Another survey of patients completed should be considered for the frail elderly, men with liver two years after they began taking sildenafil noted a pos- or kidney dysfunction, and those taking interacting sible loss of efficacy, with only 59% of patients who re- drugs that may increase the concentration of PDE5 ported an initial response still using the drug.41 Reasons drugs. (Recommendations vary among the drugs and for discontinuation included loss of efficacy in half of the are detailed in the prescribing information.) If the re- patients and side effects or no longer needing drugs for sponse to therapy is inadequate after several doses (e.g., ED in the other half. In contrast, a study of sildenafil use 3-4 doses taken on different days), the dose may be in 43 patients following prostate surgery found a greater doubled. In patients who respond to therapy but experi- long term success rate.40 After 3 years, 71% were still us- ence bothersome side effects, a trial of one-half the initial ing the drug. About a third of the patients had increased dose is appropriate. their dose from 50 to 100 mg. Clearly, there are limita- tions to surveys, but nonetheless, the data point to some Drug Interactions limitations of PDE5 therapy. Whether or not true phar- One of the important considerations for safe use of PDE5 macological tachyphylaxis occurs is unknown. To an- drugs is screening for drug interactions. PDE5 drugs swer this question would require a long term controlled can lower blood pressure. Their use in combination with clinical trial. nitrates43 or antihypertensive drugs can lead to profound lowering of blood pressure, which in turn can trigger and Dosing cardiac events including angina and myocardial infarc- The pharmacokinetic parameters of the three PDE5 tion. drugs and dosing information is presented in Table 2. Data on potential interactions is limited to small studies.

Table 2. Oral Medications for the Treatment of Erectile Dysfunction7,65

Drug (brand name) Initial Dose Onset Time to Duration Half-life Cost dose range of action peak level of action per dose*

sildenafil (Viagra®) 50 mg 25-100 mg 27 min. 1 hour 4 hours 4 hours $10.63 tadalafil (Cialis®) 10 mg 5 -20 mg 45 min. 2 hours 36 hours 17.5 hours $10.63

vardenafil (Levitra®) 10 mg 2.5 - 20 mg 26 min. 1 hour 4 hours 4 - 5 hours $10.11

* Average Wholesale price (AWP) according to the McKesson Wholesaler online catalog. Each drug is flat-priced for all strengths.

4 In particular, there is concern about the risk of interac- enzyme system, specifically isoenzyme 3A4. Any drug tions with the longer acting tadalafil. Studies looking at that interferes with CYP3A4 activity has the potential to the time-course of an interaction between a single sub- alter the effects of PDE5 drugs. To date, interactions have lingual dose and tadalafil do reveal more been documented with grapefruit juice48 and protease in- lowering of blood pressure at 24 hours, but not at 48 hibitors (e.g., ritonavir).49-51 These drugs inhibit 3A4 and hours or beyond.44 While no adverse outcomes have increase blood levels of PDE5 drugs. Although patients been seen in these studies, it is prudent to avoid nitrates are not likely to be harmed by concurrent use of PDE5 and other vasodilators for at least 24 hours after a drugs with grapefruit juice, it seems advisable to avoid tadalafil dose. The prescribing information for tadalafil the combination. The prescribing information for recommends waiting 48 hours before using nitrates and tadalafil recommends no more than 10 mg every 72 hours then only using nitrates in a setting with medical super- in patients taking potent inhibitors of CYP3A4. Lower vision. Clinical judgement must determine when the doses are recommended in the sildenafil and vardenafil potential benefits of nitrate use outweigh the risks fol- prescribing information when these agents are used to- lowing a dose of sildenafil or vardenafil. In general, gether with protease inhibitors, azole antifungal drugs or most of the PDE5 drug will have been eliminated from erythromycin. In addition, a case of -induced the body 12-15 hours after a dose. rhabdomyolysis has been attributed to its combination with sildenafil.52 Lastly, there have been two case reports Whether or not PDE5 drugs potentiate the effects of non- of priapism with the combination of dihydrocodeine and nitrate antihypertensive medications is subject to some sildenafil.53 The mechanism for this potential interaction debate. The evidence to date seems to indicate the effect is unknown. Well documented interactions of PDE5 is small.41,47 Nonetheless, the prescribing information for drugs are presented in Table 3. tadalafil and vardenafil contraindicate their use in pa- tients taking alpha blockers such as doxazosin. Like Adverse Effects sildenafil, vardenafil and tadalafil appear to be safe when taken with other antihypertensive medications. Common adverse effects of PDE5 drugs include (11-16%), flushing (3-11%), dyspepsia (4-8%), rhinitis/ All PDE5 drugs are metabolized by the nasal congestion (3-9%) and changes in the perception of

Table 3. Key Drug Interactions with Phosphodiesterase Inhibitors

Interacting drug(s) What may happen Comments Nitrates, nitrites profound All authorities consider nitrate/ use an absolute (e.g., nitroglycerin) contraindication to the use of PDE5 drugs. Protease inhibitors increased PDE5 drug Use the lowest available PDE5 drug dose only. For (e.g., ritonavir, concentrations; increased example, patients taking ritonavir should use no more indinavir) drug effects than 25 mg sildenafil every 48 hours. Opioids prolonged erection Warn patients that prolonged erections may (e.g., codeine, hydrocodone) occur, and if they do, to avoid the combination. Grapefruit juice increased PDE5 drug Instruct patients to avoid drinking grapefruit juice for concentrations; increased 12 hours (sildenafil, vardenafil) or 24 hours (tadalafil) drug effects after a PDE5 drug dose. Macrolide antibiotics inhibition of CYP3A4 metab- Alternative antibiotics should be prescribed or (erythromycin, olism; increased PDE5 drug patients should be instructed not to take PDE5 drugs clarithromycin) concentrations during macrolide use. Alpha blockers increased hypotensive Concurrent use is contraindicated with (e.g., prazosin, doxazosin, effect tadalafil (except tamsulosin 0.4 mg daily) and terazosin) vardenafil in the prescribing information. Sildenafil doses above 25 mg should not be taken within 4 hours of an alpha blocker. Non-nitrate antihypertensive increased hypotensive Use cautiously. agents effect

5 What is in those products advertised as natural Viagra? tioned. In particular, the issue of whether or not these The answer may surprise you. Many of drugs precipitate has been the sub- these natural products are in fact adulterated ject of intense debate. There is data supporting the fact with PDE5 drugs and the amount of active drug that patients taking sildenafil die more frequently.58,59 varies widely among products.45 Other "natural For example, there were an estimated 49 deaths per mil- Viagra" products contain a mixture of herbs, fre- lion sildenafil prescriptions compared to 4.5 deaths per quently including saw palmetto, ,Tribulus million Caverject® prescriptions, based on voluntary re- terrestis and Ginkgo biloba. Some of the formu- ports to the FDA. The question is, why? On one side of las are very complex. For example, BetterMAN the debate is the suggestion that the intrinsic hemody- contains a mixture of 18 Chinese herbals.46 namic effects of PDE5 drugs (e.g., vasodilation) are dan- There might be some pharmacological activity in gerous in patients with existing heart disease. On the some of these natural herbs that could improve other side of the debate is the fact that exposure to the ED. However, the lack of reliable clinical data, drugs is occurring to a greater extent in elderly men, and product quality control and herbal standardiza- the episodes of myocardial infarction are just as expected tion, coupled with the potential risk of adultera- in an elderly population. Furthermore, sexual activity is tion with PDE5 drugs, suggests that patients physical activity that increases demands on the heart should steer clear of these supplements. and may in fact be responsible for the presumed increase in deaths in men taking PDE5 drugs. Who is right? No one knows and both sides of the debate offer plausible explanations. The intense discussion has led to publica- color or brightness (< 2-3%). Less common adverse ef- tion of guidelines for drug use in patients with heart dis- fects include back pain, muscle aches, dizziness and hy- ease by notable organizations such as the American Col- potension. Priapism has occurred rarely. PDE5 drugs lege of Cardiology and the American Heart Associa- should not be used in men with conditions that increase tion.60 The ACC/AHA recommends using PDE5 drugs the risk of priapism, such as sickle cell disease. In addi- with caution in men with active coronary artery disease tion, men with conditions that cause erections to be not taking nitrates, patients with and bor- curved (e.g., Peyronie's disease) should not use PDE5 derline low blood pressure, patients on complicated, drugs. multidrug antihypertensive regimens, and patients tak- Since marketing there have been reports of migraine54, ing concurrent medications that can increase PDE5 drug seizures55, strokes56, amnesia57 and behavioral distur- levels. As discussed above (under Special Populations), bances including aggressiveness caused by sildenafil. use of PDE5 drugs appears safe in many men with hy- Whether or not these conditions are coincidental or truly pertension and/or other stable cardiac diseases. associated with sildenafil use is not known. There are at least 11 types of phosphodiesterase in the Alprostadil human body and differences in selectivity for these en- While their use has decreased, both injectable alprostadil zymes may translate to differences in side effect poten- and a urethral suppository remain on the market. These tial. Selectivity for PDE5 is greatest for tadalafil and drugs are effective in 50-80% and 65% of men with ED, least for sildenafil. The possible adverse visual effects of respectively. They continue to be useful options for pa- PDE5 drugs through inhibition of phosphodiesterase tients who fail PDE5 drugs and for those who have type 6 (an enzyme involved in color perception) have contraindications to their use. Common adverse effects been studied. Of concern are the long term outcomes of of alprostadil include pain, particularly with penile in- the transient visual changes induced by these drugs. jection, and burning. Priapism is rare, although it has Abnormal vision (e.g., changes in the perception of color been reported more frequently with alprostadil than or brightness) has been reported in 3% to 9% of men tak- with PDE5 drugs. Erections lasting longer than 4 hours ing sildenafil. Vardenafil does not appear to produce vi- should be medically evaluated. Intracavernosal sual changes more frequently than placebo. Mild hazi- alprostadil injection was preferred to oral sildenafil in ness or an increase in the perceived brightness of light is one study which included patients previously treated infrequently reported. Tadalafil does not appear to in- with intracavernosal injections.61 The response to hibit PDE6 to any significant extent and the incidence of sildenafil was considered inferior by 44% of men who color vision abnormalities is less than 0.1%. had a positive response to alprostadil. Cardiovascular Safety Ethics, Costs and Social Issues The cardiovascular safety of PDE5 drugs has been ques- The drugs used to treat ED are known as "quality of life-

The Rx Consultant (ISSN 10667741) is published monthly except August for $98 per year by CEN, Inc. 6 5325 Stonehurst Drive, Martinez, CA 94553-6619. Periodicals Postage Paid at Martinez, CA and additional mailing offices. POSTMASTER: Send address changes to THE RX CONSULTANT, P.O. Box 1516, Martinez, CA 94553-0516. Erectile Dysfunction Drugs on the Internet Yes, you can buy them - and often with a enhance or prolong sexual function in individuals who simple on-line consultation rather than a are potent. physician’s prescription. The internet trade in PDE5 drugs is clearly alarming, as patients may Summary be obtaining these drugs without the safeguards of good medical and pharmaceutical care. You The advent of PDE5 drugs truly revolutionized the treat- should recognize this danger when providing ment of ED and they are now the drugs of first choice for drugs that could interact with PDE5 drugs. When most forms of the disorder. A reasonable approach to taking a medication history, specifically ask pa- the use of these medications includes a careful evalua- tients if they take any drugs purchased on the tion by a trained clinician for the cause of ED and any internet. Counsel patients not to obtain these risks associated with the use of the medications. Treat- drugs via the internet, as the source and integrity ment goals should be realistic and must include a frank of the medication cannot be guaranteed. Suggest discussion of the efficacy limitations of PDE5 drugs as they consult their primary care provider instead. well as the risks of therapy. If PDE5 drugs are not effec- tive, a trial of alprostadil injection or intraurethral sup- pository is indicated. A small percentage of patients will fail drug therapy and should be referred to a urologist enhancing" or lifestyle medications. While erectile dys- for further evaluation. Healthcare providers should give function in men has tremendous psychological implica- patients clear information about dosing, adverse effects tions, the condition itself is not considered a source of and contraindications. In particular, providers should be morbidity or mortality. When sildenafil was first ap- very watchful for drug interactions, as they can lead to proved, it attained great public notoriety and was serious adverse events. When used within these guide- heavily promoted with direct to consumer advertising. lines, PDE5 drugs provide an effective and safe ap- This brought about a great ethical dilemma for proach to managing ED. healthcare payers, which is: To what extent or under which conditions should these drugs be provided at healthcare plan expense? There were also fears that Dr. Lopez reports no financial interest in or other relationship PDE5 drugs may be misused for recreational “sexual en- with any commercial entity discussed in this issue. hancement.” The title of an editorial from the British Medical Journal in 199962 reflects the difficult ethical and social choices posed by these medications: “Rationing of sildenafil: Nobody needs an erection at public expense.” Resources for More Information Given the high cost of PDE5 drugs and the fact that • American Urological Association healthcare resources are limited, the topic of rationing 1000 Corporate Blvd. has been discussed. In many settings, the U.S. Linthicum, MD 21090 healthcare system has had to either shift the cost of (866) 746-4282 therapy to the patient or limit the amount of medication. Non-Surgical Management of Erectile Dysfunction For example, the Department of Veterans Affairs has cre- www.urologyhealth.org/adult/index.cfm?cat=11&topic=174 ated a structured approach to the diagnosis and treat- ment of ED, but also limits dispensing of the drugs to • Erectile Dysfunction Institute four doses per month.63 10949 Bren Road East Minnetonka, MN 55343-9613 Another phenomenon in American society has been the (952) 852-5560 intense marketing of PDE5 drugs with direct to con- www.erectile-dysfunction-impotence.org sumer advertising. These marketing efforts resulted in one of the most successful drug launches ever in the case • National Kidney and Urologic Diseases Information Clearinghouse of Viagra®. More recently, advertisements for Cialis® and 3 Information Way Levitra® were prominently featured in major sporting Bethesda, MD 20892-3580 events such as the Superbowl and the World Series. (800) 891-5390 http://kidney.niddk.nih.gov/kudiseases/pubs/impotence/index.htm The perception that PDE5 drugs can enhance sexual function and bring about unabated potency has led to • Mayo Clinic Men’s Health Center misuse or abuse of the drugs.64 While PDE5 drugs are Sexual Dysfunction Information clearly beneficial in a proportion of patients who suffer www.mayoclinic.com/findinformation/conditioncenters/ from ED, there is no evidence to suggest that the drugs centers.cfm?objectid=0004FC18-621F-1B37-8D7E80C8D77A0000

7 Erectile Dysfunction: Frequently Asked Questions

• What is erectile dysfunction? is usually mild and goes away. A rare but poten- Erectile dysfunction (ED) is the inability to obtain tially dangerous side effect is prolonged erection. an erection (hardness of the penis) to be able to This is known as priapism and can lead to perma- have sexual intercourse. It can happen for a variety nent loss of potency. If an erection lasts for longer of reasons, including surgery to the prostate gland. than 4 hours, seek medical attention immediately. ED is frequently seen in combination with diabetes If any bothersome adverse effects occur, consult and heart disease. Psychological problems, such as with your prescriber or pharmacist. stress and anxiety, may also cause or contribute to • What special precautions exist for the use of ED. erectile dysfunction drugs? •How do drugs used to tr eat erectile dysfunction Generally speaking, oral ED drugs such as work? sildenafil, vardenafil and tadalafil should be used Drugs used to treat ED work in two different ways. carefully in people who have moderate to ad- Oral drugs such as sildenafil (Viagra®), vardenafil vanced heart disease, including those who have (Levitra®) and tadalafil (Cialis®) work by increasing had a heart attack, irregular heart rhythms within blood flow into the penis. With these agents, there the last 6 months, or frequent chest pain from a dis- needs to be sexual stimulation for an erection to eased heart. Since low blood pressure can occur, happen. Generally, these drugs work in about half men who already have low blood pressure should to three quarters of men who use them. Alprostadil also use these drugs carefully. This group includes is given by injection (Caverject®, Edex®) into the pe- men who have heart failure. nis or by insertion of a small suppository (Muse®) In addition, men who have problems with their pe- into the opening of the penis. Alprostadil also nis where erections are curved, such as Peyronie’s works by increasing blood flow into the penis. disease, should not use these drugs. Men at risk for prolonged, painful erections, such as those with • How do I use them? sickle cell disease, should also avoid them. Oral drugs (sildenafil, vardenafil, tadalafil) are taken between 1 and 2 hours before sexual inter- Sexual activity can be particularly strenuous for course. Sexual stimulation is necessary for an erec- people with heart disease. Always consult with tion to occur. If sildenafil is taken after a heavy your physician to see if it is safe for you to use meal, it may take longer to work. Food has little or these drugs. Do not borrow drugs for ED from no effect on vardenafil and tadalafil. You may need friends and don’t buy them on the Internet. to try these drugs 3 or 4 times to see if they work. • Can erectile dysfunction drugs interact with Correctly following the instructions for use is im- other drugs I am taking? portant: 40% of men who thought these drugs did Oral drugs used for ED can have drug interactions. not work were taking them incorrectly. Ask your prescriber or pharmacist if any of the Alprostadil is either injected into the penis or in- drugs you are taking could be a problem. One of serted into the opening at the tip of the penis as a the most serious interactions is with drugs known small suppository. Follow the package instructions as nitrates. These drugs include nitroglycerin (used carefully. for chest pain) and products known as poppers that are used to enhance orgasm. Never use nitrates or • What side effects should I expect? poppers together with oral ED drugs, as very low Oral drugs such as sildenafil, vardenafil and blood pressure can develop that could be life- tadalafil can cause flushing, upset stomach, dizzi- threatening. Another type of drug that should not ness, headache and temporary changes in color vi- be used in many cases is an alpha blocker such as sion or the perception of brightness. Excessive alco- prazosin, terazosin or doxazosin. These drugs can hol intake may worsen side effects. Alprostadil can cause blood pressure to drop to dangerously low cause a burning sensation or pain in the penis. This levels.

This page was prepared as a patient education aid. It is not intended to replace a healthcare provider’s knowledge, judgement and advice, or for direct use by patients without a healthcare provider’s guidance. Supplement to The Rx Consultant. Copyright September 2004, CEN, Inc. TEST QUESTIONS This copy of the issue was generated online. To submit your test answers, return to the website and follow the links to the "Take The Test button". Questions are based on information provided in the text, tables and Frequently Asked Questions insert. This program is valid through August 31, 2007.

1. What percentage of men with ED typically achieve a 7. Which of the following drugs is most likely to positive response to PDE5 drugs? cause dangerous hypotension if used in a. 10-20% of men c. 50-75%% of men combination with PDE5 drugs? b. 25-40% of men d. 90-95% of men a. nitroglycerin c. ritonavir b. erythromycin d. dihydrocodeine 2. Why should PDE5 prescriptions for women be questioned? 8. A man takes both sildenafil and ritonavir. What a. There is limited data on efficacy in female is the recommended dose of sildenafil? sexual dysfunction. a. no more than 25 mg every 24 hours b. Gender differences in response suggest that b. no more than 50 mg every 36 hours women may develop transient amnesia. c. the combination should be avoided c. PDE5 drugs cause a paradoxical hypertensive d. no more than 25 mg every 48 hours response in women. d. PDE5 drugs are known teratogens. 9. Which adverse effect commonly occurs with the use of PDE5 drugs? 3. Which of the following is true for patients with mild a. priapism to moderate stable heart failure who wish to take b. transient loss of smell sildenafil? c. coughing a. They will likely encounter intolerable hypotension. d. flushing b. Sildenafil causes diuresis and lowers loop requirements. 10. It is possible to get ED drugs from internet c. Sildenafil can generally be used safely as long as the sources without a valid prescription. patient is not taking nitrates. a. True b. False d. A larger than approved dose of sildenafil is required to be effective. 11.What is the primary reason PDE5 drugs are pre- ferred over alprostadil for the treatment of ED? 4. Which special population of men with ED has not a. the ease and convenience of oral dosing demonstrated a benefit with sildenafil treatment? b. fewer adverse effects a. diabetes c. direct to consumer advertising b. post-prostatectomy (non-nerve sparing) d. they are more effective c. SSRI-induced ED d. coronary artery disease 12. Which factor has prompted a discussion about limiting or rationing PDE5 drugs? 5. Which of the following drugs will take the longest a. They do not treat a life-threatening disease and amount of time to reach its peak effect? may be used recreationally. a. sildenafil c. alprostadil b. They are heavily advertised which may lead to b. tadalafil d. vardenafil heavy consumer demand. c. PDE5 drugs are costly to our healthcare system. 6. Reduction of the PDE5 drug dose should be consid- d. all of the above ered in which of the following circumstances? a. age less than 50 years c. lack of response to therapy b. kidney or liver disease d. concurrent nitrate use

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A second combination drug Long-Term Antibiotic Use And New Treatment Guidelines for lowering cholesterol Risk of Breast Cancer For Adult HIV Infection (Vytorin®) has received FDA Velicer C.M. et al. Antibiotic use in relation to approval. ® Yeni PG, Hammer SM, Hirsch MS, et al. 2004 Vytorin is a combina- the risk of breast cancer. Recommendations of the International AIDS tion of ezetimibe and JAMA 2004; 291:827-35. Society-USA Panel. JAMA. 2004;292:251-265. simvastatin. The effects of the (http://jama.ama-assn.org/) Summary: two agents are additive for low- Researchers from the The International AIDS Society-USA ering LDL and increasing HDL. Fred Hutchinson Cancer Research has provided updated antiretroviral Triglycerides are also reduced. Center used computerized pharmacy records and breast cancer screening (ARV) treatment guidelines. In the "Aspirin resistance" may be a databases to evaluate a possible link new guideline: (1) ARV therapy is primary reason for heart at- between antibiotic use and the devel- generally not recommended for pa- tacks and in individuals opment of breast cancer. They com- tients with CD4 cell counts greater on preventive aspirin therapy. pared the antibiotic use of 2,266 than 350 cells/µL. (2) The optimal Researchers are finding that 10% women with breast cancer to similar time to start ARV agents in the as- or more of aspirin users are resis- information from 7,953 women with- ymptomatic person with CD4 cell tant to its protective antiplatelet out the disease. All of the women in counts between 200 cells/µL and 350 effects. These resistant individu- the study were age twenty years and cells/µL is still unclear. (3) The deci- als have a greater likelihood of older, and a wide variety of the most sion to start therapy should be indi- heart attack, , or death frequently prescribed antibiotics vidualized and based on the risks from a cardiovascular cause than were examined. The results show and benefits of long-term ARV. those who aren't aspirin resistant. that women who took antibiotics for Preferred regimens for initial therapy Use of high dose rofecoxib more than 500 days, or had more include either an efavirenz or a (Vioxx®) may be excessive, ac- than 25 prescriptions over an aver- “ritonavir-boosted” protease inhibi- cording to a recent epidemiologi- age period of 17 years, had twice the tor-based regimen (e.g lopinavir/ cal study. It found that long-term risk of breast cancer compared to ritonavir, atazanavir/ritonavir, use of high dose rofecoxib women who had not taken any anti- saquinavir/ritonavir) in combination (50 mg) is fairly common. Doses biotics. Increase in risk was found with two nucleosides (e.g., of 12.5 mg or 25 mg are FDA ap- across all classes of antibiotics zidovudine or tenofovir plus proved for the long-term treat- studied. lamivudine or emtricitabine; or ment of arthritis. The 50 mg dose Comment: The study results do not emtricitabine plus didanosine). is only approved for acute pain mean that antibiotics cause breast Triple nucleoside regimens are no and for no longer than 5 days. In cancer; they only provide evidence longer recommended as initial the study, rofecoxib accounted of a link between breast cancer and therapy unless preferred regimens for 25% of all NSAID prescrip- frequent or long term use of are inappropriate. Subcutanenous tions. Of those filled, 71% were antibiotics. enfuvirtide (Fuzeon) is reserved for for at least 50 mg for 30 days. A those failing initial ARV regimens. By Jennifer Ting-Chan, PharmD majority of patients filled a 2nd By Betty Dong, PharmD prescription within 1-2 weeks of and Frances Wong, PharmD the end of their 30-day supply.

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8 References 1. Wysowski DK, Swann J. Use of medications for erectile dysfunction in the United States, 1996 through 2001. J Urol 2003; 169(3):1040-2. 2. Seftel AD. Erectile dysfunction in the elderly: epidemiology, etiology and approaches to treatment. J Urol 2003; 169(6):1999-2007. 3. Lue TF. Erectile dysfunction. N Engl J Med 2000; 342(24):1802-13. 4. Kaiser DR, Billups K, Mason C, et al. Impaired brachial artery endothelium-dependent and -independent vasodilation in men with erectile dysfunction and no other clinical cardiovascular disease. J Am Coll Cardiol 2004; 43(2):179-84. 5. Fink HA, MacDonald R, Rutks IR, et al. Sildenafil for male erectile dysfunction: a systematic review and meta-analysis. Arch Intern Med 2002; 162(12):1349-60. 6. Hellstrom WJ, Gittelman M, Karlin G, et al. Sustained efficacy and tolerability of vardenafil, a highly potent selective phosphodiesterase type 5 inhibitor in men with erectile dysfunction: results of a randomized, double blind, 26-week placebo controlled pivotal trial. 2003; 61(4 suppl 1)8-14. 7. Product information for: Cialis, Lilly, Indianapolis, IN. November, 2003; Levitra, Bayer Healthcare and GlaxoSmithKline, Research Triangle Park, NC, August 2003; and Viagra, Pfizer, Inc., New York, NY. September, 2002. 8. Brock GB, et al. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. J Urol 2002; 168(4 Pt 1):1332-6. 9. Paige NM, Hays RD, Litwin MS, et al. Improvement in emotional well-being and relationships of users of sildenafil. J Urol 2001; 166(5):1774-8. 10. Rajpurkar A, Dhabuwala CB. Comparison of satisfaction rates and erectile function in patients treated with sildenafil, intracavernous and penile implant surgery for erectile dysfunction in urology practice. J Urol 2003; 170(1):159-63. 11. Nurnberg HG, Lauriello J, Hensley PL, et al. Sildenafil for sexual dysfunction in women taking antidepressants. Am J Psychiatry 1999; 156(10):1664. 12. Ashton AK. Sildenafil treatment of paroxetine-induced anorgasmia in a woman. Am J Psychiatry 1999; 156(5):800. 13. Berman JR, Berman LA, Toler SM, et al; Sildenafil Study Group. Safety and efficacy of sildenafil citrate for the treatment of female sexual arousal disorder: a double-blind, placebo controlled study. J Urol 2003; 170(6 Pt 1):2333-8. 14. Caruso S, Intelisano G, Lupo L, et al. Premenopausal women affected by sexual arousal disorder treated with sildenafil: a double-blind, cross-over, placebo- controlled study. BJOG 2001; 108(6):623-8. 15. Mayor S. Pfizer will not apply for a licence for sildenafil for women. BMJ 2004; 328(7439):542. 16. Wagner G, Montorsi F, Auerbach S, Collins M. Sildenafil citrate (VIAGRA) improves erectile function in elderly patients with erectile dysfunction: a subgroup analysis. J Gerontol A Biol Sci Med Sci 2001; 56(2):M113-9 17. Porst H, Young JM, Schmidt AC, et al. International Vardenafil Study Group. Efficacy and tolerability of vardenafil for treatment of erectile dysfunction in patient subgroups. Urology 2003; 62(3):519-23; discussion 523-4. 18. Curran M, Keating G. Tadalafil. Drugs. 2003; 63(20):2203-12; discussion 2213-4. Review. Erratum in: Drugs 2003; 63(23):2703. 19. Webster LJ, Michelakis ED, Davis T, et al. Use of sildenafil for safe improvement of erectile function and quality of life in men with New York Heart Association classes II and III congestive heart failure: a prospective, placebo-controlled, double-blind crossover trial. Arch Intern Med 2004; 164(5):514-20. 20. Bocchi EA, Guimaraes G, Mocelin A, et al. Sildenafil effects on exercise, neurohormonal activation, and erectile dysfunction in congestive heart failure: a double-blind, placebo-controlled, randomized study followed by a prospective treatment for erectile dysfunction. Circulation 2002; 106(9):1097-103. 21. Kloner RA, et al. Erectile dysfunction in the cardiac patient: how common and should we treat? J Urol 2003; 170(2 Pt 2):S46-50; discussion S50. 22. DeBusk RF, et al. Efficacy and safety of sildenafil citrate in men with erectile dysfunction and stable coronary artery disease. Am J Cardiol 2004; 93(2):147-53. 23. Thadani U, Smith W, Nash S, et al. The effect of vardenafil, a potent and highly selective phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction, on the cardiovascular response to exercise in patients with coronary artery disease. J Am Coll Cardiol 2002; 40(11):2006-12. 24. Mitka M. Researchers seek new uses for sildenafil. JAMA 2003; 289(21):2784-6. 25. Michelakis ED, Tymchak W, Noga M, et al. Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation 2003; 108(17):2066-9. Epub 2003 Oct 20. 26. Vickers M, Wright EA. Erectile dysfunction in the patient with diabetes mellitus. Am J Managed Care 2004;10(supplement):S3-S11 27. Goldstein I, Young JM, Fischer J, et al. Vardenafil, a new phosphodiesterase type 5 inhibitor in the treatment of erectile dysfunction in men with diabetes: a multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care 2003; 26:777-83. 28. Rendell MS, Rajfer J, Wicker PA, et al. Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. Sildenafil Diabetes Study Group. JAMA 1999; 281(5):421-6. 29. Saenz de Tejada I, Anglin G, Knight JR, et al. Effects of tadalafil on erectile dysfunction in men with diabetes. Diabetes Care 2002;25(12):2159-64. 30. Stuckey BG, Jadzinsky MN, Murphy LJ, et al. Sildenafil citrate for treatment of erectile dysfunction in men with type 1 diabetes: results of a randomized controlled trial. Diabetes Care 2003; 26(2):279-84. 31. Nurnberg HG, et al. Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial. JAMA 2003;289(1):56-64. 32. Seidman SN, Roose SP, Menza MA, et al. Treatment of erectile dysfunction in men with depressive symptoms: results of a placebo-controlled trial with sildenafil citrate. Am J Psychiatry 2001;158(10):1623-30. 33. Brock G, Nehra A, Lipshultz LI, et al. Safety and efficacy of vardenafil for the treatment of men with erectile dysfunction after radical retropubic prostatectomy. J Urol 2003;170(4 Pt 1):1278-83. 34. Feng MI, Huang S, Kaptein J, et al. Effect of sildenafil citrate on post-radical prostatectomy erectile dysfunction. J Urol 2000; 164(6):1935-8. 35. Chen J, Mabjeesh NJ, Greenstein A, et al. Clinical efficacy of sildenafil in patients on chronic dialysis. J Urol 2001; 165(3):819-21. 36. Palmer JS, Kaplan WE, Firlit CF. Erectile dysfunction in patients with spina bifida is a treatable condition. J Urol 2000; 164(3 Pt 2):958-61. 37. Derry FA, et al. Efficacy and safety of oral sildenafil (Viagra) in men with erectile dysfunction caused by spinal cord injury. Neurology 1998;51(6):1629-33. 38. Steers WD. Viability and safety of combination drug therapies for erectile dysfunction. J Urol 2003; 170(2 Pt 2):S20-3. 39. Gonzalgo ML, Brotzman M, Trock BJ, et al. Clinical efficacy of sildenafil citrate and predictors of long-term response. J Urol 2003; 170(2 Pt 1):503-6. 40. Raina R, et al. Long-term effect of sildenafil citrate on erectile dysfunction after radical prostatectomy: 3-year follow-up. Urology 2003; 62(1):110-5. 41. El-Galley R, Rutland H, Talic R, Keane T, Clark H. Long-term efficacy of sildenafil and tachyphylaxis effect. J Urol 2001; 166(3):927-31. 42. Porst H, Padma-Nathan H, Giuliano F, et al. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized con- trolled trial.Urology 2003; 62(1):121-5; discussion 125-6. 43. Webb DJ, Freestone S, Allen MJ. Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am J Cardiol 1999; 83(5A):21C-28C. 44. Kloner RA, Hutter AM, Emmick JT, et al. Time course of the interaction between tadalafil and nitrates. J Am Coll Cardiol.2003;42(10):1855-60. 45. Mitka M. FDA issues warning on "all-natural" herbal product found to contain viagra. JAMA 2003; 289(21):2786. 46. BetterMan information at http://www.bettermannow.com. Accessed May 23, 2004. 47. Chen JS. Sildenafil and nonnitrate antihypertensive medications. JAMA 2000; 283(2):201-2. 48. Jetter A, et al. Effects of grapefruit juice on the pharmacokinetics of sildenafil. Clin Pharmacol Ther 2002; 71(1):21-9. 49. Stricker BR, Thomas GD. Viagra and HAART. South Med J 2000; 93(10):1037. 50. Nandwani R, Gourlay Y. Possible interaction between sildenafil and HIV combination therapy. Lancet 1999; 353(9155):840. 51. Colebunders R, Smets E, Verdonck K, Dreezen C. Sexual dysfunction with protease inhibitors. Lancet 1999; 353(9166):1802. 52. Gutierrez CA. Sildenafil-simvastatin interaction: possible cause of rhabdomyolysis? Am Fam Physician 2001; 63(4):636-7. 53. Goldmeier D, Lamba H. Prolonged erections produced by dihydrocodeine and sildenafil. BMJ 2002; 324(7353):1555. Additional references (#54-#65) are available on request and on The Rx Consultant website: www.rxconsultant.com. 54. Kruuse C, Thomsen LL, Birk S, et al. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain 2003; 126(Pt 1):241-7. 55. Gilad R, Lampl Y, Eshel Y, Sadeh M. Tonic-clonic seizures in patients taking sildenafil. BMJ 2002; 325(7369):869. 56. Morgan JC, Alhatou M, Oberlies J, et al. Transient ischemic attack and stroke associated with sildenafil (Viagra) use. Neurology 2001; 13;57(9):1730-1. 57. Savitz SA, Caplan LR. Transient global amnesia after sildenafil (Viagra) use. Neurology 2002; 10;59(5):778. 58. Wysowski DK, Farinas E, Swartz L. Comparison of reported and expected deaths in sildenafil (Viagra) users. Am J Cardiol 2002; 89(11):1331-4. 59. Mitka M. Some men who take Viagra die--why? JAMA 2000; 283(5):590, 593. 60. Cheitlin MD, et al. Use of sildenafil (Viagra) in patients with cardiovascular disease. Technology & Practice Executive Committee. Circulation1999; 99(1):168-77. 61. McMahon CG, Samali R, Johnson H. Efficacy, safety and patient acceptance of sildenafil citrate as treatment for erectile dysfunction. J Urol 2000; 164(4):1192-6. 62. Hayes S. Rationing of sildenafil. Nobody needs an erection at public expense. BMJ 1999; 318(7198):1620. 63. The Primary Care Management of Erectile Dysfunction. Located at http://www.vapbm.org/guidelines/edguidelines.pdf. Accessed May 21, 2004. 64. Aldridge J, Measham F. Sildenafil (Viagra) is used as a recreational drug in England. BMJ 1999; 318(7184):669. 65. Anon. Tadalafil (Cialis) for erectile dysfunction. Med lett drugs Ther 2003; 45(1172):101.