Drug Class Review
`Phosphodiesterase-5 (PDE5) Inhibitors
`In the Management of Erectile Dysfunction
`
`Sharon A. Huang; and Janette D. Lie, PharmD, BCACP
`
`INTRODUCTION
`Erectile dysfunction (ED) is the persistent inability to achieve
`or maintain an erection sufficient for satisfactory sexual per-
`formance.1 According to data from the Massachusetts Male
`Aging Study, up to 52% of men between the ages of 40 and 70
`are affected by ED.2 Based on findings from the 2001–2002
`National Health and Nutrition Examination Survey (NHANES),
`it is estimated that 18.4% of men in the U.S. who are 20 years
`of age and older have ED.
`Although ED is not an inevitable consequence of aging, there
`is a positive correlation with age. The prevalence of 5.1% in 20- to
`39-year-old men increases to 70.2% in men 70 years of age and
`older. Because the etiology of ED often involves a combination
`of vascular, neurological, endocrinological, and psychological
`factors, the condition is not limited to elderly men. Other risk
`factors such as cardiovascular disease, hypertension, diabetes,
`hypercholesterolemia, and smoking have been strongly associ-
`ated with an increased prevalence of ED.3
`Historically, a limited understanding of the physiological
`mechanism of erections restricted the treatment of ED to
`vacuum-constriction devices, prosthetic implants, intra-
`cavernosal injections, and intraurethral suppositories.4 Since its
`advent, the class of agents known as type-5 phosphodiesterase
`(PDE5) inhibitors has revolutionized the management of ED.
`PDE5 inhibitors have become the first-line therapy for ED, as
`recommended by the American Urological Association (AUA)
`and the European Association of Urology (EAU).4,5
`The four oral PDE5 inhibitors commercially available in
`the U.S. are sildenafil (Viagra, Pfizer), vardenafil (Levitra and
`Staxyn, Bayer/GlaxoSmithKline), tadalafil (Cialis, Eli Lilly),
`and a more recently approved drug, avanafil (Stendra, Vivus).
`The expansion of this class has allowed for greater flexibility
`in prescribing based on individual response.
`
`CLASSIFICATION AND HISTORY
`Sildenafil, vardenafil, tadalafil, and avanafil are classified as
`PDE5 inhibitors and are indicated for the treatment of men with
`ED. Sildenafil, the first PDE5 inhibitor, was introduced in 1998.
`More than 20 million men were treated with sildenafil in its
`first 6 years on the market.5 In 2003, vardenafil was approved,
`offering patients an alternative option. Tadalafil followed several
`months later and was also approved in 2003. Nicknamed the
`
`Sharon A. Huang is a pharmacy doctoral candidate at the Univer-
`sity of Southern California School of Pharmacy and an Intern at
`the Pharmacy Veterans Affairs Learning Opportunities Residency
`(VALOR) in the Veterans Affairs Greater Los Angeles Healthcare
`System, Los Angeles, California. Dr. Lie is Program Manager of
`Pharmacy Education and Training and Residency Program Di-
`rector, PGY1 Pharmacy Practice, in the Veterans Affairs Greater
`Los Angeles Healthcare System in Los Angeles.
`
`“weekend pill,” tadalafil’s 36-hour effectiveness offered patients
`more spontaneity.
`In 2010, a 10-mg oral disintegrating tablet (ODT) formula-
`tion of vardenafil (Staxyn) was introduced; this ODT discreet
`formulation is considered more convenient to administer.
`Several years after the introduction of tadalfil on the market,
`researchers toyed with the idea of a chronic, low-dose formula-
`tion to further enhance spontaneity. In 2008, Eli Lilly obtained
`FDA approval for the once-daily administration of tadalafil. In
`October 2011, tadalafil (Cialis) was also approved to treat be-
`nign prostatic hyperplasia (BPH) with or without ED. Avanafil
`(Stendra) was approved in April 2012, offering an onset of
`action as early as 15 minutes after administration and further
`expanding treatment options for men with ED.
`Sildenafil and tadalafil are also used to treat pulmonary
`arterial hypertension (PAH) under the trade names Revatio
`(sildenafil 20-mg tablets and 10-mg/12.5-mL single-use vial
`injections) and Adcirca (tadalafil 20-mg tablets).
`Although alternative roles exist for these agents, PDE5 in-
`hibitors for the treatment of ED are the focus of this review.
`
`PHARMACOLOGY
`During sexual arousal, nitric oxide (NO) is released from
`nerve terminals and endothelial cells in the corpus caverno-
`sum. NO activates guanylate cyclase to convert guanosine
`triphosphate (GTP) into cyclic guanosine monophosphate
`(cGMP), triggering a cGMP-dependent cascade of events.
`The accumulation of cGMP leads to smooth-muscle relax-
`ation in the corpus cavernosum and increased blood flow
`to the penis.
`PDE5 is an enzyme found primarily in the smooth muscle of
`the corpus cavernosum that selectively cleaves and degrades
`cGMP to 5′-GMP. PDE5 inhibitors are similar in structure to
`cGMP; they competitively bind to PDE5 and inhibit cGMP
`hydrolysis, thus enhancing the effects of NO. This increase in
`cGMP in the smooth muscle cells is responsible for prolonging
`an erection.
`PDE5 inhibitors lack a direct effect on corpus cavernosum
`smooth-muscle relaxation. Therefore, after administration,
`adequate sexual stimulation is necessary for an erection to
`occur.6,7
`
`Pharmacokinetics
`PDE5 inhibitors have been studied to determine their
`pharmacokinetic characteristics in absorption, distribution,
`metabolism, and excretion. A summary of the pharmacokinetic
`activity of these agents is presented in Table 1.
`
`Disclosure: The authors report that they have no commercial or
`financial relationships in regard to this article.
`
`continued on page 414
`
`
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`PDE5 Inhibitors for Erectile Dysfunction
`
`continued from page 407
`Absorption
`As a class, although PDE5 inhibitors can reach maximum
`observed plasma concentrations (Cmax) in as little as 30 min-
`utes, the median times to maximum concentration (Tmax) are
`60 minutes for sildenafil and vardenafil and 2 hours for tadalafil.
`For avanafil, a median Tmax of 30 to 45 minutes is reported,
`possibly translating to a quicker onset of action; however, the
`actual clinical significance has not been determined.
`The exact values for vardenafil ODT (Staxyn) have not been
`reported, but this drug provides a higher systemic exposure
`compared with the film-coated formulation (Levitra). For this
`reason, these two formulations are not equivalent milligram for
`milligram and therefore are not interchangeable. In addition,
`despite the perception that an ODT formulation would take
`effect more quickly, both the film-coated tablets and the ODT
`formulation have similar onsets of action.
`A comparison of agents in the PDE5 drug class is presented
`in Table 2.8–12
`Except for tadalafil, the rate and extent of absorption of PDE5
`inhibitors are diminished when they are ingested with high-fat
`meals. Despite the similar rate and extent of change observed
`with vardenafil and avanafil, only sildenafil has been found
`to have clinical significance, according to its manufacturer.
`Absorption is affected significantly with a mean reduction in
`Cmax of 29% and a mean delay in Tmax of 60 minutes. Patients are
`advised to avoid taking sildenafil after a high-fat meal to avoid
`
`a possible diminished potency and delay in the onset of effect.8
`Unique to vardenafil ODT is the effect of water on the drug’s
`absorption. When vardenafil was taken with water, the Tmax was
`shortened by 60 minutes and the area-under-the curve (AUC)
`concentration was decreased by 29%. To maintain appropriate
`onset and maximum potency, patients should not take vardenafil
`ODT with liquids.12
`
`Distribution
`High volumes of distribution (Vd) for sildenafil (105 L), var-
`denafil (208 L), and tadalafil (63 L) suggest extensive tissue
`binding; data are unavailable for avanafil. All PDE5 inhibitors are
`highly protein-bound (94%–99%), contributing to the observed
`high volume of distribution.8–12 Therefore, disease states that
`alter protein levels, such as malnutrition and liver disease (e.g.,
`cirrhosis), can be expected to cause variations in the distribu-
`tion of PDE5 inhibitors.
`
`Metabolism
`Each PDE5 inhibitor undergoes metabolism predominant-
`ly through the hepatic isoenzyme cytochrome P450 (CYP)
`3A4 pathway. Minor pathways include CYP2C9 for sildenafil,
`CYP3A5 and CYP2C for vardenafil, and CYP2C for avanafil.
`Because the metabolism of these agents relies primarily on
`CYP3A4, moderate-to-strong inhibitors, such as erythromycin
`(Ery-Tab, E-Mycin, Abbott; Eryc, Warner Chilcott), ketocon-
`
`Table 1 Phosphodiesterase-5 (PDE5) Inhibitors: Pharmacokinetic Summary
`Sildenafil
`Vardenafil
`Vardenafil ODT
`(Viagra)
`(Levitra)
`(Staxyn)
`41% (mean)
`15% (mean)
`—
`25%–63% (range)
`1 hour (median)
`0.5–2 hours (range)
`105 L
`96%
`Major: CYP3A4
`Minor: CYP2C9
`
`Tadalafil
`(Cialis)
`—
`
`Avanafil
`(Stendra)
`—
`
`2 hours (median)
`0.5–6 hours (range)
`63 L
`94%
`CYP3A4
`
`0.5–0.75 hours (range)
`
`—
`
`99%
`Major: CYP3A4
`Minor: CYP2C
`
`1.5 hours (median)
`0.75–2.5 hours (range)
`208 L
`95%
`Major: CYP3A4
`Minor: CYP3A5, CYP2C
`
`Bioavailability
`
`Tmax
`
`Vd
`Protein binding
`Metabolism
`
`1 hour (median)
`0.5–2 hours (range)
`208 L
`95%
`Major: CYP3A4
`Minor: CYP3A5,
`CYP2C
`Yes (7%)
`Desmethylation
`
`4–5 hours
`91%–95% feces
`2%–6% urine
` Cmax 18%–50%
`
`Yes (7%)
`Desmethylation
`
`4–6 hours
`91%–95% feces
`2%–6% urine
` Cmax 35%
`
`No
`
`17.5 hours
`61% feces
`36% urine
`Not affected
`
`Active metabolite
`(% effect)
`
`Yes (20%)
`N-desmethylation
`
`Half-life
`Elimination
`
`Ingestion with
`high-fat meals
`
`4 hours
`80% feces
`13% urine
` Cmax 29%
` Tmax by 1 hour
`
`Avoid
`
`PDE1, PDE6
`
`414 P&T® • July 2013 • Vol. 38 No. 7
`
`May use
`(per manufacturer)
`PDE1, PDE6
`
`May use
`(per manufacturer)
`PDE1, PDE6
`
`PDE11
`
`Additional PDE
`inhibition
`Cmax = peak concentration; CYP = cytochrome P450; ODT = oral dissolving tablet; Tmax = time to peak concentration.
`Data from prescribing information for sildenafil;8 vardenafil;9 tadalafil;10 avanafil;11 and vardenafil ODT.12
`
`Yes (4%)
`Methylation,
`glucuronidation
`5 hours
`62% feces
`21% urine
` Cmax 24-39%
` Tmax by 1.12–1.25 hours
`
`May use
`(per manufacturer)
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`PDE5 Inhibitors for Erectile Dysfunction
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`Table 2 Phosphodiesterase-5 (PDE5) Inhibitors: Product Comparison
`Sildenafil
`Vardenafil
`Vardenafil ODT
`(Viagra)
`(Levitra)
`(Staxyn)
`Bayer/
`Bayer/
`GlaxoSmithKline
`GlaxoSmithKline
`2003
`2010
`
`Manufacturer
`
`Pfizer
`
`Year of approval
`
`1998
`
`Usual dosage
`
`25–100 mg/day
`
`5–20 mg/day
`
`10 mg/day
`
`Administration
`time
`Time frame
`of efficacy
`Dosage
`adjustments
`
`Common
`adverse
`reactions
`
`1 hour before sexual
`activity
`0.5-4 hours post
`dose
`Renal
`CrCl < 30 mL/minute:
`starting dose 25 mg
`
`Hepatic
`Hepatic impairment:
`starting dose 25 mg
`
`Drug Interactions
`• Potent CYP3A4
`inhibitors: starting
`dose 25 mg
`• Ritonavir: maxi-
`mum 25 mg/48
`hours
`
`Other
`>65 years old: start-
`ing dose 25 mg
`
`1 hour before sexual
`activity
`
`1 hour before sexual
`activity
`
`—
`
`—
`
`Renal
`Do not use in
`patients receiving
`hemodialysis
`
`Renal
`Do not use in
`patients receiving
`hemodialysis
`
`Hepatic
`Moderate/severe
`impairment: do not
`use
`
`Drug Interactions
`Moderate/potent
`CYP3A4 inhibitors:
`do not use
`
`Hepatic
`• Moderate impair-
`ment: starting dose
`5 mg; maximum
`10 mg
`• Severe impair-
`ment: do not use
`
`Drug Interactions
`• Moderate CYP3A4
`inhibitors:
`maximum 5 mg/
`24 hours
`• Potent CYP3A4
`inhibitors:
`maximum
`2.5 mg/24 hours
`• Ritonavir: maxi-
`mum 2.5 mg /
`72 hours
`
`Other
`≥65 years of age:
`starting dose 5 mg
`
`Headache, flushing,
`dyspepsia, nasal
`congestion, naso-
`pharyngitis, visual
`abnormalities
`24 hours
`
`Headache, flushing,
`dyspepsia, nasal
`congestion, naso-
`pharyngitis, visual
`abnormalities
`24 hours
`
`Headache, flushing,
`dyspepsia, nasal
`congestion, naso-
`pharyngitis, visual
`abnormalities
`24 hours
`
`Tadalafil
`(Cialis)
`
`Avanafil
`(Stendra)
`
`Vivus
`
`2012
`
`50–200 mg/day
`
`0.5 hours before
`sexual activity
`As early as 0.25 hours
`post dose
`Renal
`Do not use if CrCl
`< 30 mL/minute or
`in patients receiving
`hemodialysis
`
`Hepatic
`Severe impairment:
`do not use
`
`Drug Interactions
`• Moderate CYP3A4
`inhibitors: maximum
`50 mg/day
`• Potent CYP3A4
`inhibitors: do not use
`
`Eli Lilly
`
`2003
`
`5–20 mg/day (as needed);
`2.5–5 mg/day once daily
`At least 0.5 hours
`before sexual activity
`Up to 36 hours post dose
`
`As-needed use:
`Renal
`• CrCl 30–50 mL/minute:
`starting dose 5 mg/day;
`maximum 10 mg/48 hours
`• CrCl < 30 mL/minute or if
`patient is receiving hemo-
`dialysis: maximum
`5 mg/72 hours
`
`Hepatic
`• Mild/moderate impair-
`ment: maximum 10 mg/day
`• Severe impairment: do
`not use
`
`Drug Interactions
`Potent CYP3A4 inhibitors:
`maximum 10 mg/72 hours
`
`Once-daily use:
`Renal
`CrCl <30 mL/minute or if on
`hemodialysis: do not use
`
`Hepatic
`• Mild/moderate impair-
`ment: use with caution
`• Severe impairment: do
`not use
`
`
`Drug Interactions
`Potent CYP3A4 inhibitors:
`maximum 2.5 mg/day
`Headache, flushing,
`dyspepsia, nasal
`congestion, naso-
`pharyngitis, back pain,
`myalgia
`48 hours
`
`$24.48 (20 mg)
`
`Headache, flushing,
`dyspepsia, nasal
`congestion,
`nasopharyngitis
`
`12 hours
`
`—
`
`Time required
`from last dose to
`administration
`of a nitrate (e.g.,
`nitroglycerin)
`$13.98 (10 mg)
`$21.46 (20 mg)
`$22.49 (100 mg)
`AWP unit cost
`AWP = average wholesale price; CrCl = creatinine clearance; CYP = cytochrome P450.
`Data from prescribing information for sildenafil;8 vardenafil;9 tadalafil;10 avanafil;11 vardenafil ODT;12 and Red Book Online.36
`
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`PDE5 Inhibitors for Erectile Dysfunction
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`azole (Nizoral, PriCara/ Janssen), itraconazole (Sporanox,
`Janssen), and ritonavir (Norvir, Abbott) and inducers, such as
`rifampin, phenytoin (Dilantin, Pfizer) of this isoenzyme can be
`expected to affect the blood concentrations of PDE5 inhibitors.
`Of the four agents available in the U.S., only tadalafil has
`metabolites that are not pharmacologically active. Sildenafil
`produces an active metabolite that retains approximately 50%
`of the potency of the parent drug, contributing to approxi-
`mately 20% of its total pharmacological activity.8 Vardenafil
`and avanafil produce active metabolites that contribute to the
`total pharmacological activity of each of these agents (7% and
`4%, respectively).9,11
`The precise clinical impact of these active metabolites,
`particularly in patients with impaired ability to metabolize or
`eliminate these agents, has not been determined.
`
`Elimination
`PDE5 inhibitors are eliminated predominantly as metabolites
`in the feces and, to a lesser extent, in the urine. Sildenafil,
`vardenafil, and avanafil share similar mean terminal half-lives
`of 4 to 5 hours. In contrast, tadalafil has an extended half-life
`of approximately 17.5 hours, allowing its use as a once-daily
`agent.8–12
`
`Renal Impairment
`In patients with mild-to-moderate renal impairment or with a
`creatinine clearance (CrCl) above 30 to 80 mL/minute, the phar-
`macokinetic properties of sildenafil remain unaltered. However,
`in patients with severe renal impairment (CrCl, 30 mL/minutes
`or less), the AUC concentration and the Cmax are doubled. As
`a precaution, it is recommended that sildenafil be initiated at
`25 mg per dose in men with severe renal impairment.8
`When vardenafil was studied in patients with moderate and
`severe renal impairment (CrCl, 50 mL/minute or less), the
`AUC concentration was increased by 20% to 30% compared
`with patients with a CrCl exceeding 80 mL/minute, resulting
`in no need for dosage adjustments. Because pharmacokinetic
`parameters for vardenafil have not been assessed in patients
`undergoing dialysis, this drug is not recommended in this
`population. These renal dosing recommendations also apply
`to vardenafil ODT.9,12
`When avanafil was administered to patients with mild-to-
`moderate renal impairment (a CrCl of 30–90 mL/minute or
`more), the AUC concentration and the Cmax increased slightly,
`resulting in no need for dosage adjustments. However, because
`avanafil has not been studied in patients with severe renal
`impairment or in patients on dialysis, it is not recommended
`for these patient populations.11
`When tadalafil was given to patients with mild-to-moderate
`renal impairment (a CrCl of 30–80 mL/minute or more), the
`AUC concentration doubled, resulting in changes to the dosing
`recommendations. Therefore, in patients with moderate renal
`insufficiency (CrCl, 30–50 mL/minute) who used tadalafil as
`needed, a starting dose of 5 mg no more than once daily is
`recommended, with a maximum of no more than 10 mg in
`48 hours.
`Patients who have severe renal impairment (CrCl, below
`30 mL/minute) or men who are receiving dialysis should not
`take more than 5 mg of tadalafil within 72 hours. The once-
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`416 P&T® • July 2013 • Vol. 38 No. 7
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`daily use of tadalafil is not recommended for men with severe
`renal insufficiency.10
`
`Hepatic Impairment
`Patients with mild-to-moderate hepatic impairment (Child–
`Pugh class A and B) who received sildenafil experienced in-
`creased AUC concentrations (85%) and Cmax (47%). A starting
`dose of sildenafil 25 mg is recommended for these patients.8
`In men with moderate hepatic impairment who received
`vardenafil, the AUC concentration and the Cmax were increased
`by 160% and 130%, respectively. Therefore, the recommended
`starting dose of vardenafil in patients with moderate hepatic
`impairment is 5 mg with a maximum dose of 10 mg per dose.9
`Vardenafil ODT is not recommended for use in men with mod-
`erate hepatic impairment.12
`When tadalafil is used as needed in patients with mild-to-
`moderate hepatic impairment, doses exceeding 10 mg are not
`recommended. Once-daily tadalafil has not been well studied in
`patients with mild-to-moderate hepatic impairment and should
`be used with caution.10
`In patients with moderate hepatic impairment, avanafil’s AUC
`concentration was increased by 11% and the Cmax was decreased
`by 51%. No dosage adjustments are recommended for avanafil
`in patients with mild-to-moderate hepatic impairment.11
`As a result of insufficient data, none of the four agents are
`recommended for men with severe hepatic impairment (Child–
`Pugh class C).
`
`Pharmacodynamics
`Mammalian phosphodiesterases (PDEs) comprise 11 gene
`families, which are distributed in different areas of the body.
`Each PDE family contributes to various physiological func-
`tions.13 Because the smooth muscle of the corpus cavernosum
`expresses type-5 PDEs predominantly, the specificity and se-
`lectivity of PDE5 inhibition play a crucial role in prolonging
`erections and in limiting adverse effects from nonspecific PDE
`inhibition.
`All of the currently available PDE5 inhibitors are highly
`selective for the type-5 gene family. Sildenafil and vardenafil,
`however, are less selective against PDE6, which is expressed
`in the retina.13,14 Patients have reported vision-related adverse
`effects consistent with PDE6 inhibition, such as dose-related
`impairment in color discrimination (blue/green) or cyanopsia
`(objects appearing blue).8–10 By contrast, although tadalafil is
`selective against PDE6, it also expresses selectivity against
`PDE11, which is concentrated in the prostate, testes, and skeletal
`muscles.13,14 Inhibition of the type-11 PDE isoenzyme has been
`associated with pain and myalgia.15
`
`DRUG–DRUG INTERACTIONS
`CYP3A4 Isoenzymes
`Because of their extensive CYP3A4 metabolism, PDE5 inhibi-
`tors carry a risk of interacting with potent CYP3A4 inhibitors
`and inducers. The concomitant use of potent CYP3A4 inhibitors
`increases plasma concentrations of sildenafil. When sildenafil
`100 mg was administered with erythromycin (e.g., Ery-Tab,
`E-Mycin, Eryc) and saquinavir (Invirase, Hoffman-LaRoche)
`(both are considered relatively potent CYP3A4 inhibitors), the
`AUC concentration was increased by 182% and 210%, respec-
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`PDE5 Inhibitors for Erectile Dysfunction
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`tively. More notably, when sildenafil 100 mg was adminis-
`tered with ritonavir (Norvir), a highly potent CYP3A4 inhibi-
`tor, the AUC concentration was increased by 11-fold (1,000%).
`Therefore, a starting dose of 25 mg is recommended in pa-
`tients initiating sildenafil therapy with the concomitant use of
`moderate-to-strong CYP3A4 inhibitors such as ketoconazole
`(Nizoral), itraconazole (Sporanox), erythromycin, and saqui-
`navir. Doses of sildenafil should not exceed 25 mg in 48 hours
`when it is taken with ritonavir.8
`The use of potent CYP3A4 inhibitors with vardenafil has
`also been studied. A dramatic 49-fold increase in the AUC
`concentration resulted when vardenafil 5 mg was taken
`with ritonavir 600 mg twice daily. Coadministration with
`erythromycin, ketoconazole, and indinavir (Crixivan, Merck)
`may also lead to an increase in the AUC concentration of
`vardenafil by four-fold to 16-fold. Consequently, a maximum
`dose of vardenafil 5 mg per 24 hours is recommended when it
`is used concomitantly with moderate CYP3A4 inhibitors (e.g.,
`erythromycin, ketoconazole 200 mg, and itraconazole 200 mg).
`With potent CYP3A4 inhibitors such as indinavir, saquina-
`vir, atazanavir (Reyataz, Bristol-Myers Squibb), ketoconazole
`400 mg, itraconazole 400 mg, and clarithromycin (Biaxin,
`Abbott), doses of vardenafil 2.5 mg per 24 hours should not
`be exceeded, except for ritonavir, the dose of which should not
`exceed 2.5 mg every 72 hours.9
`The concomitant use of moderate or potent CYP3A4 inhibi-
`tors with vardenafil ODT is not recommended.12
`When given with ketoconazole 400 mg daily, a single dose
`of tadalafil 20 mg increased the AUC concentration of tadalafil
`by 312%. When ritonavir 500 to 600 mg twice daily or 200 mg
`twice daily was taken with a single dose of tadalafil 20 mg,
`tadalafil’s AUC concentration increased by 32% and 124%, re-
`spectively. Nonetheless, when tadalafil is prescribed as needed,
`a maximum dose of 10 mg in a 72-hour period should not be
`exceeded when used concomitantly with any potent CYP3A4
`inhibitor. Similarly, for daily use of tadalafil, a maximum dose of
`2.5 mg/day is recommended in patients taking potent CYP3A4
`inhibitors.10
`The use of both ketoconazole 400 mg daily and ritonavir
`600 mg twice daily has been shown to increase avanafil’s AUC
`concentration by 13-fold. As recommended by the manufacturer,
`the avanafil dose should not exceed 50 mg/day in patients who
`are also taking moderate CYP3A4 inhibitors. Avanafil should
`not be used in patients taking potent CYP3A4 inhibitors.11
`Not all interactions with moderate and potent CYP3A4
`inhibitors have been studied with each PDE5 inhibitor; however,
`dosage adjustments and avoiding concomitant use altogether
`in some cases should be considered.
`
`Alpha Blockers
`Coadministration of PDE5 inhibitors with alpha-adrenergic
`blocking agents can result in additive vasodilatory effects,
`causing potentially significant reductions in blood pressure
`(BP).16 PDE5 inhibitor therapy for ED should be initiated only
`if the patient’s BP is already stable with alpha blockers and at
`the lowest recommended dose.
`Vardenafil ODT (Staxyn) is not recommended for patients
`who are taking alpha blockers, particularly new users of this
`combination. Alternatively, low-dose, film-coated vardenafil tab-
`
`lets (Levitra) can be used. Patients taking PDE5 inhibitors and
`alpha blockers concomitantly should be monitored closely.8–12
`
`Nitrates
`Nitrates such as nitroglycerin increase the production of
`cGMP. PDE5 inhibitors decrease cGMP degradation. The con-
`comitant use of these agents can cause a significant increase
`in cGMP accumulation, resulting in a synergistic reduction
`in BP. Therefore, the use of PDE5 inhibitors with any form of
`organic nitrates is contraindicated. In emergency situations,
`if patients have taken a PDE5 inhibitor and experience chest
`pain requiring treatment, a non-nitrate containing agent (e.g.,
`a calcium-channel blocker or a beta blocker) can be used as
`an alternative when appropriate.17
`A minimum of 24 hours should elapse after the last dose of
`sildenafil or vardenafil is taken before a nitrate can be used.8,9 A
`period of at least 12 hours for avanafil and 48 hours for tadalafil
`should elapse before the patient takes a nitrate.10,11,18 In such
`an event, nitrates should be administered only under close
`monitoring.
`
`CLINICAL EFFICACY
`Results from clinical trials of PDE5 inhibitors have shown
`consistent improvement in erectile functioning compared with
`placebo. Studies commonly use questionnaires based on diaries
`and event logs to evaluate efficacy and functional improvements.
`One of the most extensively used measurements is the mean
`score derived from the International Index of Erectile Function–
`Erectile Function domain (IIEF–EF). Scores range from 0 to
`30 based on 15 questions. Separate evaluation of responses
`to Question 3 (successful penile penetration) and Question 4
`(maintenance of erection after penetration) are often used to
`further determine the efficacy of PDE5 inhibitors.
`The Sexual Encounter Profile (SEP) is a diary that has also
`been used to document a patient’s sexual experiences. In par-
`ticular, responses to Question 2 (SEP2, erection sufficient for
`penetration) and Question 3 (SEP3, erection sufficient for suc-
`cessful intercourse) are used to measure efficacy outcomes.
`The Global Assessment Question (GAQ) asks the patient
`whether the treatment has improved erectile function and is
`reported as the percentage of patients responding “yes.”
`In a published systematic review and meta-analysis of ran-
`domized controlled trials by Tsertsvadze et al., the efficacy of
`oral PDE5 inhibitors was found to be consistent in the treatment
`of ED.19 In 16 trials that evaluated sildenafil in men with various
`comorbidities, the mean per-patient percentage of successful
`sexual intercourse was 69% with treatment (range, 52%–85%)
`compared with 35.5% for placebo (range, 19%–68%). Data pooled
`from four trials reported a 34.4% improvement from baseline
`in successful intercourse attempts.
`In 13 trials evaluating vardenafil in men with various co-
`morbidities using SEP3, the mean per-patient percentage of
`successful sexual intercourse attempts was 68% for vardenafil
`(range, 50%–88%) versus 35% for placebo (range, 20%–49%).
`Data pooled from two trials reported a 33.2% improvement
`from baseline in successful intercourse attempts.
`Fifteen trials that assessed the use of tadalafil in men with
`various comorbidities were conducted to determine the mean
`per-patient percentage of successful intercourse attempts.
`
`
`
`
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`PENN EX. 2035
`CFAD V. UPENN
`IPR2015-01836
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`PDE5 Inhibitors for Erectile Dysfunction
`
`Based on data collected from SEP3, tadalafil was reported as
`having a success rate of 69% (range, 50%–85%) versus 33% for
`placebo (range, 23%–52%). Data pooled from five trials revealed
`a 35.1% improvement from baseline in successful intercourse
`attempts.19
`Data supporting the safety and efficacy of once-daily tadalafil
`led to the eventual approval of this dosing option. One of the
`most cited reasons for poor response to the treatment of ED is
`the lack of spontaneity with on-demand dosing.20 By taking ad-
`vantage of the prolonged half-life of tadalafil, this new approach
`to treatment has created more “natural” sexual experiences for
`patients and has even been referred to as a “cure” for ED.21
`Chronic low-dose PDE5 inhibitor therapy has also benefited
`difficult-to-treat populations such as diabetic, post-prostatecto-
`my, and post-radiotherapy patients and may be an alternative
`for men who have not responded to other PDE5 inhibitors or
`to traditional on-demand dosing.22
`In a 1- to 2-year open-label extension study by Porst et al.,
`once-daily tadalafil 5 mg was found to be a safe and effica-
`cious option for men with ED. No serious adverse events
`attributed to the drug were observed. Upon the completion
`of the study period, 95.7% and 92.1% of patients, respectively,
`reported positive responses in GAQ1 (improved erections)
`and GAQ2 (improved ability to engage in sexual activity)
`scores. Mean IIEF–EF domain scores also increased by 10.8
`points from baseline.23
`In a multicenter, randomized, double-blind phase 3 trial, 646
`men with mild-to-moderate ED received avanafil (50 mg, 100
`mg, 200 mg) or placebo. SEP2, SEP3, and IIEF–EF domain
`scores were evaluated to determine efficacy. After 12 weeks
`of treatment, patients receiving avanafil showed statistically
`significant improvements over placebo in all primary endpoints
`studied. The mean percentage change from baseline for suc-
`cessful vaginal penetration (SEP2) was 54% for placebo vs. 64%
`to 77% for 50 to 200 mg of avanafil. The mean percentage change
`from baseline for successful sexual intercourse (SEP3) was 27%
`for placebo vs. 41% to 57% for 50 mg to 200 mg of avanafil. At
`the end of treatment, the mean IIEF–EF domain score was 15.3
`for placebo versus 18.1 to 22.2 for 50 mg to 200 mg for avanafil.
`Although all three studied strengths of avanafil were found to
`be more effective than placebo, doses of 100 mg and 200 mg
`showed greater benefit over 50 mg. No significant difference
`was noted between the higher doses.24
`Although PDE5 inhibitors have clearly shown efficacy in
`placebo-controlled trials for the treatment of ED, only a lim-
`ited number of head-to-head trials have compared the various
`agents. The evidence is inconclusive regarding the superiority
`of one agent over another; however, most men in the compara-
`tive studies cited tadalafil as the preferred agent because of its
`extended duration of action.25
`
`SAFETY AND ADVERSE EFFECTS
`PDE5 inhibitors are generally well tolerated for the treatment
`of ED. The most common adverse drug reactions reported
`include headache, flushing, nasal congestion, nasopharyngitis,
`and dyspepsia. Rare but serious reports of prolonged erections
`lasting more than 4 hours and priapism (painful erections last-
`ing more than 6 hours) have been reported with PDE5 inhibi-
`tors. Patients should be advised to seek immediate medical
`
`418 P&T® • July 2013 • Vol. 38 No. 7
`
`attention if they experience these events. Cases of priapism
`that are not immediately treated can lead to permanent penile
`tissue damage.8–12
`Visual abnormalities have been reported with PDE5
`inhibitors. In July 2005, an FDA alert recommended that
`men discontinue all such agents and seek immediate medical
`attention if they experienced a sudden loss of vision.26 Cases
`of non-arteritic anterior ischemic optic neuropathy (NAION)
`were reported during postmarketing experience with PDE5
`inhibitors.27–30 In this condition, blood flow to the optic nerve is
`blocked. Although evidence of a cause-and-effect relationship
`is insufficient, caution should be used in prescribing PDE5
`inhibitors, particularly for men with pre-existing risk factors
`for the development of NAION, such as hypertension, diabetes,
`and hyperlipidemia.
`Sudden hearing loss was also reported in postmarketing
`studies. In October 2007, the FDA requested that this potential
`risk be displayed more prominently on the labels for PDE5
`inhibitors. At the time of the announcement, 29 cases of hearing
`loss had been reported in postmarketing analyses. Additional
`cases were identified in a retrospective analysis of the clinical
`trials. Although the direct association of hearing loss with
`PDE5 inhibitor use has not been established, patients were
`advised to discontinue the use of all PDE5 inhibitors and to
`seek medical attention if they experienced a sudden decrease
`in or a loss of hearing.31
`Back pain and myalgia have been reported with tadalafil. In
`general, the pain was reported as mild to moderate in sever-
`ity, occurring 12 to 24 hours after administration and typically
`resolving within 48 hours without medical treatment. When
`treatment was necessary, acetaminophen and nonsteroidal
`anti-inflammatory drugs (NSAIDs) were generally effective
`in alleviating the reported pain.10
`
`INDICATIONS
`Sildenafil, vardenafil, tadalafil, and avanafil are approved
`for as-needed use in the treatment of ED. In 2008, tadalafil
`was granted FDA approval for once-daily use in the treatment
`of ED and in 2011, it was given an indication for BPH with or
`without ED. Sildenafil and tadalafil are also approved for PAH
`under the trade names of Revatio and Adcirca, respectively.8–12
`
`CONTRAINDICATIONS AND PRECAUTIONS
`PDE5 inhibitors are contraindicated in patients who are
`taking any form of organic nitrates, regularly or intermittently.
`Because these agents modify the cGMP and NO pathways,
`PDE5