A Comprehensive Monograph on Avanafil (Stendra/Spedra): Pharmacology, Clinical Efficacy, and Safety Profile

I. Introduction and Drug Identification

Overview of Avanafil as a Second-Generation PDE5 Inhibitor

Avanafil is a potent, reversible, and highly selective inhibitor of phosphodiesterase type 5 (PDE5), an enzyme pivotal in the regulation of blood flow to the corpus cavernosum of the penis.[1] It is classified as a second-generation agent within its therapeutic class, developed for the oral, on-demand treatment of erectile dysfunction (ED) in adult males.[2] Avanafil's clinical profile is distinguished by two key pharmacological characteristics that were optimized during its development: a remarkably rapid onset of action, with clinical efficacy observed as early as 15 minutes post-administration, and a superior selectivity for the PDE5 isoenzyme compared to other phosphodiesterases.[5] These properties translate into a therapeutic option that offers patients greater spontaneity and a potentially more favorable safety and tolerability profile compared to first-generation PDE5 inhibitors.[4]

Nomenclature

To ensure precise identification, the various names and designations for Avanafil are outlined below:

• Generic Name: Avanafil [2]
• Brand Names: The drug is marketed under the brand name Stendra in the United States and Spedra in the European Union and other regions.[2]
• Chemical Names: The formal International Union of Pure and Applied Chemistry (IUPAC) name is 4- (3−chloro−4−methoxyphenyl)methylamino -2--N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide. Various chemical databases may list syntactical variants of this name.[3]
• Code Names: During its development phase, Avanafil was identified by the code name TA-1790.[9]

Development and Regulatory History

Avanafil was developed by Vivus Inc..[9] It received its first major regulatory approval from the U.S. Food and Drug Administration (FDA) on April 27, 2012.[3] This was followed by approval from the European Medicines Agency (EMA) on June 21, 2013, solidifying its availability in key global markets.[3]

As the fourth PDE5 inhibitor to enter a mature and highly competitive market, Avanafil's development was strategically positioned to capitalize on a "latecomer advantage." The market landscape was already well-defined by the clinical experiences with sildenafil, tadalafil, and vardenafil. These first-generation agents, while highly effective, had well-documented limitations that influenced patient satisfaction and adherence. These included a relatively slow onset of action, which required patients to plan sexual activity in advance, and a range of off-target side effects stemming from the inhibition of other PDE isoenzymes, such as transient visual disturbances (PDE6 inhibition) or back pain (PDE11 inhibition).

Recognizing these unmet needs, the development program for Avanafil appears to have been deliberately focused on optimizing its molecular structure to enhance two specific parameters: the speed of absorption and the degree of selectivity for the PDE5 enzyme.[1] By engineering a molecule with a very rapid Tmax and a high affinity for the PDE5 active site relative to other isoforms, the developers created a drug profile that directly addressed the patient desires for greater spontaneity and a cleaner side-effect profile. This targeted approach allowed Avanafil to carve out a distinct therapeutic niche, not as a "me-too" product, but as a refined alternative designed to overcome the known drawbacks of its predecessors.

Table 1: Chemical and Physical Identifiers of Avanafil

The following table consolidates the key chemical and physical identifiers for Avanafil, providing a comprehensive reference for researchers, clinicians, and regulatory professionals.

Identifier/Property	Value	Source(s)
DrugBank ID	DB06237	2
CAS Number	330784-47-9	5
Molecular Formula	C23​H26​ClN7​O3​	2
Average Molecular Weight	483.951 g/mol	3
Monoisotopic Weight	483.17856544 g/mol	3
IUPAC Name	4-	(3−chloro−4−methoxyphenyl)methylamino
InChI	InChI=1S/C23H26ClN7O3/c1-34-19-6-5-15(10-18(19)24)11-27-21-17(22(33)28-13-20-25-7-3-8-26-20)12-29-23(30-21)31-9-2-4-16(31)14-32/h3,5-8,10,12,16,32H,2,4,9,11,13-14H2,1H3,(H,28,33)(H,27,29,30)/t16-/m0/s1	5
InChIKey	WEAJZXNPAWBCOA-INIZCTEOSA-N	5
Canonical SMILES	COC1=C(C=C(C=C1)CNC2=NC(=NC=C2C(=O)NCC3=NC=CC=N3)N4CCCC[C@H]4CO)Cl	13
ATC Code	G04BE10	2
Appearance	White to light yellow crystalline powder/solid	5
Solubility	Soluble in DMSO (10-20 mg/mL); practically insoluble in water; soluble in 0.1 mol/L hydrochloric acid	9
Partition Coefficient (Log P)	3.05 (in 1-Octanol/pH buffer 6.6)	17

II. Pharmacology and Mechanism of Action

The Nitric Oxide/cGMP Pathway in Penile Erection

The physiological process of penile erection is a complex neurovascular event mediated by a cascade of biochemical signals. The process is initiated by sexual stimulation, which triggers the release of the neurotransmitter nitric oxide (NO) from non-adrenergic, non-cholinergic (NANC) nerve terminals and endothelial cells within the corpus cavernosum.[1] Once released, NO diffuses into adjacent smooth muscle cells and activates the enzyme soluble guanylate cyclase (sGC). This enzyme catalyzes the conversion of guanosine triphosphate (GTP) into the second messenger cyclic guanosine monophosphate (cGMP).[3]

The accumulation of intracellular cGMP activates protein kinase G (PKG), which in turn phosphorylates various downstream targets. This leads to a decrease in intracellular calcium concentrations, resulting in the relaxation of the smooth muscle cells of the corpus cavernosum and the helicine arteries.[6] This muscular relaxation allows for a significant increase in arterial blood inflow, which engorges the sinusoidal spaces of the corpora cavernosa. The expansion of these spaces compresses the subtunical venules against the tunica albuginea, restricting venous outflow and trapping blood within the penis. This combined effect of increased inflow and decreased outflow results in the tumescence, rigidity, and elongation characteristic of a penile erection.[3]

Mechanism of Action: Selective Inhibition of Phosphodiesterase Type 5 (PDE5)

The erectile response is naturally modulated by the enzymatic degradation of cGMP. The enzyme phosphodiesterase type 5 (PDE5), which is highly expressed in the corpus cavernosum, is responsible for hydrolyzing cGMP to its inactive form, 5'-guanosine monophosphate (5'-GMP).[3] This action terminates the signaling cascade and allows the penile smooth muscle to return to its tonic, contracted state, leading to detumescence.

Avanafil exerts its therapeutic effect by acting as a strong, competitive, and reversible inhibitor of the PDE5 enzyme.[1] By binding to the active site of PDE5, Avanafil prevents the degradation of cGMP. This inhibition leads to an accumulation of cGMP within the smooth muscle cells of the corpus cavernosum in the presence of ongoing sexual stimulation and NO release. The elevated and sustained levels of cGMP amplify and prolong the relaxation of smooth muscle, thereby enhancing blood flow and facilitating the achievement and maintenance of an erection sufficient for sexual activity.[1]

It is critical to emphasize that Avanafil does not possess any direct relaxant properties on the corpus cavernosum, nor does it initiate an erection spontaneously. Its mechanism is entirely dependent on the initial release of NO triggered by sexual arousal. In the absence of sexual stimulation, there is no activation of the NO/cGMP pathway, and Avanafil has no pharmacological effect.[6]

Pharmacodynamics: Vasodilatory Effects and Hemodynamic Consequences

The vasodilatory action of Avanafil, mediated by the potentiation of the cGMP pathway, is not exclusively localized to the penile vasculature. PDE5 is also present in other vascular smooth muscle tissues throughout the body, including the pulmonary vasculature.[18] Consequently, Avanafil exhibits mild and transient systemic vasodilatory properties.[13]

This systemic effect can lead to modest, clinically insignificant reductions in supine and standing blood pressure in healthy individuals.[22] However, these hemodynamic consequences are the basis for many of the drug's common side effects, such as headache, flushing, and nasal congestion, which result from vasodilation in cranial and nasal blood vessels.[18] More importantly, this systemic vasodilatory activity is the foundation for its most critical drug interactions, particularly the potentially life-threatening hypotension that can occur when it is co-administered with other vasodilators like organic nitrates or alpha-adrenergic blockers.[21]

Enzyme Selectivity and Potency: A Cornerstone of its Profile

The clinical utility and safety profile of a PDE5 inhibitor are defined not only by its potency at the target enzyme but also by its selectivity—its ability to inhibit PDE5 without significantly affecting other PDE isoenzymes that regulate different physiological processes.

• Potency: Avanafil is a highly potent inhibitor of human PDE5, with a reported in vitro half-maximal inhibitory concentration (IC50​) value ranging from 2.2 nM to 5.2 nM.[3] This high potency allows for effective target engagement at therapeutic doses.
• Selectivity: Avanafil's defining characteristic is its exceptional selectivity profile, which surpasses that of many first-generation agents. The degree of selectivity is quantified by comparing its IC50​ for PDE5 to its IC50​ for other PDE isoforms.
• vs. PDE6: This isoenzyme is found in the retina and plays a crucial role in the phototransduction cascade. Inhibition of PDE6 is associated with transient visual disturbances, such as cyanopsia (a blue tinge to vision). Avanafil is over 100-fold more selective for PDE5 than for PDE6.[14]
• vs. Other Isoforms: Avanafil demonstrates even greater selectivity against other PDE families. It is approximately 20,000-fold more selective for PDE5 than for PDE3, an enzyme involved in the control of cardiac contractility, which is a critical factor for its cardiovascular safety.[17] For PDE1, PDE2, PDE4, and PDE7 through PDE11, the selectivity is also very high, with IC50​ values typically greater than 5,000 nM.[14]

This high degree of molecular selectivity is not merely a biochemical detail; it is a direct and powerful predictor of the drug's clinical tolerability and helps to define its therapeutic niche. The molecular structure of Avanafil was refined through medicinal chemistry to achieve a conformational fit within the catalytic site of the PDE5 enzyme that is far superior to its fit within the active sites of other PDE isoforms. This precise molecular targeting has direct clinical consequences. For instance, the well-documented visual side effects associated with sildenafil are a direct result of its off-target inhibition of PDE6.[25] Avanafil's greater than 100-fold selectivity for PDE5 over PDE6 provides a clear pharmacological basis for the observed lower incidence of such visual disturbances in clinical trials.[4] Similarly, the myalgia and back pain sometimes associated with tadalafil have been linked to its cross-inhibition of PDE11.[25] Avanafil's high selectivity against PDE11 minimizes this risk. This understanding allows for a more rational approach to drug selection. A clinician can reasonably infer that a patient who has previously discontinued sildenafil due to intolerable visual side effects could be a suitable candidate to trial Avanafil, as the risk of recurrence is pharmacologically lower. This elevates the clinical decision-making process from simple trial-and-error to a more personalized approach based on the predictable relationship between molecular selectivity and the patient's adverse event history.

III. Pharmacokinetic Profile: Absorption, Distribution, Metabolism, and Excretion (ADME)

The clinical performance of Avanafil, particularly its rapid onset and duration of action, is governed by its pharmacokinetic properties. The ADME profile has been well-characterized in clinical pharmacology studies.

Absorption Dynamics

• Speed: A hallmark of Avanafil is its rapid absorption following oral administration. In the fasted state, maximum observed plasma concentrations (Tmax​) are achieved within a median time of 30 to 45 minutes.[1] This rapid absorption is the pharmacokinetic basis for its fast clinical onset of action, which allows for administration as close as 15 minutes prior to sexual activity.[3]
• Influence of Food: The rate, but not the extent, of Avanafil absorption is affected by food. When administered with a high-fat meal, the rate of absorption is reduced, resulting in a mean delay in Tmax​ of approximately 1.25 hours and a mean reduction in the peak plasma concentration (Cmax​) of about 39% (at the 200 mg dose). However, the total drug exposure, as measured by the area under the concentration-time curve (AUC), is not significantly affected. These changes are considered to be of minimal clinical significance, and Avanafil can be taken with or without food. Nevertheless, patients may need to individualize the timing of their dose relative to food intake based on their personal clinical response.[16]

Distribution Characteristics

• Plasma Protein Binding: Avanafil is extensively bound to plasma proteins, with approximately 99% of the drug bound, primarily to albumin. This binding is independent of total drug concentration, age, or renal and hepatic function. Its two major circulating metabolites, M4 and M16, are also highly protein-bound at approximately 97% and 81%, respectively.[3]
• Volume of Distribution: The apparent volume of distribution (Vd​) of Avanafil ranges from 47 to 83 L, indicating distribution into tissues beyond the plasma volume.[3]
• Seminal Fluid Concentration: Measurements in healthy volunteers have shown that less than 0.0002% of an administered dose appears in the semen 45 to 90 minutes after dosing. This indicates minimal partitioning into this compartment and suggests that clinically significant drug concentrations are not transferred to a sexual partner.[17]

Metabolism

• Primary Pathway: Avanafil is cleared from the body almost entirely through extensive hepatic metabolism. The primary metabolic pathway is mediated by the cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4).[3] A minor contribution to its metabolism is made by other CYP2C isoforms, such as CYP2C9.[3]
• Major Metabolites: The metabolism of Avanafil results in two major circulating metabolites, designated M4 and M16. The plasma concentrations of M4 and M16 are approximately 23% and 29% of the parent compound, respectively.[3]
• Metabolite Activity: The M4 metabolite is pharmacologically active. It exhibits a PDE5 selectivity profile similar to that of the parent drug and has an in vitro inhibitory potency for PDE5 that is 18% of Avanafil's. Taking into account its plasma concentration and protein binding, the M4 metabolite is estimated to contribute approximately 12% of the total pharmacological activity.[3] The M16 metabolite is considered inactive against PDE5 and does not contribute to the clinical effect.[17]

Excretion and Elimination Half-Life

• Route of Elimination: Following oral administration and extensive metabolism, Avanafil is excreted predominantly as metabolites. The primary route of elimination is via the feces (approximately 63% of the administered dose), with a smaller portion excreted in the urine (approximately 21% of the dose).[17]
• Half-Life: The terminal elimination half-life (t1/2​) of Avanafil is variable, with studies reporting a range of approximately 6 to 17 hours.[17] Other analyses cite a functional half-life of 5 to 10 hours.[4] This duration is consistent with its intended use as an on-demand medication rather than a daily therapy.

The pharmacokinetic profile of Avanafil reveals a critical interplay between its rapid absorption and its heavy reliance on a single metabolic pathway. The fast absorption kinetics are directly responsible for its key clinical advantage—a rapid onset of action that promotes spontaneity. However, its near-total dependence on CYP3A4 for clearance creates its most significant clinical vulnerability: a high susceptibility to potent drug-drug interactions. Strong inhibitors of the CYP3A4 enzyme, such as certain antifungal agents (ketoconazole) or protease inhibitors (ritonavir), can profoundly impair Avanafil's metabolism. This leads to a dramatic accumulation of the drug in the plasma, with studies showing that strong inhibitors can increase total exposure (AUC) by as much as 13-fold and peak concentrations (Cmax​) by 3-fold.[28] Such a massive increase in exposure effectively transforms a standard therapeutic dose into a significant overdose, heightening the risk of severe adverse events, most notably profound hypotension. This is the pharmacological rationale behind the absolute contraindication for co-administration with strong CYP3A4 inhibitors.[29] Conversely, co-administration with strong CYP3A4 inducers (e.g., rifampin, St. John's Wort) would be expected to accelerate Avanafil's metabolism, drastically reducing its plasma concentrations and likely leading to therapeutic failure. This dynamic illustrates that the very property that provides Avanafil's clinical benefit (rapid absorption for fast onset) is inextricably linked to its primary risk profile (high potential for clinically significant pharmacokinetic interactions). This underscores that a thorough medication reconciliation is not merely a routine procedural step but a critical safety imperative directly dictated by Avanafil's ADME profile.

Table 2: Summary of Key Pharmacokinetic Parameters for Avanafil

Parameter	Value	Notes	Source(s)
Time to Peak Concentration (Tmax​)	30–45 minutes	In fasted state.	17
Effect of High-Fat Meal	Tmax​ delayed by ~1.25 hours; Cmax​ reduced by ~39%	Total exposure (AUC) is unaffected.	16
Plasma Protein Binding	~99%	Primarily to albumin.	3
Apparent Volume of Distribution (Vd​)	47–83 L	Indicates tissue distribution.	3
Primary Metabolic Pathway	Cytochrome P450 3A4 (CYP3A4)	Minor contribution from CYP2C isoforms.	3
Active Metabolite(s)	M4	Contributes ~12% of total pharmacological activity.	3
Terminal Elimination Half-Life (t1/2​)	6–17 hours	Supports on-demand dosing.	17
Routes of Excretion	~63% in feces; ~21% in urine	Excreted as metabolites.	17

IV. Clinical Efficacy in the Management of Erectile Dysfunction

The clinical efficacy of Avanafil for the treatment of ED has been robustly established through a series of large, randomized, double-blind, placebo-controlled Phase III clinical trials conducted in both general ED populations and specific, harder-to-treat patient subgroups.

Review of Pivotal Phase III Clinical Trials

The efficacy of Avanafil was evaluated using internationally recognized and validated endpoints for ED research. The primary outcomes consistently demonstrated a statistically significant and clinically meaningful improvement in erectile function for all tested doses of Avanafil compared to placebo.

• Primary Efficacy Endpoints:
• International Index of Erectile Function - Erectile Function Domain (IIEF-EFD): This is a patient-reported outcome measure consisting of six questions that assess the quality of erectile function, with higher scores indicating better function. Across pivotal trials, patients treated with Avanafil at doses of 50 mg, 100 mg, and 200 mg experienced a significantly greater improvement in their IIEF-EFD scores from baseline compared to those receiving placebo.[7] In a long-term open-label extension study, mean IIEF-EF domain scores improved from a baseline of 13.6 to 22.2 in the 100 mg group, and from 11.9 to 22.7 in the group that could titrate to 200 mg, indicating sustained efficacy.[8]
• Sexual Encounter Profile (SEP) Questions: These diary-based questions assess the success of individual sexual attempts. The two key co-primary endpoints are:
• SEP Question 2 (SEP2): "Were you able to insert your penis into your partner’s vagina?"
• SEP Question 3 (SEP3): "Did your erection last long enough for you to have successful intercourse?" Treatment with Avanafil resulted in a significant increase in the percentage of sexual attempts that were successful for both SEP2 and SEP3, compared to placebo.7 For example, in the general ED population, the mean percentage of attempts resulting in successful intercourse (SEP3) was approximately 57% for both the 100 mg and 200 mg Avanafil doses, compared to just 27% for placebo.33 The long-term extension study showed SEP3 success rates improving from a baseline of approximately 13% to 68% with the 100 mg dose.8

Dose-Response Relationship

Avanafil is available in three oral tablet strengths: 50 mg, 100 mg, and 200 mg.[16] Clinical studies have demonstrated a clear dose-response relationship, with higher doses generally associated with greater improvements in efficacy endpoints.[33] The recommended starting dose is 100 mg, which can be titrated up to 200 mg for enhanced efficacy or down to 50 mg to improve tolerability, with the guiding principle being to use the lowest effective dose.[16] While some studies found no statistically significant difference in efficacy between the 100 mg and 200 mg doses, the higher dose serves as an important option for patients who do not achieve a satisfactory response with the starting dose.[8] In one long-term study, 65% of patients who were non-responders to the 100 mg dose subsequently responded after titrating to 200 mg, confirming the clinical utility of the higher dose.[8]

Speed of Onset and Duration of Action in a Clinical Setting

• Onset: The rapid absorption kinetics of Avanafil translate directly into a rapid clinical onset of action. Secondary analyses of pivotal trials demonstrated that successful intercourse was achieved by a significant proportion of subjects within 15 minutes of dosing.[7] In sexual attempts made during this early post-dose interval, 64% to 71% were successful in the Avanafil groups, compared to only 27% in the placebo group, providing strong evidence for its utility as a fast-acting, on-demand therapy.[7]
• Duration: The therapeutic window of efficacy for Avanafil is sustained, with clinical studies demonstrating effectiveness for more than 6 hours after administration, consistent with its pharmacokinetic half-life.[4]

Efficacy in Special Populations

To establish the robustness of its efficacy, Avanafil was specifically evaluated in patient populations where ED is often more severe and difficult to treat due to underlying comorbidities.

• Patients with Diabetes Mellitus: In a dedicated randomized, placebo-controlled trial involving men with both type 1 and type 2 diabetes, Avanafil (100 mg and 200 mg) was found to be safe and significantly more effective than placebo. It produced clinically meaningful improvements in all primary endpoints, including IIEF-EF scores and the percentage of successful sexual attempts.[4]
• Patients Post-Bilateral Nerve-Sparing Radical Prostatectomy: ED is a common and challenging complication following this procedure due to cavernous nerve injury. In a trial of this specific population, Avanafil was again found to be effective and well-tolerated, demonstrating statistically significant improvements in erectile function over placebo.[4]

While Avanafil has proven to be statistically superior to placebo across all studied populations, a closer analysis of the data reveals an attenuation of absolute efficacy in these more complex, comorbid groups. For instance, the percentage of successful sexual attempts (SEP3) with the 100 mg or 200 mg dose was approximately 57% in the general ED population. This success rate dropped to approximately 40% in men with diabetes and to just 26% in men who had undergone a radical prostatectomy.[33]

This observed "efficacy gap" is not indicative of a failure of the drug itself but rather reflects the more severe underlying pathophysiology in these patients. ED in the context of diabetes or post-prostatectomy surgery often involves a significant neurogenic component in addition to vasculogenic and endothelial dysfunction. Post-surgical ED results from direct damage to the cavernous nerves, which impairs the initial, crucial release of NO. Similarly, long-standing diabetes can cause autonomic neuropathy and advanced endothelial dysfunction, which disrupt the NO/cGMP pathway at multiple upstream points. A PDE5 inhibitor like Avanafil acts downstream in this cascade by preserving the cGMP that is produced. If the upstream signal—the release of NO—is severely compromised, there is simply less cGMP available for the drug to "save," and its efficacy will be inherently limited. This understanding is crucial for clinical practice. It helps in setting realistic expectations with patients, making it clear that while Avanafil is a valuable therapeutic tool, it may not fully restore normal erectile function in cases of severe underlying neurovascular damage. It also highlights the potential need for multimodal treatment strategies in these complex patient populations.

V. Comparative Analysis with First-Generation PDE5 Inhibitors

The clinical positioning of Avanafil is best understood through a direct comparison with the three first-generation PDE5 inhibitors: sildenafil, tadalafil, and vardenafil. While all four drugs share the same fundamental mechanism of action, they possess distinct pharmacokinetic, pharmacodynamic, and selectivity profiles that translate into different clinical characteristics.

Pharmacokinetic and Pharmacodynamic Distinctions

• Onset of Action: Avanafil is the fastest-acting agent in the class. Its median Tmax​ of 30-45 minutes allows for a recommended dosing window as short as 15 minutes before sexual activity. This contrasts with sildenafil and vardenafil, which have a Tmax​ of approximately 60 minutes and are typically taken 30-60 minutes before intercourse, and tadalafil, which is the slowest with a Tmax​ of around 120 minutes.[4]
• Duration of Action: The drugs differ significantly in their elimination half-life, which dictates their duration of effect. Tadalafil is unique, with a long half-life of 17.5 hours that provides a therapeutic window of up to 36 hours, earning it the moniker "the weekend pill".[4] Avanafil (6-17 hours), sildenafil (~4 hours), and vardenafil (~4 hours) are all shorter-acting agents intended for on-demand use closer to the time of sexual activity.[4]
• Food Interaction: The absorption of sildenafil and vardenafil is significantly delayed by the concurrent consumption of a high-fat meal, which can postpone their onset of action by up to an hour. Avanafil's absorption is also delayed, but to a lesser extent, and its total exposure is unaffected. Tadalafil's pharmacokinetics are largely independent of food intake, offering greater flexibility.[16]
• Enzyme Selectivity: As a second-generation agent, Avanafil was designed for enhanced selectivity. It has the highest selectivity for PDE5 over PDE6 among the class, which is relevant for minimizing visual side effects.[4] Tadalafil is also highly selective against PDE6 but exhibits some cross-inhibition of PDE11, an isoenzyme found in skeletal muscle, which has been linked to its characteristic side effects of myalgia and back pain.[25]

Comparative Efficacy and Patient Preference

In terms of overall efficacy, when used at appropriate doses, all four PDE5 inhibitors have demonstrated robust and largely comparable effectiveness in treating ED, with success rates generally ranging from 60% to 85%.[4] Some head-to-head or meta-analytic data have suggested potential superior efficacy for one agent over another in specific metrics, but in broad clinical practice, all are considered highly effective.[27]

Patient preference is often driven less by absolute efficacy and more by how the drug's pharmacokinetic profile aligns with an individual's lifestyle and relationship dynamics. The long duration of tadalafil is frequently preferred by patients in long-term relationships who value spontaneity and wish to decouple medication administration from the specific timing of sexual activity.[25] In contrast, the rapid onset of Avanafil may appeal to patients who prioritize a quick response time for more immediate, on-demand use.

Divergent Safety and Tolerability Profiles

The differences in enzyme selectivity among the PDE5 inhibitors lead to distinct adverse event profiles.

• Avanafil's higher selectivity is associated with a lower incidence of certain class-specific side effects. Meta-analyses suggest that Avanafil has a more favorable overall side-effect profile compared to the first-generation agents.[4]
• Visual Disturbances: Transient changes in color perception (cyanopsia) or blurred vision are most characteristically associated with sildenafil, due to its cross-inhibition of retinal PDE6.[25] These effects are less common with Avanafil and tadalafil.
• Back Pain and Myalgia: These side effects are uniquely associated with tadalafil and are attributed to its inhibition of PDE11 in skeletal muscle.[25]
• Headache, Flushing, and Nasal Congestion: These are the most common side effects across all four drugs and are a direct consequence of their primary vasodilatory mechanism of action. Incidence rates are broadly similar, though they can vary with dose.[5]

Table 3: Comparative Profile of Commercially Available PDE5 Inhibitors

The choice of a PDE5 inhibitor for a specific patient involves a careful consideration of these differentiating characteristics. The following table provides a comparative summary to facilitate evidence-based clinical decision-making.

Feature	Avanafil (Stendra/Spedra)	Sildenafil (Viagra)	Tadalafil (Cialis)	Vardenafil (Levitra)
Recommended Onset	~15–30 min	~60 min	~30–120 min	~25–60 min
Time to Peak (Tmax​)	0.5–0.75 hours	~1 hour	~2 hours	~1 hour
Elimination Half-Life	6–17 hours	~4 hours	17.5 hours	~4 hours
Duration of Effect	>6 hours	~4–12 hours	Up to 36 hours	~4–12 hours
Effect of High-Fat Meal	Rate of absorption reduced; Cmax​ decreased	Rate of absorption significantly reduced	Minimal effect	Rate of absorption significantly reduced
Selectivity vs. PDE6	High (>100-fold)	Lower	High	Moderate
Selectivity vs. PDE11	High	High	Lower	High
Characteristic Side Effects	Headache, flushing, nasal congestion	Headache, flushing, visual disturbances (cyanopsia)	Headache, dyspepsia, back pain, myalgia	Headache, flushing, nasal congestion
Sources	4

This comparative framework allows a clinician to tailor therapy to the individual patient. For a patient who prioritizes a rapid onset and may have experienced visual side effects with sildenafil, Avanafil presents a logical choice. For a patient desiring the freedom to engage in sexual activity over a weekend without needing to time a dose, tadalafil is the clear frontrunner. This nuanced understanding of the trade-offs between the available agents is central to optimizing treatment for ED.

VI. Labeled and Off-Label Clinical Applications

Primary Indication: Erectile Dysfunction

The sole indication for which Avanafil has received regulatory approval from the FDA and EMA is the treatment of erectile dysfunction in adult males.[1] All clinical development and marketing efforts have been focused on this therapeutic area.

Exploration of Potential Off-Label Uses

The therapeutic application of drugs is often expanded beyond their approved indications through off-label prescribing, where clinicians use a medication for an unapproved use based on scientific rationale and emerging evidence. For the PDE5 inhibitor class, several such uses have been explored.

• Raynaud's Phenomenon:
• Rationale: Raynaud's phenomenon is a vasospastic disorder characterized by an exaggerated vascular response to cold or emotional stress, leading to ischemia in the extremities. The pathophysiology involves endothelial dysfunction and impaired vasodilation. Given that PDE5 inhibitors promote vasodilation by enhancing the cGMP pathway, they represent a logical therapeutic target for counteracting this vasospasm.[39]
• Evidence for the Class: A body of evidence, including small clinical trials, open-label studies, and case series, has investigated the use of PDE5 inhibitors for Raynaud's phenomenon, particularly in severe cases secondary to connective tissue diseases like systemic sclerosis (SSc). Studies with sildenafil have shown that it can reduce the frequency and duration of Raynaud's attacks and promote the healing of painful digital ulcers.[39] However, the evidence is not uniformly positive; some larger, well-controlled trials have failed to show a significant benefit over placebo, potentially confounded by a high placebo response rate or heterogeneity in the patient populations studied.[41]
• Evidence for Avanafil: One source explicitly lists Raynaud's phenomenon as a potential off-label use for Stendra (Avanafil).[45] However, this appears to be an extrapolation based on the known class effect. The provided research materials do not contain any specific clinical trials evaluating the efficacy and safety of Avanafil for this indication.[41] In fact, other sources state that there are currently no known unlabeled uses for Avanafil, highlighting a direct contradiction in the available information.[7]

This contradiction illustrates the "evidence extrapolation" dilemma inherent in off-label prescribing. Clinicians may reasonably infer that if sildenafil is effective for Raynaud's via PDE5 inhibition, then Avanafil, a more selective PDE5 inhibitor, should also be effective. This is a common clinical heuristic. However, it is an assumption that lacks rigorous, drug-specific evidence. Differences in pharmacokinetics (e.g., Avanafil's shorter duration of action compared to tadalafil) or other subtle pharmacodynamic properties could lead to different clinical outcomes in a chronic condition like Raynaud's. Therefore, while the off-label use of Avanafil for Raynaud's may occur in clinical practice, it is critical for prescribers to recognize that this is based on an inferred class effect rather than direct, high-quality evidence. This has significant implications for managing patient expectations, monitoring for safety, and navigating challenges with insurance reimbursement, which is often denied for off-label uses not supported by strong clinical data.[49]

• Other Investigated Uses for the PDE5 Inhibitor Class: While other PDE5 inhibitors have been approved or are investigated for other conditions, these are not established uses for Avanafil.
• Pulmonary Arterial Hypertension (PAH): Sildenafil (as Revatio) and tadalafil (as Adcirca) are approved for the treatment of PAH. Avanafil is not approved for this indication.[37]
• Lower Urinary Tract Symptoms (LUTS) secondary to Benign Prostatic Hyperplasia (BPH): Daily low-dose tadalafil is approved for treating LUTS/BPH, with or without co-existing ED.[19]
• Premature Ejaculation (PE): PDE5 inhibitors have been shown to increase ejaculatory latency, particularly in men with concomitant ED, but this is not an approved indication.[19]

VII. Dosage and Administration Guidelines

The proper and safe use of Avanafil requires adherence to established dosage and administration guidelines, including specific adjustments for certain patient populations and concomitant medications.

Recommended Dosing for Erectile Dysfunction

• Initial Dose: The recommended starting dose for most patients is 100 mg, taken on an as-needed basis.[18]
• Timing of Administration: A key advantage of Avanafil is its rapid onset. The 100 mg and 200 mg doses can be taken as early as 15 minutes before anticipated sexual activity. The 50 mg dose is recommended to be taken approximately 30 minutes before sexual activity.[3]
• Dose Titration and Maintenance: Based on individual efficacy and tolerability, the dose may be increased to a maximum of 200 mg or decreased to 50 mg. The clinical goal is to use the lowest dose that provides a satisfactory therapeutic benefit.[16]
• Maximum Dosing Frequency: Avanafil should not be taken more than once per day.[18]

Administration Instructions

• Route of Administration: Avanafil is administered as an oral tablet.[35]
• Relation to Food: The medication may be taken with or without food. While a high-fat meal may delay the time to peak concentration, the overall exposure is not affected, and dose adjustments are not required based on food intake.[22]

Dose Adjustments in Specific Clinical Scenarios

• Renal Impairment:
• Mild to Moderate (Creatinine Clearance [CrCl] ≥30 mL/min): No dose adjustment is necessary.[29]
• Severe (CrCl <30 mL/min) or End-Stage Renal Disease on Dialysis: Avanafil has not been studied in these populations and its use is not recommended.[29]
• Hepatic Impairment:
• Mild to Moderate (Child-Pugh Class A or B): No dose adjustment is necessary.[29]
• Severe (Child-Pugh Class C): Avanafil has not been studied in patients with severe hepatic impairment and its use is not recommended.[21]
• Concomitant Use of Alpha-Blockers: In patients who are stable on alpha-blocker therapy (e.g., for hypertension or BPH), Avanafil treatment should be initiated at the lowest dose of 50 mg to minimize the risk of symptomatic hypotension.[22]
• Concomitant Use of CYP3A4 Inhibitors: Due to Avanafil's primary metabolism by CYP3A4, co-administration with inhibitors of this enzyme requires careful dose management:
• Strong CYP3A4 Inhibitors (e.g., ketoconazole, ritonavir, atazanavir, clarithromycin, itraconazole): Concomitant use with Avanafil is contraindicated.[21]
• Moderate CYP3A4 Inhibitors (e.g., erythromycin, diltiazem, verapamil, fluconazole, aprepitant): When taken with these medications, the maximum recommended dose of Avanafil is 50 mg, not to be exceeded more than once in a 24-hour period.[22]

VIII. Safety, Tolerability, and Adverse Effects

Comprehensive Profile of Adverse Drug Reactions

The safety and tolerability of Avanafil have been evaluated in numerous clinical trials and postmarketing surveillance. Overall, it is well-tolerated, with the majority of adverse events (AEs) being mild to moderate in severity and transient in nature. The rate of discontinuation from clinical trials due to AEs was low, typically less than 3%, and comparable to placebo rates in some studies, underscoring its favorable tolerability.[4]

Common Side Effects (Incidence >2%)

The most frequently reported side effects are directly related to the vasodilatory properties of PDE5 inhibition and are consistent across the class. These include:

• Headache: The most common AE, with an incidence of up to 12.1% depending on the dose.[5]
• Flushing: A feeling of warmth or redness of the face, neck, and upper chest.[5]
• Nasal Congestion: Includes stuffy or runny nose and nasopharyngitis.[5]
• Back Pain:.[5]
• Dyspepsia/Indigestion:.[18]

In-depth Discussion of Serious and Rare Adverse Events (Class Effects)

While generally safe, Avanafil shares the potential for rare but serious adverse events that are characteristic of the PDE5 inhibitor class. Patients should be counseled on the signs and symptoms of these events and instructed to seek immediate medical attention if they occur.

• Cardiovascular Risks: Due to its vasodilatory effects, Avanafil can cause a drop in blood pressure. This effect is usually modest but can be dangerous in certain high-risk individuals. The drug is not recommended for men with recent (within the last 6 months) serious cardiovascular events such as myocardial infarction (MI) or stroke, life-threatening arrhythmias, or those with unstable angina, uncontrolled hypertension (BP>170/110 mmHg), resting hypotension (BP<90/50 mmHg), or moderate to severe heart failure.[12]
• Priapism: All PDE5 inhibitors have been associated with priapism, a painful erection lasting longer than 4 to 6 hours. This is a medical emergency that can result in permanent penile tissue damage and loss of potency if not treated immediately. Avanafil should be used with caution in patients with anatomical deformation of the penis (e.g., Peyronie's disease) or conditions that may predispose them to priapism, such as sickle cell anemia, multiple myeloma, or leukemia.[18]
• Ocular Effects:
• Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION): This is a rare but devastating cause of sudden, often permanent, vision loss in one or both eyes. Postmarketing reports have identified a temporal association between the use of all PDE5 inhibitors and the occurrence of NAION. Patients with a "crowded" optic disc may be at higher risk. Patients must be instructed to discontinue Avanafil and seek immediate medical care if they experience any sudden loss of vision.[3]
• Color Vision Changes: Transient impairment of blue/green color discrimination (cyanopsia) is a known side effect of sildenafil, resulting from its inhibition of retinal PDE6. Due to Avanafil's high selectivity for PDE5 over PDE6, this side effect is much less of a concern. However, a single case of cyanopsia was reported in a long-term open-label study, indicating that it cannot be entirely ruled out.[17]
• Otic Effects: Sudden decrease or loss of hearing has been reported in temporal association with the use of PDE5 inhibitors. These events may be accompanied by vestibular symptoms such as tinnitus and dizziness. Patients should be advised to stop taking Avanafil and seek prompt medical attention if they experience a sudden change in their hearing.[18]

Hepatotoxicity Assessment

To date, Avanafil has not been definitively linked to instances of clinically apparent liver injury in premarketing or postmarketing data. However, given its relatively recent introduction and more limited use compared to other PDE5 inhibitors, the data are less extensive. Other agents in the class, such as sildenafil and tadalafil, have been associated with rare, isolated cases of acute, self-limited cholestatic liver injury. Based on this class effect and the limited data, the potential for Avanafil to cause a similar rare form of hepatotoxicity cannot be excluded. Its hepatotoxicity likelihood score is rated as E* (unproved but suspected rare cause of clinically apparent liver injury).[18]

Table 4: Incidence of Adverse Effects by System Organ Class and Frequency

System Organ Class	Adverse Reaction	Frequency / Incidence	Source(s)
Nervous System	Headache	Very Common (up to 12.1%)	35
	Dizziness	Common (1% to 10%)	53
	Somnolence, Vertigo	Uncommon (0.1% to 1%)	53
Vascular	Flushing	Common (1% to 10%)	50
	Hypotension, Hypertension	Rare (<0.1% to Postmarketing)	53
Respiratory, Thoracic & Mediastinal	Nasal Congestion	Common (1% to 10%)	50
	Nasopharyngitis, Sinusitis	Common (1% to 10%)	53
	Dyspnea	Uncommon (0.1% to 1%)	53
Gastrointestinal	Dyspepsia, Nausea	Common (1% to 10%)	53
	Vomiting, Gastritis	Uncommon (0.1% to 1%)	53
Musculoskeletal & Connective Tissue	Back Pain	Common (1% to 10%)	50
	Myalgia, Muscle Spasms	Uncommon (0.1% to 1%)	53
Cardiac	Tachycardia, Palpitations	Rare (<0.1%)	53
	Chest Pain	Rare (<0.1%)	53
Eye Disorders	Blurred Vision	Uncommon (0.1% to 1%)	53
	Change in Color Vision	Less Common	53
Ear & Labyrinth Disorders	Vertigo	Uncommon (0.1% to 1%)	53
	Sudden Hearing Loss	Incidence not known	53
Reproductive System & Breast	Increased Erection	Uncommon (0.1% to 1%)	53
	Priapism	Postmarketing reports	53

IX. Contraindications, Warnings, and Drug Interactions

The safe prescribing of Avanafil is contingent upon a thorough understanding of its contraindications, the patient populations that require special precautions, and its extensive potential for clinically significant drug interactions.

Absolute Contraindications

The use of Avanafil is absolutely contraindicated in the following situations:

• Concomitant Use of Organic Nitrates: Co-administration of Avanafil with any form of organic nitrate (e.g., nitroglycerin, isosorbide dinitrate, isosorbide mononitrate) or nitric oxide donors (e.g., amyl nitrite, "poppers"), whether regularly or intermittently, is strictly contraindicated. The synergistic interaction between PDE5 inhibition and nitrates on the cGMP pathway can lead to a profound, precipitous, and potentially fatal drop in blood pressure.[5]
• Concomitant Use of sGC Stimulators: The use of soluble guanylate cyclase (sGC) stimulators, such as riociguat, is also contraindicated due to the risk of additive hypotensive effects.[29]
• Known Hypersensitivity: A history of a known hypersensitivity reaction to Avanafil or any of the excipients in the tablet formulation is a contraindication.[32]

Warnings and Precautions for High-Risk Patient Populations

• Cardiovascular Disease: A thorough cardiovascular assessment should be performed before prescribing Avanafil. It is not recommended for men for whom sexual activity is inadvisable due to their underlying cardiovascular status. This includes patients with a recent (within 6 months) myocardial infarction, stroke, or life-threatening arrhythmia; those with unstable angina or angina occurring during intercourse; and those with New York Heart Association (NYHA) Class II or greater heart failure, uncontrolled hypertension, or severe hypotension.[12]
• Anatomical Deformation of the Penis: Caution should be exercised in patients with anatomical deformities of the penis, such as angulation, cavernosal fibrosis, or Peyronie's disease, as well as in patients with conditions that may predispose them to priapism.[12]
• Bleeding Disorders or Active Peptic Ulceration: The safety of Avanafil has not been established in these patients, and it should be used with caution.[12]
• Severe Renal or Hepatic Impairment: Due to a lack of clinical data, the use of Avanafil is not recommended in patients with severe renal impairment (CrCl <30 mL/min), those on renal dialysis, or those with severe hepatic impairment (Child-Pugh Class C).[21]

Clinically Significant Drug Interactions

Avanafil is subject to a large number of drug interactions, with over 300 identified, of which 63 are classified as major.[54] These interactions can be broadly categorized as pharmacodynamic (additive effects on blood pressure) or pharmacokinetic (alterations in Avanafil metabolism).

• Pharmacodynamic Interactions (Additive Vasodilation):
• Nitrates: (See Absolute Contraindications). In an emergency where nitrate administration is deemed medically necessary for a life-threatening condition (e.g., acute MI), at least 12 hours should have elapsed since the last dose of Avanafil. Even then, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring.[22]
• Alpha-Blockers: Co-administration can lead to symptomatic hypotension. Patients must be hemodynamically stable on their alpha-blocker therapy before Avanafil is initiated at the lowest dose of 50 mg.[3]
• Other Antihypertensives: Additive blood pressure-lowering effects may occur when Avanafil is combined with other classes of antihypertensive drugs, such as ACE inhibitors, ARBs, beta-blockers, and calcium channel blockers. While clinical studies showed only small additional reductions in blood pressure, caution and monitoring are advised, and patients should be warned about the potential for orthostatic symptoms.[22]
• Alcohol: Substantial consumption of alcohol (defined as more than 3 units, e.g., 3 glasses of wine or 3 shots of whiskey) in combination with Avanafil can increase the risk of orthostatic hypotension, dizziness, headache, and tachycardia due to the combined mild vasodilatory effects of both substances.[3]
• Pharmacokinetic Interactions (CYP3A4-Mediated):
• Strong CYP3A4 Inhibitors: (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin, nefazodone). These drugs can dramatically increase Avanafil exposure by inhibiting its metabolism. Co-administration is contraindicated.[21]
• Moderate CYP3A4 Inhibitors: (e.g., erythromycin, aprepitant, diltiazem, verapamil, fluconazole, fosamprenavir). These drugs can cause a clinically significant increase in Avanafil exposure. When used concomitantly, the dose of Avanafil must be reduced to a maximum of 50 mg in any 24-hour period.[22]
• CYP3A4 Inducers: (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort, apalutamide, enzalutamide). These agents are expected to substantially decrease Avanafil plasma concentrations by accelerating its metabolism, which may lead to a loss of efficacy. Concomitant use is not recommended.[29]
• Grapefruit Juice: As a moderate inhibitor of intestinal CYP3A4, grapefruit juice can increase Avanafil serum concentrations. Patients should be advised to avoid or not significantly alter their intake of grapefruit products while taking Avanafil.[32]

Table 5: Avanafil Drug Interaction and Dose Management Guide

Interacting Drug/Class	Mechanism of Interaction	Clinical Consequence	Recommended Management	Source(s)
Organic Nitrates	Pharmacodynamic (Synergistic Vasodilation)	Severe, potentially fatal hypotension	CONTRAINDICATED	29
sGC Stimulators (e.g., Riociguat)	Pharmacodynamic (Synergistic Vasodilation)	Severe hypotension	CONTRAINDICATED	29
Strong CYP3A4 Inhibitors	Pharmacokinetic (Inhibition of Metabolism)	Dramatic increase in Avanafil exposure; increased risk of severe adverse effects	CONTRAINDICATED	28
Alpha-Adrenergic Blockers	Pharmacodynamic (Additive Vasodilation)	Symptomatic hypotension, dizziness, orthostasis	Patient must be stable on alpha-blocker therapy. Initiate Avanafil at 50 mg dose.	30
Moderate CYP3A4 Inhibitors	Pharmacokinetic (Inhibition of Metabolism)	Clinically significant increase in Avanafil exposure	Reduce Avanafil dose to a maximum of 50 mg, not to exceed once every 24 hours.	30
Antihypertensive Agents	Pharmacodynamic (Additive Vasodilation)	Additive blood pressure lowering; potential for hypotension	Use with caution. Monitor blood pressure. Advise patient on symptoms of orthostasis.	64
Alcohol (Substantial amounts)	Pharmacodynamic (Additive Vasodilation)	Increased risk of orthostatic hypotension, dizziness, tachycardia	Advise patient to limit alcohol intake (e.g., <3 units) when taking Avanafil.	22
CYP3A4 Inducers	Pharmacokinetic (Induction of Metabolism)	Substantial decrease in Avanafil exposure; potential loss of efficacy	Concomitant use is not recommended.	29
Grapefruit Juice	Pharmacokinetic (Inhibition of Metabolism)	Increased Avanafil exposure	Avoid or consume with caution.	32

X. Conclusion and Future Perspectives

Summary of Avanafil's Clinical Profile and Position in Therapy

Avanafil has established itself as a valuable and distinct therapeutic option in the management of erectile dysfunction. As a second-generation PDE5 inhibitor, its clinical profile is defined by a unique combination of rapid onset of action and high selectivity for the PDE5 enzyme. This pharmacological profile was strategically engineered to address specific limitations of its predecessors, offering patients a treatment that enhances spontaneity and provides a potentially more favorable safety profile. Clinical trials have robustly demonstrated its efficacy, which is comparable to other agents in the class, across a spectrum of ED severities and in challenging patient populations with comorbidities such as diabetes and post-prostatectomy status. Its primary advantages—speed and selectivity—position it as a strong choice for patients who prioritize a quick response or who have experienced intolerable off-target side effects (particularly visual disturbances) with first-generation agents.

Discussion of its Advantages and Limitations

• Advantages:
• Rapid Onset: The ability to take the medication as little as 15 minutes before sexual activity is a significant lifestyle advantage, reducing the need for extensive planning.
• High Selectivity: The enhanced selectivity for PDE5 over other isoenzymes, especially PDE6, translates into a lower incidence of certain mechanism-based side effects, improving its overall tolerability.
• Comparable Efficacy: Its efficacy in restoring erectile function is well-established and on par with the other leading PDE5 inhibitors.
• Limitations:
• Cost and Generic Availability: As a newer, brand-name-only drug in many markets, its cost can be substantially higher than that of generic sildenafil, which may be a barrier to access for some patients.[33]
• Attenuated Efficacy in Severe Comorbidities: While still effective, the absolute success rates are lower in men with severe underlying neurovascular damage, a limitation shared by all PDE5 inhibitors that reflects the pathophysiology of the disease.
• High Potential for Drug Interactions: Its near-complete reliance on the CYP3A4 metabolic pathway makes it highly vulnerable to clinically significant drug-drug interactions, necessitating careful medication review and dose adjustments or contraindications with a wide range of common medications.

Potential Avenues for Future Research and Development

While Avanafil is a well-characterized agent for ED, several avenues for future research could further refine its clinical utility and expand its potential applications.

• Head-to-Head Comparative Trials: There is a need for more large-scale, head-to-head randomized controlled trials comparing Avanafil directly with other PDE5 inhibitors, focusing not just on efficacy endpoints but also on patient-reported outcomes such as treatment satisfaction, spontaneity, and preference.
• Investigation of Off-Label Indications: The therapeutic rationale for using PDE5 inhibitors in conditions like Raynaud's phenomenon is strong. Formal clinical trials are needed to specifically evaluate the efficacy and safety of Avanafil in this and other potential off-label indications to move beyond anecdotal evidence and class-effect extrapolation and establish a firm evidence base.
• Development of Alternative Formulations: Preliminary research has explored novel drug delivery systems, such as sublingual tablets, designed to bypass first-pass metabolism.[27] Further development in this area could potentially enhance Avanafil's bioavailability, further speed its onset, and improve its pharmacokinetic profile.
• Exploration of Cardioprotective Roles: Building on the growing body of preclinical and early clinical data for the PDE5 inhibitor class, further research could investigate whether Avanafil has potential therapeutic or protective roles in other cardiovascular conditions, such as heart failure or post-ischemic recovery, where the NO/cGMP pathway is implicated.[19]

In conclusion, Avanafil represents a significant refinement in the pharmacological treatment of erectile dysfunction. Its distinct profile offers a tailored option that meets the needs of many patients, solidifying its place as a key component of the modern urological armamentarium. Future research will be crucial to fully elucidate its potential beyond its current indication and to further optimize its use in clinical practice.

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