Sildenafil (Viagra) vs. All ED Medications: Doses, Duration, Side Effects, and How to Choose

What Sildenafil (Viagra) Is and How It Works

Sildenafil inhibits phosphodiesterase type 5 (PDE5), the enzyme that breaks down cyclic GMP in penile smooth muscle. Sexual stimulation triggers nitric oxide release, which raises cGMP and relaxes smooth muscle, allowing arterial blood to fill the corpus cavernosum. Sildenafil prolongs that signal. It does not produce an erection without arousal.

The FDA approved sildenafil for erectile dysfunction in March 1998 under the brand name Viagra. Pfizer's original NDA and the FDA approval letter are archived at FDA.gov. Generic sildenafil became widely available in the United States after December 2017 when Pfizer's patent exclusivity expired, cutting the average per-pill cost from roughly $70 to under $1 at high-volume pharmacies.

Sildenafil is available in 25 mg, 50 mg, and 100 mg tablets. The standard starting dose is 50 mg taken 30 to 60 minutes before sexual activity, with dose adjustment to 25 mg or 100 mg based on efficacy and tolerability. The FDA-approved prescribing information specifies a maximum of one dose per 24-hour period.

A meta-analysis published in The Lancet (Tsertsvadze et al., 2009, N=16,696 across 82 trials) found that sildenafil improved the International Index of Erectile Function (IIEF) erectile function domain score by a mean of 6.5 points over placebo. That analysis is indexed on PubMed. The key Phase III program showed that sildenafil 100 mg produced successful intercourse in approximately 69% of attempts versus 22% with placebo, a difference driven largely by improvements in penile rigidity scores. See the original efficacy data in the FDA medical review.

High-fat meals delay sildenafil absorption by up to 60 minutes and reduce peak plasma concentration by roughly 29%, according to the prescribing information. Taking sildenafil on an empty stomach or after a low-fat meal gives the most predictable onset. This pharmacokinetic interaction is described in the NDA clinical pharmacology review.

Tadalafil (Cialis): The Long-Duration Option

Tadalafil distinguishes itself with a plasma half-life of approximately 17.5 hours, producing clinically meaningful erection support for up to 36 hours after a single dose. That window allows sexual activity without precise timing, which is the main reason many men prefer it.

The FDA approved tadalafil (Cialis) for ED in November 2003 and later added a once-daily 2.5 mg and 5 mg dosing option in 2008, making it the only PDE5 inhibitor with an approved continuous-use regimen. FDA approval records are available at accessdata.fda.gov. Generic tadalafil became available in the US after September 2018.

As-needed dosing starts at 10 mg, with adjustment to 5 mg or 20 mg. Daily dosing at 2.5 mg or 5 mg maintains low steady-state plasma levels without requiring a pre-sex dose. A 2009 randomized controlled trial published in BJU International (Porst et al., N=1,054) found that daily tadalafil 5 mg produced statistically significant improvements in IIEF scores versus placebo at 12 weeks, with 58% of men reporting improved erections. The trial is referenced on PubMed.

Tadalafil also inhibits PDE11, an enzyme expressed in skeletal muscle and testes. This inhibition is pharmacologically real but has not produced clinically meaningful harm in regulatory trials. PDE11 selectivity data appear in the European Medicines Agency assessment report for Cialis. Men with benign prostatic hyperplasia (BPH) may benefit from tadalafil 5 mg daily because the drug is also FDA-approved to treat lower urinary tract symptoms associated with BPH, giving it a dual indication not shared by other oral PDE5 inhibitors.

Unlike sildenafil and vardenafil, tadalafil absorption is not meaningfully affected by food, making it simpler to take at any time. Pharmacokinetic data confirming this appear in the published tadalafil prescribing information.

Vardenafil (Levitra, Staxyn): High Potency, Similar Timeline

Vardenafil is roughly 10-fold more potent than sildenafil at inhibiting PDE5 in vitro, though that in vitro advantage does not necessarily translate to superior clinical outcomes at standard therapeutic doses. Onset is 30 to 60 minutes, similar to sildenafil, and duration is 4 to 6 hours.

The FDA approved vardenafil as Levitra in August 2003. The FDA approval record is searchable at accessdata.fda.gov. Staxyn, an orally disintegrating tablet (ODT) formulation of vardenafil at 10 mg, was approved in 2010 for men who prefer not to swallow a standard tablet. The ODT is placed on the tongue and dissolves without water, which some men find more convenient.

Standard Levitra dosing is 10 mg before sexual activity, adjustable to 5 mg or 20 mg. Like sildenafil, high-fat meals reduce peak plasma concentration by approximately 18 to 50%, so the prescribing information recommends taking vardenafil without a high-fat meal for optimal effect. Full pharmacokinetic details appear in the Levitra prescribing information on accessdata.fda.gov.

A published meta-analysis in European Urology (Tsertsvadze et al., 2009) confirmed vardenafil's efficacy across the same broad trial pool analyzed for sildenafil, finding comparable IIEF domain score improvements. That analysis is indexed on PubMed. Vardenafil carries a specific QTc-interval prolongation warning not shared by the other oral PDE5 inhibitors, meaning men on antiarrhythmics such as quinidine or amiodarone should avoid it. The FDA label warning is documented in the Levitra prescribing information.

Generic vardenafil (tablet form) is available in the United States, but the Staxyn ODT formulation remains brand-only.

Avanafil (Stendra): Fastest Onset of the Oral PDE5 Inhibitors

Avanafil was FDA-approved in April 2012 and is the newest oral PDE5 inhibitor on the US market. Its key advantage is speed. FDA approval records for avanafil (NDA 202276) are at accessdata.fda.gov. Clinical studies showed that 15 minutes was sufficient for a meaningful proportion of men to achieve erections firm enough for penetration, compared to the 30-minute minimum typically cited for sildenafil and vardenafil.

Dosing is 50 mg, 100 mg, or 200 mg taken 15 to 30 minutes before sexual activity, with a maximum of one dose per 24 hours. Duration is approximately 6 hours. Unlike sildenafil and vardenafil, avanafil absorption is not significantly affected by a high-fat meal. Pharmacokinetic meal-effect data appear in the published Stendra prescribing information.

A Phase III trial (Goldstein et al., 2012, published in Journal of Sexual Medicine, N=646) found that avanafil 100 mg and 200 mg significantly improved IIEF erectile function domain scores versus placebo (P<0.001 for both doses) and that 64.9% of men on 200 mg reported improved erections at endpoint. The trial abstract is available on PubMed. Avanafil's greater selectivity for PDE5 over PDE6 (the retinal enzyme) may reduce the visual side effects such as blue-tinged vision that occur with sildenafil, though head-to-head data comparing rates are limited. The selectivity ratios are reported in the Stendra prescribing information.

The main drawback is cost. Avanafil has no FDA-approved generic as of early 2025, keeping per-pill prices substantially higher than generic sildenafil or tadalafil.

Alprostadil (MUSE, Caverject, Edex): When Oral Drugs Fail

Alprostadil is prostaglandin E1 (PGE1), not a PDE5 inhibitor. It directly relaxes cavernosal smooth muscle and dilates penile arteries by binding EP receptors and raising intracellular cAMP, bypassing the nitric oxide pathway entirely. This makes alprostadil effective in men whose nitric oxide signaling is severely impaired, including many post-radical-prostatectomy patients.

Three delivery forms exist:

MUSE (medicated urethral system for erection) is a small pellet inserted into the urethra with a disposable applicator. Doses range from 125 mcg to 1 to 000 mcg. Onset is 5 to 10 minutes. A key trial (Padma-Nathan et al., 1997, New England Journal of Medicine, N=1,511) showed that 64.9% of MUSE administrations resulted in an erection sufficient for intercourse versus 18.6% with placebo (P<0.001). The trial is indexed on PubMed.

Caverject and Edex are injectable alprostadil formulations delivered via intracavernosal injection directly into the corpus cavernosum. Doses range from 2.5 mcg to 40 mcg. Onset is 5 to 20 minutes and duration is up to 60 to 90 minutes. A published review in Journal of Urology reported success rates of 70 to 90% with intracavernosal alprostadil across multiple studies. A representative efficacy citation is available on PubMed. The FDA-approved labeling for Caverject is archived at accessdata.fda.gov. Caverject prescribing information is at accessdata.fda.gov.

The most serious risk with injectable alprostadil is prolonged erection (priapism). The American Urological Association defines priapism as an erection lasting more than 4 hours and requiring immediate medical intervention. AUA guidelines on priapism management are available at auanet.org and referenced in PubMed-indexed publications. Men are typically trained in self-injection technique in a clinical setting before taking injections home. Penile pain at the injection site occurs in approximately 37% of men and is the leading reason for discontinuation.

Alprostadil is absolutely contraindicated in men at risk for priapism (those with sickle cell disease, multiple myeloma, or leukemia) and in men with penile anatomical deformities that would make injection unsafe.

Side Effects Across All Five Drugs

All four oral PDE5 inhibitors share a pharmacologically predictable side-effect profile because they all reduce vascular smooth muscle tone. The most common adverse events are headache (10 to 16%), flushing (10 to 12%), nasal congestion (4 to 9%), and dyspepsia (2 to 7%). These are dose-dependent and generally mild. FDA labeling data for sildenafil cite these rates in the adverse reactions section.

Sildenafil inhibits PDE6 to a greater degree than the other agents. PDE6 is expressed in retinal photoreceptors, which explains the blue-tinge visual disturbance (cyanopsia) that some sildenafil users report at doses of 100 mg. This effect is transient and resolves as the drug is eliminated. Retinal effects of PDE5 inhibitors are reviewed in a PubMed-indexed paper.

Non-arteritic anterior ischemic optic neuropathy (NAION) has been reported in temporal association with all PDE5 inhibitors. The FDA added a labeling update in 2005 after postmarketing reports. The FDA public health advisory is accessible at fda.gov. Men with a history of NAION in one eye should not use PDE5 inhibitors.

Sudden hearing loss has also been reported; a 2007 FDA safety communication recommended that patients stop the drug and call a clinician if they experience sudden hearing loss. That safety communication is accessible at fda.gov.

The absolute contraindication shared by all PDE5 inhibitors is concurrent use of organic nitrates (nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, amyl nitrite). The combination can produce severe, potentially fatal hypotension. This contraindication is documented in all four FDA prescribing labels and is consistent with AHA cardiovascular recommendations. Tadalafil requires a nitrate-free interval of at least 48 hours given its longer half-life; sildenafil and vardenafil require at least 24 hours.

Alpha-blocker co-administration carries an additive hypotension risk with all PDE5 inhibitors. Starting doses should be reduced when adding a PDE5 inhibitor to a stable alpha-blocker regimen. Drug-interaction guidance appears in published pharmacokinetic studies indexed on PubMed.

How to Choose: A Clinical Decision Framework

Choosing an ED medication is not a simple ranking exercise. The right drug depends on at least five patient-specific variables.

Frequency of sexual activity. Men who have sex fewer than twice per week often find as-needed sildenafil or avanafil sufficient and less expensive than daily tadalafil. Men who are sexually active three or more times per week may find tadalafil 5 mg daily more cost-effective and logistically simpler than carrying on-demand tablets. A 2014 systematic review published in European Urology found that both daily and on-demand tadalafil produced equivalent IIEF score improvements, giving men genuine flexibility in how they use it. That review is indexed on PubMed.

Meal timing and spontaneity. Men who prefer not to plan around meals should choose tadalafil or avanafil, both of which show no clinically significant food interaction. Sildenafil and vardenafil users who eat high-fat meals before sex may experience delayed or blunted onset.

Cardiac and medication history. Any man taking nitrates is excluded from all four oral PDE5 inhibitors and should discuss alprostadil with his provider. Men on antiarrhythmics with QTc-prolonging effects should avoid vardenafil. The 2012 Princeton Consensus (Third Princeton Consensus Conference), published in Mayo Clinic Proceedings, stratified men with cardiovascular disease into low, intermediate, and high risk and recommended that low-risk patients can safely initiate PDE5 inhibitors without further cardiac workup. The Third Princeton Consensus is indexed on PubMed.

Post-surgical ED. Men with ED after nerve-sparing radical prostatectomy have impaired nitric oxide signaling and may respond poorly to PDE5 inhibitors early in recovery. Alprostadil injection remains effective in this group because it bypasses the NO pathway. A 2012 Cochrane systematic review of penile rehabilitation after prostatectomy found that intracavernosal alprostadil produced erection rates of 60 to 70% in this population. The Cochrane review is available at cochranelibrary.com.

Cost. Generic sildenafil at GoodRx prices can cost under $0.50 per 20 mg tablet split to make a 50 mg dose (cutting a 100 mg pill). Generic tadalafil is similarly inexpensive. Brand-name Stendra 200 mg can exceed $60 per tablet without insurance. Drug pricing data are tracked by the FDA's Orange Book and by publicly available pharmacy pricing tools.

The American Urological Association 2018 guideline (updated 2021) states: "Phosphodiesterase type 5 inhibitors are recommended as a first-line therapy for men with erectile dysfunction." AUA guideline on erectile dysfunction is referenced in PubMed-indexed publications. The guideline also notes that clinicians should encourage at least four to six attempts with an adequate dose before concluding a drug is ineffective, since many men achieve better results on subsequent trials as they become comfortable with the drug's timing and their own arousal patterns.

Dosing Reference Table

| Drug | Brand | Starting Dose | Max Dose | Onset | Duration | Food Effect | |------|-------|--------------|----------|-------|----------|-------------| | Sildenafil | Viagra | 50 mg | 100 mg | 30 to 60 min | 4, 6 h | High-fat meal delays absorption | | Tadalafil | Cialis | 10 mg (PRN) / 2.5 mg (daily) | 20 mg (PRN) / 5 mg (daily) | 30 to 45 min | Up to 36 h | None | | Vardenafil | Levitra / Staxyn | 10 mg | 20 mg | 30 to 60 min | 4, 6 h | High-fat meal reduces Cmax | | Avanafil | Stendra | 100 mg | 200 mg | 15 to 30 min | ~6 h | None | | Alprostadil (urethral) | MUSE | 250 mcg | 1 to 000 mcg | 5 to 10 min | 30 to 60 min | Not applicable | | Alprostadil (injection) | Caverject / Edex | 2.5 mcg | 40 mcg | 5 to 20 min | Up to 90 min | Not applicable |

What Happens If a PDE5 Inhibitor Stops Working

Treatment failure with one PDE5 inhibitor does not mean ED is untreatable. A systematic review in Journal of Sexual Medicine (Hatzimouratidis et al., 2016) found that switching to a different PDE5 inhibitor produces a meaningful response in 50 to 70% of men who failed their first agent. A relevant review article is indexed on PubMed.

Common reasons for apparent treatment failure include: taking the drug immediately after a high-fat meal, insufficient arousal, inadequate dose (a 50 mg dose may be under-dosed in heavier men), or drug-drug interactions such as CYP3A4 inhibitors (ketoconazole, ritonavir) that raise plasma levels unexpectedly and prompt a prescriber to lower the dose below what is actually needed. CYP3A4 interaction data are referenced in the sildenafil prescribing information.

When two or more PDE5 inhibitors fail at maximum tolerated dose, the next step per AUA guidelines is intracavernosal injection therapy, followed by vacuum erection devices, and finally penile prosthesis implantation. AUA ED management algorithm is cited in PubMed-indexed guideline publications.

Testosterone deficiency co-existing with ED reduces PDE5 inhibitor response. A 2016 study in Journal of Urology (Spitzer et al., N=140) showed that correcting testosterone deficiency in hypogonadal men with ED improved sildenafil response rates. That study is indexed on PubMed. Screening total testosterone in men with ED unresponsive to PDE5 inhibitors is recommended by the AUA, the American Association of Clinical Endocrinology, and the Endocrine Society. Endocrine Society testosterone guideline is indexed on PubMed.