What is the safest ED medicine? What the labels say by health condition

Status: FDA-approved prescription medicine for ED (sildenafil, tadalafil, vardenafil and avanafil). Source: FDA-approved prescribing information on DailyMed, checked 2026-10-17.

In short: men often ask which ED pill is the safest one, hoping for a single name. The honest answer from the FDA labels is that no pill wins for everyone. All four approved pills belong to one drug class, the PDE5 inhibitors, and they carry the same core warnings. Where they differ is in the details: how each label handles kidney disease, liver disease, older age and a few specific medicines and heart conditions. Those details are exactly what a prescriber weighs. This page lays them out side by side, so you know what the conversation will cover. Evidence level: approved drugs used for their labeled purpose, with safety drawn from each drug’s FDA label, an expert consensus on heart risk and a large network meta-analysis.

Is any ED medicine the safest?

No FDA label ranks one ED pill as safer than the others, and none of them is safest for every man. Sildenafil (Viagra), tadalafil (Cialis), vardenafil (the drug in Levitra) and avanafil (Stendra) all carry the same core contraindications and warnings, set out in sections 4 and 5 of each label (Viagra, Cialis, vardenafil and Stendra prescribing information). Our guide to how ED medications work explains why: they act on the same enzyme, so they share the same blood-vessel effects.

The closest thing to a head-to-head safety answer comes from a network meta-analysis that pooled 72 trials and more than 20,000 men for side effects. At the starting doses it compared, tadalafil had the lowest overall rate of side effects, and sildenafil had the highest rate but also the greatest effect on erections (Chen et al., Eur Urol 2015). That is a trade-off between tolerability and effect, not a safety ranking, and it says nothing about which pill fits a man with a particular heart, kidney or liver condition.

Is there an ED medicine without side effects?

No. Every approved ED pill lists side effects, most often headache, flushing, indigestion and a stuffy nose, with back pain and muscle aches also on the most-common lists of the Cialis and Viagra labels (Cialis and Viagra prescribing information). A search for the “best medicine for erectile dysfunction without side effects” is really a search for the drug whose likely side effects bother you least, which a prescriber can help with. Our overview of ED medication side effects separates the common ones from the rare emergencies, and the tadalafil side effects page compares tadalafil with sildenafil.

Who should not take PDE5 inhibitors?

Men who use nitrates in any form, men who take riociguat (and, for avanafil, vericiguat), men allergic to the drug, and men for whom sexual activity is inadvisable because of their heart should not take these pills. Nitrates and riociguat are formal contraindications in section 4 of every label; a known allergy is one on the Viagra, Cialis and Stendra labels (the vardenafil label checked for this page lists only the first two); the heart rule opens section 5 (Viagra, Cialis, vardenafil, Stendra).

The Viagra label’s nitrate contraindication covers “organic nitrites in any form,” taken regularly or now and then. That wording includes the recreational inhalants called poppers. Switching to a different ED pill does not get around the nitrate, riociguat or heart rules, because all four labels share them. Our page on sildenafil drug interactions covers the medicines that need a check rather than a hard stop.

What do the labels say for men with heart disease?

Each label says ED pills should not be used by men whose heart condition makes sexual activity inadvisable, and each lists recent or unstable heart conditions that were left out of its trials. The labels differ in wording: the Viagra label says use in those groups, if prescribed, should be “with caution,” while the Cialis, vardenafil and Stendra labels say use is not recommended until more information is available.

Sources: section 5.1 of the Viagra, Cialis, vardenafil and Stendra labels. All four also note that men with a narrowed heart valve outflow, such as aortic stenosis, can be sensitive to these drugs.

Cardiologists and urologists have a shared framework for this question. The Princeton III consensus sorts men with heart disease into low, indeterminate and high risk. It says most low-risk men can begin ED treatment without further testing, indeterminate-risk men need further evaluation such as an exercise test first, and high-risk men should defer sexual activity until the heart condition is stabilized and be referred to a cardiologist (Nehra et al., Mayo Clin Proc 2012). The same panel noted that later reviews of trial and post-marketing data showed no new concerns about heart events with these pills. Our guide to ED and heart disease explains why ED itself can be an early signal worth a heart check.

What about blood pressure medicines and alpha-blockers?

All four labels advise caution when an ED pill is combined with alpha-blockers or other blood pressure medicines, because the effects on blood pressure can add up and cause dizziness or fainting. For men on alpha-blockers, often prescribed for an enlarged prostate, the labels say the man should be stable on the alpha-blocker before an ED pill is started, and the ED pill started at the lowest dose (Viagra 5.5, Cialis 5.6). The Cialis and Stendra labels add that drinking substantial amounts of alcohol with the pill can lower standing blood pressure too. None of this means stopping a blood pressure medicine; it means the prescriber needs the full list.

What do the labels say for kidney disease?

The labels handle kidney disease differently, which is one reason the right pill can depend on kidney function. Mild kidney disease needs no change on any label, but severe disease and dialysis split them.

Sources: sections 2, 5 and 8 of the Viagra, Cialis, vardenafil and Stendra labels. This table reports what the labels say about groups; it does not suggest a dose. Setting one is the prescriber’s job.

What do the labels say for liver disease?

The liver breaks these drugs down, so liver disease raises blood levels of some of them, and every label except one draws a line at severe liver disease.

Sources: section 8 of the Viagra, Cialis, vardenafil and Stendra labels. Diabetes, high blood pressure and other long-term conditions bring their own checks; our page on chronic conditions and ED covers how they overlap with erections.

Are ED medicines safe for older men?

The labels do not bar older men, and trials found no overall difference in safety between men over and under 65, but the Viagra and vardenafil labels report clearly higher blood levels with age. Healthy men 65 and older had about 84% higher sildenafil exposure than young men, and the Viagra label says to consider a lower starting dose for that reason. The vardenafil label reports about 52% higher exposure in men 65 and older and makes the same suggestion.

The Cialis label reports about 25% higher exposure in healthy men 65 and older and the Stendra label little change; both say no dose change is needed on age alone, while asking prescribers to consider greater sensitivity to medicines in some older men. The Cialis label also notes that diarrhea was reported more often in men 65 and older in its as-needed trials (Viagra 8.5, Cialis 8.5, vardenafil 8.5, Stendra 8.5).

Which other conditions and medicines change the choice?

Several less common conditions and medicines call for caution on all four labels, and a few apply to one drug only. These are the details that can make one pill a better fit than another for a particular man.

• Conditions linked to prolonged erections, and penile shape conditions. Sickle cell anemia, multiple myeloma and leukemia, and penile shape conditions such as Peyronie’s disease, call for caution on every label.
• Past optic nerve stroke (NAION) or retinitis pigmentosa. Men who have had NAION face a higher risk of it recurring, so the labels advise use only when the expected benefit outweighs the risk. The Cialis, vardenafil and Stendra labels say use is not recommended in hereditary retinal disorders such as retinitis pigmentosa; the Viagra label says use with caution.
• Bleeding disorders or an active stomach ulcer. Safety in these groups is not established on any label.
• Heart rhythm (QT) conditions. The vardenafil label says men with congenital QT prolongation or taking certain rhythm medicines (Class 1A or Class III antiarrhythmics) should avoid it. The other three labels do not carry this warning.
• Strong CYP3A4 inhibitors, such as ritonavir or ketoconazole. These raise blood levels of the ED drug. The Stendra label says not to use avanafil with strong inhibitors; the others call for dose limits.
• Phenylketonuria. The vardenafil label checked for this page notes its tablets contain phenylalanine.

Sources: sections 5 and 7 of the four labels linked above. Combining two ED medicines, or an ED pill with another ED treatment, has not been studied, and every label advises against it.

Why is the choice a prescriber’s?

Because the safe choice depends on facts a label cannot know: your heart, your kidneys and liver, your other medicines and your goals. The American Urological Association guideline says men with ED should have a thorough medical, sexual and psychosocial history, a physical exam and selective lab tests, and should be counseled that ED is a risk marker for heart disease (AUA Erectile Dysfunction Guideline, 2018).

The same guideline calls shared decision-making the cornerstone of ED care: the man and the clinician choose together after discussing benefits and risks, and men should be told about the option of an FDA-approved oral PDE5 inhibitor unless it is contraindicated. The Princeton III panel adds that exercise tolerance should be established before ED treatment begins in all men, whatever their heart risk (Nehra et al., 2012). Bring a complete medicine list, including anything taken only occasionally, and say plainly if you have chest pain with exertion. Our guide on when to see a doctor about ED covers what that first visit looks for.

When should you talk to a clinician?

Talk to a clinician before starting any ED medicine, and again if one causes side effects that bother you or stops working. NIDDK, part of the National Institutes of Health, says to call your health care professional right away for an erection lasting longer than 4 hours or for vision or hearing loss after taking an oral ED medicine, and to talk with a professional before using dietary supplements for ED (NIDDK: Treatment for Erectile Dysfunction). If you have heart disease, kidney or liver disease, or take a nitrate, an alpha-blocker or an HIV medicine, mention it at the start of the visit.

Sources

1. Viagra (sildenafil citrate) prescribing information, Pfizer, DailyMed
2. Cialis (tadalafil) prescribing information, Eli Lilly and Company, DailyMed
3. Vardenafil hydrochloride tablets prescribing information, Lannett Company, DailyMed
4. Stendra (avanafil) prescribing information, Metuchen Pharmaceuticals, DailyMed
5. Nehra A, et al. The Princeton III Consensus recommendations for the management of erectile dysfunction and cardiovascular disease. Mayo Clin Proc. 2012
6. Burnett AL, et al. Erectile dysfunction: AUA guideline. American Urological Association, 2018
7. Chen L, et al. Phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: a trade-off network meta-analysis. Eur Urol. 2015
8. NIDDK: Treatment for Erectile Dysfunction. National Institutes of Health, last reviewed October 2024