Sildenafil

What it is

Sildenafil citrate is a small-molecule prescription drug that blocks the enzyme phosphodiesterase type 5 (PDE5). It is sold as two different products with different doses and different approved uses: Viagra, taken by mouth as needed for erectile dysfunction, and Revatio, taken three times a day for pulmonary arterial hypertension. Viagra tablets are supplied as 25 mg, 50 mg and 100 mg strengths. The two products contain the same active substance, and the US labels warn against taking them together.

What the research says

For erectile dysfunction the evidence is strong and comes from many randomised placebo-controlled trials pooled in a systematic review: sildenafil raises the proportion of intercourse attempts that succeed. For pulmonary arterial hypertension the pivotal 12-week trial (SUPER-1) showed a roughly 45 to 50 metre improvement in six-minute walk distance but no significant difference in clinical worsening, and it was not powered for mortality. Sildenafil does nothing without sexual stimulation in the erectile indication. Taken with nitrates it can drop blood pressure sharply, which is why that combination is contraindicated.

Evidence grade: Well established.

How it works

Drug class: Phosphodiesterase type 5 (PDE5) inhibitor

During sexual stimulation nerves in the penis release nitric oxide, which raises cyclic GMP and relaxes the smooth muscle of the erectile tissue so blood can flow in. Sildenafil blocks PDE5, the enzyme that breaks cyclic GMP down, so the signal lasts longer, and it has no direct relaxant effect of its own and no effect at all without sexual stimulation. (Source 1)

What it is used for

• Pooled data from 27 randomised trials in 6,659 men found successful intercourse attempts rose from 21% on placebo to 57% on sildenafil. The FDA label records the same indication as a regulatory position dated 2017. Evidence: established. (Source 2)
• In the 278-patient SUPER-1 trial, 12 weeks of sildenafil improved six-minute walk distance by 45 to 50 metres over placebo, but the incidence of clinical worsening did not differ significantly and the study was not powered for mortality. Evidence: established. (Source 3)
• The US label approves paediatric use, but in the STARTS-1/STARTS-2 programme more children died in the higher-dose groups (22% on high dose versus 9.1% on low dose), with a hazard ratio of 3.95 for high versus low dose. The investigators and the label both say the dose-mortality relationship is uncertain. Evidence: disputed. (Source 4)
• The 216-patient RELAX randomised trial found no improvement in peak oxygen consumption, six-minute walk distance or clinical status after 24 weeks of sildenafil compared with placebo. Evidence: not-supported. (Source 5)
• A series of 38 randomised n-of-1 trials of on-demand sildenafil found a high probability that it beats placebo, but the aggregated effect was judged not clinically relevant, with large differences between individual patients. Evidence: limited. (Source 6)
• A meta-analysis of 16 randomised trials in healthy people found sildenafil lowered resting pulmonary artery systolic pressure above 4,000 metres and raised exercising oxygen saturation below 4,000 metres, with effects that varied by altitude; the review reported physiological measures, not altitude illness outcomes. Evidence: limited. (Source 7)

Interactions

• Nitrates and nitric oxide donors (nitroglycerin, isosorbide, amyl nitrite 'poppers') (clinical trial): Sildenafil amplifies the blood-pressure-lowering effect of nitrates. In a crossover study that actually gave both together, a sublingual nitrate tablet dropped systolic pressure four times as far during sildenafil as during placebo. The combination is contraindicated. (Source 8)
• Nitrates (regulatory position) (label): The US label contraindicates sildenafil in anyone using organic nitrates or nitrites in any form, regularly or intermittently, and says it is not known when nitrates can safely be given after a dose. (Source 9)
• Grapefruit juice (pharmacokinetic study): Two 250 ml servings of grapefruit juice raised total sildenafil exposure by about 23% and delayed absorption slightly in 24 healthy men. The authors judged this unlikely to endanger patients but said the combination makes blood levels less predictable. Limit: The published abstract contains a typographic error that is reproduced here unchanged: the bracket opened in "[AUC(0-infinity)" is never closed. It is a printing fault in the journal's own text and does not affect any of the numbers. (Source 10)
• Alcohol (pharmacokinetic study): In a drug interaction study, sildenafil 50 mg with alcohol at 0.5 g/kg (mean peak blood alcohol 0.08%) did not add to alcohol's blood-pressure drop. The 100 mg dose was not tested in that study. (Source 11)
• Ritonavir and other strong CYP3A4 inhibitors (ketoconazole, itraconazole, saquinavir, erythromycin) (pharmacokinetic study): These drugs block the enzyme that clears sildenafil, so blood levels rise sharply. Ritonavir raised sildenafil exposure eleven-fold. (Source 12)
• Enzyme-inducing drugs and herbs that induce CYP3A (for example bosentan; St John's wort is a known CYP3A inducer) (label): CYP3A inducers lower sildenafil blood levels, so the Revatio label says the dose may need to be raised while an inducer is used and reduced again when it stops. (Source 13)
• Vitamin K antagonist anticoagulants (for example warfarin) (clinical trial): In the pulmonary hypertension trials, nosebleeds were more frequent in people taking sildenafil together with an oral vitamin K antagonist than in those who were not. (Source 14)

Stopping it

• For erectile dysfunction sildenafil is taken only when needed rather than every day, so stopping is simply not taking the next dose; the label describes no taper. (Source 15)
• For pulmonary arterial hypertension sildenafil is continuous treatment and the manufacturer's patient leaflet, a regulatory position dated 2024, tells patients not to stop it on their own. (Source 16)

What goes wrong

The US label records an approximate 2-fold increase in the risk of NAION in a case-crossover study and states the data do not establish cause. (Source 17)

• Official position, Low certainty.
• Size: Not stated; an observational case-crossover study and a similar study.
• Who: Men using PDE5 inhibitors; background NAION incidence 2.5-11.8 per 100,000 in males aged 50 and over.
• How long: Exposure within 5 half-lives before onset.
• Result: Risk estimate 2.15 (95% CI 1.06, 4.34) in one study and 2.27 (95% CI 0.99, 5.20) in another.
• Funding: Regulatory label text (Pfizer / US FDA), effective 2017-12-15.

Limit of this finding: The label describes a second study's risk estimate of 2.27 (95% CI 0.99, 5.20) as "a consistent result", but that confidence interval includes 1, so that second study did not find a statistically significant increase. Only the first estimate, 2.15 (95% CI 1.06, 4.34), excludes 1. A reader should not read the word "consistent" as meaning two studies each independently confirmed a raised risk; it means the two point estimates were of similar size.

Based on published literature, the annual incidence of NAION is 2.5–11.8 cases per 100,000 in males aged ≥ 50. An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of "crowded" optic disc, may have contributed to the occurrence of NAION in these studies. Neither the rare post-marketing reports, nor the association of PDE5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE5 inhibitor use and NAION

In fixed-dose trials, headache, flushing, dyspepsia and abnormal vision were clearly more common on sildenafil than placebo and rose with dose. (Source 18)

• Randomized trial, Moderate certainty.
• Size: 25 mg n=312, 50 mg n=511, 100 mg n=506, placebo n=607.
• Who: Men with erectile dysfunction in phase II/III fixed-dose studies.
• How long: Pre-marketing trials; over 550 patients treated longer than one year.
• Result: Headache 16% / 21% / 28% vs 7% placebo; flushing 10% / 19% / 18% vs 2%; dyspepsia 3% / 9% / 17% vs 2%; abnormal vision 1% / 2% / 11% vs 1%. Discontinuation for adverse reactions 2.5% vs 2.3% placebo.
• Funding: Manufacturer trial data reproduced in the FDA label (Pfizer)

Headache 16% 21% 28% 7% Flushing 10% 19% 18% 2% Dyspepsia 3% 9% 17% 2% Abnormal visionAbnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light, or blurred vision. 1% 2% 11% 1% Nasal congestion 4% 4% 9% 2% Back pain 3% 4% 4% 2% Myalgia 2% 2% 4% 1% Nausea 2% 3% 3% 1% Dizziness 3% 4% 3% 2% Rash 1% 2% 3% 1%

In children treated for pulmonary arterial hypertension, mortality was higher in the higher sildenafil dose groups. (Source 4)

• Randomized trial, Low certainty.
• Size: 234 children randomised in STARTS-1; 37 deaths reported by August 2011.
• Who: Treatment-naive children aged 1 to 17 with pulmonary arterial hypertension, weighing at least 8 kg.
• How long: At least 3 years from STARTS-1 baseline.
• Result: Kaplan-Meier 3-year survival 94%, 93% and 88% for low, medium and high dose. Hazard ratio for mortality 3.95 (95% CI 1.46-10.65) high versus low dose and 1.92 (95% CI 0.65-5.65) medium versus low dose.
• Funding: Industry-funded (Pfizer authors on the paper)

Limit of this finding: This paper's own conclusion is in tension with its numbers. It says "all sildenafil dose groups displayed favorable survival", while the same abstract reports a hazard ratio for death of 3.95 (95% CI 1.46-10.65) for the high dose against the low dose, an interval that excludes 1 and so is a statistically significant difference. A reader should not take the phrase "favorable survival" as reassurance that dose did not matter. What the data show is that children on higher doses died more often; what remains genuinely uncertain, on the authors' own account, is whether the dose caused it, since the trial was not randomised to compare mortality and the authors say multiple analyses raised uncertainty about the relationship.

Kaplan-Meier estimated 3-year survival rates from start of sildenafil were 94%, 93%, and 88% for patients randomized to low-, medium-, and high-dose sildenafil, respectively; 87%, 89%, and 80% were known to be alive at 3 years. Hazard ratios for mortality were 3.95 (95% confidence interval, 1.46-10.65) for high versus low and 1.92 (95% confidence interval, 0.65-5.65) for medium versus low dose; however, multiple analyses raised uncertainty about the survival/dose relationship.

The US Revatio label records the same paediatric death imbalance by dose group and states a causal link is considered unlikely. (Source 19)

• Official position, Low certainty.
• Size: 5/55, 10/74 and 22/100 in the low, medium and high dose groups.
• Who: Children in STARTS-1 and STARTS-2.
• How long: Long-term extension.
• Result: Deaths 9.1% low dose, 13.5% medium dose, 22% high dose.
• Funding: Regulatory label text (Viatris / US FDA), effective 2024-12-18.

an imbalance in the number of deaths was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively.

Sildenafil co-administered with glyceryl trinitrate produced a four-fold greater fall in systolic blood pressure than placebo plus glyceryl trinitrate. (Source 8)

• Randomized trial, Moderate certainty.
• Size: Healthy male subjects in a double-blind placebo-controlled crossover study (number not given in the abstract)
• Who: Healthy male volunteers; a second crossover study used hypertensive men taking amlodipine.
• How long: 5-day crossover periods.
• Result: Subjects were significantly less tolerant of intravenous glyceryl trinitrate on sildenafil (p <0.01); with a sublingual 500 microg tablet a 4-fold greater decrease in systolic blood pressure was seen on sildenafil.
• Funding: Industry-funded (Pfizer drug interaction programme)

During sildenafil treatment, the subjects were significantly less tolerant of intravenously administered glyceryl trinitrate than during placebo treatment, based on the occurrence of a >25 mm Hg decrease in blood pressure or the incidence of symptomatic hypotension (p <0.01). When a sublingual glyceryl trinitrate tablet was administered on day 5, a 4-fold greater decrease in systolic blood pressure was observed for the subjects during the sildenafil treatment period than during the placebo treatment period.

In a small terminated trial in pulmonary hypertension secondary to sickle cell disease, vaso-occlusive crises needing hospital admission were more common on sildenafil. (Source 20)

• Official position, Very low certainty.
• Size: Not stated; a small, prematurely terminated study.
• Who: Patients with pulmonary hypertension secondary to sickle cell disease.
• How long: Not stated.
• Result: Vaso-occlusive crises requiring hospitalization were more commonly reported on REVATIO than placebo. The label adds that the effectiveness and safety of sildenafil in this condition has not been established.
• Funding: Regulatory label text (Viatris / US FDA), effective 2024-12-18.

In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received REVATIO than by those randomized to placebo.

In adults treated for pulmonary arterial hypertension, headache, flushing, dyspepsia and myalgia were more common on sildenafil than placebo, though headache was common in both arms. (Source 21)

• Randomized trial, Moderate certainty.
• Size: 277 REVATIO-treated adults in SUPER-1 and its open-label extension; placebo n = 70.
• Who: Adults with pulmonary arterial hypertension (WHO Group I)
• How long: 12-week placebo-controlled phase plus open-label extension.
• Result: Headache 46% / 42% / 49% at 20, 40 and 80 mg three times daily vs 39% placebo; flushing 10% / 9% / 16% vs 4%; myalgia 7% / 6% / 14% vs 4%; dyspepsia 13% / 8% / 13% vs 7%. Discontinuation 3% at 20 and 40 mg and 8% at 80 mg, vs 3% on placebo.
• Funding: Manufacturer trial data reproduced in the FDA label (Viatris), effective 2024-12-18.

Headache 46% 42% 49% 39% Flushing 10% 9% 16% 4% Pain in Limb 7% 15% 9% 6% Myalgia 7% 6% 14% 4% Back Pain 13% 13% 9% 11% Dyspepsia 13% 8% 13% 7% Diarrhea 9% 12% 10% 6%

What the evidence supports

Pooled across 14 parallel-group flexible-dose trials, sildenafil raised the share of successful intercourse attempts from 21% on placebo to 57%. (Source 2)

• Meta-analysis, Moderate certainty.
• Size: 27 trials, 6,659 men (the pooled intercourse-success estimate came from 2,283 men)
• Who: Men with erectile dysfunction of organic, psychogenic and mixed causes, including diabetic and post-prostatectomy subgroups.
• How long: Trials of at least 7 days; most up to 6 months.
• Result: Successful intercourse attempts 57% vs 21% (weighted mean difference 33.7; 95% CI 29.2-38.2). At least one intercourse success 83% vs 45% (relative benefit increase 1.8; 95% CI 1.7-1.9).
• Funding: Independent (US Department of Veterans Affairs authors); the review states it obtained data from the manufacturer.

DATA SYNTHESIS: Twenty-seven trials (6659 men) met the inclusion criteria. In results pooled from 14 parallel-group, flexible as-needed dosing trials, sildenafil was more likely than placebo to lead to successful sexual intercourse, with a higher percentage of successful intercourse attempts (57% vs 21%; weighted mean difference, 33.7; 95% confidence interval [CI], 29.2-38.2; 2283 men) and a greater percentage of men experiencing at least 1 intercourse success during treatment (83% vs 45%; relative benefit increase, 1.8; 95% CI, 1.7-1.9; 2205 men).

In the pivotal dose-escalation trial, 69% of intercourse attempts succeeded on sildenafil versus 22% on placebo. (Source 22)

• Randomized trial, Moderate certainty.
• Size: 532 men in the dose-response study and 329 in the dose-escalation study.
• Who: Men with erectile dysfunction of organic, psychogenic and mixed cause.
• How long: 24 weeks (dose-response) and 12 weeks (dose-escalation), with a 32-week open-label extension.
• Result: 69% vs 22% of attempts successful (P<0.001); mean successful attempts per month 5.9 vs 1.5 (P<0.001). Headache, flushing and dyspepsia occurred in 6 to 18 percent of men.
• Funding: Industry-funded (Pfizer Sildenafil Study Group)

In the last four weeks of treatment in the dose-escalation study, 69 percent of all attempts at sexual intercourse were successful for the men receiving sildenafil, as compared with 22 percent for those receiving placebo (P<0.001).

What the evidence does not support

Sildenafil for heart failure with preserved ejection fraction did not improve exercise capacity or clinical status. (Source 5)

• Randomized trial, Moderate certainty.
• Size: 216 patients (113 sildenafil, 103 placebo)
• Who: Stable outpatients with heart failure, ejection fraction at or above 50%, and reduced exercise capacity.
• How long: 24 weeks (20 mg three times daily for 12 weeks then 60 mg three times daily for 12 weeks)
• Result: Change in peak oxygen consumption: mean between-group difference 0.01 mL/kg/min (95% CI -0.60 to 0.61), P=.90. Clinical status rank score 95.8 placebo vs 94.2 sildenafil (P=.85). Serious adverse events 16% placebo vs 22% sildenafil.
• Funding: Independent (NIH Heart Failure Clinical Research Network); authors report numerous industry ties.

At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (-0.20 [IQR, -0.70 to 1.00]) or sildenafil (-0.20 [IQR, -1.70 to 1.11]) were not significantly different (P = .90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, -0.60 to 0.61]).

Sildenafil did not increase serious cardiovascular events or death in the pooled erectile dysfunction trials, and men on sildenafil were no more likely than placebo to drop out for an adverse event. (Source 2)

• Meta-analysis, Low certainty.
• Size: 27 trials, 6,659 men.
• Who: Men with erectile dysfunction in randomised trials of at least 7 days.
• How long: Up to 6 months.
• Result: Flushing 12%, headache 11%, dyspepsia 5%, visual disturbances 3%; all significantly more likely than placebo. No significant association with serious cardiovascular events or death. Trials excluded men with unstable cardiac disease, so this does not cover that group.
• Funding: Independent (US Department of Veterans Affairs authors)

Specific adverse events with sildenafil included flushing (12%), headache (11%), dyspepsia (5%), and visual disturbances (3%); all adverse events were significantly less likely to occur with placebo. Sildenafil was not significantly associated with serious cardiovascular events or death.

On-demand sildenafil for Raynaud phenomenon beat placebo with high probability but the pooled effect was not clinically relevant. (Source 6)

• Randomized trial, Low certainty.
• Size: 38 patients completing 2 to 5 treatment blocks in a series of randomised n-of-1 trials.
• Who: Outpatients with primary or secondary Raynaud phenomenon at a French university hospital.
• How long: Repeated blocks of three one-week periods (placebo, sildenafil 40 mg, sildenafil 80 mg)
• Result: Probability of superiority over placebo greater than 90% for all outcomes except the Raynaud Condition Score at 80 mg, but the aggregated effect size was not clinically relevant.
• Funding: Academic funding (GIRCI Auvergne Rhone-Alpes) and Pfizer.

On the basis of aggregated data, the probability that sildenafil at 40 mg or 80 mg was more effective than placebo was greater than 90% for all outcomes (except for RCS with sildenafil, 80 mg). However, the aggregated effect size was not clinically relevant.

Where the evidence is mixed

In pulmonary arterial hypertension, 12 weeks of sildenafil improved six-minute walk distance by 45 to 50 metres over placebo, but clinical worsening did not differ. (Source 3)

• Randomized trial, Moderate certainty.
• Size: 278 patients.
• Who: Adults with symptomatic pulmonary arterial hypertension, idiopathic or associated with connective-tissue disease or repaired congenital shunts.
• How long: 12 weeks randomised, with a long-term extension.
• Result: Placebo-corrected six-minute walk effects 45 m (+13.0%), 46 m (+13.3%) and 50 m (+14.7%) for 20, 40 and 80 mg three times daily (P<0.001 for all). Clinical worsening did not differ significantly. At one year on monotherapy the improvement was 51 m.
• Funding: Industry-funded (Pfizer authors among the investigators)

RESULTS: The distance walked in six minutes increased from baseline in all sildenafil groups; the mean placebo-corrected treatment effects were 45 m (+13.0 percent), 46 m (+13.3 percent), and 50 m (+14.7 percent) for 20, 40, and 80 mg of sildenafil, respectively (P<0.001 for all comparisons). All sildenafil doses reduced the mean pulmonary-artery pressure (P=0.04, P=0.01, and P<0.001, respectively), improved the WHO functional class (P=0.003, P<0.001, and P<0.001, respectively), and were associated with side effects such as flushing, dyspepsia, and diarrhea. The incidence of clinical worsening did not differ significantly between the patients treated with sildenafil and those treated with placebo.

A meta-analysis of observational studies found no overall increase in non-arteritic anterior ischaemic optic neuropathy with PDE5 inhibitors as a class, but the sildenafil subgroup estimate was raised. (Source 23)

• Meta-analysis, Very low certainty.
• Size: 5 original articles with 6 clinical observations.
• Who: Users of PDE5 inhibitors in observational studies.
• How long: Exposure windows of about 1 month.
• Result: Overall RR 1.16 (95% CI 0.98-1.39, P=.09). Sildenafil subgroup RR 2.25 (95% CI 1.29-3.94, P=.004); tadalafil RR 2.14 (95% CI 1.20-3.84, P=.01).
• Funding: Not stated in the abstract.

Limit of this finding: The source contradicts itself. The same abstract reports a sildenafil subgroup relative risk of 2.25 (95% CI 1.29-3.94, P = .004), which is a statistically significant association, and then concludes that the authors "found no association between NAION and PDE5-I use". The conclusion refers to the overall, class-wide estimate, which was not significant; it does not describe the sildenafil subgroup. A reader should not take the paper's conclusion as evidence that sildenafil specifically carries no raised risk, and should not take the subgroup figure as proof that it does: these are pooled observational studies with no control for confounding, and subgroup estimates from five studies are fragile.

RESULTS: 5 original articles with 6 clinical observations were included in the meta-analysis. No significant higher risk of NAION was observed after the use of PDE5-Is within a 1-month period (RR = 1.16, 95% CI = 0.98-1.39, P = .09). Subgroup analyses indicated 2 PDE5-Is were significantly related to NAION (tadalafil: RR = 2.14, 95% CI = 1.20-3.84, P = .01; sildenafil: RR = 2.25, 95% CI = 1.29-3.94, P = .004).

In healthy people at altitude, sildenafil lowered resting pulmonary artery systolic pressure above 4,000 metres but the effects varied with altitude and with rest versus exercise. (Source 7)

• Meta-analysis, Low certainty.
• Size: 16 randomised controlled trials.
• Who: Healthy humans exposed to high-altitude hypoxia.
• How long: Short-term treatment.
• Result: Resting heart rate rose below 4,000 m (P<0.01) with no difference above 4,000 m (P>0.05); resting cardiac output improved above 5,000 m (P<0.01); exercising arterial oxygen saturation improved below 4,000 m (P<0.01); resting pulmonary artery systolic pressure fell above 4,000 m (P<0.01). The review reports physiological measures, not altitude illness outcomes.
• Funding: Authors declare no competing interests.

Short-term treatment with Sildenafil significantly elevated resting heart rate (P<0.01) at altitudes <4,000 meters. No significant differences in heart rate were observed between the Sildenafil and placebo groups at rest and during exercise at an altitude of >4,000 meters (P>0.05). Sildenafil improved resting cardiac output at an altitude of >5,000 meters (P<0.01) and exercising arterial oxygen saturation at <4,000 meters (P<0.01). Sildenafil reduced resting pulmonary artery systolic pressure (PASP) at altitudes >4,000 meters (P<0.01)

Where the research disagrees

Whether PDE5 inhibitors cause non-arteritic anterior ischaemic optic neuropathy

• Liu and colleagues, 2018 systematic review and meta-analysis, meta-analysis of observational studies: No significant higher risk of NAION was observed after the use of PDE5-Is within a 1-month period (RR = 1.16, 95% CI = 0.98-1.39, P = .09). (Source 23)
• US FDA-approved Viagra label, effective 2017-12-15, position citing observational case-crossover studies: The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). (Source 17)

Whether higher sildenafil doses increase death in children with pulmonary arterial hypertension

• Barst and colleagues, STARTS-2 investigators, long-term extension of a randomised trial: Although children randomized to higher compared with lower sildenafil doses had an unexplained increased mortality, all sildenafil dose groups displayed favorable survival for children with pulmonary arterial hypertension. (Source 4)
• US FDA-approved Revatio label, effective 2024-12-18, position citing the same paediatric studies plus an adult dose-ranging study: a causal association for the observed dose-related effect on mortality in pediatric patients is unlikely, and therefore, the available data support dosing in pediatric patients > 45 kg up to a maximum of 40 mg three times a day. (Source 19)

How much

• Reference intake: Dosing is set by the prescriber, not by the reader. As a regulatory position, the 2017 Viagra label records a usual erectile-dysfunction dose of 50 mg taken as needed about an hour before sexual activity, with a maximum frequency of once per day. (Source 15)
• Upper limit: As a regulatory position, the 2017 Viagra label gives a maximum recommended single dose of 100 mg and a maximum frequency of once per day; a 25 mg starting dose is advised with strong CYP3A4 inhibitors, in people over 65, in cirrhosis and in severe renal impairment. (Source 15)
• Studied: The erectile dysfunction trials gave 25 mg, 50 mg and 100 mg across 21 randomised placebo-controlled trials of up to 6 months in more than 3,000 men aged 19 to 87. (Source 24)
• Studied: SUPER-1 gave 20 mg, 40 mg or 80 mg three times daily for 12 weeks to 278 adults with pulmonary arterial hypertension. (Source 3)
• Studied: The RELAX trial gave 20 mg three times daily for 12 weeks then 60 mg three times daily for a further 12 weeks to people with heart failure and preserved ejection fraction. (Source 5)

A common belief, and what the research shows

The belief: Sildenafil is an aphrodisiac that produces an erection on its own.

What the research shows: It does not. The label's own pharmacology section states that sildenafil has no direct relaxant effect on isolated human erectile tissue and that at recommended doses it does nothing without sexual stimulation: "Sildenafil has no direct relaxant effect on isolated human corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation."

Questions and answers

What is it?

Sildenafil citrate is a prescription tablet that blocks an enzyme called phosphodiesterase type 5. It is sold as Viagra for erectile dysfunction and as Revatio for pulmonary arterial hypertension, and the two contain the same active drug at different doses and schedules. Viagra tablets come in 25 mg, 50 mg and 100 mg. (Source 25)

What does it do in the body?

During sexual stimulation nerves release nitric oxide, which raises a messenger called cyclic GMP and relaxes the smooth muscle of the erectile tissue so blood flows in. Sildenafil blocks the enzyme that destroys cyclic GMP, so that signal lasts longer. It has no effect at all without sexual stimulation, and no direct relaxing effect of its own on the erectile tissue. (Source 1)

Is it good or bad for you?

It depends entirely on the setting. For erectile dysfunction, pooled randomised evidence in 6,659 men shows a large benefit: 57% of intercourse attempts succeeded on sildenafil against 21% on placebo. For pulmonary arterial hypertension it improves walking distance but did not reduce clinical worsening in the pivotal trial. For heart failure with preserved ejection fraction it did nothing. And in anyone taking nitrates it is dangerous enough to be contraindicated. (Source 2)

How do you get more of it?

Sildenafil is a manufactured prescription medicine, not a nutrient, so the only way to obtain it is a prescription. There is no food or supplement that contains it. Its blood level can be pushed up by other drugs: ritonavir raised sildenafil exposure eleven-fold, and grapefruit juice raised it about 23%. Nothing here is advice about dosing, which is set by the prescriber. (Source 12)

If it is harmful, what reduces it?

Sildenafil is cleared from the body on its own; plasma levels 24 hours after a 100 mg dose are about 2 ng/mL against a peak near 440 ng/mL, though people over 65, those with cirrhosis or severe kidney impairment and those on CYP3A4 inhibitors clear it more slowly. If an erection lasts longer than 4 hours the label tells patients to seek immediate medical help, because untreated priapism can cause permanent damage. Enzyme-inducing drugs lower sildenafil levels. (Source 13)

Why might someone be low in it or missing it?

This question does not apply in the usual sense: sildenafil is not something the body makes or stores, so nobody is deficient in it. What the literature addresses instead is why someone may not be able to take it. The label contraindicates it with nitrates or riociguat and after hypersensitivity, and advises a lower starting dose in older people, cirrhosis, severe kidney impairment and with strong CYP3A4 inhibitors. (Source 9)

Which whole foods contain it or feed it?

No whole food contains sildenafil. The only food the label and the literature tie to it are grapefruit juice, which raises exposure by about 23% in a crossover study of 24 men, and alcohol, which in a 50 mg study did not add to the blood-pressure drop. Taking the drug with or without food is allowed by the label. (Source 26)

What happens if you do not have it?

Not taking sildenafil simply means the underlying condition is untreated by this drug. In erectile dysfunction the placebo arms of the pooled trials show what happens without it: 21% of intercourse attempts succeeded, against 57% on the drug, and 45% of men had at least one success, against 83%. In pulmonary arterial hypertension the untreated comparison is the placebo arm of SUPER-1, which walked 45 to 50 metres less at 12 weeks. (Source 2)

How can you test for it?

There is no routine blood test for sildenafil in ordinary care, and none is needed because the drug is taken for a symptom rather than to correct a measured level. The trials measured the condition instead. In pulmonary arterial hypertension the validated outcome was the distance walked in six minutes, together with pulmonary artery pressure and WHO functional class. In the erectile dysfunction trials the measure was whether intercourse attempts succeeded, recorded in patient diaries. (Source 3)

References

1. Pfizer Laboratories Div Pfizer Inc / DailyMed (U.S. FDA Structured Product Label, effective 2017-12-15). VIAGRA (sildenafil citrate) - 12.1 Mechanism of Action (Full Prescribing Information). 2017. Read the source
2. Archives of Internal Medicine. Sildenafil for male erectile dysfunction: a systematic review and meta-analysis.. 2002. PMID 12076233, DOI 10.1001/archinte.162.12.1349. Read the source
3. New England Journal of Medicine. Sildenafil citrate therapy for pulmonary arterial hypertension.. 2005. PMID 16291984, DOI 10.1056/NEJMoa050010. Read the source
4. Circulation. STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension.. 2014. PMID 24637559, DOI 10.1161/CIRCULATIONAHA.113.005698. Read the source
5. JAMA. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial (RELAX).. 2013. PMID 23478662, DOI 10.1001/jama.2013.2024. Read the source
6. Annals of Internal Medicine. On-Demand Sildenafil as a Treatment for Raynaud Phenomenon: A Series of n-of-1 Trials. [RESULTS]. 2018. PMID 30383134, DOI 10.7326/M18-0517. Read the source
7. Experimental and Therapeutic Medicine. Efficacy of Sildenafil on healthy humans in high-altitude hypoxia at rest and during exercise: A meta-analysis.. 2024. PMID 38274336, DOI 10.3892/etm.2024.12376. Read the source
8. American Journal of Cardiology. Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist.. 1999. PMID 10078539, DOI 10.1016/s0002-9149(99)00044-2. Read the source
9. Pfizer Laboratories Div Pfizer Inc / DailyMed (U.S. FDA Structured Product Label, effective 2017-12-15). VIAGRA (sildenafil citrate) - 4.1 Nitrates (Contraindications, Full Prescribing Information). 2017. Read the source
10. Clinical Pharmacology and Therapeutics. Effects of grapefruit juice on the pharmacokinetics of sildenafil. [RESULTS]. 2002. PMID 11823754, DOI 10.1067/mcp.2002.121236. Read the source
11. Pfizer Laboratories Div Pfizer Inc / DailyMed (U.S. FDA Structured Product Label, effective 2017-12-15). VIAGRA (sildenafil citrate) - 12.2 Pharmacodynamics, Effect of VIAGRA on Blood Pressure When Co-administered with Alcohol. 2017. Read the source
12. Pfizer Laboratories Div Pfizer Inc / DailyMed (U.S. FDA Structured Product Label, effective 2017-12-15). VIAGRA (sildenafil citrate) - 7.4 Ritonavir and other CYP3A4 inhibitors (Drug Interactions, Full Prescribing Information). 2017. Read the source
13. Viatris Specialty LLC / DailyMed (U.S. FDA Structured Product Label, effective 2024-12-18). REVATIO (sildenafil citrate) - 7 DRUG INTERACTIONS (Full Prescribing Information). 2024. Read the source
14. Viatris Specialty LLC / DailyMed (U.S. FDA Structured Product Label, effective 2024-12-18). REVATIO (sildenafil citrate) - 5.3 Epistaxis (Warnings and Precautions, Full Prescribing Information). 2024. Read the source
15. Pfizer Laboratories Div Pfizer Inc / DailyMed (U.S. FDA Structured Product Label, effective 2017-12-15). VIAGRA (sildenafil citrate) tablet, film coated - 2.1 Dosage Information (Full Prescribing Information). 2017. Read the source
16. Viatris Specialty LLC / DailyMed (U.S. FDA Structured Product Label, effective 2024-12-18). REVATIO (sildenafil citrate) - PATIENT INFORMATION, How should I take REVATIO?. 2024. Read the source
17. Pfizer Laboratories Div Pfizer Inc / DailyMed (U.S. FDA Structured Product Label, effective 2017-12-15). VIAGRA (sildenafil citrate) - 5.3 Effects on the Eye (Warnings and Precautions, Full Prescribing Information). 2017. Read the source
18. Pfizer Laboratories Div Pfizer Inc / DailyMed (U.S. FDA Structured Product Label, effective 2017-12-15). VIAGRA (sildenafil citrate) - 6.1 Clinical Trials Experience, Table 1 fixed-dose adverse reactions (Full Prescribing Information). 2017. Read the source
19. Viatris Specialty LLC / DailyMed (U.S. FDA Structured Product Label, effective 2024-12-18). REVATIO (sildenafil citrate) - 8.4 Pediatric Use (Full Prescribing Information). 2024. Read the source
20. Viatris Specialty LLC / DailyMed (U.S. FDA Structured Product Label, effective 2024-12-18). REVATIO (sildenafil citrate) - 5.8 Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Disease (Warnings and Precautions). 2024. Read the source
21. Viatris Specialty LLC / DailyMed (U.S. FDA Structured Product Label, effective 2024-12-18). REVATIO (sildenafil citrate) - 6.1 Clinical Trials Experience, SUPER-1 adverse reaction table (Full Prescribing Information). 2024. Read the source
22. New England Journal of Medicine. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. [RESULTS]. 1998. PMID 9580646, DOI 10.1056/NEJM199805143382001. Read the source
23. Sexual Medicine. The Association Between Phosphodiesterase Type 5 Inhibitor Use and Risk of Non-Arteritic Anterior Ischemic Optic Neuropathy: A Systematic Review and Meta-Analysis. [RESULTS]. 2018. PMID 29884471, DOI 10.1016/j.esxm.2018.03.001. Read the source
24. Pfizer Laboratories Div Pfizer Inc / DailyMed (U.S. FDA Structured Product Label, effective 2017-12-15). VIAGRA (sildenafil citrate) - 14 CLINICAL STUDIES (Full Prescribing Information). 2017. Read the source
25. Pfizer Laboratories Div Pfizer Inc / DailyMed (U.S. FDA Structured Product Label, effective 2017-12-15). VIAGRA (sildenafil citrate) tablet, film coated - 3 DOSAGE FORMS AND STRENGTHS (Full Prescribing Information). 2017. Read the source
26. Clinical Pharmacology and Therapeutics. Effects of grapefruit juice on the pharmacokinetics of sildenafil. [METHODS]. 2002. PMID 11823754, DOI 10.1067/mcp.2002.121236. Read the source