Sildenafil (Generic) Rare but Serious Side Effects: Adverse Events Clinicians and Patients Must Know

At a glance

• Drug / sildenafil citrate, a prescription PDE5 inhibitor for ED (Viagra) and PAH (Revatio) [2][3]
• Boxed warning / none on the Viagra or Revatio label [1][4]
• Vision / NAION reported rarely; label says stop sildenafil and seek care for sudden vision loss [1]
• Erection / label says seek immediate help for an erection lasting over 4 hours [1]
• Hearing / sudden hearing loss reported after marketing, sometimes with tinnitus and dizziness [1]
• Nitrates / any organic nitrate or organic nitrite is contraindicated [1]
• Alpha-blockers / additive hypotension; label says be stable on the alpha-blocker and start sildenafil at 25 mg [1]
• Other PDE5 inhibitors / label says not to combine Viagra with Revatio or other PDE5 inhibitors [1]

What serious side effects does sildenafil have?

Sildenafil's serious label warnings fall into four groups: sudden vision loss from NAION, priapism, sudden hearing loss, and blood-pressure effects with nitrates, alpha-blockers or antihypertensives [1]. The label also warns that sexual activity itself can be risky in men with heart disease and that sildenafil should not be combined with other PDE5 inhibitors or other ED treatments [1].

Does sildenafil have a boxed warning?

No. Neither the Viagra label nor the Revatio label has a boxed warning [1][4]. The Viagra label's contraindications are any nitric oxide donor, such as organic nitrates or organic nitrites in any form, riociguat, and known hypersensitivity to sildenafil or tablet components [1]. Revatio's contraindications are organic nitrates, riociguat, and hypersensitivity [4].

Sudden vision loss (NAION)

NAION is a rare cause of decreased vision, including permanent loss, that has been reported postmarketing in temporal association with all PDE5 inhibitors [1]. The Viagra label cites published literature that the annual incidence of NAION is 2.5 to 11.8 cases per 100,000 in males aged 50 and older, and describes observational data in PDE5 inhibitor users separately [1]. Two observational case-crossover studies suggested about a 2-fold increase in risk, with risk estimates of 2.15 (95% CI 1.06 to 4.34) and 2.27 (95% CI 0.99 to 5.20); the label says this does not substantiate a causal relationship [1].

People who have had NAION are at increased risk of another episode, and the Viagra label says sildenafil should be used with caution in these patients and only when the anticipated benefits outweigh the risks [1]. A crowded optic disc may also raise NAION risk [1]. The label says to stop sildenafil and seek medical care for sudden loss of vision in one or both eyes [1].

Priapism

The label says an erection lasting more than 4 hours needs immediate medical help, and a painful erection lasting more than 6 hours is priapism [1]. Untreated priapism can cause penile tissue damage and permanent loss of potency [1]. The label says prolonged erection and priapism have been reported infrequently since market approval [1].

The label says to use sildenafil with caution in men with anatomical penile deformation such as Peyronie's disease, and in men with sickle cell anemia, multiple myeloma or leukemia, conditions that may predispose to priapism [1]. The label also says there are no controlled data on sildenafil in sickle cell or related anemias [1].

Sudden hearing loss

Sudden decrease or loss of hearing, sometimes with tinnitus and dizziness, has been reported in temporal association with PDE5 inhibitors including sildenafil [1]. The label says it is not possible to determine whether these events are related directly to sildenafil, to underlying risk factors, or to other factors [1]. It advises stopping sildenafil and seeking prompt medical attention for sudden decrease or loss of hearing [1].

Blood pressure, nitrates and alpha-blockers

Any organic nitrate or organic nitrite in any form is contraindicated with sildenafil, whether used regularly or intermittently, because sildenafil potentiates the hypotensive effect of nitrates [1]. After sildenafil has been taken, the label says it is unknown when nitrates can safely be given; plasma levels at 24 hours are much lower than at peak, but the label says it is unknown whether nitrates are safe at that time, and it gives no safe waiting time [1].

In healthy volunteers, single sildenafil doses of 100 mg lowered supine blood pressure by a mean maximum of about 8.4/5.5 mm Hg, with similar effects at 25, 50 and 100 mg [1]. In hypertensive patients, sildenafil 100 mg with amlodipine 5 or 10 mg gave an additional mean supine blood pressure fall of 8/7 mm Hg [1]. The label says patients should be stable on the alpha-blocker before starting sildenafil, and sildenafil should start at 25 mg [1]. In a doxazosin study, sildenafil 25 mg gave a placebo-subtracted maximum standing systolic fall of 6.0 mm Hg (supine 7.4 mm Hg); one of four men given 100 mg had severe postural hypotension [1].

Heart and circulation

The label warns that sexual activity carries cardiac risk in men with preexisting cardiovascular disease, and ED drugs including sildenafil should not generally be used when sexual activity is inadvisable for cardiovascular reasons [1]. There are no controlled data on sildenafil in patients who have had a myocardial infarction, stroke or life-threatening arrhythmia within the last 6 months, or who have resting blood pressure below 90/50 or above 170/110, cardiac failure, or unstable angina [1]. The label says to use caution in left ventricular outflow obstruction, such as aortic stenosis, and in severely impaired autonomic control of blood pressure [1].

Serious cardiovascular and cerebrovascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack and pulmonary hemorrhage, have been reported postmarketing in temporal association with sildenafil [1]. Most, but not all, of these patients had preexisting cardiovascular risk factors, and the label says it is not possible to determine whether the events are related to sildenafil, sexual activity, underlying disease, or a combination [1].

If sildenafil is used for PAH (Revatio)

Revatio is a separate sildenafil product, at different doses, for pulmonary arterial hypertension [3]. Its label says sildenafil is not recommended in pulmonary veno-occlusive disease because pulmonary vasodilators may worsen cardiovascular status, and pulmonary edema should prompt consideration of PVOD [4]. In pulmonary hypertension secondary to sickle cell disease, a small, prematurely terminated study found more vaso-occlusive crises requiring hospitalization with Revatio than with placebo [4]. Epistaxis occurred in 13% of patients with PAH secondary to connective tissue disease [4].

In pediatric trials STARTS-1 and STARTS-2, deaths were 5/55, 10/74 and 22/100 in the low, medium and high dose groups; the causes were related to PAH progression, and the label judges a causal association unlikely [4]. The label caps dosing in children over 45 kg at 40 mg three times a day [4].

Other serious label warnings

Bleeding events have been reported with sildenafil, but a causal link has not been established, and safety is unknown in patients with bleeding disorders or active peptic ulcer [1]. Sildenafil offers no protection from sexually transmitted infections [1]. The label says not to combine Viagra with Revatio or other PDE5 inhibitors or other ED treatments; the combinations have not been studied and may further lower blood pressure [1].

Frequently asked questions

›What is the most important sildenafil safety warning?

Any nitrate or organic nitrite is contraindicated because sildenafil potentiates hypotension [1]. Rare serious events include NAION, priapism and sudden hearing loss [1].

›Does sildenafil have a black box warning?

No. Neither the Viagra label nor the Revatio label has a boxed warning [1][4].

›Can sildenafil cause permanent vision loss?

NAION, a cause of decreased vision including permanent loss, has been reported rarely with PDE5 inhibitors including sildenafil [1]. The label says to stop sildenafil and seek medical care for sudden vision loss in one or both eyes [1]. People who have had NAION are at increased risk of another episode, and a crowded optic disc may also raise risk [1].

›How long can an erection last before it is an emergency?

The label says to seek immediate medical help for an erection lasting longer than 4 hours. A painful erection lasting longer than 6 hours is priapism, and untreated priapism can cause penile tissue damage and permanent loss of potency [1].

›Can I take a nitrate after sildenafil?

The Viagra label contraindicates any organic nitrate or organic nitrite in any form and says it is unknown when nitrates can safely be given after sildenafil, so it gives no safe waiting time [1].

›Does sildenafil cause hearing loss?

Sudden decrease or loss of hearing, sometimes with tinnitus and dizziness, has been reported in temporal association with PDE5 inhibitors including sildenafil [1]. The Viagra label says to stop sildenafil and seek prompt medical attention for sudden decrease or loss of hearing [1].

References

1. U.S. National Library of Medicine, DailyMed. Viagra (sildenafil citrate) tablets, Viatris prescribing information. Viagra (sildenafil citrate) tablets, Viatris label
2. Drugs@FDA: FDA-Approved Drugs. Drugs@FDA: FDA-Approved Drugs
3. Drugs@FDA: FDA-Approved Drugs. Drugs@FDA: FDA-Approved Drugs
4. U.S. National Library of Medicine, DailyMed. Revatio (sildenafil) tablets, injection and oral suspension, Viatris (sildenafil citrate) prescribing information. Revatio (sildenafil) tablets, injection and oral suspension, Viatris (sildenafil citrate) label