Viagra Side Effects: Rare but Serious Adverse Events Explained

Common side effects versus the rare ones

In the label's fixed-dose trials of 25, 50 and 100 mg against placebo, headache ran 16%, 21% and 28% versus 7%; flushing 10%, 19% and 18% versus 2%; dyspepsia 3%, 9% and 17% versus 2%; abnormal vision 1%, 2% and 11% versus 1%; and nasal congestion 4%, 4% and 9% versus 2% [1]. In placebo-controlled studies, 2.5% of men taking Viagra discontinued because of adverse reactions, compared with 2.3% taking placebo [1]. More than 3,700 patients received Viagra in premarketing trials [1].

The events below include uncommon conditions and serious events reported after approval. The label says the frequency of voluntary post-approval reports cannot be reliably estimated [1].

Vision loss: NAION

Sildenafil is about 10-fold more potent against PDE5 than against PDE6 in the retina, and that lower selectivity is thought to explain the transient color-tinged vision listed among the common side effects [1]. NAION is a separate, rare condition and a cause of decreased vision including permanent loss, reported post-marketing in temporal association with all PDE5 inhibitors [1].

The label gives context. Based on published literature, it puts the annual incidence of NAION at 2.5 to 11.8 cases per 100,000 men aged 50 and over [1]. An observational case-crossover study comparing PDE5 inhibitor use in the period immediately before NAION onset with use in an earlier period suggested an approximate 2-fold increase in risk, with a risk estimate of 2.15 (95% CI 1.06 to 4.34); a similar study reported 2.27 (95% CI 0.99 to 5.20) [1]. The label's conclusion is that neither those post-marketing reports nor the observational associations substantiate a causal relationship [1].

The label says patients should stop all PDE5 inhibitors, including Viagra, and seek medical attention if vision is suddenly lost in one or both eyes [1]. People who have already had NAION in one eye are at increased risk of recurrence, and the label says PDE5 inhibitors should be used with caution in them and only when anticipated benefits outweigh risks [1]. A "crowded" optic disc is also considered a risk factor, but the label says the evidence is insufficient to support screening prospective users for it [1]. The label states there are no controlled clinical data on Viagra in men with retinitis pigmentosa [1].

Priapism and prolonged erection

Prolonged erections longer than 4 hours, and priapism (painful erections more than 6 hours in duration) have been reported infrequently since Viagra came to market [1]. In the event of an erection persisting longer than 4 hours, the label says the patient should seek immediate medical assistance, because untreated priapism can cause penile tissue damage and permanent loss of potency [1]. The label advises caution in men with anatomical deformation of the penis (angulation, cavernosal fibrosis, Peyronie's disease) or conditions that may predispose to priapism (sickle cell anemia, multiple myeloma, leukemia), and notes that there are no controlled data on safety or efficacy in sickle cell or related anemias [1].

Sudden hearing loss

Sudden decrease or loss of hearing, sometimes accompanied by tinnitus and dizziness, has been reported in temporal association with PDE5 inhibitors including Viagra, and the label says it is not possible to determine whether these events relate directly to the drug or to other factors [1]. The label says to stop taking PDE5 inhibitors and seek prompt medical attention for sudden decrease or loss of hearing [1].

Nitrates and nitrites: the absolute contraindication

The label lists as a contraindication the use of nitric oxide donors such as organic nitrates or organic nitrites in any form, regularly or intermittently, because sildenafil potentiates the hypotensive effect of nitrates [1]. The guanylate cyclase stimulator riociguat is contraindicated because PDE5 inhibitors may potentiate its hypotensive effect [1].

The label says it is unknown when nitrates, if needed, can be safely given after a patient has taken Viagra [1]. Plasma sildenafil 24 hours after a 100 mg dose is around 2 ng/mL against a peak of about 440 ng/mL, but levels at that time point are 3 to 8 times higher in men over 65, in men with liver or severe kidney impairment, and in men taking erythromycin or strong CYP3A4 inhibitors, and the label says it is unknown whether nitrates can be safely given at 24 hours [1]. The label gives no waiting time.

Blood pressure with alpha-blockers

A single 100 mg dose lowered supine blood pressure in healthy volunteers by a mean maximum of about 8.4/5.5 mmHg, not dose-related between 25 and 100 mg [1]. The label says the effect of alpha-blockers and Viagra on blood pressure is additive and that symptomatic hypotension can occur. In a doxazosin study, Viagra 25 mg produced a placebo-subtracted maximum standing systolic reduction of 6.0 mmHg (supine 7.4), and one of the four men given 100 mg had severe postural hypotension [1]. The label says patients should be stable on the alpha-blocker before Viagra is started, that Viagra should then start at 25 mg, and that combining Viagra with other PDE5 inhibitors or other ED treatments has not been studied and may further lower blood pressure [1].

Heart risk from sexual activity

The label warns that sexual activity can pose a cardiac risk for men with underlying heart disease, so treatments for erectile dysfunction, including Viagra, should not generally be used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status [1]. The label states there are no controlled clinical data on Viagra's safety or efficacy in men who have had a myocardial infarction, stroke or life-threatening arrhythmia within the previous 6 months, who have resting blood pressure below 90/50 or above 170/110, cardiac failure, or coronary disease causing unstable angina [1]. Caution is advised in left ventricular outflow obstruction such as aortic stenosis, and in severely impaired autonomic control of blood pressure [1].

Other events reported after approval

Serious cardiovascular, cerebrovascular and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage, have been reported post-marketing in temporal association with Viagra; most, but not all, of the patients had pre-existing cardiovascular risk factors, many events occurred during or shortly after sexual activity, and the label notes that voluntary reports of this kind cannot establish a causal relationship to the drug [1]. Hypersensitivity reactions including rash and urticaria are reported, and known hypersensitivity to sildenafil or any tablet component is a contraindication [1]. Bleeding events have been reported with no established causal link, and safety is unknown in bleeding disorders and active peptic ulcer [1].