Viagra Side Effects: Incidence Rates Across Clinical Trials

What the label reports, dose by dose

The Viagra label tabulates adverse reactions from fixed-dose phase II/III studies at 25, 50 and 100 mg against placebo, in 312, 511, 506 and 607 men respectively [1]. Headache led: 16% at 25 mg, 21% at 50 mg and 28% at 100 mg, against 7% on placebo. Flushing was 10%, 19% and 18% against 2%. Dyspepsia was 3%, 9% and 17% against 2%. Abnormal vision was 1%, 2% and 11% against 1% [1].

The label describes abnormal vision as mild to moderate and transient, predominantly a color tinge, but also increased sensitivity to light or blurred vision [1]. The rest of the table, in the same order (25 mg, 50 mg, 100 mg, placebo): 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% [1].

The label says the incidence of some adverse reactions increased with dose; flushing, for example, was slightly lower at 100 mg than at 50 mg. At doses above the recommended range, reactions were similar in type but generally reported more frequently [1].

A review attributes side effects such as headache, flushing, indigestion and nasal congestion to the presence of PDE5 in other tissues such as vascular smooth muscle, and describes them as dose-dependent and well tolerated [2].

Flexible-dose trials: closer to how Viagra is prescribed

The as-needed trials used flexible dosing, which the label says reflects the recommended regimen. In those studies 734 men took Viagra and 725 took placebo: headache 16% versus 4%, flushing 10% versus 1%, dyspepsia 7% versus 2%, nasal congestion 4% versus 2%, abnormal vision 3% versus 0% (one patient discontinued because of it), back pain 2% versus 2%, dizziness 2% versus 1%, and rash 2% versus 1% [1]. The label notes that the type of reactions was similar to the fixed-dose studies [1].

In the placebo-controlled studies, the discontinuation rate due to adverse reactions was 2.5% on Viagra versus 2.3% on placebo, which the label describes as not significantly different [1].

The 1998 New England Journal of Medicine trial

The pivotal paper (Goldstein and colleagues, 1998) reported two sequential double-blind studies [3]. The first was a 24-week dose-response study of 532 men given 25, 50 or 100 mg or placebo. The second was a separate 12-week flexible dose-escalation study of 329 different men, escalating to 100 mg based on efficacy and tolerance [3]. In the escalation study, 69% of intercourse attempts were successful on sildenafil versus 22% on placebo [3]. Headache, flushing and dyspepsia were the most common side effects, at 6% to 18% [3].

A separate report on a 12-week study of 329 patients (166 placebo, 163 sildenafil 50 mg with adjustment to 100 mg or 25 mg according to response) found headache, flushing and dyspepsia generally mild to moderate and rarely, under 1%, a reason for stopping treatment [4].

Visual changes, and NAION as a separate question

Sildenafil is about 10-fold more potent against PDE5 than against PDE6 in the retina, and that lower selectivity is thought to explain the color-vision changes [1]. These are the abnormal-vision entries in the table: transient, mostly a color tinge, light sensitivity or blurring, and in the flexible-dose studies only one man discontinued because of them [1].

Non-arteritic anterior ischemic optic neuropathy (NAION) is a different and rarer event. The label states that NAION, a cause of decreased vision including permanent loss of vision, has been reported rarely after marketing in temporal association with all PDE5 inhibitors, and advises stopping the drug and seeking medical attention for sudden vision loss in one or both eyes [1]. Two observational case-crossover studies suggested roughly a 2-fold increase in risk, with estimates of 2.15 (95% CI 1.06 to 4.34) and 2.27 (95% CI 0.99 to 5.20); the label says neither the post-marketing reports nor those studies substantiate a causal relationship [1]. For context, the label gives the annual incidence of NAION in men aged 50 and older as 2.5 to 11.8 cases per 100,000, a figure the label bases on published literature rather than on Viagra users [1].

A retrospective cohort of male veterans aged 50 and older found a relative risk of NAION of 1.02 (95% CI 0.92 to 1.12) among men prescribed a PDE5 inhibitor, 1.34 (95% CI 1.17 to 1.55) for possible NAION, and 1.10 (95% CI 1.02 to 1.20) for the two combined [5].

Blood pressure and nitrates

Single 100 mg doses lowered supine blood pressure in healthy volunteers by a mean maximum of about 8.4/5.5 mm Hg, with no dose relationship between 25 and 100 mg [1]. Organic nitrates and organic nitrites in any form are contraindicated, and the label states that after a patient has taken Viagra it is unknown when nitrates, if needed, can be safely given [1].

Priapism and hearing loss

The label states that prolonged erections over 4 hours and priapism (painful erections over 6 hours) have been reported infrequently since marketing, that an erection lasting more than 4 hours needs immediate medical assistance, and that untreated priapism can cause penile tissue damage and permanent loss of potency [1]. It advises caution in men with anatomical penile deformity such as Peyronie's disease and in men with sickle cell anemia, multiple myeloma or leukemia, while noting there are no controlled data in patients with sickle cell or related anemias [1].

For hearing, sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, has been reported in temporal association with PDE5 inhibitors including Viagra; the label advises stopping the drug and seeking prompt medical attention and states it is not possible to determine whether these events are related to the drug or to other factors [1].

Revatio is a different sildenafil product

Revatio is sildenafil approved for pulmonary arterial hypertension at 20 mg three times daily, a different product, strength and schedule from Viagra [6]. In the 12-week SUPER-1 trial, 278 patients received 20, 40 or 80 mg three times daily or placebo, and flushing, dyspepsia and diarrhea were among the side effects [7]. Those patients took a different dose on a three-times-daily schedule for a different disease, so the erectile-dysfunction percentages above do not carry across [6][7].

Age, liver and kidney: where the 25 mg start comes from

Healthy volunteers aged 65 and over had about 84% higher sildenafil AUC and 107% higher AUC of the active metabolite than men aged 18 to 45; after accounting for protein binding, free drug exposure was 45% and 57% higher [1]. The label says 18% of subjects in Viagra clinical studies were 65 or older, that no overall difference in safety or efficacy was observed between older and younger subjects, and that a starting dose of 25 mg should be considered because higher plasma levels may increase adverse reactions [1].

Hepatic impairment (Child-Pugh A and B) raises exposure by about 85%, and severe renal impairment (creatinine clearance below 30 mL/min) about doubles it; the label suggests a 25 mg start in both [1].

For product information, see sildenafil.

How sildenafil compares with tadalafil and vardenafil

A 2009 systematic review and meta-analysis of oral PDE5 inhibitors found that sildenafil increased the risk of any adverse event compared with placebo, with a relative risk of 1.72 (95% CI 1.53 to 1.93) [8]. In four head-to-head randomized trials comparing sildenafil, vardenafil and tadalafil, neither improvement of erectile dysfunction nor adverse events differed among the three [8]. The Viagra label itself cautions that adverse reaction rates from trials of one drug cannot be directly compared with those of another and may not reflect what happens in practice [1].