Sildenafil (Generic) Side Effects: Incidence Rates Across Clinical Trials

Where the numbers come from

Two labels cover sildenafil, and their side-effect numbers should not be mixed. The Viagra label covers sildenafil citrate tablets 25, 50 and 100 mg for erectile dysfunction; the Revatio label covers a 20 mg tablet taken three times daily for pulmonary arterial hypertension [2][3][1][4].

The ED label prints two datasets. One is a fixed-dose table: 312 men took 25 mg, 511 took 50 mg, 506 took 100 mg and 607 took placebo [1]. The other is a flexible-dose table in which the dose was adjusted, closer to as-needed use: 734 men on sildenafil and 725 on placebo [1]. Overall, more than 3,700 patients aged 19 to 87 received sildenafil in premarketing trials, and more than 550 were treated for longer than a year [1].

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Common side effects at each dose

In the fixed-dose ED studies, the label reports these rates for reactions that occurred in at least 2% of men and more often than on placebo [1]:

• Headache: 16% at 25 mg, 21% at 50 mg, 28% at 100 mg, 7% on placebo [1]
• Flushing: 10%, 19%, 18%, 2% [1]
• Dyspepsia: 3%, 9%, 17%, 2% [1]
• Abnormal vision: 1%, 2%, 11%, 1% [1]
• Nasal congestion: 4%, 4%, 9%, 2% [1]
• Back pain: 3%, 4%, 4%, 2% [1]
• Myalgia: 2%, 2%, 4%, 1% [1]
• Nausea: 2%, 3%, 3%, 1% [1]
• Dizziness: 3%, 4%, 3%, 2% [1]
• Rash: 1%, 2%, 3%, 1% [1]

Headache, dyspepsia and abnormal vision rise steadily with dose. Flushing does not: it was 19% at 50 mg and 18% at 100 mg [1].

What the flexible-dose trials show

The flexible-dose trials ran for 2 to 26 weeks, and men took sildenafil at least once weekly [1]. These are rates for the whole sildenafil group, not for a single milligram strength:

• Headache: 16% versus 4% on placebo [1]
• Flushing: 10% versus 1% [1]
• Dyspepsia: 7% versus 2% [1]
• Nasal congestion: 4% versus 2% [1]
• Abnormal vision: 3% versus 0% (one man stopped treatment because of it) [1]
• Back pain: 2% versus 2% [1]
• Dizziness: 2% versus 1% [1]
• Rash: 2% versus 1% [1]

Those figures sit below the fixed-dose rates at 50 and 100 mg for headache, flushing and dyspepsia [1].

Color vision changes

Abnormal vision, mostly color vision changes, rose from 1% at 25 mg to 11% at 100 mg, while dyspepsia rose from 3% to 17% [1]. Sildenafil is only about 10-fold more potent against PDE5 than against PDE6, the phosphodiesterase in the retina, and the label says this lower selectivity is thought to explain the color-vision changes seen at higher doses or plasma levels [1]. The label describes them as mild to moderate and transient, mostly a color tinge to vision, increased sensitivity to light, or blurred vision [1].

The Viagra label reports no controlled clinical data in people with retinitis pigmentosa and says that if the drug is prescribed, this should be done with caution [1]. The Revatio label says use in retinitis pigmentosa is not recommended [4].

The PAH program uses a different product and schedule

Revatio is sildenafil at 20 mg three times daily, titratable to 80 mg three times daily [4]. In SUPER-1, patients with PAH were assigned to placebo (70) or sildenafil 20 mg (69), 40 mg (67) or 80 mg (71) three times daily for 12 weeks [4]. At 20 mg, the label reports headache 46% versus 39% on placebo, flushing 10% versus 4%, dyspepsia 13% versus 7%, diarrhea 9% versus 6% and myalgia 7% versus 4% [4]. At 80 mg, headache was 49% and flushing 16% [4].

Headache was common in both groups in the PAH trial, 46% at 20 mg and 39% on placebo [4]. The population differs from the ED trials (PAH, 75% women in SUPER-1, and 96% in functional class II or III in the extension study) and dosing is continuous rather than as needed [4][5]. Discontinuation in SUPER-1 was 3% at 20 and 40 mg and 8% at 80 mg, against 3% on placebo [4]. In the open-label extension SUPER-2, 259 of 277 treated patients continued sildenafil, titrated to 80 mg three times daily, until the last patient completed 3 years of treatment; it was uncontrolled [5].

Cardiovascular effects and the nitrate contraindication

Neither label carries a boxed warning [1][4]. The cardiovascular issue is a contraindication plus a set of precautions, not a common side-effect rate.

Nitrates. Organic nitrates or nitrites in any form, regularly or intermittently, are contraindicated with sildenafil, as is the guanylate cyclase stimulator riociguat [1][4]. Sildenafil potentiates the hypotensive effect of nitrates, and the label says that after a dose it is unknown when nitrates can safely be given [1]. Plasma levels 24 hours after a 100 mg dose are about 2 ng/mL against a peak of about 440 ng/mL, but they are 3 to 8 times higher in men over 65, in liver or severe kidney impairment, or with erythromycin or strong CYP3A4 inhibitors [1].

Blood pressure. A single 100 mg dose 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]. In hypertensive patients, sildenafil 100 mg with amlodipine 5 or 10 mg produced an additional mean supine fall of 8/7 mm Hg [1].

Alpha-blockers. The label says patients should be stable on the alpha-blocker before sildenafil is started, and that sildenafil should be started at 25 mg [1]. In a doxazosin study, sildenafil 25 mg produced a placebo-subtracted maximum standing systolic fall of 6.0 mm Hg (7.4 supine); among the 4 men given 100 mg, one had severe postural hypotension [1].

CYP3A4 inhibitors. Ritonavir raised sildenafil AUC 11-fold, and the Viagra label caps the dose at 25 mg in 48 hours with ritonavir [1]. Saquinavir raised peak concentration by 140% and AUC by 210%; erythromycin raised them by 160% and 182%; a 25 mg starting dose should be considered [1].

Cardiac risk of sexual activity. The label says ED treatments including Viagra should not generally be used in men for whom sexual activity is inadvisable because of cardiovascular status, and that there are no controlled data in patients who had a heart attack, stroke or life-threatening arrhythmia within 6 months, resting blood pressure below 90/50 or above 170/110, cardiac failure, or unstable angina [1]. The Second Princeton Consensus Conference set out a risk stratification algorithm for sexual activity in men with cardiovascular disease [6].

Rare serious events reported after approval

Three serious events sit in the warnings rather than the incidence tables.

NAION. Non-arteritic anterior ischemic optic neuropathy has been reported rarely after marketing with all PDE5 inhibitors. Two observational case-crossover studies suggest about 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), and the label says a causal relationship is not substantiated [1]. For context, the label gives the annual incidence of NAION as 2.5 to 11.8 cases per 100,000 in men aged 50 and older [1]. The label tells patients to stop Viagra and seek medical care if vision is suddenly lost in one or both eyes, and says to use caution in people with previous NAION or a crowded optic disc [1].

Hearing loss. Sudden decrease or loss of hearing, sometimes with tinnitus and dizziness, has been reported in temporal association with PDE5 inhibitors. The label says it is not possible to determine whether these events are related to the drug or to other factors, and tells patients to stop and seek prompt medical attention [1].

Priapism. An erection lasting more than 4 hours needs immediate medical help, and a painful erection over 6 hours is priapism that, untreated, can cause permanent loss of potency [1]. The label advises caution in men with penile deformity, sickle cell anemia, multiple myeloma or leukemia [1].

The label says postmarketing reactions are reported voluntarily from a population of uncertain size, so it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure [1]. It describes priapism as reported infrequently since market approval [1].

Discontinuation and higher-exposure groups

Across the placebo-controlled ED studies, 2.5% of men on sildenafil stopped because of adverse reactions, against 2.3% on placebo [1].

Sildenafil exposure is higher in several groups, and the label advises considering a 25 mg starting dose in each: men over 65 (AUC about 84% higher), hepatic impairment (AUC 85% higher and peak 47% higher in Child-Pugh A and B), severe renal impairment (exposure roughly doubled) and strong CYP3A4 inhibitors [1].