Viagra (Sildenafil) Delayed-Onset Side Effects: What Patients and Clinicians Need to Know

What the label's side-effect data actually cover

In fixed-dose erectile dysfunction studies of 25, 50 and 100 mg against placebo, headache was reported by 16%, 21% and 28% of men against 7% on placebo; flushing by 10%, 19% and 18% against 2%; dyspepsia by 3%, 9% and 17% against 2%; abnormal vision by 1%, 2% and 11% against 1%; and nasal congestion by 4%, 4% and 9% against 2% [1]. Back pain, myalgia, nausea, dizziness and rash each fell between 1% and 4%, and 2.5% of men stopped treatment because of adverse reactions against 2.3% on placebo [1].

Abnormal vision in those trials was mild to moderate and transient, mostly a color tinge to vision, increased sensitivity to light, or blurred vision [1].

Sildenafil reaches its peak blood concentration 30 to 120 minutes after a fasting dose, and the Viagra label does not give an onset window for common side effects [1]. A high-fat meal delays the peak by about 60 minutes and lowers peak concentration by 29%, and the terminal half-life is about 4 hours for sildenafil and for its active metabolite, which carries about 50% of the parent drug's PDE5 potency and about 20% of the effect [1].

The serious events sit in a different part of the label, the postmarketing list, where reactions are volunteered from a population of uncertain size, so frequency cannot be reliably estimated and a causal relationship cannot be established [1]. NAION and prolonged erections have been reported after marketing [1]. Sudden hearing loss has been reported in temporal association with PDE5 inhibitors including Viagra, and the label says it is not possible to determine whether those events are related directly to sildenafil [1].

Who keeps sildenafil in the body longer

The label reports exposure rather than half-life for the groups that handle sildenafil more slowly. AUC is about 84% higher in healthy men aged 65 or older (107% for the active metabolite, and 45% and 57% for the unbound fractions), about doubled in severe renal impairment (creatinine clearance below 30 mL/min) and 85% higher in Child-Pugh A and B hepatic impairment [1]. The label suggests a 25 mg starting dose in each of those groups [1].

Strong CYP3A4 inhibitors raise sildenafil exposure further. Ritonavir raised sildenafil AUC 11-fold, and the label caps Viagra at a single 25 mg dose in 48 hours when ritonavir is taken [1]. Erythromycin raised peak concentration 160% and AUC 182%; saquinavir raised them 140% and 210%; ketoconazole or itraconazole are expected to have larger effects than saquinavir, and a 25 mg starting dose is suggested with these drugs [1].

NAION: the vision event the label warns about

The Viagra label advises stopping the drug and seeking medical attention for a sudden loss of vision in one or both eyes, which could be non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision including permanent loss, reported rarely in postmarketing use with all PDE5 inhibitors [1]. For context, the label gives the annual incidence of NAION as 2.5 to 11.8 cases per 100,000 in males aged 50 and older [1].

Two observational case-crossover studies looked at PDE5 inhibitor use in the period immediately before NAION onset and suggested an approximate 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 states that neither the postmarketing reports nor these associations substantiate a causal relationship [1].

A retrospective case series of five patients published in Ophthalmology in 2002 described NAION developing in one eye within minutes to hours of taking sildenafil; four of the five had no vascular risk factors for ischemic optic neuropathy, all had unilateral blurry vision, altitudinal visual field defects and optic disc edema, and each had a small cup-to-disc ratio in the unaffected eye [2].

For people who have already had NAION, the label says the risk of recurrence is increased and that PDE5 inhibitors should be used with caution and only when the anticipated benefits outweigh the risks; a crowded optic disc is also considered a risk factor, but the label says the evidence is insufficient to support screening prospective users for this uncommon condition [1]. A review of ocular safety after seven years of prescribing to more than 27 million men found no consistent pattern suggesting any long-term effect on the retina or ocular circulation, and noted that men with erectile dysfunction often have vascular risk factors that make a causal link difficult to establish [4].

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 advises stopping the drug and seeking prompt medical attention [1]. The label also states that it is not possible to determine whether these events are related directly to sildenafil or to other factors [1].

Priapism and prolonged erection

The label reports prolonged erections of more than 4 hours and priapism (painful erections of more than 6 hours) infrequently since marketing, and says to seek immediate medical assistance for an erection lasting more than 4 hours; untreated priapism can cause penile tissue damage and permanent loss of potency [1]. It also advises caution in men with anatomical deformation of the penis such as angulation, cavernosal fibrosis or Peyronie's disease, and in conditions that predispose to priapism such as sickle cell anemia, multiple myeloma or leukemia, while noting there are no controlled data in sickle cell or related anemias [1]. A review of priapism notes that the published literature is predominantly case series and that prompt diagnosis and appropriate management matter for erectile function outcomes [5].

Nitrates: a timing question with no safe interval

Organic nitrates and organic nitrites in any form, whether used regularly or intermittently, are contraindicated with Viagra, as is the guanylate cyclase stimulator riociguat [1]. The label also states that after a patient has taken Viagra it is unknown when nitrates, if needed, can safely be given [1]. Sildenafil levels 24 hours after a 100 mg dose are about 2 ng/mL against a peak of about 440 ng/mL, and are 3 to 8 times higher in men over 65, with liver or severe kidney impairment, or taking erythromycin or strong CYP3A4 inhibitors, but the label does not treat 24 hours as a safe point [1]. The label gives no waiting time.

A double-blind, placebo-controlled crossover study in healthy men gave sildenafil 25 mg three times daily for four days and then infused glyceryl trinitrate one hour after the day-4 dose: the men were significantly less tolerant of the nitrate, judged by a fall in blood pressure of more than 25 mm Hg or symptomatic hypotension (P<0.01) [6]. A 500 microgram sublingual glyceryl trinitrate tablet taken one hour after 25 mg of sildenafil produced a 4-fold greater fall in systolic blood pressure [6].

Color-tinged vision and fluid under the retina

Sildenafil is about 10-fold more potent against PDE5 than against PDE6 in the retina, and this lower selectivity is thought to explain color-vision changes [1]. Abnormal vision was reported by 1%, 2% and 11% of men taking 25, 50 and 100 mg against 1% on placebo, and is described as mild to moderate and transient [1]. A visual safety review reported transient, mild impairment of color discrimination around the time of peak plasma levels, more often at higher doses, while studies found no effect on visual acuity, visual fields or contrast sensitivity [4].

Central serous chorioretinopathy has been reported in men taking sildenafil. One review searched postmarketing databases at the FDA, the World Health Organization and the National Registry of Drug-Induced Ocular Side Effects plus the literature, and identified 11 cases; 8 patients stopped sildenafil, vision improved in 6 of those 8, effects recurred in 3 who resumed, and 2 continued to have the condition after stopping [3]. Because central serous chorioretinopathy is cyclic, the authors state that a causal relationship has not been established [3].

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