Viagra and Autoimmune Disease: What Patients and Clinicians Need to Know

What the Viagra label covers

The Viagra label's stated indication is erectile dysfunction [1][2]. Its warnings are built around cardiovascular risk during sexual activity, priapism, eye and hearing events, blood pressure effects with other vasodilators, bleeding, and interactions with nitrates, CYP3A4 inhibitors and alcohol [2]. The dosing sections adjust for age, liver and kidney function, and interacting drugs rather than for any diagnosis beyond ED [2].

PAH trial that included connective-tissue disease

Revatio is a separate sildenafil product, approved for pulmonary arterial hypertension (PAH) on 06/03/2005 as a 20 mg tablet [5]. SUPER-1 randomized 278 patients with symptomatic PAH, either idiopathic, associated with connective-tissue disease, or associated with repaired congenital systemic-to-pulmonary shunts, to placebo or sildenafil 20, 40 or 80 mg three times daily for 12 weeks [3]. The figures below are for the whole trial population, not for the connective-tissue-disease participants alone.

Six-minute walk distance rose in every sildenafil group, with placebo-corrected gains of 45 m (+13.0%), 46 m (+13.3%) and 50 m (+14.7%) at 20, 40 and 80 mg (P<0.001 for each) [3]. All three doses reduced mean pulmonary artery pressure (P=0.04, P=0.01 and P<0.001) and improved WHO functional class (P=0.003, P<0.001 and P<0.001) [3]. The walk gains were close across the three doses. The study was not powered to assess mortality, and clinical worsening did not differ significantly from placebo over 12 weeks [3].

The Viagra label states that Viagra should not be combined with Revatio or other PDE5 inhibitors, and that the combination has not been studied and may lower blood pressure further [2].

Raynaud phenomenon: one small crossover trial

Fries and colleagues published a double-blind, placebo-controlled, fixed-dose crossover study in Circulation in 2005 in 16 patients with symptomatic secondary Raynaud phenomenon that had resisted vasodilatory therapy [4]. In the trial, patients took sildenafil 50 mg or placebo twice daily for 4 weeks [4]. Mean attack frequency was 35 with sildenafil versus 52 with placebo (P=0.0064), cumulative attack duration was 581 versus 1046 minutes (P=0.0038), and the mean Raynaud Condition Score was 2.2 versus 3.0 (P=0.0386) [4]. Mean capillary blood flow velocity rose from 0.13 to 0.53 mm/s (P=0.0004), and two patients discontinued the study drug because of side effects [4].

Neither product is approved for Raynaud phenomenon: Viagra is indicated for erectile dysfunction [2] and Revatio for PAH [5].

Autoimmune medicines and CYP3A4

The Viagra label's drug interaction section covers nitrates, alpha-blockers, amlodipine, ritonavir and other CYP3A4 inhibitors, and alcohol; methotrexate, hydroxychloroquine, biologics, corticosteroids and transplant immunosuppressants are not listed there [2]. Sildenafil is cleared mainly by CYP3A4, with CYP2C9 a minor route [2]. Ritonavir raised sildenafil AUC 11-fold, and the label caps a single Viagra dose at 25 mg in a 48-hour period with ritonavir [2]. Saquinavir raised peak concentration 140% and AUC 210%; erythromycin raised them 160% and 182%; ketoconazole and itraconazole are expected to have greater effects than saquinavir, and a 25 mg starting dose is suggested with these drugs [2].

Blood pressure and cardiovascular warnings

A single 100 mg dose lowered supine blood pressure in healthy volunteers by a mean maximum of about 8.4/5.5 mm Hg [2]. In hypertensive patients, Viagra 100 mg added to amlodipine 5 or 10 mg produced a further mean supine fall of 8/7 mm Hg [2]. With alpha-blockers the effect is additive and symptomatic hypotension can occur, so the label says patients should be stable on the alpha-blocker before starting Viagra and should start at 25 mg; in a doxazosin study, Viagra 25 mg gave a placebo-subtracted maximum standing systolic fall of 6.0 mm Hg, and one of four men given 100 mg had severe postural hypotension [2].

The label says erectile dysfunction treatments should not generally be used when sexual activity is inadvisable for cardiovascular reasons, and that there are no controlled data in patients with 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 [2]. It advises caution in left ventricular outflow obstruction and severely impaired autonomic control of blood pressure [2]. The Second Princeton Consensus Conference sorts patients into low, intermediate and high risk categories for sexual activity [7].

Eye, hearing and other label warnings

NAION, a cause of sudden vision loss, has been reported rarely with all PDE5 inhibitors [2]. Observational case-crossover studies suggest roughly a 2-fold increase in risk (estimates 2.15, 95% CI 1.06 to 4.34, and 2.27, 95% CI 0.99 to 5.20), and the label states that a causal relationship is not substantiated [2]. Background annual incidence is given as 2.5 to 11.8 cases per 100,000 in men aged 50 and older [2]. The label tells patients to stop Viagra and seek medical care for sudden loss of vision, and advises caution in people with previous NAION or a crowded optic disc [2].

Sudden decrease or loss of hearing, sometimes with tinnitus and dizziness, has been reported in temporal association with PDE5 inhibitors, and the label states it is not possible to determine whether these events are drug-related [2]. A cross-sectional survey of 11,525 US men aged 40 and older found self-reported hearing impairment more common among sildenafil users (odds ratio 2.05, 95% CI 1.23 to 3.43); the design limits what it can show about cause [8].

The label also covers priapism (an erection lasting over 4 hours needs immediate medical help, and a painful erection over 6 hours is priapism), bleeding events for which a causal link has not been established, and the fact that Viagra is not indicated for use in females [2]. Common adverse reactions in fixed-dose trials at 25, 50 and 100 mg versus placebo were headache in 16%, 21% and 28% versus 7%, flushing in 10%, 19% and 18% versus 2%, and dyspepsia in 3%, 9% and 17% versus 2% [2].

Dosing from the Viagra label

The usual dose is 50 mg taken as needed about 1 hour before sexual activity, adjustable between 25 and 100 mg, with a maximum of one dose per day [2]. A 25 mg starting dose is suggested for age over 65, hepatic impairment, creatinine clearance below 30 mL/min, strong CYP3A4 inhibitors or erythromycin, and when starting in a patient already stable on an alpha-blocker [2]. Sildenafil is prescription only [1][2]. HealthRX.com offers sildenafil by prescription.