Cialis Side Effects: Rare But Serious Adverse Events Explained

Which serious risks does the Cialis label actually list?

Cialis is a PDE5 inhibitor approved for erectile dysfunction, for the signs and symptoms of benign prostatic hyperplasia, and for both conditions together [1]. Its Warnings and Precautions section covers cardiac risk during sexual activity, prolonged erection, effects on the eye, effects on hearing, and blood pressure lowering with alpha-blockers, antihypertensives or substantial alcohol [1].

The contraindications are narrower: any form of organic nitrate, guanylate cyclase stimulators such as riociguat, and a known serious hypersensitivity to tadalafil, including reported Stevens-Johnson syndrome and exfoliative dermatitis [1]. Neither Cialis nor Adcirca has a boxed warning [1]. Adcirca is tadalafil too, but a 20 mg tablet approved for pulmonary arterial hypertension at a 40 mg daily dose, and the two should not be taken together [1][3].

Vision loss: NAION

The label tells patients to stop Cialis and get medical care if vision is suddenly lost in one or both eyes, because the cause may be non-arteritic anterior ischemic optic neuropathy, a rare condition reported after marketing with all PDE5 inhibitors [1].

For scale, published literature puts the annual incidence of NAION at 2.5 to 11.8 cases per 100,000 in men aged 50 and older [1]. Two observational case-crossover studies compared PDE5 inhibitor use in the period immediately before NAION onset with use in an earlier period; they 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) [1]. The label states that neither the postmarketing reports nor these studies substantiate a causal relationship between PDE5 inhibitor use and NAION [1].

Two groups get specific mention. In men with a previous episode of NAION, the label advises caution and use only when the anticipated benefits outweigh the risks; a crowded optic disc may also raise risk [1]. In hereditary retinal disorders such as retinitis pigmentosa, Cialis is not recommended [1].

Priapism

The label reports rare cases of prolonged erections lasting more than 4 hours and priapism, defined there as painful erections lasting more than 6 hours, for this class of drugs, and states that priapism not treated promptly can cause irreversible damage to the erectile tissue [1]. Its instruction is that an erection lasting more than 4 hours, whether painful or not, warrants emergency medical attention [1]. Caution is advised in sickle cell anemia, multiple myeloma, leukemia, and anatomical deformation of the penis such as angulation, cavernosal fibrosis or Peyronie disease [1].

Sudden hearing loss

The label says to stop Cialis and seek prompt medical attention if hearing suddenly decreases or is lost [1]. Sudden hearing decrease or loss, sometimes with tinnitus and dizziness, has been reported after marketing, and the label states that it cannot be determined whether these events are related directly to tadalafil [1].

Nitrates and blood pressure

Any organic nitrate is contraindicated with Cialis [1]. Where a nitrate is considered medically necessary in a life-threatening situation, the label says at least 48 hours should have elapsed since the last Cialis dose, and the nitrate should still be given only under close medical supervision with hemodynamic monitoring [1]. That is an emergency rule, not a safe-spacing guide for routine use.

The timing was measured in a 150-man crossover study. Men took tadalafil 20 mg or placebo daily for 7 days, then received sublingual nitroglycerin 0.4 mg; standing systolic blood pressure fell below 85 mm Hg in more men on tadalafil at 4, 8 and 24 hours (P<0.05), with no difference at 48, 72 and 96 hours [4]. The authors concluded the interaction lasted 24 hours and was not seen at 48 hours, and that tadalafil should not be combined with organic nitrates [4]. The same paper notes that American College of Cardiology and American Heart Association guidance recommended withholding nitrates for 24 hours after sildenafil, whose half-life is about 4 hours [4]. Tadalafil's mean terminal half-life is 17.5 hours [1].

On its own, tadalafil is a mild vasodilator: 20 mg lowered supine blood pressure by a mean maximal 1.6/0.8 mm Hg versus placebo in healthy volunteers [1]. Alpha-blockers and tadalafil both lower blood pressure and the effect is additive [1]. With doxazosin 8 mg daily, tadalafil 20 mg produced a placebo-subtracted maximal standing systolic fall of 9.8 mm Hg (supine 3.6 mm Hg); in a second doxazosin study, 16 of 24 subjects had a systolic reading below 85 mm Hg or a fall greater than 30 mm Hg after morning tadalafil, versus 6 on placebo [1]. With tamsulosin 0.4 mg the standing fall was 1.7 mm Hg with tadalafil 10 mg and 2.3 mm Hg with 20 mg, and alfuzosin 10 mg gave 4.4 mm Hg with tadalafil 20 mg [1]. The label rule for erectile dysfunction is to be stable on the alpha-blocker first and start tadalafil at the lowest dose; for BPH it does not recommend the combination, because efficacy has not been adequately studied and blood pressure can drop [1].

Antihypertensives such as amlodipine, ARBs, bendroflumethiazide, enalapril and metoprolol produced small additional blood pressure reductions compared with placebo [1]. Substantial alcohol, 5 units or more, can increase orthostatic signs and symptoms such as a faster heart rate, lower standing blood pressure, dizziness and headache; tadalafil did not change alcohol levels and alcohol did not change tadalafil levels [1]. Guanylate cyclase stimulators are contraindicated because the combination may potentiate hypotension [1].

The label also lists cardiovascular conditions for which Cialis is not recommended because those patients were not studied: myocardial infarction within 90 days, unstable angina or angina during intercourse, NYHA class 2 or greater heart failure within 6 months, uncontrolled arrhythmia, blood pressure below 90/50 mm Hg or uncontrolled hypertension, and stroke within 6 months [1]. More broadly, Cialis should not be used by men for whom sexual activity is inadvisable because of cardiovascular status [1].

Serious skin reactions

Stevens-Johnson syndrome and exfoliative dermatitis appear in the label among reported hypersensitivity reactions, and a known serious hypersensitivity to tadalafil, Cialis or Adcirca, is a contraindication to Cialis [1]. The label gives no frequency for these reports, noting that it is not always possible to reliably estimate it [1].

CYP3A4 inhibitors that raise exposure

Tadalafil is metabolized mainly by CYP3A4, and inhibitors of that enzyme raise exposure substantially. Ketoconazole 400 mg daily raised tadalafil 20 mg exposure (AUC) by 312%, and ritonavir 200 mg twice daily raised it by 124% [1]. With CYP3A4 inhibitors the label caps as-needed Cialis at 10 mg every 72 hours and once-daily Cialis at 2.5 mg [1].

What the common side effects look like by comparison

In eight 12-week placebo-controlled trials of as-needed Cialis for ED, the 20 mg dose produced headache in 15% versus 5% on placebo, dyspepsia in 10% versus 1%, back pain in 6% versus 3%, and myalgia, nasal congestion, flushing and limb pain in 3% each versus 1% [1]. Discontinuation because of adverse events was 3.1% on 10 or 20 mg versus 1.4% on placebo, and back pain or myalgia usually began 12 to 24 hours after dosing and resolved within 48 hours [1].

Reporting a serious event

MedWatch is the FDA program that accepts reports of serious problems with medicines from patients and health professionals [5]. One caution about counting reports: FDA states that its adverse event dashboard cannot be used to estimate how often an event occurs, and that the existence of a report does not establish that the drug caused it [6]. Report counts for NAION, priapism or hearing loss therefore describe reporting, not incidence.