Tadalafil (Generic) Rare but Serious Side Effects: What Patients and Prescribers Need to Know

How often do the serious reactions happen?

Most of these events come from postmarketing reports. The Adcirca label says such reports are voluntary and come from a population of uncertain size, so frequency cannot always be estimated reliably and a causal relationship cannot always be established [3]. For context, the Cialis label gives the general-population annual incidence of NAION as 2.5 to 11.8 cases per 100,000 men aged 50 and older [1].

Sudden vision loss: NAION

The label tells patients to stop Cialis and seek medical care if vision is suddenly lost in one or both eyes, which can be a sign of NAION, a rare cause of decreased vision including permanent loss [1]. Two observational case-crossover studies of PDE5 inhibitor use as a class 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 studies substantiate a causal relationship [1].

Caution is advised in men with a history of NAION, and a crowded optic disc may add risk [1]. The Cialis label does not recommend use in people with hereditary retinal disorders such as retinitis pigmentosa [1].

Priapism and prolonged erection

The label reports rare cases of erections lasting more than 4 hours and priapism, meaning painful erections lasting more than 6 hours, with this drug class, and states that priapism not treated promptly can cause irreversible damage to erectile tissue [1]. The label's instruction is that a man with an erection lasting more than 4 hours, whether painful or not, should seek emergency medical attention [1].

Caution applies to men with sickle cell anemia, multiple myeloma or leukemia, and to men with anatomical deformation of the penis such as angulation, cavernosal fibrosis or Peyronie disease [1].

Sudden hearing loss

The label directs patients to stop Cialis and get prompt medical attention for a sudden decrease in or loss of hearing [1]. The reported cases describe hearing loss that may come with tinnitus and dizziness [1][3].

Nitrates: the contraindication that matters most

Cialis is contraindicated in anyone using any form of organic nitrate, regularly or intermittently, because tadalafil 5 to 20 mg potentiates the hypotensive effect of nitrates [1]. The label's only timing statement is for an emergency: if a nitrate is medically necessary in a life-threatening situation, at least 48 hours should pass after the last Cialis dose, and a nitrate may then be considered only under close medical supervision with appropriate hemodynamic monitoring [1]. That is an emergency exception, not a spacing schedule for routine use.

In a crossover study of 150 men, seven daily doses of tadalafil 20 mg or placebo were followed by sublingual nitroglycerin 0.4 mg at set times, and standing systolic 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 label describes a significant interaction at each time point up to and including 24 hours, a few more tadalafil-treated men with larger pressure falls at 48 hours, and no detectable interaction after 48 hours [1].

Riociguat and other guanylate cyclase stimulators are also contraindicated, since PDE5 inhibition may potentiate their blood-pressure-lowering effect [1]. The Adcirca label says not to use nitrates within 48 hours of the last dose of Adcirca [3].

Alpha-blockers, other antihypertensives and alcohol

Tadalafil and alpha-blockers are both vasodilators, the blood-pressure effect is additive, and symptomatic hypotension such as fainting can occur [1]. In healthy volunteers, tadalafil 20 mg with doxazosin 8 mg daily produced a placebo-subtracted maximal standing systolic fall of 9.8 mm Hg (supine 3.6 mm Hg), and 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, tadalafil 5 mg daily plus tamsulosin produced no outliers, and alfuzosin 10 mg gave a 4.4 mm Hg standing fall with tadalafil 20 mg [1].

For erectile dysfunction the label advises being stable on the alpha-blocker first and starting tadalafil at the lowest dose; for BPH it does not recommend the combination at all, on both efficacy and blood-pressure grounds [1].

Common antihypertensives (amlodipine, angiotensin receptor blockers, bendroflumethiazide, enalapril and metoprolol) produced small additional blood-pressure reductions versus placebo in pharmacology studies [1]. Five units of alcohol or more with Cialis can increase orthostatic signs and symptoms, including higher heart rate, lower standing blood pressure, dizziness and headache, although tadalafil did not change alcohol levels and alcohol did not change tadalafil levels [1].

Serious skin reactions

Stevens-Johnson syndrome and exfoliative dermatitis are named among reported hypersensitivity reactions, and a known serious hypersensitivity to tadalafil is a contraindication to both Cialis and Adcirca [1][3]. The Adcirca label lists urticaria, Stevens-Johnson syndrome and exfoliative dermatitis among postmarketing hypersensitivity reports [3].

Heart and circulation

Sexual activity carries its own cardiac risk, and the label says treatments for erectile dysfunction, including Cialis, should not be used by men for whom sexual activity is inadvisable because of cardiovascular status [1]. Groups not included in the trials, and for whom Cialis is therefore not recommended, are men with a 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, or a stroke within 6 months [1].

In healthy volunteers tadalafil 20 mg lowered supine blood pressure by a mean maximal 1.6/0.8 mm Hg relative to placebo [1]. Caution is advised with left ventricular outflow obstruction such as aortic stenosis and with severely impaired autonomic control of blood pressure [1]. The Second Princeton Consensus Conference corroborated an algorithm that assigns men to low, intermediate or high cardiovascular risk categories [5]. The Adcirca label lists serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations and tachycardia, reported in temporal association with tadalafil after marketing [3].

CYP3A4 inhibitors raise exposure

Tadalafil is metabolized mainly by CYP3A4, and inhibitors raise exposure sharply: ketoconazole 400 mg daily raised tadalafil 20 mg exposure (AUC) by 312% and peak concentration by 22%, ketoconazole 200 mg daily raised tadalafil 10 mg AUC by 107%, and ritonavir 200 mg twice daily raised tadalafil 20 mg AUC by 124% [1]. With these drugs the label caps as-needed Cialis at 10 mg every 72 hours and once-daily Cialis at 2.5 mg [1].

When the same drug is used for pulmonary arterial hypertension

Adcirca is tadalafil 20 mg tablets taken as 40 mg once daily for pulmonary arterial hypertension, a different product and dose from Cialis, and its label tells patients not to take other PDE5 inhibitors with it [3]. The Adcirca label says to avoid use in severe renal impairment and with potent CYP3A inhibitors or chronic potent inducers such as rifampin, and that it is not recommended in pulmonary veno-occlusive disease [3].

Other reported events

The Adcirca label lists migraine, seizure and seizure recurrence, and transient global amnesia among nervous-system events reported after marketing, and visual field defect, retinal vein occlusion and retinal artery occlusion among eye events [3].