Cialis Safety Signals and FDA Actions: What the Evidence Shows

What the FDA record actually contains

Cialis was approved on November 21, 2003 as a new molecular entity under NDA 021368 [1]. The current label covers ED, the signs and symptoms of BPH, and both together, and states that when Cialis is used with finasteride to start BPH treatment, use is recommended for up to 26 weeks [2]. Adcirca is a different tadalafil product for pulmonary arterial hypertension, listed by Drugs@FDA as a 20 mg oral tablet [3]. The Cialis label says combining Cialis with other PDE5 inhibitors or other ED treatments has not been studied [2].

No boxed warning appears on the Cialis label [2]. One marketing-status fact is easy to misread: Drugs@FDA lists the 2.5 mg Cialis tablet as discontinued and notes a Federal Register determination that this product was not discontinued or withdrawn for safety or effectiveness reasons [1]. Drugs@FDA lists the 5, 10 and 20 mg Cialis tablets as prescription products [1].

The nitrate contraindication

The Cialis label contraindicates the drug in anyone using any form of organic nitrate, regularly or intermittently, because tadalafil potentiates the hypotensive effect of nitrates [2]. The same section contraindicates guanylate cyclase stimulators such as riociguat, which can also potentiate hypotension [2].

Kloner and colleagues studied 150 men who took tadalafil 20 mg or placebo daily for seven days and then received sublingual nitroglycerin 0.4 mg [4]. Standing systolic blood pressure fell below 85 mm Hg in more men on tadalafil than on placebo at 4, 8 and 24 hours after the dose (P<0.05), with no difference in response at 48, 72 and 96 hours [4]. The label adds that at 48 hours a few more tadalafil men still had greater blood pressure falls [2]. It reserves one narrow provision for emergencies: where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should elapse after the last Cialis dose, and the nitrate should still be given only under close medical supervision with appropriate hemodynamic monitoring [2]. That is an emergency rule, not permission to combine the two drugs and not a safe-timing guide for routine use [2].

NAION: the vision warning

The Cialis label directs patients to stop Cialis and seek medical attention if sudden loss of vision occurs in one or both eyes, which could be a sign of non-arteritic anterior ischemic optic neuropathy (NAION) [2]. Published literature cited in the label puts the annual incidence of NAION at 2.5 to 11.8 cases per 100,000 in men aged 50 and older [2]. Two observational case-crossover studies estimated roughly a twofold risk: 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 rare postmarketing reports nor these associations substantiate a causal relationship between PDE5 inhibitor use and NAION [2]. The label advises caution, and only when anticipated benefits outweigh the risks, in men with a history of NAION, notes that a crowded optic disc may add risk, and states that use is not recommended in hereditary retinal disorders such as retinitis pigmentosa [2].

Sudden hearing loss

The label's hearing instruction is short: patients should stop Cialis and seek prompt medical attention in the event of sudden decrease or loss of hearing [2]. Such reports have sometimes included tinnitus and dizziness, and the label states that it cannot determine whether these events are directly related to tadalafil [2].

Priapism

The label describes rare reports of prolonged erections greater than 4 hours and of priapism, defined there as painful erections greater than 6 hours [2]. An erection lasting more than 4 hours, painful or not, is listed as a reason to seek emergency medical attention, because untreated priapism can cause irreversible damage to erectile tissue [2]. The label advises caution in men with conditions that predispose to priapism — sickle cell anemia, multiple myeloma or leukemia — and in men with anatomical penile deformity such as angulation, cavernosal fibrosis or Peyronie's disease [2].

Blood pressure, alpha-blockers and cardiac risk

The cardiovascular section of the label says treatments for ED, including Cialis, should not be used in men for whom sexual activity is inadvisable because of underlying cardiovascular status [2]. It lists groups not included in the trials and therefore not recommended for Cialis: myocardial infarction within the last 90 days; unstable angina or angina occurring during intercourse; NYHA class 2 or greater heart failure within the last 6 months; uncontrolled arrhythmias, blood pressure below 90/50 mm Hg, or uncontrolled hypertension; and stroke within the last 6 months [2]. In a clinical pharmacology study in healthy volunteers, tadalafil 20 mg lowered supine blood pressure by a mean maximal 1.6/0.8 mm Hg relative to placebo [2].

The alpha-blocker numbers come from clinical pharmacology studies: tadalafil 20 mg with doxazosin 8 mg daily produced a placebo-subtracted maximal standing systolic fall of 9.8 mm Hg; tamsulosin 0.4 mg produced a standing fall of 1.7 mm Hg with tadalafil 10 mg and 2.3 mm Hg with 20 mg; alfuzosin 10 mg produced 4.4 mm Hg with tadalafil 20 mg [2]. For ED, the label says to be stable on the alpha-blocker first and to start Cialis at the lowest dose; for BPH, it does not recommend combining Cialis with an alpha-blocker [2]. Substantial alcohol, 5 units or more, with Cialis can increase orthostatic signs and symptoms such as higher heart rate, lower standing blood pressure, dizziness and headache [2]. The label says patients who develop anginal chest pain after taking Cialis should seek immediate medical attention [2].

What the trials recorded as side effects

In eight 12-week placebo-controlled trials of as-needed Cialis for ED (placebo n=476, tadalafil 20 mg n=635), headache occurred in 15% versus 5% on placebo, dyspepsia in 10% versus 1%, back pain in 6% versus 3%, myalgia in 3% versus 1%, nasal congestion in 3% versus 1%, flushing in 3% versus 1%, and limb pain in 3% versus 1% [2]. Discontinuation for adverse events was 3.1% on tadalafil 10 or 20 mg versus 1.4% on placebo [2]. Back pain and myalgia usually began 12 to 24 hours after dosing and typically resolved within 48 hours [2]. In separate trials of Cialis 5 mg once daily for BPH or ED with BPH, headache occurred in 4.1% versus 2.3% on placebo, and dyspepsia in 2.4% versus 0.2% [2].

Hidden ingredients in 'male enhancement' products

Separate from the prescription record, the FDA publishes notifications about sexual enhancement products sold online and in stores — sometimes advertised as dietary supplements or all-natural treatments — that contain dangerous hidden drug ingredients and can lead to severe health issues and hospitalization [5]. The agency notes that its list covers only a small fraction of the contaminated products on the market [5].

HealthRX.com offers tadalafil by prescription.