Cialis Side Effects: Incidence Rates Across Clinical Trials

What the label's tables actually measure

The main safety table in the Cialis label comes from eight 12-week placebo-controlled trials of as-needed tadalafil for erectile dysfunction: 476 men on placebo, 151 on 5 mg, 394 on 10 mg and 635 on 20 mg [1]. Across the whole clinical trial program tadalafil was given to more than 9,000 men [1].

All seven appear in the table because each was reported by at least 2% of men on 10 or 20 mg and more often than on placebo [1].

Headache is the most frequent reaction at each as-needed dose

In the as-needed erectile dysfunction trials, headache was reported by 15% of men on 20 mg, 11% on 10 mg and 11% on 5 mg, against 5% on placebo — a 10-percentage-point difference at 20 mg [1].

The once-daily erectile dysfunction trials (placebo n=248, 2.5 mg n=196, 5 mg n=304) show a flatter picture: headache in 6% on 5 mg daily, 3% on 2.5 mg daily and 5% on placebo [1].

In the three 12-week trials of 5 mg once daily for BPH or for ED with BPH (placebo n=576, tadalafil n=581), headache was 4.1% on tadalafil against 2.3% on placebo, and dizziness 1.0% against 0.5% [1].

The label allows the as-needed dose to be lowered from 10 mg to 5 mg or raised to 20 mg based on efficacy and tolerability [1].

Dyspepsia, flushing, nasal congestion and limb pain

Dyspepsia rose with each step in dose: 4% at 5 mg, 8% at 10 mg and 10% at 20 mg, against 1% on placebo, a nine-percentage-point difference at the top dose [1]. On 5 mg once daily for erectile dysfunction it was 5% against 2% on placebo, and in the BPH and ED/BPH trials 2.4% against 0.2% [1].

Flushing, nasal congestion and pain in limb each sat at 3% on 20 mg against 1% on placebo, with a similar pattern at 10 mg [1].

Back pain and myalgia: timing and pattern

Back pain was reported by 6% of men on 20 mg, 5% on 10 mg, 3% on 5 mg and 3% on placebo [1]. Myalgia did not follow a clean dose order — 4% on 10 mg, 3% on 20 mg, 1% on 5 mg and 1% on placebo [1].

The label describes the pattern in detail. Back pain or myalgia generally began 12 to 24 hours after dosing and typically resolved within 48 hours [1]. The discomfort was diffuse and bilateral in the lower lumbar, gluteal, thigh or thoracolumbar muscles and was made worse by lying down; it was usually mild or moderate and resolved without treatment, and severe back pain was reported with a low frequency, under 5% of all reports [1]. When treatment was needed, acetaminophen or a non-steroidal anti-inflammatory drug was generally effective [1].

About 0.5% of men using Cialis as needed discontinued because of back pain or myalgia [1]. In a 1-year open-label extension study, back pain was reported in 5.5% and myalgia in 1.3% [1]. Diagnostic testing for inflammation, muscle injury and renal damage showed no medically significant underlying pathology [1].

How many men stop Cialis because of side effects

Discontinuation for adverse events was 3.1% in men taking 10 or 20 mg as needed versus 1.4% on placebo [1]. For once-daily use in erectile dysfunction the figures were 4.1% versus 2.8% [1]. In the BPH and ED/BPH trials of 5 mg daily, 3.6% of tadalafil-treated men stopped versus 1.6% on placebo, with headache, upper abdominal pain and myalgia each leading to discontinuation in at least two tadalafil-treated men [1].

Daily 5 mg versus as-needed 10 or 20 mg

The 5 mg daily trials reported lower headache and dyspepsia percentages than the 20 mg as-needed trials, but these separate studies cannot establish that changing schedules would lower an individual's risk. Headache was 6% with 5 mg once daily for erectile dysfunction against 15% with 20 mg as needed, and dyspepsia 5% against 10% [1]. In the BPH and ED/BPH trials, 5 mg daily gave headache in 4.1%, dyspepsia in 2.4%, back pain in 2.4%, nasopharyngitis in 2.1% and dizziness in 1.0% [1]. Once-daily dosing provides continuous plasma tadalafil levels and reaches steady state within 5 days, at about 1.6 times the exposure of a single dose [1].

For the dosing options discussed here, see tadalafil.

Vision, hearing and priapism

Sudden vision loss in one or both eyes can be non-arteritic anterior ischemic optic neuropathy (NAION), reported rarely after marketing with all PDE5 inhibitors [1]. The label cites a background annual incidence of NAION of 2.5 to 11.8 cases per 100,000 in males aged 50 and older, and two observational case-crossover studies that suggested about a twofold 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]. The label says to stop Cialis and seek medical attention for sudden vision loss, advises caution in people with prior NAION or a 'crowded' optic disc, and does not recommend use in hereditary retinal disorders such as retinitis pigmentosa [1].

Sudden decrease or loss of hearing, sometimes with tinnitus and dizziness, has been reported; the label says to stop Cialis and seek prompt medical attention and states that it cannot be determined whether the hearing events are directly related to tadalafil [1].

For priapism, the label describes rare reports of erections lasting more than 4 hours and of priapism (painful erections over 6 hours) with this class of drugs, and says an erection over 4 hours, painful or not, needs emergency care because untreated priapism can permanently damage erectile tissue [1]. Caution is advised with sickle cell anemia, multiple myeloma, leukemia, or penile angulation, cavernosal fibrosis or Peyronie's disease [1].

Blood pressure, nitrates and alpha-blockers

In healthy volunteers tadalafil 20 mg lowered supine blood pressure by a mean maximal 1.6/0.8 mm Hg compared with placebo [1]. Any form of organic nitrate is contraindicated, and where a nitrate is medically necessary in a life-threatening situation, at least 48 hours should pass after the last Cialis dose before a nitrate is considered, under close supervision with hemodynamic monitoring [1]. In a 150-man crossover study, sublingual nitroglycerin lowered standing systolic pressure below 85 mm Hg in more men on tadalafil at 4, 8 and 24 hours after dosing, with no difference at 48, 72 and 96 hours [3].

Alpha-blockers add to the blood pressure effect. 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 over 30 mm Hg after morning tadalafil, against 6 on placebo [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 combining Cialis with an alpha-blocker [1].

What trial rates cannot tell you

The label cautions that adverse reaction rates from clinical trials may not reflect the rates observed in practice [1]. Counts from the FDA adverse event reporting system have a separate limitation: reports are voluntary, unverified and duplicative, and the agency states they cannot be used to estimate how often an event occurs [4]. The label describes the rare events above as rare reports, not as rates from the trial incidence tables [1].