Cialis Side Effects Severity Distribution by Patient Phenotype

Does the Cialis label report severity by patient phenotype?

The adverse-reaction tables are organized by dose and by approved use: as-needed ED, once-daily ED, and BPH or ED with BPH, each with a placebo column for comparison [1]. Adcirca, the tadalafil 20 mg tablet labeled for pulmonary arterial hypertension at 40 mg once daily, is a different product with its own label [2]. The Cialis tables report side-effect rates by dose and use, not separate rates for patients with diabetes or impaired kidney function [1]. The label does note that diarrhea was reported more frequently in men 65 and older treated with Cialis as needed for ED [1].

What are the actual rates at each dose?

As needed for ED, from eight 12-week placebo-controlled studies (placebo n=476, tadalafil 20 mg n=635): headache 5% versus 15%, dyspepsia 1% versus 10%, back pain 3% versus 6%, myalgia 1% versus 3%, nasal congestion 1% versus 3%, flushing 1% versus 3%, and pain in limb 1% versus 3% [1]. Headache was reported by 11% of men at both 5 mg and 10 mg, versus 15% at 20 mg; rates for other reactions do not always rise with dose [1].

Once daily for ED, from three 12-week studies (placebo n=248, tadalafil 5 mg n=304): headache 5% versus 6%, dyspepsia 2% versus 5%, flushing 1% versus 3% [1].

Once daily 5 mg for BPH or ED with BPH, from three 12-week studies (placebo n=576, tadalafil n=581): headache 2.3% versus 4.1%, dyspepsia 0.2% versus 2.4%, back pain 1.4% versus 2.4%, nasopharyngitis 1.6% versus 2.1%, myalgia 0.3% versus 1.2%, pain in extremity 0% versus 1.4%, and dizziness 0.5% versus 1.0% [1].

Those three sets of numbers come from separate studies in different populations, and the label cautions that adverse reaction rates from clinical trials cannot be directly compared with rates in other trials and may not reflect the rates seen in practice [1].

How severe are the common reactions?

The label describes back pain and myalgia in more detail than other reactions, including severity. Back pain and myalgia were generally mild or moderate: they typically began 12 to 24 hours after dosing and 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. Severe back pain was reported with a low frequency, under 5% of all reports. When treatment was needed, acetaminophen or NSAIDs were generally effective. About 0.5% of men using Cialis as needed stopped treatment because of back pain or myalgia, and in a 1-year open-label extension back pain was reported in 5.5% and myalgia in 1.3%. Diagnostic testing for inflammation, muscle injury or kidney damage found no medically significant underlying pathology [1].

For headache, dyspepsia, nasal congestion and flushing the tables give frequencies without severity grades [1]. Overall discontinuation for adverse events was 3.1% with tadalafil 10 or 20 mg as needed versus 1.4% with placebo, 4.1% with once-daily tadalafil versus 2.8% with placebo, and 3.6% with 5 mg daily for BPH or ED/BPH versus 1.6% with placebo [1]. These figures show how often men stopped treatment because of adverse events; they do not show how severe each reaction was [1].

Which patient factors does the label flag?

Age. The label notes that diarrhea was reported more frequently in men 65 and older treated with Cialis as needed for ED [1]. Exposure is also about 25% higher in healthy men aged 65 or older [1].

Kidney function. For as-needed use, a creatinine clearance of 30 to 50 mL/min calls for a 5 mg start and a maximum of 10 mg no more often than every 48 hours; below 30 mL/min or on hemodialysis the maximum is 5 mg no more often than every 72 hours, and once-daily use is not recommended below 30 mL/min [1].

Liver function. With mild or moderate impairment (Child-Pugh A or B) the as-needed dose should not exceed 10 mg; Cialis is not recommended in severe impairment (Child-Pugh C) [1].

Alpha-blockers. Both drug types lower blood pressure and the effect is additive. With doxazosin 8 mg daily, tadalafil 20 mg produced a placebo-subtracted maximal standing systolic fall of 9.8 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 tadalafil versus 6 on placebo. With tamsulosin 0.4 mg the standing fall was 1.7 mm Hg at tadalafil 10 mg and 2.3 mm Hg at 20 mg; with alfuzosin 10 mg it was 4.4 mm Hg at tadalafil 20 mg [1]. For ED the label says to be stable on the alpha-blocker first and start Cialis at the lowest dose; for BPH the combination is not recommended [1].

Strong CYP3A4 inhibitors. Ketoconazole 400 mg daily raised tadalafil 20 mg exposure (AUC) by 312% and peak concentration by 22%, and ketoconazole 200 mg daily raised tadalafil 10 mg AUC by 107%; ritonavir 200 mg twice daily raised tadalafil 20 mg AUC by 124% [1]. The label limits Cialis in this setting to 10 mg every 72 hours as needed, or 2.5 mg once daily [1]. Erythromycin, itraconazole and grapefruit juice were not studied but would likely raise exposure, in the label's words [1].

Alcohol. Both alcohol and tadalafil are mild vasodilators, and substantial alcohol (5 units or more) with Cialis can increase orthostatic signs and symptoms: higher heart rate, lower standing blood pressure, dizziness and headache. Tadalafil did not change alcohol levels and alcohol did not change tadalafil levels [1].

Cardiovascular status. The label lists groups not studied in the trials, for whom Cialis is not recommended: heart attack 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]. In healthy volunteers tadalafil 20 mg lowered supine blood pressure by a mean maximal 1.6/0.8 mm Hg versus placebo, and the label says patients with severely impaired autonomic control of blood pressure may be particularly sensitive to vasodilators such as PDE5 inhibitors [1].

Which patients does the label caution about for the rare serious events?

Priapism is listed as a rare report for this drug class. The label says to seek emergency medical attention for an erection lasting more than 4 hours, painful or not, because priapism that is not treated promptly can permanently damage erectile tissue. It advises caution in people with sickle cell anemia, multiple myeloma or leukemia, and in those with anatomical deformation of the penis such as angulation, cavernosal fibrosis or Peyronie's disease [1].

For NAION, the label gives the background annual incidence in men aged 50 and older as 2.5 to 11.8 cases per 100,000. Two observational case-crossover studies suggested roughly a doubling of risk with PDE5 inhibitor use (risk estimates 2.15, 95% CI 1.06 to 4.34, and 2.27, 95% CI 0.99 to 5.20). The label says neither the postmarketing reports nor those studies establish a causal relationship, advises caution with prior NAION and with a crowded optic disc, and does not recommend use in hereditary retinal disorders such as retinitis pigmentosa [1].

Sudden hearing decrease or loss, possibly with tinnitus and dizziness, has been reported; the label says it cannot be determined whether it is directly related to the drug [1].