Pooled analysis of adverse events extracted from the studies on xanthines administered in chronic obstructive pulmonary disease patients and ranked by frequency in agreement with European Medicines Agency guidelines [64]
| Doxofylline | Theophylline | Aminophylline | |||||||
| Adverse events | Rank | Statistical notes | Adverse events | Rank | Statistical notes | Adverse events | Rank | Statistical notes | |
| Subjects n | 391 | 232 | 110 | ||||||
| Palpitations | 3 (0.77) | + | Lower frequency versus theophylline* and aminophylline*** | 7 (3.02) | ++ | Higher frequency versus doxofylline*, lower frequency versus aminophylline*** | 14 (2.73) | +++ | Higher frequency versus doxofylline*** or theophylline*** |
| Gastrointestinal discomfort | 3 (0.77) | + | No difference versus theophylline (ns), lower frequency versus aminophylline*** | 2 (0.86) | + | No difference versus doxofylline (ns), lower frequency versus aminophylline*** | 13 (11.82) | +++ | Higher frequency versus either doxofylline*** and theophylline*** |
| Insomnia | 3 (0.77) | + | Lower frequency versus theophylline** and aminophylline*** | 11 (4.74) | ++ | Higher frequency versus doxofylline**, no difference versus aminophylline (ns) | 10 (9.09) | ++ | Higher frequency versus doxofylline***, no difference versus theophylline (ns) |
| Nausea | 15 (3.84) | ++ | Lower frequency versus theophylline***, no difference versus aminophylline (ns) | 25 (10.78) | +++ | Higher frequency versus doxofylline*** or aminophylline** | 1 (0.91) | + | No difference versus doxofylline (ns), lower frequency versus theophylline** |
| Epigastralgia | 21 (5.37) | ++ | A signal of lower frequency versus theophylline (p=0.07), no difference versus aminophylline (ns) | 21 (9.05) | ++ | A signal of higher frequency versus doxofylline (p=0.07), no difference versus aminophylline (ns) | 6 (5.45) | ++ | No difference versus doxofylline (ns) or theophylline (ns) |
| Headache | 12 (3.07) | ++ | Lower frequency versus theophylline**, no difference versus aminophylline (ns) | 20 (8.62) | ++ | Higher frequency versus doxofylline** or aminophylline* | 1 (0.91) | + | No difference versus doxofylline (ns), lower frequency versus theophylline* |
| Other | 1 (0.26) | + | Lower frequency versus theophylline*** | 18 (7.76) | ++ | Higher frequency versus doxofylline*** | 0 (fnk) | fnk | nc |
| Dyspepsia | 12 (3.07) | ++ | Lower frequency versus theophylline* | 17 (7.33) | ++ | Higher frequency versus doxofylline* | 0 (fnk) | fnk | nc |
| Anxiety | 1 (0.26) | + | Lower frequency versus theophylline* or aminophylline** | 5 (2.16) | ++ | Higher frequency versus doxofylline*, no difference versus aminophylline (ns) | 5 (4.55) | ++ | Higher frequency versus doxofylline**, no difference versus theophylline (ns) |
| Arrhythmia | 2 (0.51) | + | No difference versus theophylline (ns), a signal of lower frequency versus aminophylline (p=0.06) | 2 (0.86) | + | No difference versus doxofylline (ns) or aminophylline (ns) | 4 (3.64) | ++ | A signal of higher frequency versus doxofylline (p=0.06), no difference versus theophylline (ns) |
| Flushing | 0 (fnk) | fnk | nc | 0 (fnk) | fnk | nc | 4 (3.64) | ++ | nc |
| Tremors | 1 (0.26) | + | Lower frequency versus theophylline* | 5 (2.16) | ++ | Higher frequency versus doxofylline* | 0 (fnk) | fnk | nc |
| Vomiting | 1 (0.26) | + | A signal of lower frequency versus theophylline (p=0.07) | 4 (1.72) | ++ | A signal of higher frequency versus doxofylline (p=0.07) | 0 (fnk) | fnk | nc |
| Tachycardia | 0 (fnk) | fnk | nc | 3 (1.29) | ++ | nc | 0 (fnk) | fnk | nc |
| Anorexia | 3 (0.77) | + | No difference versus theophylline (ns) | 3 (1.29) | ++ | No difference versus doxofylline (ns) | 0 (fnk) | fnk | nc |
| Chest pain | 2 (0.51) | + | No difference versus theophylline (ns) | 3 (1.29) | ++ | No difference versus doxofylline (ns) | 0 (fnk) | fnk | nc |
| Sweating | 1 (0.26) | + | No difference versus theophylline (ns) | 3 (1.29) | ++ | No difference versus doxofylline (ns) | 0 (fnk) | fnk | nc |
| Diarrhoea | 0 (fnk) | fnk | nc | 0 (fnk) | fnk | nc | 1 (0.91) | + | nc |
| Hypotension | 0 (fnk) | fnk | nc | 0 (fnk) | fnk | nc | 1 (0.91) | + | nc |
| Dizziness | 1 (0.26) | + | No difference versus theophylline (ns) | 2 (0.86) | + | No difference versus doxofylline (ns) | 0 (fnk) | fnk | nc |
| Dry mouth | 2 (0.51) | + | No difference versus theophylline (ns) | 1 (0.43) | + | No difference versus doxofylline (ns) | 0 (fnk) | fnk | nc |
| Excitation | 0 (fnk) | fnk | nc | 1 (0.43) | + | nc | 0 (fnk) | fnk | nc |
| Constipation | 2 (0.51) | + | nc | 0 (fnk) | fnk | nc | 0 (fnk) | fnk | nc |
Data are presented as n or n (%), unless otherwise stated. +: uncommon ≥1/1000 to <1/100; ++: common ≥1/100 to <1/10; +++: very common ≥1/10. ns: nonsignificant (p>0.05); fnk: frequency not known; nc: not calculable. *: p<0.05; **: p<0.01; ***: p<0.001.