Table 3. Adverse Events (Safety Population).*.
| Event | Hydroxychloroquine plus Azithromycin (N=239) |
Hydroxychloroquine (N=199) |
Azithromycin (N=50) |
Neither Hydroxychloroquine nor Azithromycin (N=177) |
Total (N=665) |
|---|---|---|---|---|---|
| Reported serious adverse event, according to classification† | 5 (2.1) | 2 (1.0) | 0 | 2 (1.1) | 9 (1.4) |
| Risk to life — no. (%) | 1 (0.4) | 1 (0.5) | 0 | 0 | 2 (0.3) |
| Extension of hospitalization — no. (%) | 2 (0.8) | 0 | 0 | 1 (0.6) | 3 (0.5) |
| Clinically significant event — no. (%) | 0 | 1 (0.5) | 0 | 1 (0.6) | 2 (0.3) |
| Death — no. (%) | 2 (0.8) | 0 | 0 | 0 | 2 (0.3) |
| Other adverse events | |||||
| Any adverse event — no. (%) | 94 (39.3) | 67 (33.7) | 9 (18.0) | 40 (22.6) | 210 (31.6) |
| QTc interval >480 msec within 7 days — no./total no. (%) | 17/116 (14.7) | 13/89 (14.6) | 0/6 | 1/58 (1.7) | 31/269 (11.5) |
| Arrhythmia — no. (%) | 3 (1.3) | 3 (1.5) | 0 | 1 (0.6) | 7 (1.1) |
| Bradycardia — no. (%) | 2 (0.8) | 1 (0.5) | 0 | 1 (0.6) | 4 (0.6) |
| Supraventricular tachycardia — no. (%) | 1 (0.4) | 2 (1.0) | 0 | 0 | 3 (0.5) |
| Ventricular tachycardia — no. (%) | 0 | 0 | 0 | 0 | 0 |
| Myocardial infarction — no. (%) | 1 (0.4) | 0 | 0 | 0 | 1 (0.2) |
| Abdominal-wall hemorrhage — no. (%) | 1 (0.4) | 0 | 0 | 0 | 1 (0.2) |
| Pulmonary embolism — no. (%) | 2 (0.8) | 0 | 0 | 0 | 2 (0.3) |
| Pneumothorax — no. (%) | 0 | 1 (0.5) | 0 | 0 | 1 (0.2) |
| Bronchospasm — no. (%) | 0 | 0 | 0 | 1 (0.6) | 1 (0.2) |
| Epistaxis — no. (%) | 2 (0.8) | 0 | 0 | 0 | 2 (0.3) |
| Bloodstream infection — no. (%) | 0 | 1 (0.5) | 0 | 0 | 1 (0.2) |
| Itching — no. (%) | 0 | 1 (0.5) | 0 | 0 | 1 (0.2) |
| Nausea — no. (%) | 6 (2.5) | 9 (4.5) | 0 | 2 (1.1) | 17 (2.6) |
| Vomiting — no. (%) | 0 | 0 | 0 | 1 (0.6) | 1 (0.2) |
| Anemia — no. (%)‡ | 23 (9.6) | 14 (7.0) | 5 (10.0) | 11 (6.2) | 53 (8.0) |
| Elevated ALT or AST level — no. (%)§ | 26 (10.9) | 17 (8.5) | 2 (4.0) | 6 (3.4) | 51 (7.7) |
| Hypoglycemia — no. (%)¶ | 0 | 1 (0.5) | 0 | 0 | 1 (0.2) |
| Elevated bilirubin level — no. (%) | 1 (0.4) | 5 (2.5) | 0 | 2 (1.1) | 8 (1.2) |
| Leukopenia — no. (%)‖ | 6 (2.5) | 3 (1.5) | 2 (4.0) | 3 (1.7) | 14 (2.1) |
| Low lymphocyte level — no. (%)** | 29 (12.1) | 17 (8.5) | 2 (4.0) | 16 (9.0) | 64 (9.6) |
| Thrombocytopenia — no. (%)†† | 17 (7.1) | 14 (7.0) | 1 (2.0) | 18 (10.2) | 50 (7.5) |
| Hypoacusis — no. (%) | 0 | 0 | 0 | 0 | 0 |
The safety population included patients according to the medications received (as treated). P<0.001 for the occurrence of any adverse events (pair-wise comparisons: P<0.001 for hydroxychloroquine plus azithromycin vs. control; P=0.01 for hydroxychloroquine alone vs. control). P=0.02 for the occurrence of a corrected QT (QTc) interval of more than 480 msec within 7 days (pair-wise comparisons: P=0.04 for hydroxychloroquine plus azithromycin vs. control; P=0.01 for hydroxychloroquine alone vs. control). P=0.02 for the occurrence of an elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level (pair-wise comparisons: P=0.01 for hydroxychloroquine plus azithromycin vs. control; P=0.09 for hydroxychloroquine alone vs. control).
Among patients who received hydroxychloroquine plus azithromycin, the serious adverse events were pulmonary embolism (in 2 patients), QTc prolongation (in 1; considered to be clinically important), myocardial infarction (in 1), and abdominal-wall hemorrhage (in 1); among patients who received hydroxychloroquine only, the serious adverse events were bradycardia (in 1) and pneumothorax (in 1); and among patients who received neither hydroxychloroquine nor azithromycin, the serious adverse events were bradycardia (in 1) and severe vomiting (in 1). The two serious adverse events leading to death were myocardial infarction and abdominal-wall hemorrhage with shock, both of which occurred in patients receiving hydroxychloroquine and azithromycin.
Anemia was defined as a hemoglobin level lower than 11 g per deciliter for men and lower than 10.5 g per deciliter for women.
An elevated ALT or AST level was defined as a level that was more than 3 times the upper limit of the normal range.
Hypoglycemia was defined as a glucose level below 40 mg per deciliter (2.2 mmol per liter).
Leukopenia was defined as less than 2500 leukocytes per cubic millimeter.
A low lymphocyte level was defined as less than 650 lymphocytes per cubic millimeter.
Thrombocytopenia was defined as a platelet count below 125,000 per cubic millimeter.