Postmarketing DigiBind and DigiFab reports submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) revealed that adverse events (AEs) were generally consistent with the safety experience observed in pre-licensure clinical trials and the products’ package inserts. |
Cardiac (bradycardia, cardiac arrest, and hypotension) and non-cardiac (nausea and hyperkalemia) AEs were among the most commonly reported for both products. |
A substantial number of death reports were attributed to glycoside poisoning with agents other than digoxin (off-label use), but no deaths were attributed to DigiBind and DigiFab. |
1 Introduction
2 Methods
2.1 FAERS Database
2.2 Data Analysis
2.2.1 Descriptive Analysis
2.2.2 Data Mining Analysis
2.2.3 Case Reviews
2.3 Ethics
3 Results
Report | DigiBinda | DigiFabb |
---|---|---|
No. (%) | No. (%) | |
Total reports | 78 (100) | 43 (100) |
Serious | 68 (87.2) | 27 (62.8) |
Sex | ||
Females | 44 (56.4) | 18 (41.9) |
Males | 22 (28.2) | 16 (37.2) |
Not specified | 12 (15.4) | 9 (20.9) |
Age (years) | ||
< 65 | 15 (19.2) | 14 (32.6) |
≥ 65 | 40 (51.3) | 17 (39.5) |
Not specified | 23 (29.5) | 12 (27.9) |
Year received at FDA | ||
1986–1990 | 27 (34.6) | N/A |
1991–1995 | 30 (38.5) | N/A |
2001–2010 | 18 (23.1) | 5 (11.6) |
2011–2019 | 3 (3.8)c | 38 (88.4) |
Type of report | ||
Expedited (15-day) | 40 (51.3) | 26 (60.5) |
Not expedited | 28 (35.9) | 11 (25.6) |
Direct | 10 (12.8) | 6 (14.0) |
Completeness scored | ||
< 20% | 11 (14.1) | 7 (16.3) |
20–39% | 30 (38.5) | 15 (34.9) |
40–59% | 9 (11.5) | 17 (39.5) |
60–79% | 20 (25.6) | 2 (4.7) |
≥ 80% | 8 (10.3) | 2 (4.7) |
Reported outcome | ||
Death | 19 (24.4) | 13 (30.2) |
Non-death | ||
Hospitalized, disabled, life-threatening, or required intervention | 27 (34.6) | 4 (9.3) |
Other | 22 (28.2) | 10 (23.3) |
Not reported | 10 (12.8) | 16 (37.2) |
3.1 Most Frequently Reported PTs for DigiBind and DigiFab
PT | DigiBind (78 total reports) | DigiFab (43 total reports) | Labeled eventb |
---|---|---|---|
No. (%) | No. (%) | ||
Total PTs | 212 | 155 | N/A |
Toxicity to various agents | 17 (8.0) | 7 (4.5) | Yes |
Off-label use | N/A | 12 (7.7) | N/A |
Drug ineffective | 14 (6.6) | 10 (6.5) | Effectiveness |
Bradycardia | 8 (3.8) | 6 (3.9) | Yes |
Blood creatinine increased | 7 (3.3) | a | Yes |
Cardiac arrest | 7 (3.3) | 6 (3.9) | Yes |
Medication error | 5 (2.4) | 6 (3.9) | No |
Completed suicide | N/A | 5 (3.2) | Yes |
Atrioventricular block complete | 5 (2.4) | a | Yes |
Cardioactive drug level increased | 5 (2.4) | 4 (2.6) | Yes |
Hypotension | 5 (2.4) | 4 (2.6) | Yes |
Renal failure | 5 (2.4) | 3 (1.9) | Yes |
Ventricular tachycardia | 5 (2.4) | a | Yes |
Arrhythmia | 4 (1.9) | a | Yes |
Nausea | 4 (1.9) | 4 (2.6) | Yes |
Overdose | 4 (1.9) | N/A | Yes |
Abdominal pain | 3 (1.4) | a | Yes |
Alanine aminotransferase increased | 3 (1.4) | N/A | No |
Aspartate aminotransferase increased | 3 (1.4) | N/A | No |
Blood urea increased | 3 (1.4) | a | Yes |
Cardiac failure congestive | 3 (1.4) | N/A | Yes |
Dermatitis | 3 (1.4) | N/A | No |
Hyperkalemia | 3 (1.4) | 3 (1.9) | Yes |
Pancreatitis | 3 (1.4) | N/A | No |
Sudden death (or death) | 3 (1.4) | 3 (1.9) | Yes |
Vomiting | 3 (1.4) | a | Yes |
Acute kidney injury | N/A | 3 (1.9) | Yes |
Drug ineffective for unapproved indication | N/A | 3 (1.9) | Effectiveness |
3.2 Data Mining (Disproportionality Analyses)
SOC | DigiBind | DigiFab | ||
---|---|---|---|---|
PT | No. | EBGM (90% CI) | No. | EBGM (90% CI) |
Cardiac disorders | ||||
Bradycardia | 8 | 5.5 (2.9–10.1) | 6 | 57.7 (25.9–113.5) |
Cardiac arrest | 7 | 4.3 (2.2–7.6) | 6 | 26.1 (5.1–65.8) |
Ventricular tachycardia | 5 | 5.1 (2.1–16.5) | a | a |
Injury, poisoning, and procedural complications | ||||
Medication error | a | a | 6 | 6.3 (2.7–20.0) |
Off-label useb | a | a | 12 | 5.2 (3.2– 8.3) |
Toxicity to various agents | 16 | 43.1 (27.9–64.2) | 7 | 5.2 (2.7– 9.8) |
Investigations | ||||
Cardioactive drug level increased | 5 | 150.6 (65.7–306.2) | 4 | 206.5 (80.0–459.0) |
Psychiatric disorders | ||||
Completed suicide | a | a | 5 | 7.6 (2.5–35.7) |
3.3 Case Review
3.3.1 Death Reports
Characteristic | DigiBind | DigiFab | |
---|---|---|---|
No. (%) | No. (%) | ||
Total death reports | 19 (100) | 13 (100) | |
Sex | |||
Females | 10 (52.6) | 5 (38.5) | |
Males | 5 (26.3) | 6 (46.2) | |
Not specified | 4 (21.1) | 2 (15.4) | |
Age (years) | |||
< 65 | 4 (21.1) | 6a (46.2) | |
≥ 65 | 8 (42.1) | 5b (38.5) | |
Not specified | 7 (36.8) | 2 (15.4) | |
Time from hospital admission to death (h) | |||
< 24 | 3 (15.8) | 7 (53.8) | |
≥ 24 | 3 (15.8) | 4 (30.8) | |
Not specified | 13 (68.4) | 2 (15.4) | |
Causes of death | |||
Digoxin toxicity | 1 (5.3) | 2 (15.4) | |
Suicide | 1 (5.3) | 7 (53.8) | |
Underlying comorbidities | 2 (10.5) | 2 (15.4) | |
Not specified | 15 (78.9) | 2 (15.4) |
3.3.2 Unlabeled AEs
3.3.3 Medication Error
3.3.4 Off-Label Use (Non-digoxin Cardiac Glycoside Poisoning)
Case # | Sex | Age | Agents | Clinical manifestations | Interval from poisoning to admission | Serum potassium (mmol/L) | Serum digoxin (ng/mL) | DigiFab (vials) | Outcome |
---|---|---|---|---|---|---|---|---|---|
1 | Female | 33 | Almendra quema grasaa | Lethargic, bradycardia, prolonged QRS | Unknown | 8.9 | N/A | 9 | Death |
2 | Male | 74 | Oleander leaves | Nausea, vomiting, bradycardia, cardio-respiratory arrest | “Couple of hours” | N/A | 3.23 | N/A | Death |
3 | Female | 33 | Cerbera odollamb | Vomiting, diaphoresis, altered mental status, bradycardia, AV block, VT | Unknown | 8.9 | 3.1 | 10 | Death |
4 | Male | 30 | C. odollam | Vomiting, bradycardia, AV block, cardiac arrest | 12 h | 10.1 | 1.6 | 13 | Death |
5 | Male | 22 | C. odollam | Vomiting, diarrhea, bradycardia, AV block | 7 h | 5.2 | 1.3 | 20 | Death |
6 | Male | 19 | Taxus baccata (English yew)c | Vomiting, tachycardia, cardiac arrest | Unknown | N/A | N/A | N/A | Death |
7 | Female | 44 | T. baccata | unconscious, bradycardia, long QT interval | Unknown | N/A | < 0.1 | 2 | Recovered |
8 | Female | 86 | Convallaria majalisd | Nausea, vomiting, abdominal pain, bradycardia, LBBB | 1 week | 7.2 | 4.9 | 10 | Unknown |
9 | Female | 16 | Crataegus mexicanae | Nausea, vomiting, diarrhea, drowsiness, bradycardia, AV block | 8 h | N/A | 0.7 | 2 | Recovered |
10 | Male | 29 | Toad headf | Vomiting, bradycardia | Unknown | 6.9 | 0.98 | 10 | Recovered |
11 | Male | 49 | Jamaican stonesg | Nausea, vomiting, abdominal pain, bradycardia | 2 h | 6.1 | N/A | 3 | Recovered |
12 | Male | 39 | Piedra China | Vomiting, diaphoresis, bradycardia, AV block, cardiac arrest | Unknown | 4.6 | 1.14 | 33 | Death |