Apixaban Auto-intoxication: Toxicokinetics and Coagulation Tests

Mast, L.; Verheul, Rolf J.; Reijnen, Resi; Rossen, Ralph; Overdiek, J. W. P. M.; Wilms, Erik B

doi:10.1160/th17-07-0474

Cited by 6 publications

(11 citation statements)

References 7 publications

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“…As previously reported, the apixaban plasma concentration vs. time profile exhibited a multiphasic elimination profile, with an initial rapid decline followed by a more gradual terminal phase [4]. Apixaban was eliminated with a terminal half-life of 8.2 h. The half-life described in adults overdose was between 6 h and 15 h depending on the patient and other co-administered drugs [6][7][8][9]. The rapid elimination may explain the absence of bleeding despite high concentrations.…”

Section: Discussion/conclusionsupporting

confidence: 53%

“…Apixaban has linear pharmacokinetics, and concentration-related pharmacodynamic effects have been described in adults [4]. Many clinical cases reported severe self-poisoning with apixaban among adult patients [5][6][7][8][9]. To date, there is no available data about apixaban pharmacokinetics in children, and no intoxication has previously been described.…”

Section: Introductionmentioning

confidence: 99%

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Accidental apixaban intoxication in a 23-month-old child: a case report

et al. 2020

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Background Direct oral anticoagulants, such as apixaban, are increasingly used in everyday practice in order to treat or prevent thromboembolic diseases. To date, there is no available data about apixaban pharmacokinetics in children, and no intoxication has previously been described. Case presentation A 23-month-old boy, with no medical history, was admitted to the emergency department 2 h after accidentally ingesting 40 mg apixaban and 0.75 mg digoxin. No adverse event was observed. Digoxin trough level was within therapeutic values. Apixaban blood concentration increased up to 1712 μg/L at H + 6 (1000–2750 μg/L using 2–5 mg/kg of apixaban in adults). The terminal half-life was 8.2 h (6–15 h in adults). The rapid elimination may explain the absence of bleeding despite high concentrations. Conclusions Despite an important intake of apixaban and a real disturbance in routine coagulation assays, no clinical sign of bleeding was observed, perhaps due to wide therapeutic range of apixaban. It may also be explained by its rapid elimination. Considering the high Cmax and a possible enteroenteric recycling, the use of activated charcoal should be considered in such situations in order to prevent eventual bleeding.

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Section: Discussion/conclusionsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Accidental apixaban intoxication in a 23-month-old child: a case report

et al. 2020

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“…Another important finding is that anti‐Xa activity seems to be linearly related to concentrations up to 4000 μg l −1 . This is the fourth published case of self‐poisoning with Apixaban , with the highest concentrations reported so far. The apparent half‐life is close to the usual value at therapeutic doses (mean/SD: 11.7 h/3.3) .…”

Section: Discussionmentioning

confidence: 77%

Self‐poisoning with 60 tablets of Apixaban, a pharmacokinetics case report

Franck¹,

Dulaurent²,

Balkhi³

et al. 2018

Brit J Clinical Pharma

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A 67‐year‐old man was admitted to the emergency department about 5 h after deliberate self‐poisoning with 300 mg of Apixaban. The clinical examination did not show any organ dysfunctions or haemorrhagic signs, and the patient's life was not in danger. The first analysis, upon admission, showed a concentration of 2655 μg l−1 of Apixaban. The Cmax was observed 17 h after the intake (3654 μg l−1), about four times the classical Tmax value (median [range]: 4 h [2–4]). The Apixaban was then eliminated following a first order elimination with a calculated half‐life of 10.8 h. The anti‐Xa activity seems to be linearly related to concentration up to 4000 μg l−1. This report suggests that the use of activated charcoal should be effective up to 17 h after a massive intake.

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“…34 Finally, a 48-year-old woman who ingested 280 mg apixaban developed minimal bleeding despite a superficial knife cut in her left elbow. 25 Overall, neither plasma DOAC levels nor coagulation parameters correlated well with bleeding. In our series, the observed peak concentrations did not correlate with the presumed ingested dose.…”

Section: Discussionmentioning

confidence: 91%

“…Overall, 29 additional cases mostly involving intentional exposure to dabigatran ( n = 15), rivaroxaban ( n = 8) and apixaban ( n = 6) were published (Table 3). 12–35 Only 10 of these 29 cases presented bleeding. A 53‐year‐old man who co‐ingested 200 mg apixaban presented minor oozing from his femoral venous line insertion site, easily controlled with direct pressure and prothrombin complex concentrate 13 .…”

Section: Discussionmentioning

confidence: 99%

Case series of massive direct oral anticoagulant ingestion—Treatment and pharmacokinetics data

Delrue

Chevillard

Stépanian

et al. 2022

Eur J Clin Investigation

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Background Direct oral anticoagulants (DOAC) are widely used due to favourable benefit/risk ratio. However, consequences of massive ingestion have been poorly investigated. Objectives We aimed to report outcome and pharmacokinetic parameters in patients who massively ingested DOACs. Methods We conducted a 5‐year cohort study including consecutive massive DOAC ingestion patients admitted to two critical care departments. Patients were managed in accordance with standards of care. We collected the main history, clinical, laboratory, management and outcome data. The time‐course of plasma DOAC concentrations measured using specific assays was modelled. Results Twelve patients (3F/9M; age, 55 years [41–63], median [25th–75th percentiles]) were included. Ingestions involved rivaroxaban (n = 7), apixaban (n = 3) and dabigatran (n = 2), with presumed doses of 9.4‐fold [5.0–22.0] the full daily dose. Six patients received activated charcoal but no antidote nor blood‐derived product. No bleeding was observed. One patient died due to refractory cardiogenic shock related to bisoprolol co‐intoxication. Highest observed peak plasma concentrations were 1720 ng/ml (rivaroxaban), 750 ng/ml (apixaban) and 644 ng/ml (dabigatran). Times to reach DOAC concentration below 50 ng/ml were ~20–45 h (rivaroxaban), ~125 h (apixaban) and ~30–50 h (dabigatran). Elimination half‐lives were 2.5–25.5 h (rivaroxaban), 22.0 and 36.5 h (apixaban), and 5.8 and 15.5 h (dabigatran), with substantial interindividual variability and prolongation in case of cardiovascular failure related to co‐intoxicants. Charcoal administration, even if delayed, may have contributed to limit toxicity, possibly by reducing absorption and/or enteroenteric recycling. Conclusion No bleeding was observed in this series of massive DOAC ingestions despite elevated plasma concentrations. No patient required specific haemostatic agents. Charcoal administration should be considered to limit toxicity.

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Apixaban Auto-intoxication: Toxicokinetics and Coagulation Tests

Cited by 6 publications

References 7 publications

Accidental apixaban intoxication in a 23-month-old child: a case report

Accidental apixaban intoxication in a 23-month-old child: a case report

Self‐poisoning with 60 tablets of Apixaban, a pharmacokinetics case report

Case series of massive direct oral anticoagulant ingestion—Treatment and pharmacokinetics data

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