An Observational Study of the Factor Xa Inhibitors Rivaroxaban and Apixaban as Reported to Eight Poison Centers.

STUDY OBJECTIVE: Rivaroxaban and apixaban are part of a new group of oral anticoagulants targeting factor Xa and approved by the Food and Drug Administration in 2011 and 2012. These oral anticoagulants are administered at fixed daily doses, without the need for laboratory-guided adjustments. There are limited data available on supratherapeutic doses or overdose of the oral Xa inhibitors. This study characterizes the clinical effect in patients exposed to rivaroxaban and apixaban. METHODS: A retrospective study collected data from 8 regional poison centers covering 9 states. Cases were initially identified by a search of the poison centers' databases for case mentions involving a human exposure to Xarelto, rivaroxaban, Eliquis, or apixaban. Inclusion criteria included single-substance exposure. Exclusion criteria were animal exposure, polysubstance exposure, or information call. Data for the study were collected by individual chart review, including case narratives, and compiled into a single data set. RESULTS: There were 223 patients: 124 (56%) were female patients, mean age was 60 years, and 20 were children younger than 12 years (9%). One hundred ninety-eight patients ingested rivaroxaban (89%) and 25 ingested apixaban (11%). Dose was reported in 182 rivaroxaban patients, with a mean dose of 64.5 mg (range 15 to 1,200 mg), and in 21 apixaban patients, with a mean dose of 9.6 mg (range 2.5 to 20 mg). For rivaroxaban, prothrombin time was measured in 49 patients (25%) and elevated in 7; partial thromboplastin time, measured in 49 (25%) and elevated in 5; and international normalized ratio, measured in 61 (31%) and elevated in 13. For apixaban, prothrombin time was measured in 6 patients (24%) and elevated in none; partial thromboplastin time, measure in 6 (24%) and elevated in none; and international normalized ratio, measured in 5 patients (20%) and elevated in none. Bleeding was reported in 15 patients (7%): 11 rivaroxaban and 4 apixaban. The site of bleeding was gastrointestinal (8), oral (2), nose (1), bruising (1), urine (1), and subdural (1). The subdural bleeding occurred after fall and head injury. All cases with bleeding involved long-term ingestions. Coagulation test results were normal in most patients with bleeding: prothrombin time 5 of 6 (83%), partial thromboplastin time 5 of 6 (83%), and international normalized ratio 5 of 9 (55%). Blood products were used in 7 rivaroxaban patients (1 suicide) and 3 apixaban patients. No bleeding or altered coagulation test results occurred in children, which all involved a one-time ingestion. All 12 suicide attempts involved rivaroxaban: altered coagulation test results occurred for 5 patients (42%), no bleeding occurred in any suicide attempt patient, 1 patient was treated with fresh frozen plasma (international normalized ratio 12.47), and dose by patient history did not predict risk of altered coagulation or bleeding. Two rivaroxaban patients experienced elevation of hepatic transaminase levels greater than 1,000 U/L. CONCLUSION: Bleeding after Xa inhibitor ingestion as a single agent is uncommon. Prothrombin time, partial thromboplastin time, or international normalized ratio may be elevated in a minority of cases but appears unreliable to measure risk of bleeding. Massive acute ingestion in suicide attempt may result in significant anticoagulation. Single exploratory ingestion by children was not associated with toxicity.

Benzonatate Ingestion Reported to the National Poison Center Database System (NPDS).

Little has been published on benzonatate ingestion, with the few case reports suggesting significant risk of seizures after poisoning. A 7-year retrospective review of all single substance ingestion of benzonatate reported to the National Poison Center Database System (NPDS) from 2000 to 2006. In this review, there were 2,172 patients, of which 1,280 (58%) were female. Mean age was 20 years, with 676 (30%) <6 years. Serious outcomes occurred in 116 (moderate, n = 81, 4%; major, n = 31, 1%; and death, n = 4, 0.2%). Mean age of those with serious outcome was 21 years, with 41 (35%) in children less than 6 years old. Forty-nine percent (1,084) patients were treated in a healthcare facility (HCF) of which 148 (7%) were admitted for medical care. Clinically significant effects that were documented included tachycardia (n = 31, 1%), agitation (n = 30, 1%), seizure (n = 23, 1%), coma (n = 14, 0.6%), ventricular dysrhythmia (n = 9, 0.4%), cardiac arrest (n = 8, 0.3%), hypotension (n = 7, 0.3%), and asystole (n = 6, 0.2%). Of patients with seizures reported, eight patients (0.4%) had multiple/discrete seizures and two had status epilepticus documented. Dysrhythmias but not seizures occurred in all fatalities in this review. Significant CNS and cardiac effects occurred in a small subset of this study (<1%), while half the patients received direct medical care in an HCF. No correlation between age and severity of medical outcome was detected by statistical analysis. A prospective study to better evaluate potential HCF triage criteria such as dosage, age, or preexisting conditions may be warranted. The fatalities from this study were due to dysrhythmias rather than seizures as previously reported in previous case reports. There were no clinical correlations between severity of outcomes and dose ingested. A median dose of 200 mg or greater suggests a potential for producing serious outcomes in a benzonatate exposure.

Increasing burden of pill identification requests to US Poison Centers.

INTRODUCTION: Information calls to poison centers, particularly for pill identification (PID), have been increasing. METHODS: Retrospective review of information calls reported to U.S. poison centers for 2002-2007. RESULTS: Total number of information calls increased by 44%, while calls related to human exposures increased by 4.3%. The subcategory "pill identification" was exclusively responsible for the increase in information calls with an increase of greater than 90%. Over the 6 years, PID requests from the public, police, and healthcare facility changed by +110, +144, and -24%, respectively. PID requests from the public, police, and healthcare facility were 78, 12 and 10%, respectively. Other information calls showed a decrease or no change: calls for poison information (-17%), medical information (-2.5%), and drug information (non-PID) (+1%). Twenty-five percent of all calls to U.S. poison centers are now to identify a pill unrelated to an exposure. Sixty-four percent of all identified pills were drugs with abuse potential. DISCUSSION: Drugs with abuse potential are less than 4% of pharmaceutical sales, yet greater than 60% of all PID requests involved drugs with abuse potential. This suggests that PID is strongly driven by interest in drugs with abuse potential. CONCLUSIONS: PID calls are increasing dramatically and taxing limited poison center resources. The majority requests for identification of an unknown pill involved drugs with abuse potential.

Toxicity from modafinil ingestion.

INTRODUCTION: Modafanil, a non-amphetamine stimulant, is used for narcolepsy, sleep apnea, and shift work sleep disorder. There is little available information on the toxicity of modafinil overdose. METHOD: We performed a retrospective multi-poison center chart review of patients from 11 states who had a single substance ingestion of modafanil with follow up to a known outcome for the years 2000-2007. Data collected included age, gender, dose ingested, clinical effects, length of hospital stay, and medical outcome. RESULTS: There were 137 patients, of whom 85 (63%) were female. Ages ranged from 1 to 82 years with a mean and median of 22 years (+18) and 20 years, respectively, with 43 patients (31%) aged <6 years. Most frequently reported clinical effects were tachycardia (n = 38), insomnia (n = 33), agitation (n = 27), dizziness (n = 25), and anxiety (n = 24). Forty-five patients were managed at home and 92 in a health-care setting, with only 23 (17%) requiring a medical admission. Therapies included benzodiazepines (n = 14), diphenhydramine (n = 5), beta-blockers (n = 3), haloperidol (n = 2), IV fluid hydration (n = 2), and one each of nitroglycerin, epinephrine, benztropine, and promethazine. CONCLUSIONS: In this case series, clinical effects of modafinil overdoses were generally mild with predominantly tachycardia and CNS toxicity. However, clinically significant effects warranting specific therapy occurred in a minority of patients.