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Introduction: Chronic tricyclic antidepressant toxicity is rarely described in children. Symptoms include confusion, ataxia, and seizures. Toxicity may result from dosing error, CYP2C19 and CYP2D6 genetic variability, and drug-drug interactions. Chronic doxepin toxicity has not been previously reported in children. Doxepin is prescribed for insomnia and depression, with a maximum off-label dose of 3 mg/kg in children. We present a case of chronic doxepin toxicity mimicking epilepsy in a child attributable to three potential factors: supratherapeutic dosing, pharmacogenomic variability, and drug-drug interactions., Case Report: A 10-year-old boy with insomnia, diagnosed with epilepsy 6 months prior, presented to an emergency department with confusion, ataxia, and increasing seizure frequency. He was prescribed doxepin for insomnia and four antiepileptics for seizures. After admission, he had two seizures and remained confused. EKGs showed QRS prolongation, suggesting doxepin toxicity. Doxepin-nordoxepin combined serum concentration was 1419 ng/mL (therapeutic 100-300 ng/mL), confirming doxepin toxicity. Outpatient records showed onset of confusion and seizures as doxepin dose was gradually uptitrated to 300 mg nightly (4.41 mg/kg). Symptoms worsened following addition of clobazam (CYP2D6 inhibitor) and topiramate (CYP2C19 inhibitor). Following doxepin discontinuation, all symptoms resolved. CYP2D6 testing showed intermediate metabolizer phenotype (CYP2D6*1/*4; activity score = 1.0; copy number = 2.0). No seizures have occurred in more than one year since doxepin discontinuation., Discussion: Caution must be exercised when prescribing doxepin. Pharmacogenomics, dose, drug-drug interactions, and age should be considered. Chronic toxicity should be contemplated in patients taking doxepin without acute overdose who present with persistent neurologic abnormalities including seizure., (© 2023. American College of Medical Toxicology.)

Introduction: Recurrent physostigmine shortages present a challenge to healthcare providers treating antimuscarinic delirium. Other centrally acting acetylcholinesterase inhibitors such as rivastigmine may represent a therapeutic alternative or adjunct during physostigmine shortage; however, previous reports of use have not documented serum antimuscarinic toxin concentrations, limiting evaluation of effectiveness. Combination therapy with physostigmine and rivastigmine has not been described. In this report, the authors present a case of diphenhydramine-induced antimuscarinic delirium with elevated diphenhydramine serum concentrations treated with physostigmine and transdermal rivastigmine without observed adverse effect., Case Report: A 48-year-old female presented to an emergency department after ingesting 3.75 g (41.2 mg/kg) of diphenhydramine. She had antimuscarinic delirium with a presenting serum diphenhydramine concentration of 1500 ng/mL (therapeutic range, 25-112 ng/mL) and required two doses of physostigmine to avert intubation prior to intensive care unit (ICU) admission. At hospital hour 22, in the ICU, antimuscarinic delirium persisted but no further physostigmine was available due to hospital shortage. Therefore, a 9.5-mg transdermal rivastigmine patch was applied. By hospital hour 24, her delirium had resolved. A serum diphenhydramine concentration at hospital hour 25 was elevated at 760 ng/mL. Transdermal rivastigmine was discontinued at hospital hour 48 without recurrent delirium. Despite persistent normal mental status after rivastigmine discontinuation, the patient had a dry mouth, difficulty urinating, and mydriasis until hospital day 5. She never developed muscarinic toxicity., Discussion: Transdermal rivastigmine may be a useful treatment alternative or adjunct during physostigmine shortage for antimuscarinic delirium and has a long duration of action without aspiration risk. Muscarinic toxicity was not observed., (© 2022. American College of Medical Toxicology.)

Introduction: Warfarin induces coagulopathy. Guidelines protocolize reversal of supratherapeutic international normalized ratio (INR) in patients dependent on anticoagulation, but practices vary for reversing warfarin-induced coagulopathy after overdose in non-warfarin-dependent patients., Case Report: This is the report of a 15-year-old female who ingested her father's warfarin (100-200 mg) in a self-harm attempt. At hour 24 post-ingestion, her INR was 2.00 and she was admitted for monitoring. Reversal of coagulopathy was initially deferred pending the INR trend. The INR was 5.10 at hour 60 and 2.5 mg oral vitamin K 1 (VK1) was given. At hour 85, the INR peaked at 6.67 and she received a second oral dose of 2.5 mg VK1. On day 8, she was medically cleared with an INR of 1.31. On day 11, she developed lower abdominal pain and diarrhea. Imaging revealed a duodenal hematoma, and symptoms improved spontaneously. She was again medically cleared 13 days post-ingestion. Her serum warfarin concentration peaked at 19 mcg/mL at hour 46. Serial warfarin concentrations were obtained, demonstrating first-order elimination kinetics and a 30-hour half-life., Conclusion: A restrictive approach to coagulopathy reversal in non-warfarin-dependent patients with intentional warfarin overdose may result in worsening coagulopathy, bleeding, and lengthy hospital stay. Given the risk for significant, prolonged coagulopathy, these patients should be treated early with VK1, with subsequent serial INR monitoring and probable additional VK1 dosing. Delayed peak warfarin concentrations support consideration of gastrointestinal decontamination in late presenters., (© 2022. American College of Medical Toxicology.)

Background: Prescription drug monitoring programs (PDMPs) exist in 49 states to guide opioid prescribing. In 40 states, clinicians must check the PDMP prior to prescribing an opioid. Data on mandated PDMP checks show mixed results on opioid prescribing., Objectives: This study sought to examine the impact of the Massachusetts mandatory PDMP check on opioid prescribing for discharges from an urban tertiary emergency department (ED)., Methods: This was a retrospective cohort study of discharges from one ED from 7/1/2010-10/15/2018. The primary outcome was the monthly percentage of patients discharged from the ED with an opioid prescription. The intervention was Massachusetts mandating a PDMP check for all opioid prescriptions. Prescribing was compared pre- and post-mandate. Interrupted time series (ITS) analysis accounted for known declining trends in opioid prescribing., Results: Of 273,512 ED discharges, 35,050 (12.8%) received opioid prescriptions. Mean monthly opioid prescribing decreased post-intervention from 15.1% (SD ± 3.5%) to 5.1% (SD ± 0.9%; p < 0.001). ITS showed equal pre and post-intervention slopes (-0.002, p = 0.819). A small immediate decrease occurred in prescribing around the mandated check: a 3-month level effect decrease of 0.018 (p = 0.039), 6-month level effect 0.019 (p = 0.023), and a 12-month level effect of 0.020 (p = 0.019). The 24-month level effect was not decreased., Conclusion: Prior to the mandated PDMP check, ED opioid prescribing was declining. The mandate did not change the rate of decline but was associated with a non-sustained drop in opioid prescribing immediately following enactment.

Introduction: Medications are compounded when a formulation of a medication is needed but not commercially available. Regulatory oversight of compounding is piecemeal and compounding errors have resulted in patient harm. We review compounding in the United States (US), including a history of compounding, a critique of current regulatory oversight, and a systematic review of compounding errors recorded in the literature., Methods: We gathered reports of compounding errors occurring in the US from 1990 to 2020 from PubMed, Embase, several relevant conference abstracts, and the US Food and Drug Administration "Drug Alerts and Statements" repository. We categorized reports into errors of "contamination," suprapotency," and "subpotency." Errors were also subdivided by whether they resulted in morbidity and mortality. We reported demographic, medication, and outcome data where available., Results: We screened 2155 reports and identified 63 errors. Twenty-one of 63 were errors of concentration, harming 36 patients. Twenty-seven of 63 were contamination errors, harming 1119 patients. Fifteen errors did not result in any identified harm., Discussion: Compounding errors are attributed to contamination or concentration. Concentration errors predominantly result from compounding a prescription for a single patient, and disproportionately affect children. Contamination errors largely occur during bulk distribution of compounded medications for parenteral use, and affect more patients. The burden falls on the government, pharmacy industry, and medical providers to reduce the risk of patient harm caused by compounding errors., Conclusion: In the US, drug compounding is important in ensuring access to vital medications, but has the potential to cause patient harm without adequate safeguards.