Severe Accidental Overdose of 4-Aminopyridine Due to a Compounding Pharmacy Error

Abstract

Background: 4-Aminopyridine (4-AP) is a potassium channel-blocking drug used to ameliorate symptoms of multiple sclerosis and spinal cord injury by facilitating neural impulse conduction. It is not Food and Drug Administration (FDA) approved, but information about it is disseminated via the Internet, and it is currently available from compounding pharmacies with a physician's prescription. Dose-related toxicity is frequent and includes dizziness, insomnia, paresthesia, asthenia, headache, tremor, delirium, choreoathetosis, and seizures. Objectives: To report a case of life-threatening accidental overdose of 4-AP resulting from a pharmacy error. Case Report: A 42-year-old man with a history of C3 spinal cord injury with residual left-sided weakness and anesthesia, taking 4-AP, presented to the Emergency Department with the sudden onset of abdominal pain, vertigo, anxiety, profuse diaphoresis, hypersalivation, hypertension, bradycardia, agitation, and choreoathetosis, followed by status epilepticus. Toxicity due to 4-AP was suspected and the patient was treated symptomatically. He recovered with permanent short-term memory loss after a prolonged and complicated hospital course. Analysis of the pills, which had been prescribed for him by a physician and specially compounded by a pharmacist, showed that they contained approximately 10 times the dose indicated on the label, a dose that reliably produces severe toxicity. Conclusion: Emergency physicians should be familiar with the signs of 4-AP toxicity. Additionally, they should be aware that 4-AP and other non-FDA-approved medications may be available to patients from compounding pharmacies, and that quality control of made-to-order drug compounding may not be up to the standard that is expected with mass-produced pharmaceuticals.

Introduction

4-Aminopyridine (4-AP) is an orphan drug used to ameliorate symptoms of multiple sclerosis and spinal cord injury by facilitating neural impulse conduction (1). It is not Food and Drug Administration (FDA) approved, but information about it is disseminated via the Internet, and it is currently available from both brick-and-mortar and Internet compounding pharmacies with a physician's prescription (2, 3). Typical doses are 10–50 mg/day. A slow-release formulation of 4-AP (Fampridine SR 25 mg) has recently undergone phase 3 clinical trials (4). It is also marketed for agricultural use as Avitrol, which is used for repelling and killing bird pests (5). 4-AP selectively blocks voltage-gated potassium channels in nerve and other excitable tissues, prolonging the action potential, increasing presynaptic calcium influx, thus facilitating both interneuronal and neuromuscular transmission (6). Dose-related toxicity is frequent and includes dizziness, insomnia, paresthesia, asthenia, headache, diaphoresis, hypersalivation, tremor, delirium, choreoathetosis, and seizures (7). Despite the fact that 4-AP blocks potassium channels in experimental animal cardiac muscle preparations, it does not prolong the QT interval in therapeutic doses, nor has it yet been reported to produce torsade de pointes in overdose (8, 9). I report here a case of life-threatening accidental overdose of 4-AP resulting from a pharmacy error.