Safety of Antiepileptics During Drug Shortages

Andrew C. Fritschle-Hilliard, PharmD, BCPS, BCCCP; Patrick D. Walker, PharmD; Ryan Hakimi, DO, MS

Recent natural disasters and market consolidation of many drug manufacturers has resulted in widespread, critical national drug shortages. Many categories of pharmaceuticals have been affected, with IV fluids being one of the largest. Numerous health systems have implemented unique conservation tactics to maintain supply of small-volume parenteral solutions, resorting to strategies such as the administration of antibiotics via IV bolus and oral rehydration solutions. Additional management modalities might include use of oral/enteral medications when appropriate. Because of uncertainty associated with resolution of these shortages, additional agents often administered with assistance of a diluent product should be considered for small-volume IV or oral administration; one potential class is antiepileptic drugs (AEDs).

Clinical Considerations and Safety
The management of seizures and status epilepticus is centered on urgent administration of appropriately dosed AEDs. In the intensive care unit (ICU), this usually begins with IV formulations even when oral formulations are available. The use of IV AEDs is prudent in the first 24 to 48 hours of seizure activity, given rapid absorption and decreased time to achieve target serum concentrations; however, continued use of IV administration should be evaluated beyond 48 hours in patients who remain seizure-free.

Transition to Oral Formulation
Conversion from IV to oral formulation of AEDs that are not highly protein bound is reasonable in patients whose seizures have abated and who have no risk for malabsorption. Although institutional costs of AEDs are highly variable, IV formulations are generally more expensive than the equivalent oral formulations. Therefore, this management approach also reduces costs. Because of the potential for drug-drug and drug-food interactions, a uniform IV-to-oral conversion policy may not be appropriate for highly protein-bound medications such as phenytoin. For example, the presence of concomitant continuous enteral nutrition with phenytoin reduces the bioavailability of the drug, which may result in subtherapeutic serum concentrations. As such, the administration of interacting medications (e.g., binding resins), enteral nutrition, and highly protein-bound AEDs should be separated in time to circumvent this interaction. The common practice of maintaining patients on IV formulations as long as they are on continuous enteral nutrition should be reconsidered to prevent unnecessary continuation of a high-cost and non-superior formulation. Instituting multidisciplinary education of common drug-drug and drug-food interactions with clearly defined instructions in the electronic medical record for timing of administration will allow for appropriate conversion without risk of reduced efficacy.

Risk factors for malabsorption of oral AEDs include:

• Gastrointestinal hypermotility (persistent diarrhea, gastroenteritis, Clostridium difficile colitis)
• Delayed or decreased gut motility (bowel obstruction, ileus, gastroparesis, concomitant barbiturate use)
• High-dose vasopressors (norepinephrine equivalents of 12.5 µg/min)¹
• Induced hypothermia
• Drug-drug or drug-food interactions without adjustments to administration times

Alternative Method of IV Administration
It should be acknowledged that oral administration of AEDs might not be appropriate for all patients, despite seizure freedom. Therefore, given the nationwide IV diluent shortage, alternative methods of IV preparation warrant consideration. A potential solution is small volume administered via slow IV bolus or by using a smart infusion pump syringe module. Evaluating the appropriateness of this method of preparation requires review of maximum concentration limits, rate of administration, final product size, and risk for induction of hemodynamic instability. Administration time should not exceed 5 minutes for medications administered via IV bolus. For doses requiring administration beyond 5 minutes, use of a smart infusion pump syringe module is an alternative; this method requires being aware that the total volume infused must not exceed 60 mL. Table 1 provides a summary of alternative methods of IV administration for some AEDs.

Drug shortages often require unique management strategies. Clinical appropriateness and safety risks must be considered when altering prescription and administration to mitigate a change in supply of medications.

References

1. Mancl EE, Muzevich KM. Tolerability and safety of enteral nutrition in critically ill patients receiving intravenous vasopressor therapy. JPEN J Parenter Enteral Nutr.2013 Sep;37(5):641-651.
2. Brophy GM, Bell R, Claassen J, et al; Neurocritical Care Society Status Epilepticus Guideline Writing Committee. Guidelines for the evaluation and management of status epilepticus. Neurocritic Care. 2012 Aug;17(1):3-23.
3. Lexicomp Online. Pediatric and Neonatal Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc.; 2013; March 29, 2018.
4. Wheless JW, Clarke D, Hovinga CA, et al. Rapid infusion of a loading dose of intravenous levetiracetam with minimal dilution: a safety study. J Child Neurol. 2009 Aug;24(8):946-951.
5. Limdi NA, Knowlton RK, Cofield SS, et al. Safety of rapid intravenous loading of valproate. Epilepsia. 2007 Mar;48(3):478-483.