Managing Patients with Epilepsy during COVID-19, Pharmacotherapy-related Recommendations

Prepared by a Task Force of the AES Council on Clinical Activities:

• Timothy Welty, PharmD, College of Pharmacy and Health Sciences, Drake University, Des Moines, IA
• Jon Cokley, PharmD, Texas Childrens Hospital, Houston, TX
• Barry Gidal, PharmD, School of Pharmacy, University of Wisconsin, Madison, WI

Reviewed by the AES Treatments Committee and approved by the committee and the AES Council on Clinical Activities.  

Medication Adherence and Supply

• Patients/caregivers should get refills 2 weeks prior to running out of medications.
• Patients/caregivers should work with their local pharmacy to synchronize prescription refills, so all medications can be refilled at the same time.
• When possible, prescribers should write prescriptions of maintenance medications for 90-day supplies.
• Patients or caregivers should maintain a routine schedule of taking medications, even during times when daily activities are disrupted. Using various reminders (e.g., alarms, pill boxes, calendars) are very helpful.
• Patients may receive different strengths of drugs, should there be a shortage of a specific strength, as long as the total daily dose is not different than the prescribed dose.
• Patients or caregivers should be updated on how to handle missed doses of medications.
• Seizure rescue plans should be developed. Sample rescue plans are available at Epilepsy.com (https://www.epilepsy.com/learn/managing-your-epilepsy/seizure-response-plans-101). If medications are involved in seizure rescue plans, patients should have these medications on hand with no less than a 6-month expiration date.
• Pharmacists should discuss with patients a seizure rescue plan (https://www.epilepsy.com/learn/managing-your-epilepsy/seizure-response-plans-101) and refer patients to their healthcare provider if rescue medications (e.g., benzodiazepines) are appropriate.
• The EF is monitoring the FDA and American Society of Health-system Pharmacists Websites for medication shortages. Patients and prescribers should be alerted to shortages if they occur.
• Generic products have been shown to be safe and effective in multiple studies. Healthcare professionals (e.g., physicians, pharmacists, nurses, APPs) should allay any concerns of patients and caregivers regarding the use of generic medication products. Patients may need to take various generic products should medication shortages occur.
• Physicians and other prescribers should work with patients to establish alternate treatment plans should severe shortages of the patient’s medication occur. This could include switching to another antiseizure medications (ASM), alteration of dosing, or a variety of other possible actions.

Use of Non-prescription Medications and Natural Products

• Patients should always check with their pharmacist or physician regarding the selection and use of nonprescription medications. The pharmacist is the best source of information, since they usually have the full medication history of the patient and understand the various nonprescription products that are available.
• There has been controversy around the use of ibuprofen and possibly other nonsteroidal anti-inflammatory drugs (NSAID) and worsening of COVID-19 disease. Acetaminophen is the preferred drug for treating fever, myalgias, and other COVID-19 symptoms. Caution should be taken to not overdose on acetaminophen, with the maximum daily adult dose being 4 grams. However, if acetaminophen is unavailable, NSAIDs should be used to reduce fever.
• It is generally best for patients to limit use of products that contain decongestants. Oral decongestants should be used for a short duration, as effectiveness will wane over a few days. Nasal decongestant products should be avoided.
• In some places, herbal products that contain various constituents, such as Ma Huang (ephedra), have been used in treating COVID-19. These products should be avoided in patients with epilepsy as they may interact with ASM and could exacerbate seizures.
• Patients should always be asked about nonprescription medication and natural product use when taking a medication history.

Possible Drugs for Treating COVID-19

• Several different drugs are being studied for treating COVID-19. While some of these medications may be effective, they all have adverse effects and some have potential drug interactions. Some of the adverse effects can include seizures.
• Patients should never take these medications outside of the care and management of a physician knowledgeable in their use.
• Patients should never use products that may contain these medications, but are not intended for human use.
• Chloroquine and hydroxychloroquine are known to prolong QT intervals. Combinations with other drugs may cause cardiac arrhythmias, including Torsades de Pointes. Examples of medications, but not limited to, common in epilepsy patients include SSRIs, antipsychotics, and ASM that may alter cardiac rhythm. Close monitoring of cardiac rhythm is advised with these combinations.
• The following Table 1 contains a list of possible medications for treating COVID-19, their common or serious adverse effects, and possible drug interactions with ASM.

Table 1. Possible medications for treating COVID-19, their common or serious adverse effects, and possible drug interactions with antiseizure medications (April 17, 2020 update)

¹ Information on proven drug interactions is limited. These are possible interactions based on hepatic routes of metabolism or the ability of a drug to induce or inhibit metabolic enzymes. Additionally, other interactions may occur. Increased patient monitoring for potential drug interactions is recommended. 

Remdesivir Metabolism and Drug Reactions

Background: Remdesivir is an antiviral that was developed to treat ebola. Preliminary studies have indicated possible efficacy in treating patients with SARS-CoV-2 and severe COVID-19 disease. It is an adenosine nucleotide prodrug that is metabolized to the active nucleoside triphosphate metabolite in cells where it distributes.

Pharmacokinetics, Metabolism, and Possible Drug Interactions: Little data on its pharmacokinetics and drug-drug interactions (DDI) has been published. Information from the manufacturer indicates that remdesivir is a substrate of CYP 2C8, CYP 2D6, and CYP 3A4. Remdesivir is a substrate of the transporters OATP (Organic Anion Transporter Polypeptide) 1B1 and P-glycoprotein (Pg-P). Inducers and inhibitors of these enzyme systems, including antiseizure medications (ASM), could alter response to remdesivir. The manufacturer of remdesivir does not anticipate major drug interactions due to the basic pharmacokinetics of remdesivir and dosing protocols that are being used.

Remdesivir does inhibit CYP 3A4, OATP1B1, OATP1B3, Bile Salt Export Pump (BSEP), Multidrug Resistance Protein (MRP4), and Sodium taurocholate co-transporting polypeptide (NTCP) in vitro, but the clinical relevance of these studies has not been established. The very short half-life of remdesivir reduces the likelihood of interactions with substrates of these enzyme systems.

Conclusion: The manufacturer of remdesivir has not identified and does not anticipate DDI, based on its pharmacokinetic profile and usual dosing regimen in COVID-19 disease. If possible DDI are observed in clinical practice, they should be reported to the FDA MedWatch surveillance program.

References

1. Gilead Sciences Inc. Remdesivir: pharmacokinetic profile. Personal communication. April 14, 2020.
2. Gilead Sciences Inc. Fact sheet for healthcare providers emergency use authorization (EUA) of remdesivir. https://www.gilead.com/-/media/files/pdfs/remdesivir/eua-fact-sheet-for-hcps_01may2020.pdf. Accessed May 22, 2020.

Antiseizure Medications and Vitamin D

Background: Some studies have indicated a possible link between susceptibility to and severity of COVID-19 infection and low vitamin D (25-OHD) concentrations. Patients with epilepsy often have low vitamin D (25-OHD) concentrations.

Information: No definite data exist that indicate increased susceptibility or COVID-19 disease severity in patients with epilepsy and treated with antiseizure medications that decrease 25-OHD concentration. However, monitoring of 25-OHD concentrations and appropriate vitamin D supplementation to treat any deficiency may be beneficial. There is an increased risk of low 25-OHD concentrations in patients taking enzyme-inducing antiseizure medications.

Conclusion: Patients with epilepsy should have 25-OHD concentrations routinely measured. If a 25-OHD deficiency is identified appropriate vitamin D supplementation should be initiated to correct any deficiencies. Ongoing 25-OHD monitoring in these patients is advised.

References

1. Hastie CE, Mackay DF, Ho F, et.al. Vitamin D concentration and COVID-19 infection in UK Biobank. Diabetes Metab Syndro 2020;14(4):561-565. doi: 10.1016/j.dsx.2020.04.050.
2. Menninga N, Koukounas Y, Margolis A, et.al. Effects of enzyme-inducing antiseizure medication in vitamin D dosing in adult veterans with epilepsy. Epilepsy Res 2020;161:106287. doi: 10.1016/j.eplepsyres.2020.106287.
3. Teagarden DL, Meador KJ, Loring DW. Low vitamin D levels are common in patients with epilepsy. Epilepsy Res 2014;108(8):1352-56. doi: 10.1016/j.eplepsyres.2014.06.008.

COVID-19, Anticoagulation, and Antiseizure Medications

Background: Patients with severe COVID disease appear to be at increased risk for ischemic changes and thrombotic events due to the development of a hypercoagulable state. Observations from China and elsewhere suggest that worsening of respiratory symptoms may be accompanied by increases in D-dimer levels and prolonged prothrombin time, along with decreases in fibrinogen and platelet count1. It has been suggested that anticoagulation with both heparinoids as well as non-Vit K antagonist, direct oral anticoagulants (DOAC) may reduce microthrombus formation2,3.

Anticoagulants and Antiseizure Medications: Several DOAC agents have been introduced in the past few years. From a pharmacokinetic perspective, these agents may be susceptible to multiple drug interactions with commonly used antiseizure medications (ASM), given that the DOACs are substrates for the intestinal transporter, P-glycoprotein (Pgp), and most are substrates, at least in part, for cytochrome  p-450 3A4 (CYP3A4). While there are very limited clinical data, clinicians should be aware, and anticipate, potentially meaningful drug-drug interactions with ASMs.

In general, drugs that are inducers of CYP3A4 and or intestinal PgP, may be expected to reduce systemic exposure, and therefore reduce clinical activity of DOACs. Concomitant treatment with inducers of either metabolism or drug transport should be used with caution.

Strong CYP3A/PgP inducers:

• Carbamazepine, phenytoin, phenobarbital
• Modest CYP3A inducers:
• Topiramate, oxcarbazepine, eslicarbazepine, felbamate

In addition, it has been suggested that levetiracetam and valproic acid may interfere with DOAC efficacy via PgP interactions.

Table 1. Pharmacokinetics of DOAC (adapted from Steffel, J., et al.⁴)

More detailed information on possible interactions between ASM and DOAC is available in a practical guide published by the European Society of Cardiology4. More extensive clinical guidance can be found in the References.

Conclusion: There are limited clinical data documenting interactions between ASM and DOAC. However, there is a potential for enzyme-inducing ASM to reduce the effectiveness of some DOAC. Care should be exercised in selecting a DOAC in patients receiving ASM to minimize the possibility of drug-drug interactions (DDI). If possible DDI are observed, a report should be filed with the FDA MedWatch surveillance program5.

References

1. Li T, Lu H, Zhang W. Clinical observation and management of COVID-19 patients. Emerg Microbes Infect. 2020;9(1):687‐690. doi:10.1080/22221751.2020.1741327
2. Stöllberger C, Finsterer J. Interactions between non-vitamin K oral anticoagulants and antiepileptic drugs. Epilepsy Res. 2016;126:98‐101. doi:10.1016/j.eplepsyres.2016.06.003
3. Taha M, Li W, Schmidt CM, Gonzalez-Castellon M, Taraschenko O. The interactions between anticonvulsants and non-vitamin K antagonist oral anticoagulant agents: A systematic review. Epilepsy Res. 2020;162:106304. doi:10.1016/j.eplepsyres.2020.106304
4. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39(16):1330‐1393. doi:10.1093/eurheartj/ehy136.
5. U.S. Food and Drug Administration. Medwatch: The FDA Safety Information and Adverse Event Reporting program. https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program. Accessed May 26, 2020.