Table 2.
Potential drug-drug interactions between antiseizure drugs (ASMs) and COVID-19 candidate drugs*.
| A) List of drug-drug interactions with documented proof of evidence- | ||||
|---|---|---|---|---|
| COVID-19 candidate drug | Lopinavir b/ Ritonavir | Dexamethasone | ||
| Antiseizure medication | Relevant effect on enzymes | Inhibition of CYP3A4^ | Inducer/ Inhibitor of CYP3A subfamily | |
| Enzyme Inducers | Carbamazepine | Induction of CYP3A4 | Decrease in concentration of LPV/RTV Increase in concentration of CBZ (83 %) (Burman and Orr, 2000) |
Decrease in concentration of DEX Decrease in concentration of CBZ (Clearance rate ↑ by 1.41) (Bénit and Vecht, 2015) |
| + + + | ++ | |||
| Phenobarbital | Induction of CYP3A4 | Decrease in concentration of DEX Decrease in concentration of PB (Clearance rate ↑ by 1.79) (Bénit and Vecht, 2015) |
||
| ++ | ||||
| Phenytoin | Induction of CYP3A4 | Decrease in concentration of DEX Decrease in concentration of PHT (50 %) (Bénit and Vecht, 2015) |
||
| ++ | ||||
| Enzyme Inhibitor | Valproic acid | Increase in concentration of LPV (38 %) (DiCenzo et al., 2004) |
||
| + + | ||||
| Others | Lamotrigine | Decrease in concentration of LTG (50 %) (van der Lee et al., 2006) |
||
| + + | ||||
| Midazolam | Increase in concentration of MDZ (by a factor of 25) (Greenblatt et al., 2009) |
|||
| + + | ||||
| B) List of drug-drug interactions with potential risk hypothesized based on literature- | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| COVID-19 candidate drug | Remdesivir c | Chloroquine/ Hydroxy-chloroquine a | Lopinavir b/ Ritonavir | Ivermectin | Dexamethasone | Tocilizumab d | Anakinra e | ||
| Antiseizure medication | Relevant effect on enzymes | Inhibition of CYP3A4 | Inhibition of CYP3A4^ | Inducer/ Inhibitor of CYP3A subfamily | Increase in CYP3A4 (indirect effect) |
Increase in CYP3A4 (indirect effect) |
|||
| Enzyme Inducers | Carbamazepine | Induction of CYP3A4 | Decrease in concentration of RDV | Decrease in concentration of CLQ/HCLQ | Decrease in concentration of IVM | Decrease in concentration of CBZ | Decrease in concentration of CBZ | ||
| + | + + + | ++ | + | + | |||||
| Eslicarbazepine | Induction of CYP3A4 | Decrease in concentration of CLQ/HCLQ | Decrease in concentration of LPV/RTV | Decrease in concentration of IVM | Decrease in concentration of DEX Decrease in concentration of ESL |
||||
| ― | + + | + + | ++ | ++ | ― | ― | |||
| Oxcarbazepine | Induction of CYP3A4 | Decrease in concentration of CLQ/HCLQ | Decrease in concentration of LPV/RTV | Decrease in concentration of IVM | Decrease in concentration of DEX Decrease in concentration of OXC |
||||
| ― | + + | + + | ++ | ++ | ― | ― | |||
| Phenobarbital | Induction of CYP3A4 | Decrease in concentration of RDV | Decrease in concentration of CLQ/HCLQ | Decrease in concentration of LPV/RTV | Decrease in concentration of IVM | Decrease in concentration of PB | Decrease in concentration of PB | ||
| + | + + + | + + + | ++ | + | + | ||||
| Phenytoin | Induction of CYP3A4 | Decrease in concentration of RDV | Decrease in concentration of CLQ/HCLQ | Decrease in concentration of LPV/RTV | Decrease in concentration of IVM | Decrease in concentration of PHT | Decrease in concentration of PHT | ||
| + | + + + | + + + | ++ | + | + | ||||
| Primidone | Induction of CYP3A4 | Decrease in concentration of RDV | Decrease in concentration of CLQ/HCLQ | Decrease in concentration of LPV/RTV Decrease in concentration of PRM $ |
Decrease in concentration of IVM | Decrease in concentration of DEX Decrease in concentration of PRM |
Decrease in concentration of PRM | Decrease in concentration of PRM | |
| + | + + + | + + + | ++ | ++ | + | + | |||
| Rufinamide | Induction of CYP3A4 | Decrease in concentration of CLQ/HCLQ | Decrease in concentration of LPV/RTV | Decrease in concentration of IVM | Decrease in concentration of DEX Decrease in concentration of RFN |
||||
| ― | + + | + + | ++ | ++ | ― | ― | |||
| Others | Cannabidiol | Inhibition of CYP3A4 | Increase in concentration of CLQ/HCLQ | Increase in concentration of CBD | Decrease concentration of corticosteroid # | Decrease in concentration of CBD | |||
| ― | + + | + + | ― | + | + | ― | |||
|
Clonazepam Clobazam Diazepam (BZDs) |
Increase in concentration of BZDs | ||||||||
| ― | ― | + + | ― | ― | ― | ― | |||
| Ethosuximide | Increase in concentration of ESM | ||||||||
| ― | ― | + + | ― | ― | ― | ― | |||
| Felbamate | Induction of CYP3A4 | Decrease in concentration of CLQ/HCLQ | Decrease in concentration of LPV/RTV | ||||||
| ― | + + | + + | ― | ― | ― | ― | |||
| Perampanel | Increase in concentration of PER | ||||||||
| ― | ― | + + | ― | ― | ― | ― | |||
| Sultiame | Increase in concentration of STM | ||||||||
| ― | ― | + + | ― | ― | ― | ― | |||
| Tiagabine | Increase in concentration of TGB | ||||||||
| ― | ― | + + | ― | ― | ― | ― | |||
Degree of drug-drug interactions:
Serious (+ + +)Potentially serious clinical consequences. Drugs not to be co-administered.
Moderate (+ +)Drugs that might require dose adjustment and periodic monitoring due to potential interaction.
Minor (+)Drugs expected to have potential weak interaction. Dose adjustment not necessary.
None (―)No clinical evidence exhibiting significant interaction.
enzymes that are relevant for a possible interaction between ASMs and COVID-19 candidate drugs based on the current state of knowledge.
For ASMs not mentioned in the above table including Gabapentin, Levetiracetam, Lorazepam, Pregabalin, Retigabine, Vigabatrin and Zonisamide, no significant evidence exists for drug-drug interactions with the COVID-19 candidate drugs.
BZD-Benzodiazepines; CLZ-Clonazepam; CBD-Cannabidiol; CBZ-Carbamazepine; CLQ/HCLQ-Chloroquine/ Hydroxychloroquine; DEX-Dexamethasone; ELS-Eslicarbazepine: ETS-Ethosuximide; IVM- Ivermectin; LPV/RTV-Lopinavir/Ritonavir; LTG-Lamotrigine; MDZ-Midozolam: OXC-Oxcarbazepine; PB-Phenobarbital; PER-Perampanel; PHT-Phenytoin; PRM-Primidone; RDV-Remdesivir; RFN- Rufinamide; STM-Sultiame; TGB-Tiagabine.
The information summarized in this table considered information provided by Russo and Iannone at the International League Against Epilepsy (ILAE) website (Russo, 2020) and has been updated with information released by the Liverpool Drug Interaction Group (University of Liverpool, UK, in collaboration with the University Hospital of Basel (Switzerland) and Radboud UMC (Netherlands)) (http://www.covid19-druginteractions.org/). Please note that we only provide information about the compound’s effects on metabolic.
It is recommended that Chloroquine and Hydroxychloroquine are not administered in patients with recurring seizures. Both are metabolized by CYP3A4 and CYP2D6, and are also known to prolong QT interval and exhibit proarrythmic potential and hence, their administration should in general be closely monitored.
Lopinavir is metabolized by CYP3A4.
There is only limited clinical information for the investigational drug Remdesivir. However, it might be necessary to consider evidence suggesting that remdesivir is sensitive to CYP3A4.
Tocilizumab causes suppression of IL-6 concentrations. IL-6 can reduce the expression of Cthe expression of P450 enzymes including CYP3A4, CYP2C9 and CYP2C19. As a consequence disease-associated increases in IL-6 as well as pharmacological reduction and control of IL-6 concentrations can affect the rate of hepatic metabolism in the opposite direction.
Anakinra normalizes the increased concentration of metabolizing cytochromes (CYP450) due to inflammation, thereby it may decrease the systemic concentration of drugs metabolized by these enzymes.
Ritonavir is a potent inhibitor of CYP3A4.
Primidone is metabolized by CYP3A4 to phenobarbital, which induces CYP3A4.
Cannabidiol inhibits CYP3A4 and thus concomitant admnistration with glucocorticoids like hydroxycortisone and prednisolone decrease glucocorticoid clearance, thereby increasing their systemic concentration (Wilson-Morkeh et al., 2019).