Polypharmacy with Lacosamide, Levetiracetam (Keppra), and Phenytoin for Seizures
Yes, it is possible to be on lacosamide, levetiracetam (Keppra), and phenytoin simultaneously for seizure management, though this represents polypharmacy that should be reserved for refractory cases where monotherapy or dual therapy has failed. However, one critical caveat exists: in the specific context of CAR T-cell therapy patients, first-line anti-seizure medications with unfavorable cardiotoxicity profiles such as lacosamide and phenytoin should be avoided when possible 1.
Clinical Context for Multi-Drug Regimens
When Triple Therapy Is Appropriate
Refractory status epilepticus is the primary scenario where multiple antiepileptic drugs are used concurrently, following a stepwise escalation algorithm 1, 2.
The standard treatment algorithm progresses as follows: first-line benzodiazepines → second-line agents (phenytoin/fosphenytoin, valproate, levetiracetam, or phenobarbital) → third-line anesthetic agents (midazolam, propofol, or pentobarbital) for refractory cases 1, 2.
Multiple antiepileptic drugs are standard practice for neurological ICU patients who cannot obtain seizure control with monotherapy 3.
Evidence for Concurrent Use
Levetiracetam does not influence plasma concentrations of other AEDs, and these AEDs do not influence the pharmacokinetics of levetiracetam, making combination therapy pharmacokinetically feasible 4.
A 2016 study demonstrated that lacosamide, levetiracetam, valproic acid, and phenytoin were equally effective as second- and third-line therapy for benzodiazepine-nonresponsive status epilepticus, with no significant difference in outcomes 5.
The concurrent use of phenytoin and levetiracetam has been analyzed for ICU patients in convulsive or silent status epilepticus, though randomized controlled trials specifically assessing this combination are lacking 3.
Important Safety Considerations
Cardiotoxicity Concerns
In CAR T-cell therapy recipients with CNS disease or seizure history, levetiracetam (10 mg/kg up to 500 mg every 12 hours for 30 days) is the preferred prophylactic agent, while lacosamide and phenytoin should be avoided due to unfavorable cardiotoxicity profiles 1.
Phenytoin carries a 12% risk of hypotension and potential for severe cardiac arrhythmias up to ventricular fibrillation and death, requiring continuous ECG and blood pressure monitoring 1, 2.
Drug Interaction Profile
Phenytoin is a strong enzymatic inducer that may render ineffective several drugs used simultaneously with antiepileptic treatment 6.
Levetiracetam has minimal drug interactions, circulates largely unbound (<10% bound) to plasma proteins, and does not affect cytochrome P450 isoforms or glucuronidation enzymes 4.
There is approximately a 22% increase in apparent total body clearance of levetiracetam when coadministered with enzyme-inducing AEDs like phenytoin, though dose adjustment is not typically recommended 4.
Practical Algorithm for Multi-Drug Use
Step 1: Establish Treatment Failure
- Confirm inadequate seizure control on optimized monotherapy at maximum tolerated doses before adding second agent 7.
- Assess compliance and obtain serum drug levels to rule out non-adherence as cause of breakthrough seizures 7.
Step 2: Sequential Addition
- Add one agent at a time rather than multiple simultaneously to identify which medication provides benefit 7.
- For status epilepticus: benzodiazepines first → add one second-line agent (levetiracetam 30 mg/kg IV, valproate 20-30 mg/kg IV, or fosphenytoin 20 mg PE/kg IV) → if refractory, add third agent or escalate to anesthetic agents 1, 2.
Step 3: Monitor for Adverse Effects
- Combination therapy introduces increased risk of drug interactions, higher adverse event burden, and greater complexity affecting compliance 7.
- Phenytoin requires therapeutic-level monitoring and can cause purple glove syndrome, severe hypotension, and allergic reactions 6, 8.
- Levetiracetam may cause behavioral changes (aggression, agitation, anxiety, depression) and in rare cases psychotic symptoms 4.
Common Pitfalls to Avoid
Never use neuromuscular blockers alone (such as rocuronium), as they only mask motor manifestations while allowing continued electrical seizure activity and brain injury 2.
Do not skip directly to third-line anesthetic agents until benzodiazepines and at least one second-line agent have been tried 2.
Avoid valproate in women of childbearing potential due to significantly increased risks of fetal malformations and neurodevelopmental delay 7.
Never stop antiepileptic drugs suddenly, as this may precipitate withdrawal seizures—always taper when discontinuing 7.
In specific high-risk populations (CAR T-cell recipients), prioritize levetiracetam and avoid lacosamide and phenytoin due to cardiotoxicity concerns 1.