Can You Prescribe Flexeril with Keppra?
Yes, you can prescribe cyclobenzaprine (Flexeril) to a patient taking levetiracetam (Keppra), but exercise caution due to a documented case of cardiac toxicity when these medications were combined in overdose.
Drug Interaction Profile
The FDA label for Keppra explicitly states that levetiracetam is unlikely to produce pharmacokinetic interactions, as it circulates largely unbound to plasma proteins (<10% bound) and does not significantly interact with cytochrome P450 enzymes 1. This suggests minimal risk of metabolic drug-drug interactions at therapeutic doses.
However, one case report documents cardiac arrest in a patient who overdosed on both medications together 2. A 16-year-old ingested 4.5g lacosamide, 120mg cyclobenzaprine, and levetiracetam, resulting in QRS prolongation, terminal right axis deviation, and pulseless ventricular tachycardia. While the cyclobenzaprine level was therapeutic (16 ng/mL) and levetiracetam was 22.7 μg/mL (therapeutic range 12-46 μg/mL), the combination appeared to cause sodium channel blockade leading to cardiac arrest 2.
Clinical Considerations
When Prescribing Together:
- At therapeutic doses, no formal contraindication exists based on the Keppra drug label 1, which only lists hypersensitivity as a contraindication
- Monitor for additive CNS depression: Both medications can cause somnolence and dizziness 1
- Avoid in patients with cardiac conduction abnormalities: The case report suggests potential for additive sodium channel effects, though this occurred in overdose 2
- Counsel patients about drowsiness: Warn against driving or operating machinery until they know how the combination affects them 1
Red Flags to Avoid This Combination:
- History of cardiac arrhythmias or conduction delays
- Concurrent use of other sodium channel blockers
- Baseline QRS prolongation on ECG
- Patients at high risk for intentional overdose
Monitoring Parameters:
- Baseline ECG if cardiac risk factors present
- Assess for excessive sedation at follow-up
- Monitor for behavioral changes (levetiracetam can cause mood alterations including aggression, depression, and irritability) 1
Bottom Line
The combination is generally safe at therapeutic doses for muscle spasm management in seizure patients, but requires clinical judgment based on individual cardiac risk factors. The documented toxicity occurred in overdose with multiple medications, not at prescribed doses. If prescribing together, document your risk-benefit assessment and consider baseline ECG in patients with cardiac history.