Cyclobenzaprine and Ozanimod: Clinically Significant Drug Interaction
Cyclobenzaprine (Flexeril) should NOT be used concurrently with ozanimod (Zeposia) due to the risk of serious adverse reactions including hypertensive crisis and serotonin syndrome. This combination involves two distinct but overlapping mechanisms of concern: cyclobenzaprine's serotonergic properties and ozanimod's monoamine oxidase-B (MAO-B) inhibition.
Mechanism of Interaction
Ozanimod's active metabolites (CC112273 and CC1084037) inhibit MAO-B, which can potentiate the effects of serotonergic and adrenergic drugs 1, 2.
Cyclobenzaprine is structurally similar to tricyclic antidepressants and modulates both noradrenergic and serotonergic systems centrally, making it a serotonergic agent despite being marketed as a muscle relaxant 3, 4.
Case reports document serotonin syndrome occurring with cyclobenzaprine when combined with other serotonergic agents (specifically SSRIs), establishing cyclobenzaprine as a medication capable of precipitating this toxidrome 5.
Guideline-Based Contraindication
The Journal of Crohn's and Colitis guidelines explicitly list serotonergic/adrenergic drugs (including tricyclic antidepressants) as having potential for serious adverse reactions including hypertensive crisis when used with ozanimod 1.
Ozanimod is contraindicated with opioid drugs and serotonergic/adrenergic drugs due to potential MAO inhibition by ozanimod metabolites 1, 2.
Given that cyclobenzaprine functions through modulation of noradrenergic and serotonergic systems and is structurally a tricyclic compound, it falls squarely within this contraindicated drug class 3, 4.
Clinical Risk Assessment
Serious adverse reactions documented with ozanimod and serotonergic drugs include hypertensive crisis, which represents a life-threatening emergency 1, 2.
The risk is mechanistically plausible because ozanimod's MAO-B inhibition combined with cyclobenzaprine's serotonergic activity creates the pharmacological conditions for both serotonin syndrome and hypertensive crisis 1, 2, 5.
Cyclobenzaprine has documented anticholinergic side effects and toxicity potential, particularly in combination with other substances 4.
Practical Management Recommendations
Review all patient medications for drug interactions with ozanimod through available online databases or consult with a pharmacist before initiating ozanimod 1.
If a patient on ozanimod requires muscle relaxation, consider alternative agents that lack serotonergic properties, such as methocarbamol or tizanidine, which do not share cyclobenzaprine's tricyclic structure or serotonergic mechanism 4.
Patients should be counseled to inform their physician of any new prescribed medications to allow for review of potential drug-drug interactions 1.
If the combination cannot be avoided in exceptional circumstances, baseline assessment including vital signs, mental status, and neurological examination is essential, though avoidance remains the preferred strategy 1.
Common Pitfalls to Avoid
Do not assume cyclobenzaprine is safe simply because it is labeled as a "muscle relaxant" - its tricyclic structure and serotonergic mechanism place it in the same risk category as antidepressants 3, 4, 5.
Do not rely solely on the absence of specific "cyclobenzaprine" mentions in ozanimod prescribing information - it falls under the broader category of serotonergic/adrenergic drugs and tricyclic compounds that are contraindicated 1.
Avoid underestimating the severity of potential interactions; hypertensive crisis and serotonin syndrome are medical emergencies with significant morbidity and mortality risk 1, 2, 5.