Drug Interactions between Flexeril and fluoxetine

MONITOR CLOSELY: Concomitant use of cyclobenzaprine with other agents that possess serotonergic activity such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

A case report suggests that coadministration of cyclobenzaprine and fluoxetine may prolong QT interval of the electrocardiogram. The authors theorize that fluoxetine may inhibit the CYP450 3A4 metabolism of cyclobenzaprine, resulting in increased plasma concentrations of cyclobenzaprine and its dose-related cardiac effects. In the report, a 59-year-old woman who had been receiving long-term fluoxetine (30 mg daily) and cyclobenzaprine (10 mg daily) therapy demonstrated a prolonged baseline QTc (i.e., QT interval corrected for heart rate) of 497 msec five days prior to admission for surgery. Her other medications included amlodipine, diclofenac, and triamterene/HCTZ. During surgery, the patient developed torsade de pointes and then ventricular fibrillation presumably induced by the preoperative administration of droperidol, a drug with well-known QT prolonging and proarrhythmic effects. The patient had no known history of cardiac problems except for hypertension, and other potential causes such as congenital long QT syndrome and electrolyte abnormalities were ruled out. She received defibrillation and cardiopulmonary resuscitation, and QT interval returned to normal after the discontinuation of cyclobenzaprine and droperidol.

MANAGEMENT: Caution is advised if cyclobenzaprine and fluoxetine are used concomitantly or sequentially. Patients should be closely monitored for symptoms of the serotonin syndrome during treatment. Particular caution is advised when increasing the dosages of these agents. If serotonin syndrome develops or is suspected during the course of therapy, all serotonergic agents should be discontinued immediately and supportive care rendered as necessary. Moderately ill patients may also benefit from the administration of a serotonin antagonist (e.g., cyproheptadine, chlorpromazine). Severe cases should be managed under consultation with a toxicologist and may require sedation, neuromuscular paralysis, intubation, and mechanical ventilation in addition to the other measures.

Although data are weak, it may be advisable to also monitor the patient for development ventricular arrhythmias during coadministration of cyclobenzaprine and fluoxetine. ECG should be considered in susceptible patients, including those with underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). Any drug that can prolong the QT interval should be avoided with this combination if possible. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

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