Why is cyclobenzaprine (Flexeril) contraindicated for use with linezolid (Zyvox)?

From the Guidelines

Cyclobenzaprine is contraindicated for use with linezolid due to the risk of serotonin syndrome, a potentially life-threatening drug interaction. Patients should never take these medications together. Cyclobenzaprine is a muscle relaxant with a chemical structure similar to tricyclic antidepressants, while linezolid is an antibiotic that also functions as a reversible monoamine oxidase inhibitor (MAOI) 1. When combined, these medications can cause excessive serotonin accumulation in the brain, leading to symptoms such as agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, hyperthermia, and in severe cases, seizures or death. The interaction occurs because linezolid inhibits the breakdown of serotonin, while cyclobenzaprine increases serotonin levels, creating a dangerous synergistic effect.

Some key points to consider when managing patients on cyclobenzaprine and linezolid include:

• Concomitant use of cyclobenzaprine with monoamine oxidase inhibitors, such as linezolid, may increase the potential for serotonin syndrome 1
• Linezolid should generally not be administered to patients taking serotonergic agents, such as monoamine oxidase inhibitors, because of the potential for serious CNS reactions, such as serotonin syndrome 1
• Alternative muscle relaxants that don't affect serotonin, such as methocarbamol or tizanidine, may be considered if muscle relaxation therapy is necessary during linezolid treatment
• If a patient requires linezolid therapy but is currently taking cyclobenzaprine, the muscle relaxant should be discontinued at least 14 days before starting linezolid to minimize the risk of serotonin syndrome.

It is essential to prioritize the patient's safety and well-being by avoiding this potentially life-threatening drug interaction. The most recent and highest quality study, 1, supports this recommendation, emphasizing the importance of careful medication management to prevent adverse reactions.

From the FDA Drug Label

Contraindications Section Hypersensitivity to any component of this product. Concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after their discontinuation. Warnings Section Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with Cyclobenzaprine Hydrochloride when used in combination with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase (MAO) inhibitors. CONTRAINDICATIONS ZYVOX formulations are contraindicated for use in patients who have known hypersensitivity to linezolid or any of the other product components. Monoamine Oxidase Inhibitors Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within two weeks of taking any such medicinal product Cyclobenzaprine is contraindicated for use with linezolid because linezolid is a monoamine oxidase inhibitor and the concomitant use of cyclobenzaprine with MAO inhibitors is contraindicated due to the risk of serotonin syndrome and hyperpyretic crisis 2, 2, 3.

From the Research

Cyclobenzaprine and Linezolid Interaction

• Cyclobenzaprine is contraindicated for use with linezolid due to the risk of serotonin syndrome, a potentially life-threatening condition caused by excessive serotonin activity 4.
• Linezolid is a mild monoamine oxidase inhibitor that can increase the risk of serotonin syndrome when combined with other serotonergic agents, including cyclobenzaprine 5, 6, 7.
• The combination of cyclobenzaprine and linezolid can lead to symptoms of serotonin syndrome, such as autonomic instability, agitation, and severe agitation, which can be fatal if left untreated 4.
• Studies have shown that the incidence of serotonin syndrome is low when linezolid is used alone or in combination with other serotonergic agents, but the risk is still present and should be closely monitored 6, 7.
• Discontinuation of cyclobenzaprine and linezolid can lead to resolution of serotonin syndrome symptoms, highlighting the importance of careful medication management and monitoring 4, 7.

Mechanism of Interaction

• Cyclobenzaprine is a serotonin-enhancing drug that can increase the risk of serotonin syndrome when combined with other serotonergic agents, including linezolid 4.
• Linezolid's monoamine oxidase inhibiting properties can increase the levels of serotonin in the body, leading to an increased risk of serotonin syndrome when combined with other serotonergic agents 5, 6, 7.
• The combination of cyclobenzaprine and linezolid can lead to an additive effect on serotonin levels, increasing the risk of serotonin syndrome 4.