Does cyclobenzaprine (Flexeril) interact with sertraline (Zoloft)?

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Last updated: March 24, 2025View editorial policy

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From the Guidelines

Yes, Flexeril (cyclobenzaprine) and Zoloft (sertraline) can interact, potentially increasing the risk of serotonin syndrome, and caution is advised when co-administering these medications, especially in the first 24 to 48 hours after dosage changes 1. When considering the interaction between cyclobenzaprine and sertraline, it's essential to note that sertraline, an SSRI, may interact with drugs metabolized by CYP2D6, and cyclobenzaprine is a muscle relaxant that can also affect serotonin levels in the brain.

  • The interaction between these two medications can lead to excessive serotonin accumulation, resulting in symptoms such as agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, tremor, excessive sweating, diarrhea, and in severe cases, seizures or loss of consciousness.
  • To minimize the risk of interaction, healthcare providers may recommend starting the second medication at a low dose, increasing the dose slowly, and monitoring for symptoms, especially in the first 24 to 48 hours after dosage changes 1.
  • It's crucial for patients to be vigilant for any unusual symptoms and seek immediate medical attention if they experience signs of serotonin syndrome.
  • Healthcare providers should carefully weigh the benefits and risks of co-administering cyclobenzaprine and sertraline, and patients should never adjust their dosage or stop taking either medication without consulting their healthcare provider.

From the FDA Drug Label

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Cyclobenzaprine Hydrochloride and 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 Postmarketing cases of serotonin syndrome have been reported during combined use of Cyclobenzaprine Hydrochloride and 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 If concomitant treatment with Cyclobenzaprine Hydrochloride and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases

Yes, cyclobenzaprine (Flexeril) interacts with sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), and this combination may increase the risk of serotonin syndrome. Careful observation is advised if these medications are used concomitantly 2 2.

From the Research

Interaction between Cyclobenzaprine and Sertraline

  • There is no direct evidence in the provided studies that discusses the interaction between cyclobenzaprine (Flexeril) and sertraline (Zoloft) 3, 4, 5, 6, 7.
  • The studies primarily focus on the efficacy, tolerability, and pharmacokinetic properties of sertraline in treating depression and anxiety disorders 3, 4, 5, 6.
  • One study examines the pharmacodynamic and pharmacokinetic properties of sertraline, noting its low potential for pharmacokinetic drug interactions due to not being a potent inhibitor of any cytochrome P450 isoenzyme systems 5.
  • Another study investigates the clinical effectiveness of sertraline in primary care, finding it unlikely to reduce depressive symptoms within 6 weeks but observing improvements in anxiety, quality of life, and self-rated mental health 6.
  • The only study related to cyclobenzaprine discusses its mechanism of action as a skeletal muscle relaxant and its potent non-competitive antagonism of histamine H1 receptors, which may contribute to its sedative effects 7.
  • Since there are no studies directly addressing the interaction between cyclobenzaprine and sertraline, it is essential to consult a healthcare professional or a reliable drug interaction resource for guidance on potential interactions between these medications.

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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