What agent has a potential pharmacodynamic drug-drug interaction with rizatriptan (a selective 5-hydroxytryptamine (5-HT)1 receptor agonist)?

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Last updated: March 2, 2025 • View editorial policy

From the Guidelines

Fluoxetine has a potential pharmacodynamic drug-drug interaction with rizatriptan, as it can cause excessive serotonergic effects, potentially leading to serotonin syndrome, a serious and potentially life-threatening condition. This interaction occurs because fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that increases serotonin levels in the brain, while rizatriptan is a triptan medication that also affects serotonin by acting as a serotonin receptor agonist 1. When these medications are used together, they can cause symptoms such as agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, and hyperthermia. Some key points to consider when evaluating this interaction include:

  • The type and rate of occurrence of side effects appear to be acceptable to most patients and typically include nausea, dry mouth, drowsiness and reduced libido 1.
  • Isolated cases of more serious complications, such as mania and withdrawal symptoms, and potential drug interactions also have been associated with the use of SRIs, including pharmacodynamic drug interactions resulting in a “serotonergic syndrome” characterized in mild cases by headache, nausea, sweating, and dizziness and in severe cases by hyperthermia, rigidity, delirium, and coma 1.
  • Pharmacodynamic drug interactions resulting in a “serotonergic syndrome” have been reported rarely with concomitant use of monoamine oxidase inhibitors, lithium, sumatriptan and tryptophan, which suggests that rizatriptan, a medication similar to sumatriptan, may also have this interaction with fluoxetine 1. Healthcare providers typically recommend avoiding this combination or using it with extreme caution, with reduced rizatriptan dosing and careful monitoring for signs of serotonin syndrome.

From the FDA Drug Label

Monoamine oxidase inhibitors: Rizatriptan is principally metabolized via monoamine oxidase, 'A' subtype (MAO-A). Plasma concentrations of rizatriptan may be increased by drugs that are selective MAO-A inhibitors (e.g., moclobemide) or nonselective MAO inhibitors [type A and B] (e.g., isocarboxazid, phenelzine, tranylcypromine, and pargyline).

Propranolol: In a study of concurrent administration of propranolol 240 mg/day and a single dose of rizatriptan 10 mg in healthy adult subjects (n=11), mean plasma AUC for rizatriptan was increased by 70% during propranolol administration, and a four-fold increase was observed in one subject

The agents that have a potential pharmacodynamic drug-drug interaction with rizatriptan are:

  • Monoamine oxidase inhibitors (e.g., moclobemide, isocarboxazid, phenelzine, tranylcypromine, and pargyline) due to increased plasma concentrations of rizatriptan.
  • Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, may have a potential interaction, but according to the label, paroxetine did not affect the plasma concentrations of rizatriptan.
  • Propranolol may increase the plasma AUC of rizatriptan, but this is a pharmacokinetic interaction rather than pharmacodynamic.

    The most relevant pharmacodynamic interaction is with monoamine oxidase inhibitors. [2] [3]

From the Research

Potential Pharmacodynamic Drug-Drug Interactions with Rizatriptan

  • Rizatriptan is a selective 5-hydroxytryptamine (5-HT)1 receptor agonist, and its potential pharmacodynamic drug-drug interactions can occur with other agents that affect the serotonergic system.
  • One such agent is fluoxetine, a selective serotonin reuptake inhibitor (SSRI), which can increase the levels of serotonin in the brain 4.
  • The concomitant administration of fluoxetine and rizatriptan may lead to an increased risk of serotonergic syndrome, a potentially life-threatening condition characterized by excessive serotonin activity.
  • Studies have shown that rizatriptan is effective in the management of migraine, with a fast onset of action and a high response rate 5, 6, 7.
  • However, the potential pharmacodynamic interaction between rizatriptan and fluoxetine highlights the need for caution when co-administering these agents.
  • Other triptans, such as sumatriptan, zolmitriptan, and naratriptan, may also interact with fluoxetine, although the extent of this interaction may vary depending on the specific agent and dosage form 8.

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.