Are there any interactions between Rizatriptan and the patient's current medications, including Fluoxetine, Fremanezumab, Semaglutide, Metformin, Ondansetron, and Levothyroxine?

Drug Interactions with Rizatriptan in This Patient

The most clinically significant interaction is between rizatriptan and fluoxetine, which carries a risk of serotonin syndrome, though this risk is considered low and these medications are commonly co-prescribed with appropriate monitoring. 1

Critical Interaction: Rizatriptan + Fluoxetine (SSRI)

Monitor closely for serotonin syndrome when combining rizatriptan with fluoxetine, particularly in the first 24-48 hours after dosing. 1 The theoretical risk exists but is substantially lower than initially feared, and this combination is frequently used in clinical practice since migraine and depression commonly co-occur. 1, 2

Serotonin Syndrome Warning Signs to Monitor:

• Neuromuscular symptoms: Tremor, hyperreflexia, myoclonus, ataxia, incoordination 3, 4
• Autonomic symptoms: Diaphoresis, tachycardia, hyperthermia, mydriasis (though miosis can occur) 3, 5
• Mental status changes: Agitation, confusion, anxiety 6, 5

Clinical Context:

• Case reports document serotonin syndrome with triptan-SSRI combinations, including a documented case with rizatriptan and venlafaxine (SNRI) 3, and sumatriptan with fluvoxamine 4
• Canadian post-marketing surveillance identified 6 cases showing varying degrees of interaction between fluoxetine and sumatriptan 2
• However, the Mayo Clinic consensus states the theoretical risk is low and these medications are commonly co-prescribed 1

Interaction: Rizatriptan + Ondansetron (5-HT3 Antagonist)

Exercise caution when combining rizatriptan with ondansetron as both are serotonergic agents. 1 While ondansetron works on different serotonin receptors (5-HT3 vs 5-HT1B/1D), there is documented risk of atrial fibrillation with ondansetron 7, and the combination adds to overall serotonergic burden.

• Start with low doses when adding a second serotonergic medication 1
• The patient is using ondansetron intermittently (as needed), which reduces continuous exposure risk

No Significant Interactions with Other Medications

Fremanezumab (CGRP monoclonal antibody): No interaction—works via calcitonin gene-related peptide pathway, completely different mechanism from serotonergic agents 7

Semaglutide (GLP-1 agonist): No interaction—metabolic agent without serotonergic or cardiovascular effects relevant to triptans

Metformin: No interaction—no cytochrome P450 involvement or serotonergic effects 6

Levothyroxine: No interaction—no pharmacokinetic or pharmacodynamic overlap with triptans 6

Critical Contraindications NOT Present in This Patient

The patient's medication list does NOT include these absolute contraindications 1, 6:

• Ergot-containing medications (must avoid within 24 hours of rizatriptan)
• Other triptans (must avoid within 24 hours)
• MAO inhibitors (contraindicated within 2 weeks)
• Propranolol (requires dose reduction of rizatriptan to 5mg maximum due to increased blood levels)

Practical Management Recommendations

Continue current regimen with enhanced monitoring:

• Educate patient on serotonin syndrome symptoms (tremor, confusion, sweating, rapid heart rate, muscle twitching) 6, 5
• Advise patient to report any unusual symptoms within 24-48 hours of taking rizatriptan 1
• Consider limiting rizatriptan to maximum twice weekly to prevent medication-overuse headache 7
• Document that patient is already on fremanezumab for migraine prevention, which is appropriate given frequent triptan use 7

Additional Serotonergic Agents to Avoid:

Counsel patient to avoid over-the-counter serotonergic medications including dextromethorphan, St. John's Wort, and L-tryptophan supplements while on this combination 1

Key Clinical Pitfall

The long half-life of fluoxetine (4-6 days for parent compound, 4-16 days for active metabolite) means interaction risk persists for weeks after discontinuation. 1, 8 If fluoxetine were to be stopped, adequate washout of 4-5 weeks would be needed before the interaction risk fully resolves.