Does methylene blue interact with tirzepatide, omeprazole, prochlorperazine, metoprolol, metformin, fluticasone-salmeterol, umeclidinium, buprenorphine-naloxone, albuterol, acetaminophen, or hydromorphone?

Methylene Blue Drug Interactions with This Medication List

Yes, methylene blue has a critical and potentially life-threatening interaction with Suboxone (buprenorphine-naloxone) and Compazine (prochlorperazine) on this medication list, and should be avoided or used with extreme caution.

Critical Serotonergic Interaction

Methylene blue acts as a potent monoamine oxidase inhibitor and can precipitate serotonin syndrome when combined with serotonergic medications. 1 This interaction has resulted in severe CNS toxicity and even fatal outcomes. 2, 3

High-Risk Medications on This List:

• Suboxone (buprenorphine-naloxone): Buprenorphine has serotonergic properties and is specifically listed as a drug that can cause serotonin syndrome when combined with MAOIs like methylene blue 4
• Compazine (prochlorperazine): As an antipsychotic with serotonergic effects, this poses risk for interaction 4

Mechanism and Severity:

• Methylene blue reaches CNS concentrations that inhibit monoamine oxidase A at doses as low as 0.75-1 mg/kg IV 2
• Serotonin syndrome can occur even at standard therapeutic doses (1-2 mg/kg) used for methemoglobinemia 5, 2
• The interaction has caused severe toxicity including altered mental status, hyperthermia, muscle rigidity, and death 6, 3

Opioid Interaction Concerns

Hydromorphone (Dilaudid) has a documented interaction warning with methylene blue in its FDA labeling. 4

• The FDA label specifically warns that MAOIs (including methylene blue) can cause serotonin syndrome or opioid toxicity when combined with opioids 4
• Hydromorphone use with MAOIs is "not recommended" within 14 days of MAOI exposure 4
• This creates a clinical dilemma if methylene blue is needed emergently

Lower-Risk Medications

The following medications on this list have no significant documented interactions with methylene blue:

• Zepbound (tirzepatide): No documented interaction 5
• Omeprazole: Proton pump inhibitors may have possible reduction in renal elimination of some drugs, but this is not a major concern with methylene blue 1
• Metoprolol: No documented interaction 5
• Metformin: Interestingly, methylene blue has been used as treatment for metformin toxicity, not as an interacting agent 7
• Advair (fluticasone-salmeterol): No documented interaction 5
• Incruse (umeclidinium): No documented interaction 5
• Albuterol: No documented interaction 5
• Acetaminophen: No documented interaction 5

Clinical Recommendations

If methylene blue is being considered for this patient:

1. Discontinue Suboxone at least 14 days before elective methylene blue administration 4, 2
2. Hold Compazine before methylene blue use 1, 5
3. Avoid or minimize hydromorphone during and after methylene blue administration 4
4. If methylene blue is emergently needed (e.g., for methemoglobinemia):
   • Weigh the life-threatening risk of untreated methemoglobinemia against serotonin syndrome risk 5
   • Use the lowest effective dose (1 mg/kg rather than 2 mg/kg) 5
   • Monitor intensively for serotonin syndrome signs: altered mental status, autonomic instability, neuromuscular hyperactivity 2, 6
   • Have benzodiazepines and supportive care immediately available 6

Important Caveat

The risk of serotonin syndrome is dose-dependent but can occur at any therapeutic dose of methylene blue. 2 Even doses used for diagnostic purposes (0.75 mg/kg) have caused toxicity in patients on serotonergic agents. 2 This is not a theoretical risk—it has caused deaths. 3