Drug Interactions between amitriptyline / chlordiazepoxide and methylene blue

CONTRAINDICATED: Coadministration of methylene blue with serotonergic agents may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 5-HT2A receptors. Current research suggests that methylene blue has structural properties similar to monoamine oxidase inhibitors (MAOIs). As such, it may enhance serotonergic effects by inhibiting serotonin metabolism. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea. Serotonin syndrome has been reported when methylene blue was administered intravenously at dosages ranging from 1 to 8 mg/kg to patients exposed to drugs that interfere with serotonin reuptake. Several cases required admission to the intensive care unit. The risk of administering methylene blue intravenously at dosages less than 1 mg/kg or by non-intravenous routes (e.g., orally or by local injection) is unclear, although the potential for interaction with serotonergic agents should be considered.

MANAGEMENT: In general, the combination of intravenous methylene blue and serotonergic agents is not recommended. The product labeling for some agents with serotonergic activity consider this combination to be contraindicated; however, others provide additional warnings and precautions if their concomitant use is considered necessary. Most serotonergic psychiatric drugs should be stopped 1 to 2 weeks (i.e., 4 to 5 half-lives) prior to treatment with methylene blue if possible, while others such as fluoxetine may require discontinuation up to 5 weeks in advance due to its prolonged half-life. Treatment with serotonergic medications may be resumed 24 hours after the last dose of methylene blue. In patients receiving methylene blue who require urgent treatment of a psychiatric condition, other interventions including hospitalization should be considered. Conversely, when urgent treatment with methylene blue is required (e.g., methemoglobinemia, ifosfamide-induced encephalopathy, cyanide poisoning) in patients receiving serotonergic agents, the benefit of methylene blue treatment should be weighed against the risk of serotonin toxicity. If a decision is made to use methylene blue, the serotonergic drug must be immediately stopped, and the patient closely monitored for emergent symptoms of CNS toxicity for two weeks (five weeks if fluoxetine was taken; three weeks if vortioxetine was taken) or until 24 hours after the last dose of methylene blue, whichever comes first. Patients and/or their caregivers should be advised to seek medical attention if potential symptoms of serotonin syndrome develop. The product labeling for the concomitant medication(s) should be consulted for more specific recommendations.

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.