Drug interactions between Adapin and UriSym

doxepin ↔ methylene blue

Applies to:Adapin (doxepin) and UriSym (hyoscyamine/methenamine/methylene blue/phenyl salicylate)

CONTRAINDICATED: Concomitant use of methylene blue injectable with serotonin reuptake inhibitors or other 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 2A receptors. Current research suggests that methylene blue has structural properties similar to monoamine oxidase inhibitors, which are known to precipitate serotonin toxicity when coadministered with serotoninergic agents, especially selective serotonin reuptake inhibitors. 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 as low as 1 mg/kg to patients exposed to drugs that interfere with serotonin reuptake. Several cases required admission to the intensive care unit.

MANAGEMENT: Serotonergic agents should not be used in patients receiving methylene blue injectable. If possible, patients treated with serotonergic agents should discontinue these medications for at least 4 to 5 half-lives prior to administration of methylene blue injectable. Most serotonergic psychiatric drugs should be stopped at least 2 weeks in advance of methylene blue treatment, while fluoxetine should be stopped at least 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 emergency situations requiring urgent treatment with methylene blue (e.g., methemoglobinemia, ifosfamide-induced encephalopathy, cyanide poisoning), the availability of alternative interventions should be considered and the benefit of methylene blue treatment should be weighed against the risk of serotonin toxicity. If methylene blue is required in a patient receiving a serotonergic drug, 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) 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.

doxepin ↔ hyoscyamine

Applies to:Adapin (doxepin) and UriSym (hyoscyamine/methenamine/methylene blue/phenyl salicylate)

MONITOR: Agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; disopyramide) may have additive effects when used in combination. Excessive parasympatholytic effects may result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures. Central nervous system-depressant effects may also be additively or synergistically increased when these agents are combined, especially in elderly or debilitated patients. Use of neuroleptics in combination with other neuroleptics or anticholinergic agents may increase the risk of tardive dyskinesia.

MANAGEMENT: Caution is advised when agents with anticholinergic properties are combined, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication such as abdominal pain, fever, heat intolerance, blurred vision, confusion, and/or hallucinations. Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A reduction in anticholinergic dosages may be necessary if excessive adverse effects develop.