Drug Interaction Report

MONITOR CLOSELY: Concomitant use of agents with serotonergic activity such as serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, 5-HT1 receptor agonists, ergot alkaloids, cyclobenzaprine, lithium, St. John's wort, phenylpiperidine opioids, dextromethorphan, and tryptophan 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. 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.

MANAGEMENT: In general, the concomitant use of multiple serotonergic agents should be avoided if possible, or otherwise approached with caution if potential benefit is deemed to outweigh the risk. Patients should be closely monitored for symptoms of the serotonin syndrome during treatment. Particular caution is advised when increasing the dosages of these agents. The potential risk for serotonin syndrome should be considered even when administering serotonergic agents sequentially, as some agents may demonstrate a prolonged elimination half-life. For example, some experts suggest a 5-week washout period following use of fluoxetine and 3 weeks following the use of vortioxetine before administering another serotonergic agent. Individual product labeling for washout periods should be consulted for current recommendations. If serotonin syndrome develops or is suspected during the course of therapy, all serotonergic agents should be discontinued immediately and supportive care rendered as necessary. Moderately ill patients may also benefit from the administration of a serotonin antagonist (e.g., cyproheptadine, chlorpromazine). Severe cases should be managed under consultation with a toxicologist and may require sedation, neuromuscular paralysis, intubation, and mechanical ventilation in addition to the other measures.

CONTRAINDICATED: Coadministration of monoamine oxidase inhibitors (MAOIs) and dibenzazepine derivatives (e.g., tricyclic and tetracyclic antidepressants, cyclobenzaprine, carbamazepine) may produce significant adverse reactions including nausea, vomiting, flushing, dizziness, tremor, myoclonus, rigidity, diaphoresis, hyperthermia, autonomic instability, hypertensive crises, disseminated intravascular coagulation, severe convulsive seizures, coma, and death. The exact mechanism of interaction is unknown, but may involve excessive serotonergic activity in the central nervous system (i.e., serotonin syndrome). Clinically, the interaction has been reported primarily in patients treated with MAOIs (including reversible, irreversible, selective, and nonselective) and tricyclic antidepressants, especially imipramine and clomipramine, which are the most potent serotonin reuptake inhibitors of the class. Other dibenzazepine-type drugs may also interact based on their structural and pharmacologic similarities to the tricyclic antidepressants, although data are limited. An isolated case has been reported for phenelzine and cyclobenzaprine, while no cases have been reported with carbamazepine. On the contrary, there have been published reports citing a lack of interaction as well as successful use of carbamazepine with MAOIs.

MANAGEMENT: In general, dibenzazepine derivatives should not be used concurrently with MAOIs or other agents that possess MAOI activity (e.g., furazolidone, methylene blue, procarbazine). At least 14 days should elapse between discontinuation of MAOI therapy and initiation of treatment with tricyclic antidepressants, and vice versa. Although it remains controversial, some experts have suggested that certain MAOIs and tricyclic antidepressants (except imipramine and clomipramine) may be used together for the treatment of refractory depression under special circumstances and close supervision, with the following empirical guidelines: the current tricyclic or MAOI should be discontinued for 10 to 14 days; both drugs should then be started at low dosages; the drugs should not be administered parenterally; dose changes should be made in small increments; serotonin reuptake inhibitors must not be used concurrently; and patients should be closely monitored for signs of adverse serotonergic effects.

CONTRAINDICATED: By inhibiting serotonin metabolism, monoamine oxidase inhibitors (MAOIs) may potentiate the pharmacologic activity of serotonergic agents such as serotonin reuptake inhibitors, 5-HT1 receptor agonists, ergot alkaloids, buspirone, dextromethorphan, and most antidepressants. The result may be an increased 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. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucinations, 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.

MANAGEMENT: In general, serotonergic agents should not be used concurrently with MAOIs or other agents that possess MAOI activity (e.g., furazolidone, methylene blue, procarbazine). At least 14 days should elapse between discontinuation of MAOI therapy and initiation of treatment with serotonergic agents. A washout period of 5 to 14 days is usually recommended when switching from another antidepressant to an MAOI; however, the individual product labeling should be consulted.

CONTRAINDICATED: Foods that contain large amounts of tyramine may precipitate a hypertensive crisis in patients treated with monoamine oxidase inhibitors (MAOIs). The mechanism is inhibition of MAO-A, the enzyme responsible for metabolizing exogenous amines such as tyramine in the gut and preventing them from being absorbed intact. Once absorbed, tyramine is metabolized to octopamine, a substance that is believed to displace norepinephrine from storage granules.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of MAOIs. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: In general, patients treated with MAOIs or other agents that possess MAOI activity (e.g., furazolidone, linezolid, procarbazine) should avoid consumption of products that contain large amounts of amines and protein foods in which aging or breakdown of protein is used to increase flavor. These foods include cheese (particularly strong, aged or processed cheeses), sour cream, wine (particularly red wine), champagne, beer, pickled herring, anchovies, caviar, shrimp paste, liver (particularly chicken liver), dry sausage, salamis, figs, raisins, bananas, avocados, chocolate, soy sauce, bean curd, sauerkraut, yogurt, papaya products, meat tenderizers, fava bean pods, protein extracts, yeast extracts, and dietary supplements. Caffeine may also precipitate hypertensive crisis so its intake should be minimized as well. At least 14 days should elapse following discontinuation of MAOI therapy before these foods may be consumed. Specially designed reference materials and dietary consultation are recommended so that an appropriate and safe diet can be planned. Patients should be advised to promptly seek medical attention if they experience potential signs and symptoms of a hypertensive crisis such as severe headache, visual disturbances, difficulty thinking, stupor or coma, seizures, chest pain, unexplained nausea or vomiting, and stroke-like symptoms. Patients should also be counseled not to use MAOIs with alcohol, and to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete 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.

GENERALLY AVOID: Concomitant use of ethanol and a tricyclic antidepressant (TCA) may result altered TCA plasma levels and efficacy, and additive impairment of motor skills, especially driving skills. Acute ethanol ingestion may inhibit TCA metabolism, while chronic ingestion of large amounts of ethanol may induce hepatic TCA metabolism.

MANAGEMENT: Patients should be advised to avoid alcohol during TCA therapy. Alcoholics who have undergone detoxification should be monitored for decreased TCA efficacy. Dosage adjustments may be required.

MONITOR: Smoking cessation may lead to elevated plasma concentrations and enhanced pharmacologic effects of drugs that are substrates of CYP450 1A2 (and possibly CYP450 1A1) and/or certain drugs with a narrow therapeutic index (e.g., flecainide, pentazocine). One proposed mechanism is related to the loss of CYP450 1A2 and 1A1 induction by polycyclic aromatic hydrocarbons in tobacco smoke; when smoking cessation agents are initiated and smoking stops, the metabolism of certain drugs may decrease leading to increased plasma concentrations. The mechanism by which smoking cessation affects narrow therapeutic index drugs that are not known substrates of CYP450 1A2 or 1A1 is unknown. The clinical significance of this interaction is unknown as clinical data are lacking.

MANAGEMENT: Until more information is available, caution is advisable if smoking cessation agents are used concomitantly with drugs that are substrates of CYP450 1A2 or 1A1 and/or those with a narrow therapeutic range. Patients receiving smoking cessation agents may require periodic dose adjustments and closer clinical and laboratory monitoring of medications that are substrates of CYP450 1A2 or 1A1.