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Interactions with Nortriptyline

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If you are currently being treated with any of the following medications, you should not use Nortriptyline without reading these interactions.

Acetazolamide

Acetazolamide may decrease urinary excretion of tricyclic antidepressants by alkalinizing the urine. This interaction is unlikely to be clinically important.

Propafenone

A single case report suggests that propafenone may increase the pharmacologic and toxic effects of tricyclic antidepressants (TCAs). A patient experienced increased desipramine serum concentrations, dry mouth, dizziness, and tremors when propafenone was added to his regimen. The proposed mechanism is inhibition of TCA clearance and/or metabolism by propafenone. It is unknown whether other tricyclic antidepressants may also interact.

Cholestyramine

Cholestyramine may interfere with the absorption of oral tricyclic antidepressants, resulting in a moderate reduction of antidepressant serum concentrations. The clinical significance is unknown. The effectiveness of tricyclic antidepressants may be reduced. Monitoring the patient for altered therapeutic effects may be advisable. If an interaction is suspected, tricyclic antidepressants should be administered at least two hours before or four to six hours after cholestyramine.

Cisapride (oral)

CONTRAINDICATED: Cisapride can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of cisapride with other medications that can prolong the QT interval is considered contraindicated.

Phenelzine, Tranylcypromine, Selegiline (oral), Procarbazine, Isocarboxazid, Selegiline (transdermal), Rasagiline

CONTRAINDICATED: Coadministration of monoamine oxidase inhibitors (MAOIs) and dibenzazepine derivatives (e.g., tricyclic and tetracyclic antidepressants, cyclobenzaprine, carbamazepine) may rarely 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 is unknown but may be related to excessive serotonergic activity in the CNS (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 their class. However, other dibenzazepine-type drugs may theoretically produce this interaction also, based on their structural and pharmacologic similarities to the tricyclic antidepressants.

MANAGEMENT: In general, dibenzazepine derivatives should not be used concurrently with MAOIs or other agents that possess MAOI activity (e.g., furazolidone, 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.

Potassium citrate

CONTRAINDICATED: Concomitant use of agents with anticholinergic properties (e.g., antihistamines, antispasmodics, neuroleptics, phenothiazines, skeletal muscle relaxants, tricyclic antidepressants, class IA antiarrhythmics, especially disopyramide) may potentiate the risk of upper gastrointestinal mucosal damage associated with oral solid formulations of potassium citrate. The proposed mechanism involves increased gastrointestinal transit time due to reduction of stomach and intestinal motility by anticholinergic agents, thereby increasing the contact time of potassium with GI mucosa. In clinical studies with potassium chloride, coadministration of wax-matrix or microencapsulated formulations with an anticholinergic agent such as glycopyrrolate resulted in more frequent and more serious endoscopic lesions than potassium therapy alone. However, the lesions were not accompanied by bleeding or epigastric symptoms. Some studies have reported a higher incidence of upper GI lesions with wax-matrix than microencapsulated formulations, although data are conflicting.

MANAGEMENT: Use of agents with anticholinergic properties at sufficient doses to exert anticholinergic effects should be avoided in patients treated with oral solid formulations of potassium citrate (some manufacturers consider this combination to be contraindicated). Alternatively, a liquid formulation may be considered. Patients prescribed a solid oral formulation should be advised to discontinue potassium therapy and contact their doctor if they experience potential symptoms of upper GI injury such as severe vomiting, abdominal pain, distention, and gastrointestinal bleeding.

Grepafloxacin

CONTRAINDICATED: Grepafloxacin can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of grepafloxacin with other medications that can prolong the QT interval is considered contraindicated.

Halofantrine

CONTRAINDICATED: Halofantrine can cause dose-related prolongation of the QT interval at recommended therapeutic doses. QTc interval prolongation and death have been reported during combination use of halofantrine and mefloquine. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of halofantrine with other medications that can prolong the QT interval is considered contraindicated. Halofantrine should also not be given to patients who have previously taken mefloquine. The manufacturer recommends performing an ECG before initiating halofantrine therapy and monitoring cardiac rhythm during and for 8 to 12 hours after completion of therapy.

Mesoridazine

CONTRAINDICATED: Mesoridazine can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. Mesoridazine overdosage has been associated with ventricular arrhythmias and death.

MANAGEMENT: The concurrent use of mesoridazine with other medications that can prolong the QT interval is considered contraindicated.

Pimozide (oral)

CONTRAINDICATED: Pimozide can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of pimozide with other medications that can prolong the QT interval is considered contraindicated.

Bepridil

CONTRAINDICATED: Possible QT interval prolongation associated with tricyclic antidepressant drugs and bepridil may be additive. The combination of tricyclic antidepressants and bepridil may result in serious arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsade de pointes.

MANAGEMENT: The manufacturer considers the concurrent use of other QT interval-prolonging drugs contraindicated with bepridil.

Sparfloxacin

CONTRAINDICATED: Quinolones such as gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, and sparfloxacin may cause dose-related prolongation of the QT interval in some patients. Coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. Torsade de pointes have been reported in a few patients receiving sparfloxacin alone and with antiarrhythmic agents like amiodarone and disopyramide. There have also been isolated case reports of clinically significant interactions with sotalol, a class III antiarrhythmic agent, for both gatifloxacin and moxifloxacin. Levofloxacin, lomefloxacin, norfloxacin, and ofloxacin alone have been associated with extremely rare cases of torsade de pointes and ventricular tachycardia.

MANAGEMENT: Product labelings for some quinolones recommend avoiding concomitant therapy with class IA (e.g., disopyramide, quinidine, procainamide) and class III (e.g., amiodarone, dofetilide, ibutilide, sotalol) antiarrhythmic agents, as well as bepridil. Sparfloxacin is additionally contraindicated for use with any other medication that can prolong the QT interval such as cisapride, erythromycin, some antipsychotics, and tricyclic antidepressants.

Ranolazine

CONTRAINDICATED: Ranolazine can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. With repeat dosing, the mean effect of ranolazine (1000 mg twice daily) on QTc at Tmax is about 6 msec. However, in 5% of the population, the prolongation of QTc is 15 msec. The relationship between ranolazine plasma level and QTc remains linear over a concentration range up to 4-fold greater than the concentrations produced by a dosage of 1000 mg twice a day, and this relationship is not significantly affected by age, weight, gender, race, heart rate, congestive heart failure NYHA class, or diabetes.

MANAGEMENT: The concurrent use of ranolazine with other medications that can prolong the QT interval is considered contraindicated.

Ziprasidone

CONTRAINDICATED: Ziprasidone can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of ziprasidone with other medications that can prolong the QT interval is considered contraindicated.

Levothyroxine, Liothyronine, Dextrothyroxine, Thyroid (desiccated)

Exogenous thyroid may accelerate the onset or potentiate the action of tricyclic antidepressant effects. The mechanism and clinical significance is unknown. Some clinicians have used this interaction therapeutically. However, individual cases of paroxysmal tachycardia, hypothyroidism, and thyrotoxicosis have been reported.

Arsenic trioxide

GENERALLY AVOID: Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. Theoretically, coadministration with other agents that can prolong the QT interval may increase the risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. During clinical studies involving 40 patients receiving arsenic trioxide for acute promyelocytic leukemia, 16 of them (40%) had at least one ECG tracing with a QTc interval greater than 500 msec. Prolongation of QTc was observed between 1 and 5 weeks after arsenic trioxide infusion and returned towards baseline by the end of 8 weeks. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: If possible, medications that are known to prolong the QT interval should be discontinued prior to initiating therapy with arsenic trioxide and withheld for at least several weeks after completion of therapy. Caution is advised if concomitant use cannot be avoided. Patients should have frequent ECGs and be monitored for arrhythmias when QT intervals are prolonged. An absolute QT interval exceeding 500 msec will require immediate action to correct concomitant risk factors, if any, as well as a thorough assessment of the need for continued therapy. Patients who develop syncope or arrhythmia should be hospitalized for clinical and laboratory monitoring. Arsenic trioxide should be temporarily discontinued until symptoms resolve, the QTc interval regresses to below 460 msec, and electrolyte abnormalities are corrected.

Charcoal

GENERALLY AVOID: Charcoal may reduce the absorption of many drugs and can absorb enterohepatically circulated drugs. Clinical utility may be the reduction either of the effects or of the toxicity of many drugs. Activated charcoal may absorb any therapeutic agents administered while it is in the gastrointestinal tract.

MANAGEMENT: The regular ingestion of charcoal should be avoided by patients requiring maintenance medications. If concomitant use is necessary, the dosage or route of administration may need to be altered.

Disopyramide, Sotalol, Sotalol AF

GENERALLY AVOID: Class IA (e.g., disopyramide, quinidine, procainamide) and class III (e.g., amiodarone, dofetilide, sotalol) antiarrhythmic agents can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: The concurrent use of class IA or class III antiarrhythmic agents with other medications that can prolong the QT interval should preferably be avoided unless benefits are anticipated to outweigh the risks. Caution and clinical monitoring are recommended if these agents are prescribed together, especially to patients with underlying risk factors. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsades de pointes such as dizziness, palpitations, or syncope.

Thioridazine (oral)

GENERALLY AVOID: Coadministration of thioridazine with another phenothiazine or a tricyclic antidepressant (TCA) may result in elevated plasma concentrations of both drugs. Most phenothiazines and (TCAs) have been found to undergo metabolism by CYP450 2D6, thus competitive inhibition of the enzyme may occur when more than one of these agents are administered. Clinically, significant adverse effects associated with this interaction have not been reported. However, the possibility of an increased risk of serious adverse effects such as central nervous system depression, hypotension, prolongation of the QT interval, and torsade de pointes should be considered. Many of these agents alone, especially thioridazine, can and have produced these effects.

MANAGEMENT: Because of the additive risk due to overlapping pharmacologic actions and/or elevated plasma levels of these drugs, concurrent use should be avoided.

Fluoxetine

GENERALLY AVOID: Coadministration with fluoxetine may significantly increase the plasma concentrations of some tricyclic antidepressants (TCAs). The proposed mechanism is fluoxetine inhibition of CYP450 2D6, the isoenzyme responsible for the metabolic clearance of many antidepressant and psychotropic drugs. Seizures and delirium have been reported, as well as a fatality attributed to fluoxetine-induced chronic amitriptyline toxicity. Pharmacodynamically, the combination of fluoxetine (or any other selective serotonin reuptake inhibitor) and a TCA may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5HT1A receptors.

MANAGEMENT: In general, the use of fluoxetine (or other SSRIs) with TCAs should be avoided if possible, or otherwise approached with caution if potential benefit is deemed to outweigh the risk. Pharmacologic response and plasma TCA levels should be monitored more closely whenever fluoxetine is added to or withdrawn from therapy in patients stabilized on their existing antidepressant regimen, and the TCA dosage adjusted as necessary. Patients should be monitored closely for signs and symptoms of TCA toxicity (e.g., sedation, dry mouth, blurred vision, constipation, urinary retention) and/or excessive serotonergic activity (e.g., CNS irritability, altered consciousness, confusion, myoclonus, ataxia, abdominal cramping, hyperpyrexia, shivering, pupillary dilation, diaphoresis, hypertension, and tachycardia). Due to the long half-life of fluoxetine and its active metabolite, norfluoxetine, the risk of interaction may persist for several weeks after discontinuation of fluoxetine.

Fluvoxamine

GENERALLY AVOID: Coadministration with fluvoxamine may significantly increase the plasma concentrations of some tricyclic antidepressants (TCAs). The proposed mechanism is fluvoxamine inhibition of multiple hepatic microsomal enzymes involved in the metabolic clearance of TCAs. Mild to moderate increases in plasma levels have been reported for desipramine, while significant increases of several fold have been reported for clomipramine, imipramine, and trimipramine. Pharmacodynamically, the combination of fluvoxamine (or any other selective serotonin reuptake inhibitor) and a TCA may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5HT1A receptors.

MANAGEMENT: In general, the use of fluvoxamine (or other SSRIs) with TCAs should be avoided if possible, or otherwise approached with caution if potential benefit is deemed to outweigh the risk. Pharmacologic response and plasma TCA levels should be monitored more closely whenever fluvoxamine is added to or withdrawn from therapy in patients stabilized on their existing antidepressant regimen, and the TCA dosage adjusted as necessary. Patients should be monitored closely for signs and symptoms of TCA toxicity (e.g., sedation, dry mouth, blurred vision, constipation, urinary retention) and/or excessive serotonergic activity (e.g., CNS irritability, altered consciousness, confusion, myoclonus, ataxia, abdominal cramping, hyperpyrexia, shivering, pupillary dilation, diaphoresis, hypertension, and tachycardia).

Paroxetine

GENERALLY AVOID: Coadministration with paroxetine may significantly increase the plasma concentrations of some tricyclic antidepressants (TCAs). The proposed mechanism is paroxetine inhibition of CYP450 2D6, the isoenzyme responsible for the metabolic clearance of many antidepressant and psychotropic drugs. Several-fold increases in plasma levels and decreases in metabolic clearance have been reported for desipramine and nortriptyline, while smaller changes have been reported for amitriptyline and imipramine, presumably because other CYP450 isoenzymes are also involved in their metabolism. Pharmacodynamically, the combination of paroxetine (or any other selective serotonin reuptake inhibitor) and a TCA may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5HT1A receptors.

MANAGEMENT: In general, the use of paroxetine (or other SSRIs) with TCAs should be avoided if possible, or otherwise approached with caution if potential benefit is deemed to outweigh the risk. Pharmacologic response and plasma TCA levels should be monitored more closely whenever paroxetine is added to or withdrawn from therapy in patients stabilized on their existing antidepressant regimen, and the TCA dosage adjusted as necessary. Patients should be monitored closely for signs and symptoms of TCA toxicity (e.g., sedation, dry mouth, blurred vision, constipation, urinary retention) and/or excessive serotonergic activity (e.g., CNS irritability, altered consciousness, confusion, myoclonus, ataxia, abdominal cramping, hyperpyrexia, shivering, pupillary dilation, diaphoresis, hypertension, and tachycardia).

Potassium chloride

GENERALLY AVOID: Concomitant use of agents with anticholinergic properties (e.g., antihistamines, antispasmodics, neuroleptics, phenothiazines, skeletal muscle relaxants, tricyclic antidepressants, class IA antiarrhythmics especially disopyramide) may potentiate the risk of upper gastrointestinal mucosal damage associated with oral solid formulations of potassium chloride. The proposed mechanism involves increased gastrointestinal transit time due to reduction of stomach and intestinal motility by anticholinergic agents, thereby increasing the contact time of potassium chloride with GI mucosa. In clinical studies, coadministration of wax-matrix or microencapsulated formulations of potassium chloride with an anticholinergic agent such as glycopyrrolate resulted in more frequent and more serious endoscopic lesions than potassium therapy alone. However, the lesions were not accompanied by bleeding or epigastric symptoms. Some studies have reported a higher incidence of upper GI lesions with wax-matrix than microencapsulated formulations, although data are conflicting.

MANAGEMENT: Use of agents with anticholinergic properties at sufficient doses to exert anticholinergic effects should be avoided in patients treated with oral solid formulations of potassium chloride (U.S. manufacturers of potassium chloride consider this combination to be contraindicated). Alternatively, a liquid formulation of potassium chloride may be considered. Patients prescribed a solid oral formulation should be advised to discontinue potassium therapy and contact their physician if they experience potential symptoms of upper GI injury such as severe vomiting, abdominal pain, distention, and gastrointestinal bleeding.

Tacrine, Donepezil (oral), Rivastigmine, Galantamine

GENERALLY AVOID: Due to opposing effects, agents that possess anticholinergic activity (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; class IA antiarrhythmics especially disopyramide; carbamazepine; cimetidine; ranitidine) may negate the already small pharmacologic benefits of acetylcholinesterase inhibitors in the treatment of dementia. These agents may also adversely affect elderly patients in general. Clinically significant mental status changes associated with anticholinergic agents can range from mild cognitive impairment to delirium, and patients with Alzheimer's disease and other dementia are especially sensitive.

MANAGEMENT: Drugs that possess anticholinergic activity should generally be avoided in patients with Alzheimer's disease or other cognitive impairment, regardless of whether they are receiving an acetylcholinesterase inhibitor. For patients requiring treatment for adverse effects of acetylcholinesterase inhibitor therapy (e.g., gastrointestinal intolerance, urinary problems), an agent without anticholinergic properties should be used whenever possible. Otherwise, a dosage reduction, slower titration, or even discontinuation of the acetylcholinesterase inhibitor should be considered. In patients who are already receiving an acetylcholinesterase inhibitor with anticholinergic agents, every attempt should be made to discontinue the latter or substitute them with less anticholinergic alternatives. Caution is required, however, since anticholinergic withdrawal may occur. Seizures have been reported following abrupt discontinuation of anticholinergics during acetylcholinesterase inhibitor therapy.

Iopamidol

GENERALLY AVOID: Intrathecal administration of iodinated contrast media may induce seizures. Although clinical data are generally lacking, there may be a theoretical risk of increased seizure potential when used with selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics), monoamine oxidase inhibitors, neuroleptic agents, central nervous system stimulants, opioids, tricyclic antidepressants, other tricyclic compounds (e.g., cyclobenzaprine, phenothiazines), and/or any substance that can reduce the seizure threshold (e.g., carbapenems, cholinergic agents, fluoroquinolones, interferons, chloroquine, mefloquine, lindane, theophylline). These agents are often individually epileptogenic and may have additive effects when combined.

MANAGEMENT: Drugs that can lower the seizure threshold should preferably be withheld for at least 48 hours prior to and 24 hours following intrathecal administration of iodinated contrast media, provided that temporary interruption of therapy does not pose an undue risk to the patient. Otherwise, close monitoring is advised during and after contrast administration. The manufacturers typically recommend avoiding concomitant administration of phenothiazines (including those used for their antihistamine properties), monoamine oxidase inhibitors, tricyclic antidepressants, central nervous system stimulants, and psychoactive drugs.

Dofetilide

GENERALLY AVOID: Like other class III antiarrhythmic agents, dofetilide can cause dose-related QT interval prolongation. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: The use of dofetilide in conjunction with other medications that can prolong the QT interval has not been studied and is not recommended.

Flumazenil

GENERALLY AVOID: Severe adverse effects, including fatalities, have been reported following the administration of flumazenil to multiple-drug-overdose patients who have taken large quantities of tricyclic antidepressants. The effects have included seizures and arrhythmias (including ventricular tachycardia). The mechanism of this interaction may be related to a decrease in the protective antiseizure effects of benzodiazepines that patients may have taken concomitantly with overdoses of tricyclic antidepressants.

MANAGEMENT: Administration of flumazenil should be avoided in patients who are known or suspected to have received overdoses of tricyclic antidepressants.

Yohimbine

GENERALLY AVOID: Some antidepressants such as the tricyclics may potentiate the pressor effect of yohimbine. The mechanism is a synergistic sympathomimetic effect due to stimulation of norepinephrine release by yohimbine and inhibition of norepinephrine reuptake by certain antidepressants.

MANAGEMENT: Yohimbine should be avoided in patients undergoing concurrent treatment with tricyclic antidepressants or other drugs that interfere with neuronal uptake or metabolism of norepinephrine.

Sodium oxybate

GENERALLY AVOID: The central nervous system (CNS)- and respiratory-depressant effects of sodium oxybate may be potentiated by other agents with CNS-depressant effects.

MANAGEMENT: Agents with CNS depressant effects should be avoided during sodium oxybate therapy.

Phenylephrine, Dobutamine, Norepinephrine, Epinephrine injection

GENERALLY AVOID: Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents and vasoconstrictor-containing local anesthetics. Several-fold increases in the effects of norepinephrine and, to a lesser extent, epinephrine and phenylephrine were reported in healthy subjects pretreated with desipramine, imipramine, or nortriptyline. The mechanism is TCA inhibition of norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, hypertension, throbbing headache, tremor, palpitation, chest pain, and cardiac dysrhythmia have been reported in association with this interaction. Various TCAs have been implicated including amitriptyline, desipramine, imipramine, nortriptyline, and protriptyline. It is not known whether the interaction also occurs with mixed-acting sympathomimetic agents (e.g., dopamine, ephedrine, metaraminol).

MANAGEMENT: Parenteral administration of direct-acting sympathomimetic agents should preferably be avoided during therapy with tricyclic antidepressants except in cases of emergency (e.g., treatment of anaphylaxis). If concomitant use is necessary, initial dose and rate of administration of the sympathomimetic should be reduced, and cardiovascular status including blood pressure should be monitored closely. Although clinical data are lacking, it may be prudent to follow the same precaution with mixed-acting sympathomimetic agents.

Guanadrel

GENERALLY AVOID: Tricyclic antidepressants (TCAs) may reduce the antihypertensive effects of guanethidine. Loss of blood pressure control may result. The mechanism is TCA-induced inhibition of guanethidine uptake into adrenergic neurons. Hypotensive reactions may occur when the tricyclic antidepressant is discontinued. Other adrenergic neurone blockers may also be affected.

MANAGEMENT: Either a different antidepressant or a different antihypertensive agent (such as an ACE inhibitor or beta-blocker) should be considered. If patients do receive this combination, their blood pressure should be closely monitored when initiating or discontinuing either drug.

Ginkgo

Ginkgo toxin (found in both the Ginkgo leaf and seed) is a known neurotoxin. Some investigators have concluded that the amount of toxin is too low to exert a detrimental effect. However, avoiding use of Ginkgo with medications known to decrease the seizure threshold such as antidepressants has been recommended.

Desipramine, Amitriptyline, Atropine, Benztropine, Chlorpheniramine, Diphenhydramine, Doxepin, Imipramine, Propantheline, Thiothixene, Clemastine, Tripelennamine, Dexchlorpheniramine, Brompheniramine, Cyproheptadine, Azatadine, Phenindamine, Cyclizine, Meclizine, Dimenhydrinate, Trimipramine, Amoxapine, Protriptyline, Clomipramine, Molindone, Loxapine, Hydroxyzine, Cyclobenzaprine, Orphenadrine, Procyclidine, Trihexyphenidyl, Biperiden, Hyoscyamine, Belladonna, Methscopolamine, Clidinium, Glycopyrrolate, Dicyclomine, Risperidone (oral), Olanzapine, Oxybutynin (oral), Oxybutynin (transdermal), Triprolidine, Maprotiline, Scopolamine, Flavoxate, Carbinoxamine, Scopolamine topical, Quetiapine, Tolterodine, Aripiprazole, Memantine, Trospium, Solifenacin

MONITOR: Agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; class IA antiarrhythmics especially 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.

Alfuzosin

MONITOR: Alfuzosin may cause modest prolongation of the QTc interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. During a clinical study involving 45 healthy male subjects, average prolongation of QTc interval at peak plasma concentrations was less with single doses of alfuzosin 10 mg than with alfuzosin 40 mg, and both were less than with moxifloxacin 400 mg. Heart rate increased by an average of 5.2 bpm with alfuzosin 10 mg, 5.8 bpm with alfuzosin 40 mg, and 2.8 bpm with moxifloxacin 400 mg. Torsade de pointes has not been reported with alfuzosin. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended when alfuzosin is administered concomitantly with drugs that prolong the QT interval, especially to patients with underlying risk factors. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope. If taking drugs that also cause CNS or orthostatic effects, patients should be made aware of the possibility of additive effects (e.g., drowsiness, dizziness, lightheadedness) and counseled to avoid activities requiring mental alertness until they know how these agents affect them.

Acetohexamide, Glipizide, Glyburide, Tolazamide, Tolbutamide, Glimepiride

MONITOR: Case reports suggest that tricyclic antidepressants may increase the hypoglycemic effects of sulfonylureas. The mechanism is unknown. Causality has not been definitely determined and one small trial demonstrated no pharmacokinetic changes with amitriptyline and tolbutamide.

MANAGEMENT: Patients receiving this combination should be advised to regularly monitor their blood sugar, counseled on how to recognize and treat hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, tremor, hunger, weakness, or palpitations) and to notify their physician if it occurs. The sulfonylurea dosage may require reduction in affected patients.

Clonazepam

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking clonazepam and tricyclic antidepressants. However, one case report has described decreased desipramine levels during concurrent administration with clonazepam. The mechanism is unknown.

MANAGEMENT: Patients should be monitored for excessive or prolonged CNS and respiratory depression. Ambulatory patients should made aware of the possibility of additive CNS effects (e.g., drowsiness, dizziness, lightheadedness, or confusion) and counseled to avoid activities requiring alertness until they know how these agents affect them. Patients should also be advised to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Diazepam, Lorazepam, Alprazolam, Chlordiazepoxide, Clorazepate, Ethosuximide, Fentanyl topical, Flurazepam, Hydromorphone (oral), Methsuximide, Metoclopramide, Morphine, Oxycodone, Temazepam, Triazolam, Levorphanol, Oxymorphone, Trimethobenzamide, Dronabinol, Halazepam, Zolpidem, Estazolam, Quazepam, Mephenytoin, Ethotoin, Paramethadione, Trimethadione, Carisoprodol, Chlorphenesin, Chlorzoxazone, Metaxalone, Methocarbamol, Baclofen, Dantrolene, Felbamate, Gabapentin, Lamotrigine, Chloral hydrate, Chloral hydrate rectal, Diazepam rectal, Fentanyl (buccal), Fentanyl citrate (oral transmucosal), Hydromorphone (injection), Hydromorphone (rectal), Meprobamate, Buprenorphine (oral), Buprenorphine (injection), Pramipexole (oral), Ropinirole (oral), Tiagabine, Butorphanol, Tolcapone, Thalidomide, Zaleplon, Entacapone, Levetiracetam, Oxcarbazepine, Nabilone, Eszopiclone, Ziconotide, Pregabalin, Rotigotine (transdermal)

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.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. 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.

Gemifloxacin

MONITOR: Certain quinolones, including gemifloxacin, may cause dose-related prolongation of the QT interval in some patients. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. No cardiovascular morbidity or mortality attributable to QTc prolongation occurred with gemifloxacin treatment in over 6775 patients during clinical trials, including 653 patients concurrently receiving drugs known to prolong the QTc interval and 5 patients with hypokalemia. The maximal change in QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Although the risk of a serious interaction is probably low, caution is recommended when gemifloxacin is administered concomitantly with drugs that prolong the QT interval, especially to patients with underlying risk factors. Since the magnitude of QTc prolongation may increase with increasing plasma concentrations of gemifloxacin, the recommended dosage should not be exceeded, especially in patients with renal or hepatic impairment. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Levofloxacin

MONITOR: Certain quinolones, including levofloxacin, norfloxacin, and ofloxacin, may cause dose-related prolongation of the QT interval in some patients. Coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. During postmarketing surveillance, rare cases of torsade de pointes and ventricular tachycardia have been reported in patients taking levofloxacin, norfloxacin, and ofloxacin. The levofloxacin cases primarily involved patients with underlying medical conditions or taking concomitant medications that may have been contributory. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Although the risk of a serious interaction is probably low, caution is recommended when levofloxacin, norfloxacin, or ofloxacin is administered concomitantly with drugs that prolong the QT interval, especially to patients with underlying risk factors. Since the magnitude of QTc prolongation increases with increasing plasma concentrations of the quinolone, recommended dosages and intravenous infusion rates should not be exceeded. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Topiramate (oral)

MONITOR CLOSELY: Certain drugs such as carbonic anhydrase inhibitors and drugs with anticholinergic activity (e.g., antihistamines, antispasmodics, neuroleptics, phenothiazines, skeletal muscle relaxants, tricyclic antidepressants, class IA antiarrhythmics especially disopyramide) may potentiate the risk of oligohidrosis and hyperthermia associated occasionally with the use of topiramate, particularly in pediatric patients. These agents may alter electrolyte and fluid balance (carbonic anhydrase inhibition), inhibit peripheral sweating mechanisms (anticholinergic effect), and/or interfere with core body temperature regulation in the hypothalamus (neuroleptics and phenothiazines), resulting in the inability to adjust to temperature changes, especially in hot weather. Also, agents with anticholinergic activity frequently cause drowsiness and other central nervous system-depressant effects, which may be additively or synergistically increased in patients also treated with topiramate.

MANAGEMENT: Caution is advised when topiramate is prescribed with other drugs that predispose patients to heat-related disorders, including carbonic anhydrase inhibitors and drugs with anticholinergic activity. Patients, particularly pediatric patients, should be monitored closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather. Proper hydration before and during vigorous activities or exposure to warm temperatures is recommended. Patients (or their guardians or caregivers) should contact their physician immediately if they are not sweating as usual, with or without a fever. Ambulatory patients treated with topiramate and agents with anticholinergic activity should also be made aware of the possibility of additive CNS effects (e.g., drowsiness, dizziness, lightheadedness, confusion) and counseled to avoid activities requiring mental alertness until they know how these agents affect them.

Zonisamide

MONITOR CLOSELY: Certain drugs such as carbonic anhydrase inhibitors and drugs with anticholinergic activity (e.g., antihistamines, antispasmodics, neuroleptics, phenothiazines, skeletal muscle relaxants, tricyclic antidepressants) may potentiate the risk of oligohidrosis and hyperthermia associated occasionally with the use of zonisamide, particularly in pediatric patients. These agents may alter electrolyte and fluid balance (carbonic anhydrase inhibition), inhibit peripheral sweating mechanisms (anticholinergic effect), and/or interfere with core body temperature regulation in the hypothalamus (neuroleptics and phenothiazines), resulting in the inability to adjust to temperature changes, especially in hot weather. Also, agents with anticholinergic activity frequently cause drowsiness and other central nervous system-depressant effects, which may be additively or synergistically increased in patients also treated with zonisamide.

MANAGEMENT: Caution is advised when zonisamide is prescribed with other drugs that predispose patients to heat-related disorders, including carbonic anhydrase inhibitors and drugs with anticholinergic activity. Patients, particularly pediatric patients, should be monitored closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather. Proper hydration before and during vigorous activities or exposure to warm temperatures is recommended. Patients (or their guardians or caregivers) should contact their physician immediately if they are not sweating as usual, with or without a fever. Ambulatory patients treated with zonisamide and agents with anticholinergic activity should also be made aware of the possibility of additive CNS effects (e.g., drowsiness, dizziness, lightheadedness, confusion) and counseled to avoid activities requiring mental alertness until they know how these agents affect them.

Moxifloxacin, Gatifloxacin

MONITOR CLOSELY: Certain quinolones, including gatifloxacin and moxifloxacin, may cause dose-related prolongation of the QT interval in some patients. Coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. During postmarketing surveillance, rare cases of torsade de pointes have been reported in patients taking gatifloxacin. These cases primarily involved patients with underlying medical conditions for which they were receiving concomitant medications known to prolong the QTc interval. Rare cases of tachycardia have been reported with moxifloxacin. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended when gatifloxacin or moxifloxacin is administered concomitantly with drugs that prolong the QT interval, especially to patients with underlying risk factors. Since the magnitude of QTc prolongation increases with increasing plasma concentrations of the quinolone, recommended dosages and intravenous infusion rates should not be exceeded. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Clozapine

MONITOR CLOSELY: Coadministration with other psychotropic agents may potentiate the adverse effects of clozapine on cardiovascular function. Orthostatic hypotension with or without syncope, in rare cases accompanied by profound collapse and respiratory and/or cardiac arrest, has occurred during initiation of clozapine treatment alone and in patients receiving other psychotropic agents. The risk is greatest during initial titration in association with rapid dose escalation and may even occur on the first dose. In one report, initial doses as low as 12.5 mg were associated with collapse and respiratory arrest. Other adverse effects that may be increased during use of clozapine with other psychotropic agents include CNS depression, tardive dyskinesia, tachycardia, and ECG changes. Anticholinergic effects of these agents may also be additively increased. Excessive anticholinergic effects may result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of anticholinergic 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.

MANAGEMENT: Caution is advised when clozapine is initiated in patients receiving other psychotropic drugs. Vital signs should be closely monitored. Patients who have had even a brief interval off clozapine (i.e. 2 or more days since the last dose) should be restarted with 12.5 mg once or twice daily. Particular caution is recommended 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 (e.g., abdominal pain, fever, heat intolerance, blurred vision, confusion, hallucinations) or cardiovascular toxicity (e.g., dizziness, palpitations, arrhythmias, syncope). Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A dosage reduction in one or both drugs may be necessary if excessive adverse effects develop.

Sertraline

MONITOR CLOSELY: Coadministration with sertraline may increase the plasma concentrations of some tricyclic antidepressants (TCAs). The proposed mechanism is sertraline inhibition of CYP450 2D6, the isoenzyme responsible for the metabolic clearance of many antidepressant and psychotropic drugs. Moderate to significant increases (up to 250%) in plasma levels have been reported for desipramine and nortriptyline. Pharmacodynamically, the combination of sertraline (or any other selective serotonin reuptake inhibitor) and a TCA may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5HT1A receptors. The syndrome has been reported in a case involving sertraline and amitriptyline.

MANAGEMENT: Caution is advised if sertraline (or other SSRIs) is prescribed with TCAs. Pharmacologic response and plasma TCA levels should be monitored more closely whenever sertraline is added to or withdrawn from therapy in patients stabilized on their existing antidepressant regimen, and the TCA dosage adjusted as necessary. Patients should be monitored closely for signs and symptoms of TCA toxicity (e.g., sedation, dry mouth, blurred vision, constipation, urinary retention) and/or excessive serotonergic activity (e.g., CNS irritability, altered consciousness, confusion, myoclonus, ataxia, abdominal cramping, hyperpyrexia, shivering, pupillary dilation, diaphoresis, hypertension, and tachycardia).

Buspirone, Trazodone, Venlafaxine (oral), Nefazodone, Mirtazapine, Sibutramine (oral), Citalopram (oral), St. John's wort, Linezolid, 5-hydroxytryptophan, L-tryptophan, Escitalopram, Duloxetine

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, lithium, St. John's wort, phenylpiperidine opioids, dextromethorphan, and 5-hydroxytryptophan 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 receptors.

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. Close monitoring is recommended for signs and symptoms of excessive serotonergic activity such as CNS irritability, altered consciousness, confusion, myoclonus, ataxia, abdominal cramping, hyperpyrexia, shivering, pupillary dilation, diaphoresis, hypertension, and tachycardia. Particular caution is advised when increasing the dosages of these agents. The potential risk of serotonin syndrome should be considered even when administering one serotonergic agent following discontinuation of another, as some agents may demonstrate a prolonged elimination half-life. For example, a 5-week washout period is recommended following use of fluoxetine before administering another serotonergic agent.

Propoxyphene

MONITOR CLOSELY: Concomitant use of propoxyphene and tricyclic and tetracyclic antidepressants (TCAs) may result in additive central nervous system (CNS) depressant effects. Misuse of propoxyphene, either alone or in combination with other CNS depressants, has been a major cause of drug-related deaths, particularly in patients with a history of emotional disturbances, suicidal ideation, or alcohol and drug abuse. In a large Canadian study, propoxyphene use was also associated with a 60% increased risk of hip fracture in the elderly, and the risk was further increased by concomitant use of psychotropic agents including antidepressants, presumably due to additive psychomotor impairment. Therefore, these drugs may constitute a dangerous combination in certain susceptible populations. Pharmacokinetically, propoxyphene is a CYP450 2D6 inhibitor and may increase the plasma concentrations of TCAs such as clomipramine, desipramine, doxepin, maprotiline, and nortriptyline that are primarily metabolized by the isoenzyme. In one case report, doxepin serum concentrations doubled in an 89-year-old patient following the addition of propoxyphene, resulting in lethargy. A retrospective study also found that the plasma concentration/dose ratio of nortriptyline was nearly 40% higher in patients treated concomitantly with propoxyphene than in patients treated with nortriptyline alone.

MANAGEMENT: Caution is advised if propoxyphene is prescribed with TCAs, particularly in the elderly and in patients with a history of emotional disturbances, suicidal ideation, or alcohol and drug abuse. Serum TCA levels should be monitored more closely following the addition or withdrawal of propoxyphene, and the TCA dosage adjusted as necessary. Patients should be warned not to exceed recommended dosages of either drug, to avoid alcohol, and to notify their physician if they experience symptoms of toxicity such as lethargy, excessive sedation, dizziness, syncope, seizures, and/or irregular heartbeat. In addition, they should avoid activities requiring mental alertness until they know how these agents affect them.

Dolasetron

MONITOR CLOSELY: Dolasetron can cause dose-related prolongation of the QT interval via its pharmacologically active metabolite, hydrodolasetron. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. In clinical trials, ECG interval prolongations usually returned to baseline within 6 to 8 hours after administration but lasted more than 24 hours in some patients. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended when dolasetron is administered concomitantly with drugs that prolong the QT interval (including cumulative high-dose anthracycline therapy), especially to patients with underlying risk factors. ECG monitoring may be appropriate in high-risk patients. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Altretamine

MONITOR CLOSELY: The coadministration of altretamine with a monoamine oxidase inhibitor (MAOI) or tricyclic antidepressant may result in severe orthostatic hypotension. The mechanism of interaction has not been established. According to one case report, four patients over 60 years of age experienced symptomatic hypotension after 4 to 7 days of concomitant therapy with altretamine and one of the following: amitriptyline, imipramine, or phenelzine. All patients became asymptomatic within 24 to 96 hours after discontinuing the antidepressant. One patient subsequently received and tolerated nortriptyline without clinical symptoms, although a postural drop in systolic blood pressure was observed.

MANAGEMENT: Caution is advised if altretamine must be used with a MAOI or tricyclic antidepressant, particularly in elderly patients. All patients receiving the combination should be advised to avoid rising abruptly from a sitting or lying position and to contact their physician if they experience symptoms of hypotension such as dizziness, lightheadedness, or fainting.

Bupropion (oral)

MONITOR CLOSELY: The concomitant use of bupropion and tricyclic antidepressants (TCAs) may potentiate the risk of seizures. These agents are individually epileptogenic and may have additive effects on the seizure threshold. Additionally, bupropion can increase the plasma concentrations of some TCAs due to inhibition of CYP450 2D6. In one case report, plasma levels of imipramine and its metabolite, desipramine, increased approximately fourfold in a 64-year-old woman following the addition of bupropion 225 mg/day. Plasma levels of desipramine were increased twofold more than the imipramine levels, which is consistent with the fact that desipramine is primarily metabolized by CYP450 2D6 while imipramine is also metabolized by other CYP450 isoenzymes. Similarly, a 62-year-old woman with no history of seizures developed a generalized tonic-clonic seizure in association with toxic trimipramine plasma levels following the addition of bupropion. No further seizures occurred following dosage reductions of both drugs. In a study of 15 male volunteers who were extensive metabolizers of CYP450 2D6, pretreatment with bupropion (150 mg twice daily) increased the peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and half-life of desipramine (50 mg single dose) by an average of 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion.

MANAGEMENT: The manufacturer advises extreme caution if bupropion is coadministered with TCAs. Low initial TCA dosages with gradual titration are recommended. In patients who are already stabilized on TCA therapy, plasma TCA levels and pharmacologic response should be monitored more closely whenever bupropion is added to or withdrawn from therapy, and the TCA dosage adjusted as necessary. Patients should be advised to notify their physician if they experience seizures or increased TCA adverse effects such as somnolence, dry mouth, urinary retention, orthostasis, tachycardia, or irregular heartbeats.

Tramadol

MONITOR CLOSELY: The risk of seizures may be increased during coadministration of tramadol with selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics), monoamine oxidase inhibitors, neuroleptic agents, central nervous system stimulants, opioids, tricyclic antidepressants, other tricyclic compounds (e.g., cyclobenzaprine, phenothiazines), and/or any substance that can reduce the seizure threshold (e.g., carbapenems, cholinergic agents, fluoroquinolones, interferons, chloroquine, mefloquine, lindane, theophylline). These agents are often individually epileptogenic and may have additive effects when combined. Many of these agents also exhibit CNS- and/or respiratory-depressant effects, which may be enhanced during their concomitant use with tramadol.

MANAGEMENT: Caution is advised if tramadol is administered with any substance that can reduce the seizure threshold, particularly in the elderly and in patients with epilepsy, a history of seizures, or other risk factors for seizures (e.g., head trauma, brain tumor, metabolic disorders, alcohol and drug withdrawal, CNS infections).

Fluphenazine, Prochlorperazine, Promethazine (oral), Perphenazine, Thiethylperazine, Trifluoperazine, Promethazine (rectal), Promethazine (injection)

MONITOR: Coadministration of a phenothiazine with a tricyclic antidepressant (TCA) may result in elevated plasma concentrations of one or both drugs as well as additive adverse effects. Most phenothiazines and TCAs have been found to undergo metabolism by CYP450 2D6, thus competitive inhibition of the enzyme may occur when more than one of these agents are administered. Although these drugs have been used together clinically, the possibility of increased risk of serious adverse effects such as central nervous system depression, tardive dyskinesia, hypotension, and prolongation of the QT interval should be considered, as many of these agents alone can and have produced these effects. In addition, excessive anticholinergic effects may occur in combination use, which can result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of anticholinergic 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.

MANAGEMENT: Concurrent use of phenothiazines and TCAs should be approached with caution, 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 (e.g., abdominal pain, fever, heat intolerance, blurred vision, confusion, hallucinations) or cardiovascular toxicity (e.g., dizziness, palpitations, arrhythmias, syncope). Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A dosage reduction in one or both drugs may be necessary if excessive adverse effects develop.

Apomorphine

MONITOR: Coadministration of apomorphine with other agents that can prolong the QT interval may result in an elevated risk of ventricular arrhythmias including ventricular tachycardia and torsade de pointes. In addition, some of these agents may cause additive sedative and hypotensive effects with apomorphine. Apomorphine doses greater than 6 mg have been associated with minimal increases of the QT interval. The average QTc prolongation was 1 msec at 6 mg and 7 msec at 8 mg. Two patients experienced large increases of more than 60 msec with 2 mg and 6 mg doses. Torsade de pointes has not been reported with apomorphine alone at recommended doses. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended when apomorphine is administered concomitantly with drugs that prolong the QT interval, especially to patients with underlying risk factors. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope. If taking drugs that also cause CNS or orthostatic effects, patients should be made aware of the possibility of additive effects (e.g., drowsiness, dizziness, lightheadedness) and counseled to avoid activities requiring mental alertness until they know how these agents affect them.

Celecoxib (oral)

MONITOR: Coadministration with celecoxib may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by celecoxib.

MANAGEMENT: Caution is advised if celecoxib must be used concurrently with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever celecoxib is added to or withdrawn from therapy.

Cinacalcet

MONITOR: Coadministration with cinacalcet may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by cinacalcet, which is expected to occur in patients who are CYP450 2D6 extensive metabolizers (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent). Concurrent administration of cinacalcet (25 or 100 mg) increased the systemic exposure of amitriptyline (50 mg) and its active metabolite, nortriptyline, by approximately 20% in CYP450 2D6 extensive metabolizers. However, because amitriptyline is metabolized by multiple CYP450 isoenzymes in addition to 2D6, the degree of interaction with cinacalcet may be less than that expected for other drugs that are primarily metabolized by 2D6.

MANAGEMENT: Caution is advised if cinacalcet must be used concurrently with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range (e.g., class IC antiarrhythmic agents, phenothiazines, certain beta blockers, and most tricyclic antidepressants). Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever cinacalcet is added to or withdrawn from therapy.

Darifenacin

MONITOR: Coadministration with darifenacin may increase the plasma concentrations of drugs that are metabolized by CYP450 2D6, including many psychotherapeutic drugs such as tricyclic antidepressants, phenothiazines, and other neuroleptics. The mechanism is decreased clearance due to inhibition of the CYP450 2D6 isoenzyme by darifenacin. According to the product labeling, darifenacin (30 mg once daily) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of imipramine by 57% and 70%, respectively. These changes were accompanied by a 3.6-fold increase in the mean Cmax and AUC of desipramine, the active metabolite of imipramine. Pharmacodynamically, anticholinergic effects may also increase when darifenacin is used in combination with these drugs. Excessive parasympatholytic effects may result in mydriasis, blurred vision, flushed face, dry skin and mucous membranes, tachycardia, urinary retention, constipation, paralytic ileus, hyperthermia, and heat stroke.

MANAGEMENT: Caution is advised if darifenacin must be used concomitantly with tricyclic antidepressants, phenothiazines, or other neuroleptics. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever darifenacin is added to or withdrawn from therapy. Clinicians should also be alerted to the potential for additive anticholinergic effects during concomitant administration. 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.

Loperamide (oral)

MONITOR: Coadministration with drugs that possess significant anticholinergic activity may potentiate the antimotility effect of loperamide. An isolated case report describes an incident of fatal gastroenteritis during concomitant treatment with clozapine and loperamide. A 36-year-old man who had been treated with clozapine 500 mg/day and was previously in good health died after taking a total of 6 mg of loperamide during an outbreak of intestinal disease in a Finnish hospital. The patient received no other medications. The authors theorized that the anticholinergic effect of clozapine in combination with the antimotility effect of loperamide may have led to toxic megacolon. However, causality has not been determined.

MANAGEMENT: Until further information is available, loperamide should be used with caution in combination with drugs that possess significant anticholinergic activity (e.g., antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; class IA antiarrhythmics especially disopyramide). Ambulatory patients should also be made aware of the possibility of additive CNS effects (e.g., drowsiness, dizziness, lightheadedness, confusion) and counseled to avoid activities requiring mental alertness until they know how these agents affect them.

Imatinib (oral)

MONITOR: Coadministration with imatinib may increase the plasma concentrations of drugs that are substrates of CYP450 2C9, 2D6 and/or 3A4. The mechanism is decreased clearance due to inhibition of these isoenzymes by imatinib. According to the manufacturer, imatinib increased the mean peak plasma concentration and area under the concentration-time curve of simvastatin (a CYP450 3A4 substrate) by 2- and 3.5-fold, respectively. Data for other substrates are not currently available, although human liver microsome studies indicate that imatinib is a potent competitive inhibitor of all three isoenzymes.

MANAGEMENT: Caution is advised if imatinib must be used concomitantly with medications that undergo metabolism by CYP450 2C9, 2D6 and/or 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever imatinib is added to or withdrawn from therapy.

Ritonavir

MONITOR: Coadministration with ritonavir may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. The mechanism is decreased clearance due to competitive inhibition of CYP450 2D6 activity by ritonavir. The systemic exposure (AUC) of some coadministered drugs has been reported to increase by up to twofold.

MANAGEMENT: Caution is advised if ritonavir must be used concurrently with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ritonavir is added to or withdrawn from therapy.

Terbinafine

MONITOR: Coadministration with terbinafine may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by terbinafine, which is expected to occur in patients who are CYP450 2D6 extensive metabolizers (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent). A case of nortriptyline (a CYP450 2D6 substrate) intoxication corresponding to significantly increased serum drug concentrations was reported in a patient shortly after the addition of terbinafine. Rechallenge in the patient produced similar results.

MANAGEMENT: Caution is advised if terbinafine must be used concurrently with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever terbinafine is added to or withdrawn from therapy. Due to the long elimination half-life of terbinafine, especially following prolonged use, such interactions may be observed for several months after discontinuation of terbinafine therapy.

Brimonidine ophthalmic

MONITOR: Concomitant use of tricyclic antidepressants can diminish the effects of centrally acting alpha-agonists. The clinical significance, if any, of this interaction with ophthalmic alpha-agonists is unknown, however caution is recommended if the combination is used. In addition, central nervous system (CNS) depressant effects may be additively or synergistically increased in patients using brimonidine ophthalmic solution in combination with other drugs that can also cause these effects, especially in elderly or debilitated patients.

MANAGEMENT: Patients prescribed brimonidine ophthalmic drops with other agents that can cause CNS depression should be made aware of the possibility of additive CNS effects (e.g., drowsiness, dizziness, lightheadedness, confusion) and counseled to avoid activities requiring mental alertness until they know how these agents affect them. Patients should be advised to contact their doctor if they experience excessive or prolonged CNS depression.

Cetirizine

MONITOR: Concurrent use of cetirizine or levocetirizine with alcohol or other central nervous system (CNS) depressants may result in additive impairment of mental alertness and performance. Several studies have shown no effect of racemic cetirizine on cognitive function, motor performance, or sleep latency as indicated by objective measurements. However, there have been reports of somnolence, fatigue, and asthenia in some patients treated with cetirizine or levocetirizine in clinical trials.

MANAGEMENT: Concomitant use of cetirizine or levocetirizine with alcohol or other CNS depressants should generally be avoided if possible. In the event that they are used together, 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.

Dasatinib

MONITOR: In vitro data suggest that dasatinib has the potential to prolong QT interval of the electrocardiogram. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. In single-arm clinical studies involving patients with leukemia treated with dasatinib, the mean QTc interval changes from baseline using Fridericia's method (QTcF) were 3 to 6 msec; the upper 95% confidence intervals for all mean changes from baseline were less than 8 msec. Nine patients had QTc prolongation reported as an adverse event, three of whom (less than 1%) experienced a QTcF greater than 500 msec. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended when dasatinib is administered concomitantly with cumulative high-dose anthracycline therapy or other drugs that prolong the QT interval , especially to patients with underlying risk factors. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Carvedilol

MONITOR: Limited data suggest that labetalol can increase the plasma concentrations of tricyclic antidepressants. The proposed mechanism is competition for the same metabolic pathway. In a study (n=13), imipramine AUC increased by 53% in subjects taking labetalol compared to placebo. Carvedilol may also interact.

MANAGEMENT: Close monitoring for clinical response and tolerance is recommended whenever labetalol is added to or discontinued from an antidepressant regimen. Patients should be advised to notify their physician if they experience excessive antidepressant effects such as dry mouth, blurry vision, irregular or fast heartbeat, constipation, urinary retention, dizziness, or orthostatic hypotension. Dose adjustments may be necessary.

Lindane topical

MONITOR: Lindane penetrates human skin and has the potential to cause central nervous system toxicity. Seizures have been reported after excessive use or oral ingestion of lindane. There may be a theoretical risk of increased seizure potential when lindane is used with selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics), monoamine oxidase inhibitors, neuroleptic agents, central nervous system stimulants, opioids, tricyclic antidepressants, other tricyclic compounds (e.g., cyclobenzaprine, phenothiazines), and/or any substance that can reduce the seizure threshold (e.g., carbapenems, cholinergic agents, fluoroquinolones, interferons, chloroquine, mefloquine, theophylline). These agents are often individually epileptogenic and may have additive effects when combined.

MANAGEMENT: Caution is advised if lindane is used with any substance that can reduce the seizure threshold, particularly in the very young or the elderly and in patients with epilepsy, a history of seizures, or other risk factors for seizures (e.g., head trauma, brain tumor, metabolic disorders, alcohol and drug withdrawal, CNS infections). Lindane should be used according to recommended dosage and directions for application.

Mefloquine

MONITOR: Mefloquine is a myocardial depressant and can cause ECG abnormalities. Theoretically, coadministration with other agents that can affect cardiac conduction (e.g., antiarrhythmic agents, beta blockers, calcium channel blockers, certain antihistamines, tricyclic antidepressants, phenothiazines, some neuroleptics) may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential. Parenteral studies in animals have shown that mefloquine possesses 20% of the antifibrillatory action of quinidine and can cause 50% of the increase in PR interval reported with quinine. ECG alterations reported with mefloquine include sinus bradycardia, sinus arrhythmia, first degree AV block, prolongation of the QTc interval, and abnormal T waves. According to mefloquine labeling, there has been one report of cardiopulmonary arrest, with full recovery, in a patient who was taking a beta blocker (propranolol).

MANAGEMENT: Caution and clinical monitoring are recommended if mefloquine is used concurrently with other medications that can prolong the QT interval or otherwise affect cardiac conduction. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of arrhythmia such as dizziness, palpitations, or syncope.

Midodrine

MONITOR: Midodrine, an alpha-1 adrenergic agent may lead to bradycardia if administered concomitantly with any agent that directly or indirectly reduces heart rate. This may be most important for beta blockers and tricyclic antidepressants.

MANAGEMENT: Patients should be advised to discontinue midodrine if they experience signs or symptoms of decreased heart rate (i.e., slow pulse, dizziness, syncope, cardiac awareness) and to contact their provider for reevaluation.

Guanfacine

MONITOR: One case report suggests that tricyclic antidepressants may decrease the antihypertensive effect of guanfacine. The mechanism is unknown.

MANAGEMENT: The patient's blood pressure should be monitored during concomitant therapy and after discontinuation or dose change of the antidepressant. An alternative antihypertensive (e.g., beta adrenergic blocking agent, diuretic) may be considered.

Atazanavir (oral)

MONITOR: Product labeling for certain protease inhibitors (PIs) such as amprenavir and atazanavir states that serious and/or life-threatening drug interactions may occur with tricyclic antidepressants (TCAs), presumably due to PI inhibition of TCA metabolism via CYP450 3A4. High plasma levels of TCAs could conceivably lead to serious adverse reactions including QT interval prolongation and ventricular arrhythmias such as ventricular tachycardia and torsade de pointes. However, the clinical significance of such an interaction is unknown, as it has not been studied and there are no case reports of it published in the medical literature. Moreover, many TCAs are thought to be substrates of multiple CYP450 isoenzymes, thus the effects of CYP450 3A4 inhibition alone are unknown. Some TCAs such as desipramine, doxepin, and nortriptyline are also thought to be primarily metabolized by CYP450 2D6, which is not known to be inhibited by most PIs (except ritonavir) to any significant extent.

MANAGEMENT: Until further information is available, caution is advised if protease inhibitors must be used with certain TCAs. Pharmacologic response and plasma TCA levels should be monitored more closely whenever a PI is added to or withdrawn from therapy, and the TCA dosage adjusted as necessary.

Tizanidine

MONITOR: Sedation is a major side effect of tizanidine and may be potentiated by coadministration with other substances that have central nervous system-depressant effects or that may commonly cause drowsiness.

MANAGEMENT: Use of tizanidine with other substances that commonly cause sedation should be approached with caution, particularly in elderly or debilitated patients. 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.

Telithromycin

MONITOR: Telithromycin has the potential to prolong the QT interval of the electrocardiogram in some patients. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. No cardiovascular morbidity or mortality attributable to QTc prolongation occurred with telithromycin treatment in 4780 patients during clinical trials, including 204 patients having a prolonged QTc at baseline. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Although the risk of a serious interaction is probably low, caution is recommended when telithromycin is administered concomitantly with drugs that prolong the QT interval, especially to patients with underlying risk factors. Since the magnitude of QTc prolongation may increase with increasing plasma concentrations of telithromycin, the recommended dosage should not be exceeded, particularly in patients with renal or hepatic impairment. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Methylphenidate, Methylphenidate (transdermal), Dexmethylphenidate

MONITOR: The coadministration with methylphenidate may increase the serum concentrations of tricyclic antidepressants (TCAs). Case reports involving primarily methylphenidate and imipramine have suggested favorable as well as unfavorable clinical effects from this combination. In vitro studies suggest that methylphenidate may inhibit the metabolism of imipramine and other TCAs, although the extent is probably subject to considerable interindividual variation.

MANAGEMENT: Pharmacologic response to TCAs should be monitored more closely whenever methylphenidate (racemic) or dexmethylphenidate (the more pharmacologically active d-enantiomer) is added to or withdrawn from therapy, and the TCA dosage adjusted as necessary.

Amiloride, Bumetanide, Fosinopril, Isosorbide dinitrate, Isosorbide mononitrate, Nitroglycerin (oral/buccal/sublingual/spray), Nitroglycerin topical (patches and ointment), Quinapril, Reserpine, Terazosin, Ethacrynic acid, Carteolol, Bisoprolol, Doxazosin, Ramipril, Benazepril, Lisinopril, Phenoxybenzamine, Torsemide, Losartan, Moexipril, Trandolapril, Betaxolol, Esmolol, Penbutolol, Irbesartan, Eprosartan, Candesartan, Telmisartan, Perindopril, Olmesartan, Eplerenone

MONITOR: The concomitant administration of agents with hypotensive effects and psychotherapeutic agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics), narcotic analgesics, alcohol, or muscle relaxants may additively increase hypotensive and/or central nervous system depressant effects.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for hypotension and excessive or prolonged CNS depression. Ambulatory patients should be made aware of the possibility of additive effects (e.g., drowsiness, dizziness, lightheadedness, confusion, orthostasis, fainting) and be cautioned about driving, operating machinery, or performing other hazardous tasks, and to arise slowly from a sitting or lying position. Patients should also be advised to notify their doctor if they experience excessive side effects that interfere with their normal activities, or dizziness and fainting.

Divalproex sodium

MONITOR: The concomitant administration of valproic acid or its derivatives may increase serum concentrations of tricyclic antidepressants. In one study, the amitriptyline area under the curve was increased 31% in subjects taking divalproex sodium (n=15). A case report has described increased nortriptyline levels and toxicity after sodium valproate was added to the regimen. The proposed mechanism of action is inhibition of CYP450 hepatic metabolism. CNS and/or respiratory depressant effects may be additively or synergistically increased in patients taking multiple drugs which cause these effects. Other tricyclic antidepressants may exhibit a similar interaction. Additionally, tricyclic antidepressants may counteract the anticonvulsive effects of valproic acid and divalproex by lowering the seizure threshold.

MANAGEMENT: It may be advisable to monitor patients for altered efficacy and safety. Dose adjustments or alternate therapy may be necessary if an interaction is suspected.

Isoproterenol inhalation

MONITOR: The concomitant use of isoproterenol and tricyclic antidepressants may increase the risk of arrhythmias, especially at high doses. The mechanism is not clear. Tachycardia has been reported in clinical studies. Rare cases of malignant cardiac arrhythmias have also been reported in patients who took oral isoproterenol and tricyclic antidepressants; however causality was not clearly established due to excessive doses ingested and the presence of other drugs.

MANAGEMENT: Patients receiving this combination should be monitored and advised to notify their physician if they experience a fast or irregular pulse.

Carbachol ophthalmic, Pilocarpine ophthalmic, Demecarium bromide ophthalmic, Echothiophate iodide ophthalmic, Physostigmine ophthalmic

MONITOR: Theoretically, anticholinergic agents and other agents with significant anticholinergic activity (e.g., antihistamines, antispasmodics, neuroleptics, phenothiazines, skeletal muscle relaxants, tricyclic antidepressants, class IA antiarrhythmics especially disopyramide) may antagonize the effects of topically administered cholinergic agents such as acetylcholine, carbachol, demecarium, echothiophate, isoflurophate, physostigmine, and pilocarpine. The proposed mechanism involves opposing pharmacodynamic action on muscarinic receptor sites in ocular tissue. This interaction is sometimes desirable and is the basis for using atropine in the treatment of excessive muscarinic side effects and cholinergic crisis induced by cholinergic overdose.

MANAGEMENT: Patients receiving long-term therapy with anticholinergic agents should be monitored for potentially diminished therapeutic (miotic) response to ophthalmic cholinergic therapy, and dosages adjusted as necessary.

Flecainide, Quinine, Tamoxifen, Terfenadine, Astemizole, Ondansetron, Daunorubicin, Doxorubicin, Idarubicin, Vasopressin, Ondansetron (injection), Tacrolimus (oral), Doxorubicin liposomal, Daunorubicin liposomal, Epirubicin, Palonosetron, Vardenafil, Abarelix, Paliperidone, Lapatinib

MONITOR: Theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may increase the risk of ventricular arrhythmias, including ventricular tachycardia and torsades de pointes, due to additive arrhythmogenic potential related to their effects on cardiac conduction. The risk of an individual agent or a combination of these agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution and clinical monitoring are recommended if multiple agents associated with QT interval prolongation are prescribed together. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsades de pointes such as dizziness, palpitations, or syncope.

Aminolevulinic acid

MONITOR: Theoretically, photosensitivity reactions of actinic keratoses may be additively or synergistically increased in patients taking photosensitizing drugs during aminolevulinic acid therapy.

MANAGEMENT: The patient's response to photodynamic therapy should be monitored. Patients should be advised to avoid exposure to sunlight or bright indoor light during the period between application of aminolevulinic acid and photoactivation.

Desmopressin oral and injectable, Desmopressin nasal

MONITOR: The use of selective serotonin reuptake inhibitors (SSRIs) has rarely been associated with hyponatremia, sometimes secondary to development of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). These events have generally been reversible following discontinuation of SSRI therapy and/or medical intervention. SSRI-related hyponatremia may be more common in elderly female patients and those who are volume-depleted or receiving concomitant diuretic therapy. Other drugs, including tricyclic antidepressants, chlorpromazine, chlorpropamide, carbamazepine, and nonsteroidal anti-inflammatory agents (NSAIDS), may also potentiate the effects of DDAVP and increase the risk of water intoxication and hyponatremia.

MANAGEMENT: Caution may be warranted during concomitant use. Serum electrolytes, especially sodium as well as BUN and plasma creatinine, should be monitored regularly.

Phenylpropanolamine, Amphetamine, Dextroamphetamine, Phentermine, Benzphetamine, Phendimetrazine, Diethylpropion, Mazindol, Ma huang (ephedra), Lisdexamfetamine

MONITOR: The use of tricyclic antidepressants in combination with amphetamines or sympathomimetic appetite suppressants may produce additive cardiovascular effects, increasing the risk of hypertension, cardiac arrhythmias, tachycardia, and fever. The mechanism involves additive pharmacodynamic effects resulting from increased norepinephrine release by sympathomimetic agents and inhibition of norepinephrine reuptake by tricyclic antidepressants. A pharmacokinetic interaction is also possible between tricyclic antidepressants and amphetamines, since many of these agents are metabolized by CYP450 2D6. Increased plasma levels of one or both drugs may occur during coadministration.

MANAGEMENT: Close monitoring of cardiovascular status is recommended for patients receiving this combination. Patients should be advised to promptly report symptoms such as fever, headache, or fast or irregular heartbeats.

Apraclonidine ophthalmic

MONITOR: Tricyclic antidepressants and sympathomimetic agents may theoretically inhibit the effect of apraclonidine ophthalmic on intraocular pressure. Clinical data have not been reported; however, the hypotensive effects of clonidine, a related alpha-2 adrenergic agonist, have been reduced by tricyclic agents. In addition, potentiation of CNS depression (e.g., drowsiness, dizziness) may occur with the tricyclic antidepressants.

MANAGEMENT: Monitoring for altered efficacy and safety is recommended during concomitant administration.

Pentobarbital, Phenobarbital, Primidone, Secobarbital, Mephobarbital

MONITOR: Tricyclic antidepressants may counteract the anticonvulsive effects of barbiturates by lowering the seizure threshold. Barbiturates may decrease the serum levels and effects of tricyclic antidepressants by induction of hepatic metabolism. In addition, the respiratory-depressant effects of both agents may be increased due to additive pharmacologic effects.

MANAGEMENT: If the barbiturate is being taken for a seizure disorder, patients should be closely monitored for loss of seizure control. Dose adjustments may be required. Monitoring for clinical evidence of additive toxicity and for clinical and/or laboratory evidence of reduced antidepressant effect is also advisable.

Albuterol inhalation, Metaproterenol, Isoetharine inhalation, Terbutaline inhalation, Bitolterol inhalation, Pirbuterol inhalation, Salmeterol (inhalation), Albuterol, Terbutaline (oral), Levalbuterol, Formoterol, Arformoterol inhalation

MONITOR: Tricyclic antidepressants (TCAs) can potentiate the cardiovascular effects of beta adrenergic agonists. TCAs possess peripheral sympathetic activity and can increase blood pressure and heart rate, thus they may have additive effects with beta adrenergic agonists.

MANAGEMENT: Caution is advised if beta adrenergic agonists are used with TCAs, or within two weeks of discontinuation of the latter. Pulse and blood pressure should be closely monitored.

Disulfiram

The combination of disulfiram and tricyclic antidepressants may reportedly result in acute organic brain syndrome or dementia. The mechanism is unknown and causality has not been definitely established. Patients should be monitored for symptoms of an interaction.

Atomoxetine

The concomitant administration of atomoxetine with drugs that affect norepinephrine (e.g., norepinephrine reuptake inhibitors) may theoretically result in additive or synergistic pharmacologic effects. The clinical significance is unknown. Caution is advisable if these drugs are used together.

Modafinil

The concomitant administration of modafinil may result in altered plasma levels and effects of tricyclic antidepressants (TCA). Modafinil is a modest CYP450 2C19 inhibitor in vitro and this is an alternate TCA metabolic pathway for patients who are deficient in CYP450 2D6 (approximately 7-10% of Caucasians). Although a study found no interaction between clomipramine and modafinil, one case of increased clomipramine levels has been reported. If these drugs are to be used together, monitoring of the patient for altered efficacy and safety is recommended, especially if the patient is known to be a poor debrisoquine metabolizer. Dose adjustments may be required if an interaction is suspected.

Estradiol oral, Estradiol transdermal, Conjugated estrogens, Esterified estrogens, Estropipate, Chlorotrianisene, Estradiol topical (for use on skin), Estradiol vaginal (systemic), Estradiol injection, Estramustine, Estradiol (topical), Estradiol vaginal (local), Conjugated estrogens (vaginal)

The effects of tricyclic antidepressants (TCAs) may be altered in women receiving estrogen-containing therapy. Simultaneous TCA toxicity and reduced effects have been reported. Akathisia has also been reported in some women taking this combination. The mechanism of interaction is unknown but may be related to increased TCA bioavailability or inhibition of hepatic TCA metabolism. The clinical significance of this interaction has not been established. Monitoring for altered effects may be advisable during concomitant therapy. Dose adjustments of the TCA may be required if an interaction is suspected.

Ipratropium inhalation, Ipratropium (nasal), Tiotropium inhalation

Theoretically, the potential exists for additive anticholinergic effects such as mydriasis, blurred vision, heat intolerance, fever, dry mouth, tachycardia, urinary retention, and constipation when ipratropium, oxitropium or tiotropium is used with each other or other agents with anticholinergic properties (e.g., antihistamines, antispasmodics, neuroleptics, phenothiazines, skeletal muscle relaxants, tricyclic antidepressants, class IA antiarrhythmics especially disopyramide). However, due to the poor systemic absorption of ipratropium, oxitropium, and tiotropium when administered locally, the interaction would be unlikely at regularly recommended dosages.

Levodopa

Tricyclic antidepressants may slightly reduce the serum concentrations of levodopa and carbidopa and reduce their effects. The mechanism may be related to slowed gastric emptying and increased gastric degradation. Anecdotal reports also suggest that coadministration of tricyclic antidepressants and levodopa or carbidopa may occasionally result in hypertensive episodes; however, causality was not clearly established. The mechanism is unknown. Until more information is available, it may be prudent to monitor patients for altered efficacy and safety.

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