Nortriptyline Hcl (nortriptyline HCl)

Dosage of nortriptyline hydrochloride is expressed in terms of nortriptyline. There is a wide range of dosage requirements and dosage must be carefully individualized. Initial dosages should be low and may be gradually adjusted to the level that produces maximal therapeutic effect with minimal toxicity.

Patients should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment. (See Cautions: Precautions and Contraindications, in the Tricyclic Antidepressants General Statement 28:16.04.28.)

Nortriptyline hydrochloride is administered orally. Although nortriptyline has been administered in up to 4 divided doses throughout the day, it is long-acting and the entire daily dose may be administered at one time.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antidepressants/Sibutramine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Sibutramine has demonstrated antidepressant effects. (1)

CLINICAL EFFECTS: Concurrent use of sibutramine and an antidepressant may result in additive or synergistic central nervous system (CNS) effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. The Australian,(2) Canadian,(1) and UK(3) manufacturers of sibutramine formerly stated that concurrent use with antidepressants is contraindicated. The Canadian manufacturer also states that concurrent use of St. John's wort is contraindicated.(1)

DISCUSSION: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. The use of sibutramine with other CNS-active agents has not been evaluated.(1-3)

Selected Antidepressants/Iomeprol

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Both iomeprol and selected antidepressants may lower the seizure threshold.(1)

CLINICAL EFFECTS: Use of iomeprol in a patient receiving selected antidepressants may increase the risk of seizure.(1) Antidepressants included in this monograph are tricyclic antidepressants (except formulations which also include benzodiazepines), bupropion, and oral monoamine oxidase(MAO) inhibitors used to treat depression.

PREDISPOSING FACTORS: Iomeprol associated seizures are more likely in patients with intracranial tumors or epilepsy.(1)

PATIENT MANAGEMENT: The manufacturer of iomeprol states that tricyclic antidepressants and MAO inhibitors should be discontinued 48 hours before iomeprol use. Treatment with an antidepressant should not be resumed until 24 hours post-procedure.(1) The UK manufacturer of bupropion states that it must not be used in the presence of predisposing risk factors such as medicinals which are known to lower the seizure threshold unless there is a compelling clinical justification that concurrent use outweighs the potential increased risk of seizure.(2)

DISCUSSION: Because selected antidepressants may lower seizure threshold, antidepressants should be discontinued 48 hours before iomeprol use. Treatment with an antidepressant should not be resumed until 24 hours post-procedure.(1)

Selected Tricyclic Compounds/Lumefantrine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Lumefantrine may inhibit the metabolism of some tricyclic antidepressants by CYP2D6.(1,2)

CLINICAL EFFECTS: Concurrent administration of lumefantrine and some tricyclic antidepressants may result in elevated levels of the tricyclic antidepressants and toxicity.(1,2)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: The UK manufacturer of artemether-lumefantrine states that the concurrent use of artemether-lumefantrine is contraindicated in patients receiving drugs that are metabolized by CYP2D6, such as some tricyclic antidepressants.(1) The US manufacturer of artemether-lumefantrine states that the concurrent use of artemether-lumefantrine should be avoided in patients receiving drugs that are metabolized by CYP2D6, such as some tricyclic antidepressants.(2)

DISCUSSION: Lumefantrine has been shown in vitro to inhibit CYP2D6. This may be clinically relevant for agents with a low therapeutic index that have cardiac effects.(1,2)

Tricyclic & Tetracyclic Compounds/Cisapride

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The concurrent use of cisapride with a tricyclic or tetracyclic compound may result in additive effects on the QT interval.(1,2)

CLINICAL EFFECTS: Concurrent use may result in prolongation of the QT interval, which may result in potentially life-threatening arrhythmias.(1,2)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The manufacturer of cisapride states that cisapride should not be concomitantly administered with agents known to prolong the QT interval such as certain tricyclic antidepressants and certain tetracyclic antidepressants.(1) The manufacturer of amitriptyline states under contraindications that amitriptyline should not be given with cisapride.(2) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: The manufacturer of cisapride states that QT prolongation, torsades de pointes (sometimes with syncope), cardiac arrest, and sudden death have been reported in patients who were not taking agents known to increase cisapride levels. Some of these patients were taking agents known to prolong the QT interval, such as certain tricyclic antidepressants and certain tetracyclic antidepressants. The manufacturer of cisapride states that cisapride should not be concomitantly administered with agents known to prolong the QT interval.(1) The manufacturer of amitriptyline states under contraindications that amitriptyline should not be given with cisapride due to the potential for increased QT interval and increased risk of arrhythmia.(2)

Tricyclic Compounds/Arbutamine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The exact mechanism of the interaction is unknown.

CLINICAL EFFECTS: The exact clinical effects are not stated.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of arbutamine states that arbutamine should not be administered with tricyclic antidepressants.(1)

DISCUSSION: The manufacturer of arbutamine states that arbutamine should not be administered with tricyclic antidepressants.(1) There is no published documentation for this interaction.

Tricyclic Compounds/Grepafloxacin; Sparfloxacin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Unknown. Possibly additive or synergistic effects on the QTc interval.

CLINICAL EFFECTS: Increased QTc intervals which may result in life-threatening arrhythmias such as torsades de pointes.

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: Concurrent administration of grepafloxacin and agents known to produce an increase in the QTc interval and/or torsades de pointes such as tricyclic antidepressants is contraindicated unless appropriate cardiac monitoring can be assured.(1) Concurrent administration of sparfloxacin and agents known to produce an increase in the QTc interval and/or torsades de pointes is contraindicated. The manufacturer of sparfloxacin states that concurrent administration of sparfloxacin and tricyclic antidepressants should be avoided.(2) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: There is no published documentation to support this potential drug interaction. The product information for grepafloxacin states that prolongation of the QTc interval has been observed in healthy subjects receiving grepafloxacin.(1) The product information for sparfloxacin states that torsades de pointes has been reported in patients receiving sparfloxacin and disopyramide and amiodarone. Therefore, concurrent administration of sparfloxacin and agents known to produce an increase in the QTc interval and/or torsades de pointes, such as tricyclic antidepressants, is contraindicated.(2)

Tricyclic Compounds/Halofantrine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Possibly additive effects on the QTc interval.

CLINICAL EFFECTS: Concurrent use of halofantrine and tricyclic antidepressants may pre-dispose patients to development of prolonged QTc intervals.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of halofantrine states under the contraindications section of the prescribing information that unless there are compelling clinical reasons, halofantrine should not be used with tricyclic antidepressants.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: There is no published documentation to support this potential interaction. Because concurrent use may pre-dispose patients to prolongation of the QTc interval, the manufacturer of halofantrine states under the contraindications section of the prescribing information that halofantrine should not be used with tricyclic antidepressants unless compelling clinical reasons exist.(1)

Tricyclic; Tetracyclic Compounds/Maois

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Some MAO inhibitors may enhance the effects of tricyclic and tetracyclic compounds indirectly through inhibition of microsomal enzymes.(1) Tricyclic and tetracyclic compounds may sensitize post-synaptic receptors to amines that are accumulating extraneuronally as a result of MAO inhibition.(2) Similarity between cyclobenzaprine and TCAs warrants consideration of TCA interactions for cyclobenzaprine.(6) Mirtazapine, a tetracyclic antidepressant, should also be considered for this interaction.(7)

CLINICAL EFFECTS: Concurrent use may result in a severe reaction including hyperpyrexia, convulsions, excitability, fluctuations in blood pressure, convulsions, grand mal seizures, serotonin syndrome, coma, and death.(1,3-10) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(11)

PREDISPOSING FACTORS: High doses of tricyclics or tetracyclics, or concurrent use of multiple drugs which increase CNS serotonin levels may increase risk for serotonin syndrome.

PATIENT MANAGEMENT: The concurrent use of tricyclic antidepressants, cyclobenzaprine or mirtazapine and MAO inhibitors is contraindicated by the manufacturers of tricyclic antidepressants, cyclobenzaprine, mirtazapine, and tranylcypromine.(1,3-10) The manufacturers of tricyclic antidepressants, cyclobenzaprine and mirtazapine recommend at least 14 days between switching therapies.(1,3-9) The manufacturer of tranylcypromine recommends a medication-free interval of at least a week when initiating tranylcypromine in patients who have previously received a tricyclic antidepressant, then initiating tranylcypromine at a reduced dosage of 50% for one week.(10) The US manufacturer of phenelzine states that at least 14 days should elapse between the discontinuation of phenelzine and the initiation of another antidepressant. If phenelzine is used concurrently with or within 10 days of another antidepressant, the patient should be cautioned regarding the possibility of an adverse drug interaction.(8) The US manufacturer of selegiline states that at least 14 days should elapse between the discontinuation of selegiline and the initiation of a tricyclic antidepressant.(9) In emergency situations in patients maintained on tricyclics or tetracyclics, weigh the availability and safety of alternatives to methylene blue against the risk of serotonin syndrome. If methylene blue therapy is required, the patient's tricyclic, cyclobenzaprine or tetracyclic should be immediately discontinued. Patients should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first.(12) In non-emergency situations in patients maintained on tricyclics, cyclobenzaprine or tetracyclics when methylene blue therapy is planned, discontinue the patient's tricyclic or tetracyclic at least 2 weeks in advance of methylene blue therapy. The patient's tricyclic or tetracyclic therapy may be resumed 24 hours after the last dose of linezolid or methylene blue.(12) Do not initiate tricyclic, cyclobenzaprine or tetracyclic therapy in patients receiving methylene blue until 24 hours after the last dose of these agents.(12) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: It should be noted that if this interaction occurs, the consequences will be immediate and severe. Effects may continue to be seen for several days after discontinuing the MAOI. The interaction has been reported with tricyclic antidepressants and selegiline.(9) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(14,15) Metaxalone is a weak inhibitor of MAO.(34,35) The FDA AERS contains reports of serotonin syndrome with concurrent injectable methylene blue and citalopram, clomipramine, escitalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine. The risk of serotonin syndrome with other psychiatric drugs is unclear.(13) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Catecholamines/Iobenguane I 123

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine)

Agents That Affect Catecholamines/Iobenguane I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

Agents That May Cause Respiratory Depression/Sodium Oxybate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Oxybate by itself may be associated with severe somnolence or respiratory depression. Concurrent use with other CNS depressants may further increase the risk for respiratory depression or loss of consciousness.(1-3)

CLINICAL EFFECTS: Concurrent use of sodium oxybate and sedative hypnotics or alcohol may further increase the risk for profound sedation, respiratory depression, coma, and/or death.(1,2) Fatalities have been reported.(3)

PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3)

PATIENT MANAGEMENT: Avoid use of concomitant opioids, benzodiazepines, sedating antidepressants, sedating antipsychotics, general anesthetics, or muscle relaxants, particularly when predisposing risk factors are present. If combination use is required, dose reduction or discontinuation of one or more CNS depressants should be considered. If short term use of an opioid or general anesthetic is required, consider interruption of sodium oxybate treatment.(1,2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)

DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS)and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3)

Anticholinergics/Clozapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clozapine has potent anticholinergic properties and inhibits serotonin receptors, including 5-HT3.(1-4) Both of these properties may cause inhibition of gastrointestinal (GI) smooth muscle contraction, resulting in decreased peristalsis.(3,4) These effects may be compounded by concurrent use of anticholinergic agents.(1-6)

CLINICAL EFFECTS: Concurrent use of clozapine with other anticholinergic agents may increase the risk of constipation (common) and serious bowel complications (uncommon), including complete bowel obstruction, fecal impaction, paralytic ileus and intestinal ischemia or infarction.(1-6)

PREDISPOSING FACTORS: The risk for serious bowel complications is higher with increasing age, higher frequency of constipation, and in patients on higher doses of clozapine or multiple anticholinergic agents.(1,5)

PATIENT MANAGEMENT: Avoid the use of other anticholinergic agents with clozapine.(1-6) If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(2) Consider a prophylactic laxative in those with a history of constipation or bowel obstruction.(2) Review patient medication list for other anticholinergic agents. When possible, decrease the dosage or number of prescribed anticholinergic agents, particularly in the elderly. Counsel the patient about the importance of maintaining adequate hydration. Encourage regular exercise and eating a high-fiber diet.(2)

DISCUSSION: In a prospective cohort study of 26,720 schizophrenic patients in the Danish Central Psychiatric Research Registry, the odds ratio (OR) for ileus was 1.99 with clozapine and 1.48 with anticholinergics. The OR for fatal ileus was 6.73 with clozapine and 5.88 with anticholinergics. Use of anticholinergics with 1st generation antipsychotics (FGA) increased the risk of ileus compare to FGA alone, but this analysis was not done with clozapine.(5) A retrospective cohort study of 24,970 schizophrenic patients from the Taiwanese National Health Insurance Research Database found that the hazard ratio (HR) for clozapine-induced constipation increased from 1.64 when clozapine is used alone, to 2.15 when used concomitantly with anticholinergics. However, there was no significant difference in the HR for ileus when clozapine is used with and without anticholinergics (1.95 and 2.02, respectively).(6) In the French Pharmacovigilance Database, 7 of 38 cases of antipsychotic-associated ischemic colitis or intestinal necrosis involved clozapine, and 5 of these cases involved use of concomitant anticholinergic agents. Three patients died, one of whom was on concomitant anticholinergics.(3) In a case series, 4 of 9 cases of fatal clozapine-associated GI dysfunction involved concurrent anticholinergic agents.(4)

Anticholinergics/Glucagon (Diagnostic)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Glucagon and anticholinergic agents may have additive effects on inhibition of gastrointestinal motility.(1)

CLINICAL EFFECTS: Concurrent use of glucagon with anticholinergic agents may increase the risk of gastrointestinal hypomotility, including constipation and bowel complications.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of glucagon as a diagnotic aid is not recommended with the use of anticholinergic agents.(1) If concurrent use is necessary, evaluate the patient's bowel function. Monitor for symptoms of constipation and gastrointestinal hypomotility.

DISCUSSION: Both glucagon and anticholinergic agents may have additive effects on inhibition of gastrointestinal motility and increase the risk of gastrointestinal adverse effects.(1)

Anticholinergics/Solid Oral Potassium Capsules

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concentrated potassium may damage the lining of the GI tract. Anticholinergics delay gastric emptying, resulting in the potassium product remaining in the gastrointestinal tract for a longer period of time.(1-16))

CLINICAL EFFECTS: Use of solid oral dosage forms of potassium in patients treated with anticholinergics may result in gastrointestinal erosions, ulcers, stenosis and bleeding.(1-16)

PREDISPOSING FACTORS: Diseases or conditions which may increase risk for GI damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic gastroparesis, elderly status, or insufficient oral intake to allow dilution of potassium.(1-10,21) Other drugs which may add to risk for GI damage include: nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21)

PATIENT MANAGEMENT: Regulatory agency and manufacturer recommendations regarding this interaction: - In the US, all solid oral dosage forms (including tablets and extended release capsules) of potassium are contraindicated in patients receiving anticholinergics at sufficient dosages to result in systemic effects.(2-8) Patients receiving such anticholinergic therapy should use a liquid form of potassium chloride.(2) - In Canada, solid oral potassium is contraindicated in any patient with a cause for arrest or delay in tablet/capsule passage through the gastrointestinal tract and the manufacturers recommend caution with concurrent anticholinergic medications.(1,9-10) Evaluate each patient for predisposing factors which may increase risk for GI damage. In patients with multiple risk factors for harm, consider use of liquid potassium supplements, if tolerated. For patients receiving concomitant therapy, assure any potassium dose form is taken after meals with a large glass of water or other fluid. To decrease potassium concentration in the GI tract, limit each dose to 20 meq; if more than 20 meq daily is required, give in divided doses.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Patients should be instructed to immediately report any difficulty swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In clinical trials, there was a higher incidence of gastric and duodenal lesions in patients receiving a high dose of a wax-matrix controlled-release formulation with a concurrent anticholinergic agent. The lesions were asymptomatic and not accompanied by bleeding, as shown by a lack of positive Hemoccult tests.(1-17) Several studies suggest that the incidence of gastric and duodenal lesions may be less with the microencapsulated formulation of potassium chloride.(14-17)

Anticholinergics/Solid Oral Potassium Tablets

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concentrated potassium may damage the lining of the GI tract. Anticholinergics delay gastric emptying, resulting in the potassium product remaining in the gastrointestinal tract for a longer period of time.(1-16)

CLINICAL EFFECTS: Use of solid oral dosage forms of potassium in patients treated with anticholinergics may result in gastrointestinal erosions, ulcers, stenosis and bleeding.(1-16)

PREDISPOSING FACTORS: Diseases or conditions which may increase risk for GI damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic gastroparesis, elderly status, or insufficient oral intake to allow dilution of potassium.(1-10,21) Other drugs which may add to risk for GI damage include: nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21)

PATIENT MANAGEMENT: Regulatory agency and manufacturer recommendations regarding this interaction: - In the US, all solid oral dosage forms (including tablets and extended release capsules) of potassium are contraindicated in patients receiving anticholinergics at sufficient dosages to result in systemic effects.(2-8) Patients receiving such anticholinergic therapy should use a liquid form of potassium chloride.(2) - In Canada, solid oral potassium is contraindicated in any patient with a cause for arrest or delay in tablet/capsule passage through the gastrointestinal tract and the manufacturers recommend caution with concurrent anticholinergic medications.(1,9-10) Evaluate each patient for predisposing factors which may increase risk for GI damage. In patients with multiple risk factors for harm, consider use of liquid potassium supplements, if tolerated. For patients receiving concomitant therapy, assure any potassium dose form is taken after meals with a large glass of water or other fluid. To decrease potassium concentration in the GI tract, limit each dose to 20 meq; if more than 20 meq daily is required, give in divided doses.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Patients should be instructed to immediately report any difficulty swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In clinical trials, there was a higher incidence of gastric and duodenal lesions in patients receiving a high dose of a wax-matrix controlled-release formulation with a concurrent anticholinergic agent. Some lesions were asymptomatic and not accompanied by bleeding, as shown by a lack of positive Hemoccult tests.(1-17) Several studies suggest that the incidence of gastric and duodenal lesions may be less with the microencapsulated formulation of potassium chloride.(14-17)

Anticholinergics; Opioids/Eluxadoline

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Eluxadoline is a mixed mu-opioid and kappa-opioid agonist and delta-opioid antagonist and may alter or slow down gastrointestinal transit.(1)

CLINICAL EFFECTS: Constipation related adverse events that sometimes required hospitalization have been reported, including the development of intestinal obstruction, intestinal perforation, and fecal impaction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid use with other drugs that may cause constipation. If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(1) Instruct patients to stop eluxadoline and immediately contact their healthcare provider if they experience severe constipation. Loperamide may be used occasionally for acute management of severe diarrhea, but must be discontinued if constipation develops.(1)

DISCUSSION: In phase 3 clinical trials, constipation was the most commonly reported adverse reaction (8%). Approximately 50% of constipation events occurred within the first 2 weeks of treatment while the majority occurred within the first 3 months of therapy. Rates of severe constipation were less than 1% in patients receiving eluxadoline doses of 75 mg and 100 mg.(1)

Higher Strength Tricyclics/Fluoxetine; Paroxetine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Fluoxetine is a moderate inhibitor of CYP2C19 and a strong inhibitor of CYP2D6.(1) Paroxetine is a strong inhibitor of CYP2D6.(1,2) Doxepin and trimipramine are metabolized by CYP2C19 and CYP2D6.(1) Desipramine and nortriptyline are metabolized by CYP2D6.(1)

CLINICAL EFFECTS: Concurrent administration of fluoxetine or paroxetine with selected cyclic agents which are metabolized by CYP2D6 or CYP2C19 may result in an increase in serum levels, toxicities (e.g. risk for seizures, severe anticholinergic effects), and/or clinical effects of the tricyclic agent. Elevated levels of tricyclics may increase the risk of QT prolongation and the risk for torsades de pointes.

PREDISPOSING FACTORS: Higher doses or higher systemic concentrations of fluoxetine or paroxetine may increase the magnitude of this interaction. The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3,4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibitors its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3,4) The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(5)

PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds when concurrent therapy with fluoxetine or paroxetine is started or if the dosage of either agent is increased. Plasma concentrations of the tricyclic compound should be monitored and the dosage adjusted accordingly. If fluoxetine or paroxetine is discontinued in a patient receiving a cyclic antidepressant, the dosage may need to be adjusted upward as the effects of enzyme inhibition wane. The effects of fluoxetine on hepatic metabolism may last for up to 5 weeks after fluoxetine discontinuation. A tricyclic antidepressant started after the discontinuation of fluoxetine should be started at a lower initial dosage. When concurrent therapy may be associated with QT prolongation, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, and fainting.

DISCUSSION: Case reports have shown that the addition of fluoxetine to a tricyclic compound therapy can result in an increase of 100-300% in the tricyclic compound plasma concentration as well as an increase in adverse effects, including seizures and delirium. In an 83 year-old patient, the combination of clomipramine and fluoxetine resulted in high clomipramine concentrations and cardiac side effects. In a 70 year old patient, the use of venlafaxine, fluoxetine, and nortriptyline was associated with severe anticholinergic side effects. This interaction was thought to be due to increased nortriptyline levels. QTc prolongation also exists with some antidepressants. In a case report, the combination of levofloxacin, imipramine, and fluoxetine was associated with a QTc of 509msec. The authors concluded that this interaction was due to the pharmacodynamic additive effect among fluoxetine, imipramine, and levofloxacin. Cyclic antidepressants included in this monograph are desipramine (all strengths), doxepin (> 25 mg), nortriptyline (> 30 mg), and trimipramine (> 25 mg).

Selected Tricyclic Antidepressants/Quinidine; Thioridazine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Quinidine and thioridazine are strong inhibitors of CYP2D6.(1) Doses as low as 50 mg to 100 mg of thioridazine or 30 mg of quinidine will convert most individuals with a CYP2D6 extensive metabolizer (EM) genotype to a poor metabolizer (PM) phenotype.(2,3,7) CYP2D6 is the primary metabolic pathway for desipramine and nortriptyline; amitriptyline, clomipramine, doxepin, and imipramine are metabolized by both CYP2D6 and CYP2C19 pathways.

CLINICAL EFFECTS: Concurrent use of quinidine or thioridazine and selected tricyclic antidepressants (TCAs) may increase levels of the TCA and the risk for toxicities from either or both drugs. Risks include seizures, anticholinergic, sedative, and alpha-blocking effects.(1,3,4)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(8)

PATIENT MANAGEMENT: Alternative antipsychotics or antidepressants are available and should be used whenever possible due to the potential morbidity associated with this combination. If concomitant treatment is necessary, begin with a lower than usual TCA starting dose and closely monitor serum levels of the tricyclic antidepressant.(3,5) Dosages of desipramine above 40 mg daily with Nuedexta (dextromethorphan-quinidine) are not recommended.(6) If concurrent use with doxepin is warranted, monitor doxepin plasma concentrations and reduce the doxepin dose based on doxepin plasma concentrations.(9)

DISCUSSION: TCAs vary in their sensitivity to CYP2D6 inhibition: Paroxetine, another strong CYP2D6 inhibitor, increases the plasma concentration of amitriptyline by 60 percent. However, paroxetine is a more potent inhibitor for nortriptyline (active metabolite of amitriptyline) yielding a nortriptyline AUC ratio of 4.8. Desipramine is described as sensitive substrate at CYP2D6. Other strong CYP2D6 inhibitors, fluoxetine and paroxetine, increase desipramine AUC ratio by 7.8 and 5.4 respectively. Use of a combination product containing dextromethorphan-quinidine (30 mg/30 mg) increased steady state levels of desipramine (25 mg) by 8-fold.(6)

Tricyclic Compounds/Guanethidine; Guanadrel

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Uptake of guanethidine is blocked by tricyclic antidepressants at the adrenergic neuron.

CLINICAL EFFECTS: Concurrent use of tricyclic antidepressants may result in decreased guanethidine or guanadrel effectiveness. The effects may be seen for several days after discontinuation of the tricyclic antidepressant.

PREDISPOSING FACTORS: Possibly concurrent administration of drugs that inhibit hepatic enzymes.

PATIENT MANAGEMENT: Avoid concomitant administration of these drugs. If both drugs are administered, adjust the guanethidine dose as needed based on blood pressure.

DISCUSSION: This interaction is well documented. Similarity between cyclobenzaprine and TCA's warrants consideration of TCA interactions for cyclobenzaprine.

Tricyclic Compounds/Select Indirect-Acting Sympathomimetics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unknown. However, it is speculated that indirect-acting sympathomimetics would have decreased activity due to tricyclic blockage of their uptake into the adrenergic neuron.

CLINICAL EFFECTS: Decreased effect of indirect acting sympathomimetics.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use of tricyclic compounds and indirect-acting sympathomimetics should be approached with caution. Monitor patients receiving concurrent therapy for decreased sympathomimetic efficacy.

DISCUSSION: The pressor effects of the indirect-acting sympathomimetic amines (e.g., amphetamines, ephedrine, and methylphenidate) are antagonized by tricyclic antidepressants.

Tricyclic Compounds/Select Mixed Acting Sympathomimetics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unknown. However, it is speculated that mixed acting sympathomimetics will show effects based on the predominance of either direct or indirect activity. Agents with predominate effects of direct-acting sympathomimetic amines are expected to have an enhanced effect due to tricyclic blockage of norepinephrine reuptake. Agents with predominate effects of indirect-acting sympathomimetics would have decreased activity due to tricyclic blockage of their uptake into the adrenergic neuron.

CLINICAL EFFECTS: Mixed acting sympathomimetics will show effects based on the predominance of either direct or indirect activity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider avoiding the concurrent use of mixed-acting sympathomimetics and tricyclic compounds. If concurrent is warranted, the initial dose of the sympathomimetic should be lowered and the patient should be monitored for adverse cardiovascular effects.

DISCUSSION: Epinephrine and other direct-acting sympathomimetic amines exert enhanced cardiovascular effects (e.g., arrhythmias, hypertension, and tachycardia) in individuals concurrently receiving or previously treated with tricyclic antidepressants. Other direct and mixed acting sympathomimetic amines have also been reported to interact with tricyclic antidepressants. These include norepinephrine, phenylephrine, dopamine, and methoxamine. The pressor effects of the indirect-acting sympathomimetic amines (i.e., amphetamines, ephedrine, methylphenidate, pseudoephedrine, and tyramine) are antagonized by tricyclic antidepressants. Protriptyline, amitriptyline, and desipramine have also been reported to interact with direct-acting sympathomimetics.

Tricyclic Compounds/Selected Direct-Acting Sympathomimetics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unknown. However, it is speculated that direct-acting sympathomimetic amines have an enhanced effect due to tricyclic blockage of norepinephrine reuptake.

CLINICAL EFFECTS: Increased effect of direct acting sympathomimetics.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider avoiding the concurrent use of direct-acting sympathomimetics and tricyclic compounds. If concurrent use of direct-acting sympathomimetics and tricyclic compounds is warranted, the initial dose of the sympathomimetic should be lowered and the patient should be monitored for adverse cardiovascular effects. Use of tricyclic compounds and other sympathomimetics should be approached with caution.

DISCUSSION: Epinephrine and other direct-acting sympathomimetic amines exert enhanced cardiovascular effects (e.g., arrhythmias, hypertension, and tachycardia) in individuals concurrently receiving or previously treated with tricyclic antidepressants. Other direct and mixed acting sympathomimetic amines have also been reported to interact with tricyclic antidepressants. These include norepinephrine, phenylephrine, dopamine, and methoxamine. Protriptyline, amitriptyline, and desipramine have also been reported to interact with direct-acting sympathomimetics.

Tricyclic Compounds; Carbamazepine/Tapentadol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tapentadol and tricyclic compounds may lower the seizure threshold.(1) Tapentadol and tricyclic compounds may result in additive effects on serotonin levels.(1) Although not used therapeutically as an antidepressant, carbamazepine is a tricyclic compound.

CLINICAL EFFECTS: Concurrent use of tapentadol and a tricyclic compound may result in seizures or serotonin syndrome.(1)

PREDISPOSING FACTORS: Risk of seizures may be increased in patients with epilepsy, a history of seizures, head trauma, metabolic disorders, alcohol or drug withdrawal, or infections of the central nervous system.(1)

PATIENT MANAGEMENT: Tapentadol should be used with caution in patients taking tricyclic compounds, including carbamazepine. Monitor patients closely for serotonin syndrome.(1)

DISCUSSION: Concurrent use of tapentadol with tricyclic compounds may result in additive blockage of serotonin reuptake, leading to central serotonergic hyperstimulation. Cases of serotonin syndrome have been reported with tapentadol in combination with other serotonergic drugs.(1) Use of tapentadol has been associated with increased seizure frequency in patients with seizure disorders.(1)

Tricyclic Compounds; Carbamazepine/Tramadol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tramadol and tricyclic compounds may lower the seizure threshold.(1) Tramadol inhibits the reuptake of serotonin and norepinephrine but has weak opioid effects. M1, tramadol's active metabolite, is a stronger opioid and up to 6 times more potent than tramadol in producing analgesia.(1) Carbamazepine induces the metabolism of this tramadol opioid metabolite.

CLINICAL EFFECTS: Concurrent use of tramadol and a tricyclic compound may result in seizures or serotonin syndrome and may increase the risk of suicide.(1) Concurrent use of tramadol and carbamazepine may significantly reduce the analgesic effect of tramadol.(1) Although not used therapeutically as an antidepressant, carbamazepine is a tricyclic compound.

PREDISPOSING FACTORS: Risk of seizures may be increased in patients with epilepsy, a history of seizures, head trauma, metabolic disorders, alcohol or drug withdrawal, or infections of the central nervous system.(1)

PATIENT MANAGEMENT: Tramadol should be used with caution in patients taking tricyclic compounds.(1) The use of tramadol and carbamazepine is not recommended.(1) Carbamazepine induces metabolism (glucuronidation) of the tramadol opioid metabolite (M1). In patients on long-term carbamazepine when tramadol is started, achieving adequate analgesia may be difficult. Prescribing higher tramadol doses would be associated with higher parent drug levels which may result in serotonin and norepinephrine associated adverse effects. In patients receiving chronic tramadol treatment when carbamazepine is started, anticipate a reduction in analgesic effects. The maximal effects of carbamazepine on tramadol efficacy may not be seen for 2 or more weeks. Monitor for decreased tramadol efficacy, including symptoms of opioid withdrawal, after carbamazepine is initiated or when carbamazepine dosage is increased. If carbamazepine is to be discontinued in patients stabilized on the combination of tramadol and carbamazepine, gradually decrease the carbamazepine dose to decrease the risk of withdrawal seizures. As carbamazepine induction wanes, systemic tramadol metabolite concentrations will rise. The tramadol dose may need to be decreased to prevent tramadol toxicity.

DISCUSSION: The use of tramadol in patients treated with tricyclic compounds may increase the risk of seizures.(1) A review of 124 reports of seizures following tramadol therapy received by the FDA through July 31, 1996 revealed that 23% of the patients were also taking tricyclic antidepressants.(2) Therefore, the manufacturer of tramadol states that tramadol should be used with caution in patients treated with tricyclic compounds.(1) The manufacturer of tramadol also states that the use of tramadol with carbamazepine is not recommended.(1) In a case report, a 79 year-old female developed serotonin syndrome three days after the addition of tramadol to amitriptyline therapy. Over the next four days, her condition deteriorated and she died.(3)

Tricyclic; Tetracyclic Agents; Carbamazepine/Linezolid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Linezolid is a weak, reversible inhibitor of monoamine oxidase.(1) Tricyclic and tetracyclic compounds may sensitize post-synaptic receptors to amines that are accumulating extraneuronally as a result of MAO inhibition.(2) Carbamazepine is structurally related to the tricyclic antidepressants.(3) Similarity between cyclobenzaprine and tricyclics warrants consideration of tricyclic interactions for cyclobenzaprine.(4) Mirtazapine, a tetracyclic antidepressant, should also be considered for this interaction.(5)

CLINICAL EFFECTS: Concurrent use with linezolid may result in a severe reaction including hyperpyrexia, convulsions, excitability, fluctuations in blood pressure, convulsions, grand mal seizures, serotonin syndrome, coma, and death.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(6)

PREDISPOSING FACTORS: High doses of tricyclics or tetracyclics, or concurrent use of multiple drugs which increase CNS serotonin levels may increase risk for serotonin syndrome.

PATIENT MANAGEMENT: The manufacturers of the tricyclic antidepressants, carbamazepine, cyclobenzaprine and mirtazapine state that coadministration with MAO inhibitors is contraindicated. Concurrent linezolid is specifically contraindicated by the manufacturers of clomipramine, desipramine, mirtazapine, nortriptyline, and trimipramine.(1,3-5,7-12) The manufacturer of linezolid does not contraindicate the use of serotonergic agents but states that they should not be coadministered unless clinically appropriate and the patient is closely monitored.(1) This recommendation is consistent with the 2011 FDA Drug Safety Communication on linezolid and serotonergic psychiatric medications.(13,14) In non-emergency situations in patients maintained on tricyclics or tetracyclics when linezolid therapy is planned, discontinue the patient's tricyclic or tetracyclic at least 2 weeks in advance of linezolid therapy. In emergency situations in patients maintained on tricyclics or tetracyclics, weigh the availability and safety of alternatives to linezolid against the risk of serotonin syndrome. If linezolid therapy is required, the patient's tricyclic or tetracyclic should be immediately discontinued. Patients should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid, whichever comes first. The patient's tricyclic or tetracyclic therapy may be resumed 24 hours after the last dose of linezolid.(13) Clinical studies have found a low incidence of serotonin syndrome in patients on concomitant linezolid and serotonergic agents, ranging from 0.24% to 4%, depending on the quality and size of the study. While linezolid-associated serotonin syndrome is potentially serious and fatal, if treated early, it is quickly reversible with discontinuation of offending agents and supportive care. Therefore, some authors suggest that use of serotonergic medications should not preclude the use of linezolid but that the clinical situation should be assessed. If concurrent use or use of linezolid without a washout is warranted, the patient should be closely monitored.(15-20) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: It should be noted that if this interaction occurs, the consequences will be immediate and severe. Effects may continue to be seen for several days after discontinuing linezolid. The FDA FAERS contains reports of serotonin syndrome with the concurrent use of linezolid and citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine. The risk of serotonin syndrome with other psychiatric drugs is unclear.(14)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Agents With Hyponatremia Risk/Desmopressin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Carbamazepine, chlorpromazine, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants increase the risk of hyponatremia.(1-3)

CLINICAL EFFECTS: Concurrent use may increase the risk of hyponatremia with desmopressin.(1-3)

PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (glucocorticoids, loop diuretics).

PATIENT MANAGEMENT: The concurrent use of agents with a risk of hyponatremia with desmopressin may increase the risk of hyponatremia. If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83 mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1)

DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4)

Amitriptyline; Clomipramine; Nortriptyline/Valproic Acid

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Valproic acid may inhibit the metabolism of amitriptyline, clomipramine, and nortriptyline.

CLINICAL EFFECTS: Concurrent use of valproic acid may result in elevated levels of and toxicity from amitriptyline, clomipramine, and nortriptyline.

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for signs of toxicity. Monitor tricyclic levels carefully during initiation, titration, and discontinuation of valproic acid. The dosage of the tricyclic antidepressant may need to be adjusted.

DISCUSSION: In a study in 15 healthy subjects, pretreatment with divalproex sodium (500 mg every 12 hours for 9 doses) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of amitriptyline (50 mg) by 31% and 17%, respectively. The AUC and Cmax of nortriptyline increased by 55% and 28%, respectively. The sum of amitriptyline and nortriptyline AUC and Cmax increased by 42% and 19%, respectively.(2) In a study in 20 subjects with depression receiving amitriptyline (125 mg daily), 10 subjects received valpromide (600 mg daily). Amitriptyline and nortriptyline levels increased 50% and 65%, respectively, in subjects receiving concurrent valpromide.(3) There are case reports of encephalopathy and myoclonus,(4) status epilepticus,(5) and increased clomipramine levels(6) have been reported following concurrent administration of valproic acid and clomipramine. In a case report, a patient previous maintained on desipramine and valproic acid developed elevated desipramine levels following the discontinuation of valproic acid.(7) Extrapyramidal symptoms(8) and increased nortriptyline levels(9) have been reported with concurrent nortriptyline and valproic acid.

Amitriptyline; Nortriptyline/Fluconazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Amitriptyline and nortriptyline are primarily metabolized via CYP2C19 and CYP2D6. Fluconazole is a strong inhibitor of CYP2C19 and inhibits the metabolism of amitriptyline and nortriptyline via this route.

CLINICAL EFFECTS: Syncopal episodes, tachycardia, prolonged QT, and delirium have been noted in case reports.(1-3) One patient died due to complications after cardiac arrest.(1)

PREDISPOSING FACTORS: Higher amitriptyline or nortriptyline or fluconazole doses would be expected to increase the risk for a clinically significant interaction. Concomitant prescribing of agents (e.g. bupropion, paroxetine) which inhibit CYP2D6, the other major amitriptyline and nortriptyline metabolic pathway, would further increase amitriptyline and nortriptyline levels and risk for toxicity. The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(6)

PATIENT MANAGEMENT: For patients already on amitriptyline or nortriptyline when fluconazole is started, consider monitoring amitriptyline and/or nortriptyline blood levels, especially for patients with risks for toxicity including renal impairment or who are taking moderate to higher doses of either agent. 5-Nortriptyline and/or S-amitriptyline metabolite levels may be measured at initiation of combination therapy with fluconazole and repeated after 1 week. The dosage of the tricyclic should be adjusted, if necessary.(5) Monitor for adverse effects of tricyclics such as drowsiness, dizziness or anticholinergic effects. Consider lowering the dose in patients with troublesome adverse effects prior to addition of fluconazole or if patient is a fall risk. If patient is already on fluconazole when amitriptyline or nortriptyline is started, begin with a lower than usual dose for the patient's indication, then gradually increase dose if tolerated.

DISCUSSION: Five amitriptyline-fluconazole cases are described in the attached citations. In one case report(2) a patient receiving amitriptyline 75 mg twice daily and bupropion 75 mg twice daily was started on fluconazole 200 mg daily. Four days later the patient began having a series of syncopal episodes accompanied by heart rates of 115 to 253 beats/minute. Symptoms persisted for the duration of concomitant therapy. Discontinuation of fluconazole led to resolution of symptoms. Subsequently, while still on amitriptyline, fluconazole was again added to the treatment regimen, leading to a return of syncopal symptoms.

Anticholinergics/Topiramate

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Topiramate can cause decreased sweating and elevated body temperature. Agents with anticholinergic activity can predispose patients to heat-related disorders.(1-2)

CLINICAL EFFECTS: Concurrent use of topiramate with agents with anticholinergic activity may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death.

PREDISPOSING FACTORS: Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1)

PATIENT MANAGEMENT: The manufacturer of topiramate states that caution should be used when topiramate is prescribed with other medicinal products that predispose to heat-related disorders, such as agents with anticholinergic activity (e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1) Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered.

DISCUSSION: Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment.(1) A 64-year old woman developed non-exertional hyperthemia while taking multiple psychiatric medications with topiramate.(2)

Anticholinergics/Zonisamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Zonisamide can cause decreased sweating and elevated body temperature. Agents with anticholinergic activity can predispose patients to heat-related disorders.(1-2)

CLINICAL EFFECTS: Concurrent use of zonisamide with agents with anticholinergic activity may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death.

PREDISPOSING FACTORS: Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1)

PATIENT MANAGEMENT: The UK and US manufacturers of zonisamide state that caution should be used in adults when zonisamide is prescribed with other medicinal products that predispose to heat-related disorders, such as agents with anticholinergic activity.(1-2) Pediatric and adolescent patients must not take anticholinergic agents (e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1) Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered.

DISCUSSION: Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment and resulted in death.(1)

Higher Strength Select Tricyclics/Cinacalcet

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cinacalcet may inhibit the CYP2D6 mediated metabolism of amitriptyline, desipramine, nortriptyline, and trimipramine.(1,2)

CLINICAL EFFECTS: Concurrent use of cinacalcet and amitriptyline, desipramine, nortriptyline, or trimipramine may result in elevated levels of and toxicity from these tricyclic antidepressants.(1,3)

PREDISPOSING FACTORS: Higher doses of either agent are expected to increase the severity of the interaction. In patients with moderate to severe hepatic impairment, cinacalcet exposure is 2.4 to 4.2-fold higher and the mean half-life increased from 49 to 65-84 hours compared with healthy volunteers.(1) The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The manufacturer describes cinacalcet as a strong inhibitor of CYP2D6. Dose adjustments may be required for concomitant medications predominantly metabolized by CYP2D6, particularly if they have a narrow therapeutic index.(1) Cinacalcet has a long elimination half-life of 49 hours so the time to maximal inhibition of a CYP2D6 metabolized drug may not be seen for a week or more after starting or increasing the dose of cinacalcet. In an interaction study, cinacalcet 90 mg daily increased desipramine exposure (AUC, area-under-curve) 264%.(1) Instruct patients to report seizures, fainting, irregular heartbeat, new or worsening blurred vision, urinary retention, mental or mood changes, confusion, dry mouth or constipation.

DISCUSSION: In an interaction study, fourteen subjects who were extensive metabolizers of CYP2D6 received one dose of desipramine 50 mg, either alone or after 7 days of pretreatment with cinacalcet 90 mg daily. Compared with desipramine alone, cinacalcet administration increased desipramine exposure (AUC, area-under-curve) and maximum concentration (Cmax) 3.6 and 1.8-fold respectively. Desipramine half-life was also longer when it was coadministered with cinacalcet (21.0 versus 43.3 hs). Fewer subjects reported adverse events following treatment with desipramine alone than when receiving desipramine with cinacalcet (33% versus 86%).(2) In an interaction study, subjects who were extensive metabolizers of CYP2D6 received one dose of amitriptyline 50 mg with a single dose of cinacalcet (25 or 100 mg) resulting in a change in AUC and Cmax for amitriptyline of 21-22% and 13-21%, respectively. The change in AUC and Cmax for nortriptyline was 17-23% and 11-15%, respectively.(1)

Selected Sensitive Cyp2d6 Substrates/Mirabegron

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Mirabegron is considered a moderate inhibitor of CYP2D6. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate 2 to 5 fold.(1,2)

CLINICAL EFFECTS: Concurrent use of mirabegron may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP2D6 pathway.(1) Agents linked to this monograph are: atomoxetine, clomipramine, desipramine, duloxetine, imipramine, metoprolol, nebivolol, nortriptyline and yohimbine.

PREDISPOSING FACTORS: With desipramine, clomipramine, imipramine and nortriptyline, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: Mirabegron has a long half-life of approximately 50 hours so extended monitoring over 10 to 13 days may be required to evaluate the full effect of this interaction. The manufacturer of mirabegron recommends appropriate monitoring and dose adjustment if necessary for drugs with a narrow therapeutic index.(1) Weigh the risks versus benefits of mirabegron treatment for overactive bladder symptoms based upon the interacting medication and patient specific characteristics.

DISCUSSION: The manufacturer of mirabegron conducted interaction studies with two sensitive substrates of CYP2D6: desipramine and metoprolol.(1) Mirabegron 160 mg daily for 5 days increased the AUC of a single dose of metoprolol 100mg by 229%. Mirabegron 100 mg daily for 18 days increased the AUC of a single dose of desipramine by 241%.

Selected Tricyclic Compounds/Desvenlafaxine; Venlafaxine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Desvenlafaxine or venlafaxine may impair the oxidative hepatic metabolism of tricyclic compounds via CYP2D6.

CLINICAL EFFECTS: Concurrent administration of desvenlafaxine or venlafaxine with a tricyclic compound may result in an increase in serum levels, toxicities, and/or clinical effects of the tricyclic compound.

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(5)

PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds at the initiation of concurrent therapy with desvenlafaxine or venlafaxine. Plasma concentrations of the tricyclic compound should be monitored and the dosage adjusted accordingly. If desvenlafaxine or venlafaxine is discontinued in a patient receiving a tricyclic compound, the dosage of the tricyclic compound may need to be adjusted. The US manufacturer of desvenlafaxine recommends the dose of desipramine be reduced by up to one-half when administered with desvenlafaxine 400 mg.

DISCUSSION: In a 70 year old patient, the use of venlafaxine, fluoxetine, and nortriptyline was associated with severe anticholinergic side effects. This interaction was thought to be due to increased nortriptyline levels. A case report of anticholinergic toxic syndrome with venlafaxine and desipramine combination exist as well. Concomitant administration of desvenlafaxine 400 mg with a single 50 mg dose of desipramine resulted in an increase in the Cmax and AUC of desipramine by approximately 50% and 90%. The affinity of the different SSRIs, SNRIs, and tricyclics for CYP P-450 may vary.

Selected Tricyclic Compounds/Duloxetine; Fluvoxamine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Duloxetine or fluvoxamine may impair the oxidative hepatic metabolism of tricyclic compounds.

CLINICAL EFFECTS: Concurrent administration of duloxetine or fluvoxamine with a tricyclic compound may result in an increase in serum levels, toxicities (e.g. torsades de pointes), and/or clinical effects of the tricyclic compound.

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(9)

PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds at the initiation of concurrent therapy with duloxetine or fluvoxamine. Plasma concentrations of the tricyclic compound should be monitored and the dosage adjusted accordingly. If duloxetine or fluvoxamine is discontinued in a patient receiving a tricyclic compound, the dosage of the tricyclic compound may need to be adjusted.

DISCUSSION: In a study, pretreatment with duloxetine (60 mg twice daily) increased the area-under-curve (AUC) of a single dose of desipramine (50 mg) by 3-fold. Fluvoxamine has been shown in an in vitro study to inhibit the metabolism of imipramine. Three case reports have shown increased serum levels of imipramine (32%, 198%, and 470% increases) and an increase in adverse effects (anticholinergic effects, confusion, and sedation) during concurrent administration with fluvoxamine. Two case reports of adverse effects (tonic-clonic seizure, tremors, dizziness, and confusion) and increased plasma desipramine levels (79% and 54% increases) with concurrent administration of fluvoxamine exist. Increased plasma levels of clomipramine (586%) and amitriptyline (100-150%) without signs of clinical toxicity were seen following the addition of fluvoxamine to a tricyclic compound therapy. The affinity of the different SSRIs, SNRIs, and tricyclics for CYP450 may vary.

Selected Tricyclic Compounds/Sertraline

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Sertraline may impair the oxidative hepatic metabolism of tricyclic compounds.

CLINICAL EFFECTS: Concurrent administration of sertraline with a tricyclic compound may result in an increase in serum levels, toxicities, and/or clinical effects of the tricyclic compound.

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(8)

PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds at the initiation of concurrent therapy with sertraline. Plasma concentrations of the tricyclic compound should be monitored and the dosage adjusted accordingly. If sertraline is discontinued in a patient receiving a tricyclic compound, the dosage of the tricyclic compound may need to be adjusted.

DISCUSSION: Sertraline has been shown to increase the maximum concentration (Cmax) and AUC of desipramine by 31% and 23%, respectively.(5) The affinity of the different SSRIs, SNRIs, and tricyclics for CYP P-450 may vary.

Tricyclic Antidepressants/Bupropion

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Depending upon the antidepressant, one or two mechanisms may be involved. Both bupropion and tricyclic antidepressants are known to lower the seizure threshold.(1,2) Bupropion, a strong inhibitor of CYP2D6, may increase systemic exposure (AUC, area-under-curve) to tricyclic antidepressants that are metabolized by this pathway. Antidepressants which are very sensitive to CYP2D6 inhibition are: desipramine, doxepin, and trimipramine. Antidepressants which are moderately sensitive to CYP2D6 inhibition are: amitriptyline, imipramine, maprotiline, and nortriptyline. Antidepressants which are metabolized by CYP2D6 but less susceptible to CYP2D6 inhibition includes clomipramine.(3)

CLINICAL EFFECTS: Concurrent use of bupropion and a tricyclic antidepressant may result in additive effects on the seizure threshold, increasing the risk of seizures.(1,2) Concurrent use may also increase levels of and side effects from antidepressants metabolized by CYP2D6, such as amitriptyline, clomipramine, imipramine, maprotiline, and nortriptyline.(3)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids).(1,2) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The concurrent use of bupropion and tricyclic antidepressants should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1) If concurrent use of doxepin and bupropion is warranted, monitor doxepin plasma concentrations and reduce the doxepin dose based on doxepin plasma concentrations.(5)

DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and antidepressants should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) In a study in 15 male subjects who were extensive metabolizers of CYP2D6, bupropion (150 mg twice daily) increased the maximum concentration (Cmax), area-under-curve (AUC), and half-life (T1/2) of a single dose of desipramine (50 mg) by 2-fold, 5-fold, and 2-fold, respectively.(1,2)

Tricyclic Antidepressants/St. John's Wort

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: St. John's wort may induce the metabolism of tricyclic antidepressants (TCAs) by the CYP P-450 isoenzyme system.(1)

CLINICAL EFFECTS: The concurrent administration of TCAs and St. John's wort may result in decreased levels and clinical effects of the TCA.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving both of these medications should be alerted to the possibility of decreased effects of the TCA.(1) Observe the patient for loss of the therapeutic effect of the TCA and consider monitoring TCA levels during concurrent therapy. The dosage of the TCA may need to be adjusted if St. John's wort is added to or discontinued from concurrent therapy. St. John's wort may need to be discontinued.

DISCUSSION: St. John's wort has been shown to decrease levels of indinavir in healthy subjects.(2) Because TCAs (amitriptyline, amoxapine, imipramine) are metabolized by the same metabolic pathway, the FDA recommends that patients taking tricyclic antidepressants be alerted to the possibility of a drug interaction resulting in decreased levels and/or effects of the TCA.(1) In a study in 12 subjects, the addition of St. John's wort (900 mg day) decreased the area-under-curve (AUC) of amitriptyline (75 mg twice daily) by 22%. The AUC of nortriptyline decreased 41%.(3)

Tricyclic Antidepressants; Mianserin/Carbamazepine;Phenobarb

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Carbamazepine and phenobarbital may induce the metabolism of tricyclic antidepressants (TCAs) and mianserin by the CYP P450 isoenzyme system.(1,2)

CLINICAL EFFECTS: The concurrent administration of TCAs or mianserin with carbamazepine or phenobarbital may result in decreased levels and clinical effects of the TCA or mianserin.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving both of these medications should be alerted to the possibility of decreased effects of the TCA or mianserin.(1,2) Observe the patient for loss of the therapeutic effect of the TCA or mianserin and consider monitoring TCA or mianserin levels during concurrent therapy.(3,4) Consider dose adjustment of the TCA or mianserin if carbamazepine or phenobarbital is added to or discontinued from concurrent therapy.(2,4)

DISCUSSION: A study of 22 psychiatric patients examined the effects of carbamazepine on serum levels of several antidepressants. Carbamazepine lowered amitriptyline levels by 60%, doxepin levels by 55%, and mianserin levels by 70%. The authors recommended carefully monitoring antidepressant drug levels when carbamazepine is coadministered.(3) A large retrospective study found that patients on carbamazepine with amitriptyline or nortriptyline had concentration/dose (C/D) ratios for the antidepressants that were about 50% lower than the C/D ratios for patients not on carbamazepine. The authors suggest that therapeutic drug monitoring is valuable for managing drug interactions.(4) In healthy volunteers, carbamazepine 200 mg twice daily for 28 days increased desipramine clearance by 31%.(6) In a study of 13 patients with depression, carbamazepine 400 mg per day decreased total imipramine levels by 39.5% and desipramine levels by 24.5% but levels of the pharmacologically active free drugs were not affected. The authors suggested that dose adjustment of imipramine may not be necessary.(7) A pharmacokinetic study found that carbamazepine 400 mg per daily for 4 weeks decreased plasma concentrations of mianserin by 34-45%. A doubling of the mianserin dose was proposed when coadministered with carbamazepine.(5)

Tricyclic Compounds/Cimetidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cimetidine inhibits the hepatic metabolism of tricyclic antidepressants.

CLINICAL EFFECTS: The pharmacological and toxic effects of tricyclic antidepressants may be increased.

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(9)

PATIENT MANAGEMENT: Observe the patient for an increased or decreased response to tricyclic antidepressant therapy if cimetidine is started or stopped. Adjust the dose of the tricyclic agent accordingly. This interaction can probably be avoided by administration of an H-2 receptor antagonist other than cimetidine (e.g., famotidine, nizatidine, ranitidine).

DISCUSSION: Both controlled studies and case reports have demonstrated that concurrent administration of tricyclic antidepressants and cimetidine can result in an increase in plasma tricyclic antidepressant concentrations. Adverse effects have been reported. Similarity between cyclobenzaprine and TCA's warrants consideration of TCA interactions for cyclobenzaprine.

Tricyclic Compounds/Fosamprenavir; Tipranavir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Fosamprenavir and tipranavir may inhibit the metabolism of tricyclic compounds.(1,2)

CLINICAL EFFECTS: Concurrent use of fosamprenavir(1) or tipranavir(2) with tricyclic compounds may result in elevated levels of the tricyclic agents and serious and/or life-threatening effects.

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The manufacturer of fosamprenavir(1) recommends caution with concurrent use of these agents with tricyclic compounds, along with concentration monitoring of the tricyclics. The manufacturer of tipranavir recommends dosage reduction and concentration monitoring of desipramine when coadministered with tipranavir/ritonavir.(2)

DISCUSSION: Amprenavir has been shown to be a potent inhibitor of CYP3A4.(1,3) Fosamprenavir is a prodrug of amprenavir.(1) Therefore, the manufacturer of amprenavir(3) and fosamprenavir(1) recommends caution with concurrent use of these agents with tricyclic compounds, along with concentration monitoring of the tricyclic compounds. No interaction studies have been performed on the combination of tipranavir-ritonavir and desipramine. Desipramine is a sensitive substrate of CYP2D6 while tipranavir-ritonavir is a moderate CYP2D6 inhibitor.(5,6) In one clinical study, six subjects were given 50 mg desipramine on three occasions: alone, after a 60 mg dose of fluoxetine (strong CYP2D6 inhibitor), and after eight daily 60 mg doses of fluoxetine. Fluoxetine significantly reduced oral clearance of desipramine by up to 10-fold and prolonged the half-life of desipramine by up to 4-fold.(7)

Tricyclic Compounds/Inhaled Direct-Acting Sympathomimetics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown. However, it is speculated that direct-acting sympathomimetic amines have an enhanced effect due to tricyclic blockage of norepinephrine reuptake.

CLINICAL EFFECTS: Increased effect of direct acting sympathomimetics.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of inhaled sympathomimetics and tricyclic compounds or the use of these agents within 14 days of each other should be approached with extreme caution.

DISCUSSION: Epinephrine and other direct-acting sympathomimetic amines exert enhanced cardiovascular effects (e.g., arrhythmias, hypertension, and tachycardia) in individuals concurrently receiving or previously treated with tricyclic antidepressants. Protriptyline, amitriptyline, and desipramine have also been reported to interact with direct-acting sympathomimetics. Similarity between cyclobenzaprine and the tricyclic antidepressants consideration of tricyclic antidepressant interactions for cyclobenzaprine.

Tricyclic Compounds/Inhaled Indirect-Acting Sympathomimetics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown. However, it is speculated that indirect-acting sympathomimetics would have decreased activity due to tricyclic blockage of their uptake into the adrenergic neuron.

CLINICAL EFFECTS: Decreased effect of indirect acting sympathomimetics.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of inhaled sympathomimetics and tricyclic compounds or the use of these agents within 14 days of each other should be approached with extreme caution.

DISCUSSION: Epinephrine and other direct-acting sympathomimetic amines exert enhanced cardiovascular effects (e.g., arrhythmias, hypertension, and tachycardia) in individuals concurrently receiving or previously treated with tricyclic antidepressants. Similarity between cyclobenzaprine and the tricyclic antidepressants warrants consideration of tricyclic antidepressant interactions for cyclobenzaprine.

Tricyclic Compounds/Inhaled Mixed-Acting Sympathomimetics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown. However, it is speculated that indirect-acting sympathomimetics would have decreased activity due to tricyclic blockage of their uptake into the adrenergic neuron.

CLINICAL EFFECTS: Decreased effect of indirect acting sympathomimetics.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of inhaled sympathomimetics and tricyclic compounds or the use of these agents within 14 days of each other should be approached with extreme caution.

DISCUSSION: Mixed acting sympathomimetic amines have also been reported to interact with tricyclic antidepressants. These include norepinephrine, phenylephrine, dopamine, and methoxamine. Similarity between cyclobenzaprine and the tricyclic antidepressants consideration of tricyclic antidepressant interactions for cyclobenzaprine.

Tricyclic Compounds/Terbinafine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Terbinafine may inhibit the metabolism of tricyclic compounds by CYP2D6.(1-5)

CLINICAL EFFECTS: Concurrent use of terbinafine may result in elevated levels of and toxicity from the tricyclic agent.

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(6)

PATIENT MANAGEMENT: Monitor tricyclic levels in patients receiving concurrent therapy with terbinafine. The dose of the tricyclic agent may need to be adjusted if terbinafine is initiated or discontinued. The effect of terbinafine on tricyclics may last for up to four weeks after terbinafine discontinuation.

DISCUSSION: In a study in 12 healthy subjects, a single dose of desipramine (50 mg) was given alone, after 21 days of terbinafine (250 mg daily), and 2 and 4 weeks after discontinuation of terbinafine. Administration after 21 days of terbinafine therapy increased the area-under-curve (AUC) and maximum concentration (Cmax) of desipramine by 5-fold and 2-fold, respectively. The AUC and Cmax of desipramine were still elevated when desipramine was administered 4 weeks after the completion of terbinafine therapy.(1,2) There are case reports of toxicity during concurrent terbinafine and desipramine,(3) imipramine,(4) and nortriptyline.(5,7-8) In the UK manufacturer states that terbinafine decreased the clearance of desipramine by 82%.(9)

Tricyclic Compounds; Mirtazapine/Clonidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Clonidine decreases blood pressure via alpha-2 agonism.(1) Tricyclic compounds(2) and mirtazapine(3) antagonize alpha-2, which may result in a loss of effect of clonidine.

CLINICAL EFFECTS: The concurrent use of clonidine and tricyclic compounds(1,3,4-16) and mirtazapine(3,17) may result in decreased effectiveness of clonidine and hypertensive crisis.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent use of clonidine with tricyclic compounds or mirtazapine. Consider using an alternative agent in patients maintained on clonidine. If concurrent administration is warranted, blood pressure should be carefully monitored, particularly in the first two weeks of therapy, when this interaction is most likely to occur. The dosage of clonidine may need to be adjusted or the tricyclic compound or mirtazapine may need to be discontinued.

DISCUSSION: This interaction has been reported in patients receiving amitriptyline,(6) clomipramine,(7,8) desipramine,(2,9-11) imipramine(12-16), and protriptyline.(11) In one patient, a hypertensive crisis resulted. Other patients experienced a decrease in blood pressure control. A controlled trial demonstrated a decrease in anti-hypertensive effect when desipramine was added to a clonidine regimen. This decrease in hypertensive-control may be overcome by increasing the dose of clonidine and monitoring blood pressure closely. Cyclobenzaprine is structurally related to the tricyclic antidepressants and, especially at higher dosages, has similar effects.(18) Therefore, it is prudent to consider cyclobenzaprine in this interaction. Hypertensive crisis has been reported during concurrent clonidine and mirtazapine therapy.(3,17) Mianserin(19,20) and maprotiline,(21) tetracyclic antidepressants, have been shown not to affect the antihypertensive effects of clonidine.

Tricyclic Compounds; Mirtazapine/Moxonidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moxonidine decreases blood pressure via imidazoline-1 and alpha-2 receptor agonism.(1) Tricyclic compounds(2) and mirtazapine(3) antagonize alpha-2, which may result in a loss of effect of moxonidine.

CLINICAL EFFECTS: The concurrent use of moxonidine and tricyclic compounds and mirtazapine may result in decreased effectiveness of moxonidine and decreased blood pressure control.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of moxonidine with tricyclic compounds or mirtazapine is not recommended.(1) Consider using an alternative agent in patients maintained on moxonidine. If concurrent administration is necessary, blood pressure should be carefully monitored. The dosage of moxonidine may need to be adjusted or the tricyclic compound or mirtazapine may need to be discontinued.

DISCUSSION: Moxonidine is an imidazoline-1 and alpha-2 receptor agonist.(1) Since tricyclic antidepressants and mirtazapine may reduce the effectiveness of centrally acting antihypertensive agents, the concurrent use of moxonidine is not recommended. No studies have evaluated the current use of moxonidine with tricyclic antidepressants or mirtazapine. Loss of blood pressure control and hypertensive crisis have been reported with clonidine,(4-22) and a similar interaction may occur with moxonidine. The sedative effect of tricyclic antidepressants can be potentiated by moxonidine.

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• 30 day risk period post-myocardial infarction
• Serotonin syndrome

• Alcohol use disorder
• Angle-closure glaucoma
• Bipolar disorder
• Cardiac arrhythmia
• Cerebrovascular accident
• Coronary artery disease
• Paralytic ileus
• Risk of angle-closure glaucoma due to narrow angle of anterior chamber of eye
• Suicidal ideation
• Urinary retention

• Benign prostatic hyperplasia
• CYp2d6 poor metabolizer
• Hyperthyroidism
• Lower seizure threshold
• Renal failure
• Schizophrenia
• Seizure disorder
• Severe hepatic disease

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Less Frequent

• Abnormal sexual function
• Bradycardia
• Cardiac arrhythmia
• Erectile dysfunction
• Hypotension
• Parkinsonism
• Tremor

Rare or Very Rare

• Abnormal ECG
• Abnormal hepatic function tests
• Accidental fall
• Acute myocardial infarction
• Agranulocytosis
• Angioedema
• Blood dyscrasias
• Cerebrovascular accident
• Drug-induced psychosis
• Eosinophilia
• Heart block
• Hyperbilirubinemia
• Purpura
• Secondary angle-closure glaucoma
• Seizure disorder
• Serotonin syndrome
• Skin photosensitivity
• Suicidal ideation
• Tinnitus
• Ventricular fibrillation
• Ventricular tachycardia

More Frequent

• Accommodation disorder
• Anticholinergic toxicity
• Dizziness
• Drowsy
• Dysgeusia
• Headache disorder
• Increased appetite
• Palpitations
• Weight gain
• Xerostomia

Less Frequent

• Acute cognitive impairment
• Blurred vision
• Constipation
• Diarrhea
• Dysuria
• Hallucinations
• Heartburn
• Hyperhidrosis
• Insomnia
• Libido changes
• Nervousness
• Upper respiratory infection
• Vomiting

Rare or Very Rare

• Aggressive behavior
• Agitation
• Akathisia
• Allergic dermatitis
• Alopecia
• Anorexia
• Delusional disorder
• Facial edema
• Galactorrhea not associated with childbirth
• Gynecomastia
• Hostility
• Hyperglycemia
• Hypertension
• Hypoglycemic disorder
• Hypomania
• Impulse control disorder
• Irritability
• Manic disorder
• Mydriasis
• Nausea
• Nightmares
• Panic disorder
• Paresthesia
• Pruritus of skin
• Skin rash
• Symptoms of anxiety
• Tachycardia
• Testicular swelling

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