Raldesy (trazodone HCl)

There is a wide range of individual trazodone hydrochloride dosage requirements, and dosage must be carefully adjusted according to individual tolerance and response, using the lowest possible effective dosage.

Patients receiving trazodone 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.)

Trazodone hydrochloride is administered orally. The drug should be taken shortly after a meal or light snack. If drowsiness occurs, a major portion of the daily dose may be given at bedtime or dosage may be reduced.

No dosing information is available for this tab.

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)

Sedative Hypnotics; Alcohol/Sodium Oxybate

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: Oxybate may be associated with respiratory depression. As oxybate is taken at bedtime, concurrent use with alcohol or hypnotics may increase the risk for respiratory depression or loss of consciousness.(1-3) Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Concurrent use of sodium oxybate and sedative hypnotics or alcohol may further increase the risk for respiratory depression and profound sedation or coma.(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: The FDA states that sodium oxybate is contraindicated in patients also taking hypnotics or alcohol.(1,2) Significant quantities of alcohol may be present in medicinal products. Alcohol is is used to improve docetaxel and paclitaxel solubility. - The quantity of alcohol in paclitaxel injection formulations (0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg dose contains approximately 13 grams of alcohol. - The quantity of alcohol in docetaxel formulations varies approximately 3-fold depending upon the manufacturer. FDA data on alcohol content (4): Product Manufacturer Alcohol/200 mg dose Docetaxel Inj. Pfizer 6.4 grams Docetaxel Inj. Sandoz 5.5 grams Docetaxel Inj. Accord 4.0 grams Taxotere-one vial Sanofi 4.0 grams formulation Docetaxel Inj. Hospira 3.7 grams Docefrez Sun Pharma 2.9 grams Taxotere-two vial Sanofi 2.0 grams formulation

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 upward 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)

Serotonergic Agents/Dapoxetine

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: Concurrent administration of dapoxetine with other serotonergic agents may result in additive effects on serotonin, resulting in serotonin syndrome.(1,2)

CLINICAL EFFECTS: Concurrent use of dapoxetine with other serotonergic agents may result in serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: Use of multiple drugs which increase serotonin levels is associated with an increased risk for this toxidrome.

PATIENT MANAGEMENT: Dapoxetine should not be administered with other serotonergic agents such as the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), L-tryptophan, triptans, tramadol, lithium, and/or St. John's Wort.(1,2) Dapoxetine should not be initiated within 14 days of receiving other serotonergic agents. Other serotonergics should not be initiated within 7 days of receiving dapoxetine.(2)

DISCUSSION: This interaction is based on class labeling for these agents. Although there is no clinical documentation for an interaction between dapoxetine and either the elective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), L-tryptophan, triptans, tramadol, lithium, and/or St. John's Wort, caution is still warranted. This syndrome has been reported with the selective serotonin reuptake inhibitors and other serotonergic agents, including sumatriptan and dihydroergotamine.

Trazodone/Saquinavir

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: Saquinavir may inhibit the metabolism of trazodone by CYP3A4.(1,2) Trazodone has been shown to prolong the QT interval.(1)

CLINICAL EFFECTS: Concurrent use of saquinavir may result in elevated levels of and adverse effects from trazodone,(1,2) including nausea, dizziness, hypotension, syncope, and cardiac arrhythmias such as QT prolongation or torsades de pointes, which may be life-threatening.(1)

PREDISPOSING FACTORS: This interaction may be more severe with larger and/or routine doses of trazodone. 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.(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 inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)

PATIENT MANAGEMENT: The US manufacturer of saquinavir states that concurrent use of trazodone is contraindicated.(1) One US manufacturer of trazodone recommends consideration of a lower dose of trazodone in patients receiving potent CYP3A4 inhibitors such as a protease inhibitor.(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: In a study in 10 healthy subjects, short-term ritonavir (four doses of 200 mg twice daily) increased the area-under-curve (AUC) and half-life of a single dose of trazodone (50 mg) by 2.4-fold and 2.2-fold, respectively. The maximum concentration (Cmax) of trazodone increased 34% and its clearance decreased 52%. Three subjects experienced nausea, dizziness, or hypotension and one of these subjects also experienced syncope during concurrent administration.(2,3)

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

Possible Qt Prolonging Agents/Anagrelide

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

MECHANISM OF ACTION: Concurrent use of anagrelide with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-4)

CLINICAL EFFECTS: The concurrent use of anagrelide with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-4)

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.(5) 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, and/or renal/hepatic dysfunction).(5)

PATIENT MANAGEMENT: The US manufacturer of anagrelide states that anagrelide should not be used in patients taking medications known to prolong the QT interval.(1) The Australian, Canadian, and UK manufacturers of anagrelide state use of anagrelide should be approached with caution in patients taking medications that can prolong the QTc interval.(2-4) If concurrent therapy is warranted, 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: In a thorough QT study, dose-related QT changes were observed with anagrelide. The maximum mean change in QTcI (95% CI) in comparison to placebo was 7.0 (9.8) ms and 13.0 (15.7) msec following doses of 0.5 mg and 2.5mg, respectively.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(6) 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.

Serotonergic Agents That Prolong Qt/Ziprasidone

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

MECHANISM OF ACTION: Ziprasidone is a 5-HT1A agonist and serotonin and norepinephrine reuptake inhibitor. Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity. Current use may also result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: Concurrent use of ziprasidone and other serotonergic agents may result in serotonin syndrome, a potentially life-threatening condition with symptoms including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.(1) Additive QTc prolongation may also occur, resulting in potentially life-threatening arrhythmias like torsades de pointes.(1)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2) 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: Caution patients about the risk of serotonin syndrome with the concomitant use of ziprasidone with other serotonergic drugs. Instruct patients to contact their healthcare provider, or report to the emergency room, should they experience signs or symptoms of serotonin syndrome.(1) The manufacturer of ziprasidone states under contraindications that ziprasidone should not be used with other drugs that prolong the QT interval such as dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus.(1) It would be prudent to avoid the use of ziprasidone with medicines suspected of prolonging the QT interval. 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: Several cases of serotonin syndrome have been reported in patients receiving ziprasidone.(4-6) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(7)

Trazodone (> 100 Mg)/Maois

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

MECHANISM OF ACTION: Trazodone is primarily an inhibitor of 5HT2A serotonin receptors, H1 histamine, and alpha-1 receptors.(1) At low doses, inhibition of serotonin reuptake is weak and estimated to be 1/20th of 5HT2A inhibiting activity. At high trazodone doses receptor specificity may be diminished and serotonin reuptake inhibition could be clinically important. In addition, one route of trazodone metabolism leads to formation of an active metabolite, m-chlorophenylpiperazine (mCPP) which is pharmacologically distinct from trazodone in that it is an agonist at a variety of serotonin receptors.(1) MCPP concentrations may be clinically important at antidepressant doses of trazodone. MCPP is converted to an inactive metabolite by CYP2D6.(3) MAO Inhibitors increase serotonin levels via inhibition of its metabolism.

CLINICAL EFFECTS: Concurrent administration could increase the risk for serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(2)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of trazodone, mCPP or more potent MAO inhibitors would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2) Concomitant treatment with inhibitors of CYP2D6 (e.g. bupropion, cinacalcet, dacomitinib, fluoxetine, paroxetine, quinidine, or systemic terbinafine)(4) may increase mCPP concentration, increasing the risk for serotonin toxicity. Patients who are poor metabolizers at CYP2D6 would be expected to have higher mCPP concentrations compared with extensive metabolizers.

PATIENT MANAGEMENT: Trazodone doses greater than 100 mg should not be prescribed in patients who require treatment with any MAOI and a strong inhibitor of CYP2D6 (e.g. bupropion, cinacalcet, dacomitinib, fluoxetine, paroxetine, quinidine, systemic terbinafine) or any other agent with serotonin-increasing effects (e.g. tramadol, meperidine, most antidepressants). Patients known to be poor metabolizers of CYP2D6 should not receive greater than 100 mg of trazodone per day if they require treatment with a MAOI. To minimize serotonin reuptake inhibition and accumulation of mCPP, limit dosage of trazodone to less than or equal to 100 mg daily in patients receiving MAO inhibitors. If the benefit of higher dose trazodone is judged to be greater than the risk for serotonin toxicities, assure that the patient and health care team are aware of and monitor for signs and symptoms of serotonin syndrome. 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: In a case report, a 37 year-old male developed serotonin syndrome following the addition of linezolid to citalopram and trazodone.(5) In a case report, a patient developed serotonin syndrome with concurrent trazodone, isocarboxazid, and methylphenidate.(6) In a case report, a patient developed serotonin syndrome following the abrupt replacement of trazodone with moclobemide.(7) An open study evaluated the efficacy and safety of low dose trazodone for the treatment of MAOI-associated insomnia. Twenty-one patients successfully treated with a MAOI for unipolar or bipolar depression but with persistent insomnia participated in the study. Trazodone 25 to 75 mg was given at bedtime. Patients with a fair or good response to trazodone were monitored for a minimum of 4 months to assess efficacy and safety of treatment. Eleven patients had a resolution of insomnia, 9 had a partial response, and one had no benefit. Side effects noted were nausea in 2 patients, persistent morning grogginess in one patient and memory problems in one patient.(8) A small double-blind placebo controlled study evaluated the efficacy and safety of trazodone 50 mg to treat insomnia due to brofaromine, a MAO-A inhibitor. All seven patients had responded to brofaromine and had been in remission for at least 3 months. Three patients received trazodone on week 1, followed by placebo on week 2, while the other 4 patients received placebo on week 1 and trazodone on week 2. At the end of the trial 4 patients elected to continue trazodone and 3 patients discontinued therapy due to adverse effects (nausea, constipation, vertigo, dry mouth, palpitations, or heartburn). The authors stated no patients had symptoms suggestive of serotonin syndrome.(9) Metaxalone is a weak inhibitor of MAO.(10,11) The FDA AERS contains reports of serotonin syndrome with the concurrent use of linezolid and citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine as well as 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 linezolid and other psychiatric drugs is unclear.(12,13)

Trazodone (> 75 Mg)/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) Trazodone is metabolized by CYP3A4 and its metabolite, mCPP, is pharmacologically active. MCPP is metabolized by CYP2D6 and when it accumulates may be associated with adverse effects.

CLINICAL EFFECTS: Concurrent administration of fluoxetine or paroxetine with trazodone may result in an increase in serum trazodone levels. Elevated levels of trazodone may increase the risk of QT prolongation and the risk for torsades de pointes and serotonin syndrome.

PREDISPOSING FACTORS: Higher systemic concentrations of fluoxetine or paroxetine may increase the magnitude of this interaction. Concurrent use of multiple drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(3) 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.(4,5) 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).(4,5) 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).

PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of trazodone at the initiation of concurrent therapy with fluoxetine or paroxetine. If fluoxetine or paroxetine is discontinued in a patient receiving trazodone, 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. If trazodone is started after the discontinuation of fluoxetine, it should be started at a lower initial dosage. Patients receiving fluoxetine or paroxetine and trazodone should be monitored for serotonin syndrome. Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus. Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus. Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity. 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: There is one case report of serotonin syndrome during concurrent therapy with paroxetine and trazodone.(6) There have also been case reports of serotonin syndrome with trazodone and fluoxetine.(7) In a 24 year-old patient, the use of fluoxetine and trazodone resulted in severe irritability, anger, anxiety, and anorexia.(8) In a study in 11 patients, concurrent administration of trazodone 100 mg/day and fluoxetine 20 mg/day increased the concentrations of trazodone and its active metabolite mCPP by 65% and 231%.(9)

Trazodone (>= 100 Mg)/Qt Prolonging Agents

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

MECHANISM OF ACTION: Concurrent use of trazodone with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: The use of trazodone in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(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.(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 US manufacturer of trazodone states that concurrent use with agents known to prolong the QT interval should be avoided.(1) If concurrent therapy is warranted, 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: Trazodone has been reported to prolong the QT interval.(1) A thorough QT study in 20 subjects evaluated the effects of trazodone at doses of 20 mg, 60 mg and 140 mg. There was no evidence of QTc prolongation at the lowest trazodone dose of 20mg (mean effect on QTc of 4.5 ms 95% CI 3.7-5.3 ms), but at 60 mg and 140 mg, there was a significant effect that exceeds the E14 FDA Guidelines threshold of prolonging the QT/QTc interval by more than 5 ms. The study found a dose-dependent effect on QTc prolongation starting at 60 mg with a mean effect on QTc of 12.3 ms (95% CI 11-13.6 ms) and increasing with a 140 mg dose to a mean effect on QTc of 19.8 ms (95% CI 17.6-22.1).(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)

Trazodone/Select Cyp3a4 Inhibitors That Prolong Qt

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

MECHANISM OF ACTION: CYP3A4 inhibitors may inhibit the metabolism of trazodone.(1-7) Trazodone has been shown to prolong the QT interval. Other agents that prolong the QT interval may have an additive effect. Trazodone's active metabolite meta-chlorophenylpiperazine (m-CPP) is metabolized by CYP2D6. Telithromycin and lopinavir-ritonavir are also weak CYP2D6 inhibitors.(1)

CLINICAL EFFECTS: Concurrent use of CYP3A4 inhibitors may result in elevated levels of and adverse effects from trazodone, including nausea, dizziness, hypotension, syncope, serotonin syndrome, and cardiac arrhythmias including QT prolongation or torsades de pointes, which may be life-threatening.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: This interaction may be more severe with larger and/or routine doses of trazodone. 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.(8) 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).(8)

PATIENT MANAGEMENT: The US manufacturer of trazodone states that concurrent use with agents known to prolong the QT interval should be avoided.(1) If concurrent use is warranted, a lower dose of trazodone should be considered in patients receiving CYP3A4 inhibitors.(1-7) If concurrent therapy is warranted, 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. In addition to QT prolongation, 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: In a cross-over study in 10 healthy subjects, pretreatment with clarithromycin (500 mg, 4 doses given over 32 hours) increased the maximum concentration, (Cmax) half-life, and area-under-curve (AUC) of a single dose of trazodone (50 mg) by 35% (p<0.005), 96% (p<0.02), and 99% (p<0.001), respectively. Trazodone oral clearance decreased by 46% (p<0.001). Pharmacodynamic effects of trazodone were also increased, as shown by changes in self-rated sedation, observer-rated sedation, digit-symbol substitution test (DSST) scores.(9) In a study in 10 healthy subjects, short-term ritonavir (four doses of 200 mg twice daily) increased the AUC and half-life of a single dose of trazodone (50 mg) by 2.4-fold and 2.2-fold, respectively. The Cmax of trazodone increased 34% and its clearance decreased 52%. Three subjects experienced nausea, dizziness, or hypotension and one of these subjects also experienced syncope during concurrent administration.(1-3) In a single case report, a female experienced serotonin syndrome characterized by high blood pressure (240/120 mmHg); intermittent numbness of the right side of her lips and nose and fingers of the right hand; nausea; loose stools; flushed, pruritic skin; confusion; and difficulty concentrating four days after the addition of trazodone (25-50 mg daily) to nefazodone.(7) An in vitro study in human liver microsomes showed that indinavir, ketoconazole, and ritonavir inhibited the metabolism of trazodone.(6) Strong and moderate CYP3A4 inhibitors linked to this monograph include: ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir/ritonavir, posaconazole, ribociclib, telithromycin, and voriconazole are considered to be potent inhibitors of the CYP3A4 isoenzyme.(10) Fluconazole's inhibition of CYP3A4 is dose dependent.(11)

Trazodone/Selected Cyp3a4 Inhibitors

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

MECHANISM OF ACTION: CYP3A4 inhibitors may inhibit the metabolism of trazodone.(1) Trazodone has been shown to prolong the QT interval. Trazodone's active metabolite meta-chlorophenylpiperazine (m-CPP) is metabolized by CYP2D6. Cobicistat is also a weak CYP2D6 inhibitor.(1)

CLINICAL EFFECTS: Concurrent use of CYP3A4 inhibitors may result in elevated levels of and adverse effects from trazodone, including nausea, dizziness, hypotension, syncope, serotonin syndrome,(9) and cardiac arrhythmias including QT prolongation or torsades de pointes, which may be life-threatening.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: This interaction may be more severe with larger and/or routine doses of trazodone. 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.(10) 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).(10)

PATIENT MANAGEMENT: A lower dose of trazodone should be considered in patients receiving CYP3A4 inhibitors.(1-7) Instruct patients to report dizziness, any irregular heartbeat, fainting episodes or excessive daytime sedation. If concurrent therapy is warranted, 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. In addition to QT prolongation, 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: In a cross-over study in 10 healthy subjects, pretreatment with clarithromycin (500 mg, 4 doses given over 32 hours) increased the maximum concentration, (Cmax) half-life, and area-under-curve (AUC) of a single dose of trazodone (50 mg) by 35% (p<0.005), 96% (p<0.02), and 99% (p<0.001), respectively. Trazodone oral clearance decreased by 46% (p<0.001). Pharmacodynamic effects of trazodone were also increased, as shown by changes in self-rated sedation, observer-rated sedation, digit-symbol substitution test (DSST) scores.(11) In a study in 10 healthy subjects, short-term ritonavir (four doses of 200 mg twice daily) increased the AUC and half-life of a single dose of trazodone (50 mg) by 2.4-fold and 2.2-fold, respectively. The Cmax of trazodone increased 34% and its clearance decreased 52%. Three subjects experienced nausea, dizziness, or hypotension and one of these subjects also experienced syncope during concurrent administration.(3) In a single case report, a female experienced serotonin syndrome characterized by high blood pressure (240/120 mmHg); intermittent numbness of the right side of her lips and nose and fingers of the right hand; nausea; loose stools; flushed, pruritic skin; confusion; and difficulty concentrating four days after the addition of trazodone (25-50 mg daily) to nefazodone.(9) An in vitro study in human liver microsomes showed that indinavir, ketoconazole, and ritonavir inhibited the metabolism of trazodone.(8) Amprenavir, atazanavir, boceprevir, cobicistat, darunavir, ensitrelvir, fosamprenavir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, relacorilant, tipranavir, telaprevir, and tucatinib are considered to be potent inhibitors of the CYP3A4 isoenzyme.(12)

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

Possible Qt Prolonging Agents/Citalopram

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

MECHANISM OF ACTION: Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-3)

CLINICAL EFFECTS: The use of citalopram in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-3)

PREDISPOSING FACTORS: Higher doses of citalopram, especially doses greater than 40 mg, may increase the risk of QT prolongation. 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.(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 inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)

PATIENT MANAGEMENT: Concurrent use of citalopram with agents known to prolong the QT interval should be avoided. Due to the risk of QT prolongation, citalopram doses greater than 40 mg once daily are not recommended. Citalopram doses should be limited to 20 mg once daily in patients who are CYP2C19 poor metabolizers or patients receiving CYP2C19 inhibitors. If patients have a persistent QTc measurement > 500 ms, discontinue citalopram. If a patient develops symptoms including dizziness, palpitations, or syncope, further evaluation is warranted included cardiac monitoring. The manufacturer recommends ECG monitoring in patients for whom citalopram is not recommended, including those receiving concurrent therapy with agents known to prolong the QT interval. Citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.(1-2) Consider obtaining serum calcium, magnesium, and potassium levels at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Citalopram has been associated with dose-depended increases in the QTc interval. In healthy subjects, the maximum mean difference in QTc interval seen with 20 mg of citalopram and 60 mg of citalopram were 8.5 msec (90% CI = 6.2-10.8 msec) and 18.5 msec (90% CI = 16.0-21.0 msec), respectively. Based on extrapolation, a 40 mg dose of citalopram is expected to produce a mean increase in the QTc interval of 12.6 msec (90% CI = 10.9-14.3 msec).(1) In a clinical trial of use of citalopram for agitation in Alzheimer's disease, citalopram (30 mg daily) was associated with a mean increase in QTc of 18.1 msec.(5) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(6)

Possible Qt Prolonging Agents/Dexmedetomidine Sublingual

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

MECHANISM OF ACTION: Dexmedetomidine sublingual has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of dexmedetomidine sublingual with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade 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 torsade 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 dexmedetomidine sublingual states that concurrent use should be avoided with other agents known to prolong the QTc interval.(1) If concurrent therapy is warranted, 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: In a QT study, dexmedetomidine sublingual had a concentration dependent effect on the QT interval. The mean QTc (95% confidence interval) increased from baseline by 6 (7) msec with a 120 mcg single dose, 8 (9) msec with 120 mcg followed by 2 additional doses of 60 mcg (total 3 doses), 8 (11) msec with a single 180 mcg dose, and 11 (14) msec with 180 mcg followed by 2 additional doses of 90 mcg (total 3 doses), respectively.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Possible Qt Prolonging Agents/Dordaviprone

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

MECHANISM OF ACTION: Dordaviprone has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of dordaviprone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade 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 torsade 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: If possible, avoid the use of dordaviprone with other agents known to prolong the QTc interval. If current use cannot be avoided, separate administration of dordaviprone and the QT-prolonging agent. The manufacturer does not provide details about how to separate administration and states that the exposure-response relationship and time course of pharmacodynamic response is not fully characterized. Dordaviprone's time to maximum concentration (Tmax) occurs at 1.4 hours (0.5, 5.6 hours) and mean terminal half-life is 11 hours.(1) Baseline and periodic monitoring of ECG and electrolytes is recommended.(1) Increase the frequency of monitoring in patients with congenital long QT syndrome, existing QTc prolongation, history of ventricular arrhythmias, electrolyte abnormalities, heart failure, or are taking strong or moderate CYP3A4 inhibitors.(1) If QTc interval prolongation occurs, dose modifications are warranted. If QTc is >500 msec or the change from baseline is >60 msec, interrupt dordaviprone therapy until QTc interval is <= 480 msec or returns to baseline. If the patient has Torsades de pointes, polymorphic ventricular tachycardia, or signs or symptoms of serious or life-threatening arrhythmia, permanently discontinue dordaviprone.(1) If concurrent therapy is warranted, 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: Dordaviprone causes concentration-dependent QTc prolongation.(1) In a QT study, the estimated change in QTcF was 11.8 msec (90% CI: 9.8, 13.7) with dordaviprone (1.2 times the maximum recommended dose).(1) In a pooled safety analysis, out of 82 patients with baseline ECG, 6% of patients had an increase in QTc of >60 msec from baseline and 1.2% had an increase in QTc >500 msec. Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)

Possible Qt Prolonging Agents/Fexinidazole

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

MECHANISM OF ACTION: Fexinidazole has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of fexinidazole with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade 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 torsade 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, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of fexinidazole states that fexinidazole should be avoided in patients receiving other drugs known to cause QT prolongation.(1) Avoid use of fexinidazole in patients who have a baseline QTcF interval greater than 470 msec, a history of torsade de pointes, congenital long QT syndrome, cardiac arrhythmias, uncompensated heart failure, or family history of sudden death, or uncorrected hypokalemia.(1) If patients are, or need to be, treated with drugs known to prolong QTcF interval or to induce bradycardia do not initiate therapy with fexinidazole until such drugs are eliminated from the body (allow a washout period of 5 half-lives for such other drugs). Do not start such drugs until fexinidazole therapy is eliminated (allow a washout period of 7 days).(1) If concurrent therapy is warranted, 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: In clinical studies, fexinidazole was associated with a concentration-dependent QTcF prolongation. At recommended therapeutic doses, the mean (upper 90% confidence interval) increase in QTcF is predicted to be 19.0 msec (23.3 msec). The observed increase in QTcF appears to be associated with the M2 (sulfone) metabolite of fexinidazole.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)

Possible Qt Prolonging Agents/Firmonertinib

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

MECHANISM OF ACTION: Firmonertinib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of firmonertinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade 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 torsade 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 firmonertinib states that firmonertinib should be avoided in patients with risk factors that may increase the risk of QTc interval prolongation or arrhythmic events, such as heart failure, hypokalemia, or congenital long QT syndrome.(1) Concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating firmonertinib, during concomitant use, and as clinically indicated. More frequent ECG monitoring may be necessary. The manufacturer of firmonertinib states patients with at least two independent ECG tests indicating a QTc > 500 ms should temporarily discontinue firmonertinib until QTc < 481 ms or returns to baseline levels (e.g., baseline QTc > or = 481 ms). Patients with QTc prolongation and severe arrhythmic symptoms or signs should permanently discontinue firmonertinib.(1) If concurrent therapy is warranted, 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: In clinical trials, among 446 patients treated with firmonertinib at a dose of 80 mg, 57 (12.8%) experienced QT interval prolongation on an ECG, of which 6 (1.3%) were grade 3 and the rest were grade 1-2. Of these, 7 (1.6%) experienced dose interruption, 5 (1.1%) experienced dose reduction, and 1 (0.2%) experienced permanent discontinuation of treatment.(1) In another study, QTc interval prolongation was reported as an adverse event in 6% of 130 patients (in 20 mg, 40 mg, 80 mg, and 160 mg groups; n=2 each). All were classified as grade 1 or grade 2 and assessed as possibly related to treatment. Two events (grade 2 at 80 mg, grade 2 at 160 mg) led to dose interruption before resolution. QT prolongation in the remaining patients was resolved without intervention, except for one event (grade 1) reported as worsening.(3)

Possible Qt Prolonging Agents/Gadofosveset

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

MECHANISM OF ACTION: QT prolongation has been reported following gadofosveset administration. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The use of gadofosveset in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade 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 torsade 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: In patients maintained on agents known to prolong the QT interval, consider a baseline ECG prior to administration of gadofosveset to asses the risk/benefit of gadofosveset. If gadofosveset is used, consider ECG monitoring for 72 hours until the majority of gadofosveset is eliminated. Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Counsel patients to report any irregular heartbeat, dizziness, or fainting episodes during this time frame.(1)

DISCUSSION: In clinical trials, 6% of patients experienced an increase in QTc of 30 msec to 60 msec 45 minutes after the administration of gadofosveset and 0.4% of patients experienced a QTc increase of greater than 60 msec at 45 minutes post-administration.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)

Possible Qt Prolonging Agents/Gepotidacin

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

MECHANISM OF ACTION: Gepotidacin may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of gepotidacin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade 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 torsade 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 gepotidacin states that the concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating gepotidacin, during concomitant use, and as clinically indicated.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: The effect of gepotidacin on the QTc interval was evaluated in a randomized, active (moxifloxacin 400 mg) and placebo-controlled, double-blind cross-over trial in healthy subjects who received single intravenous (IV) infusions of gepotidacin over 2 hours. A dose- and concentration-dependent QTc prolongation effect of gepotidacin was observed. The mean placebo-corrected change from baseline QTcF values around Tmax were 12 msec at 1,000 mg IV and 22 msec at 1,800 mg IV (not approved dosing regimens and route of administration). Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Possible Qt Prolonging Agents/Givinostat

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

MECHANISM OF ACTION: Givinostat may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of givinostat with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade 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 torsade 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 givinostat states that the concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating givinostat, during concomitant use, and as clinically indicated.(1) If the QTc interval is greater than 500 ms or the change from baseline is greater than 60 ms, withhold givinostat therapy.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a QT study, the largest mean increase in QTc interval of 13.6 ms (upper confidence interval of 17.1 ms) occurred 5 hours after administration of givinostat 265.8 mg (approximately 5 times the recommended 53.2 mg dose in patients weighing 60 kg or more).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Possible Qt Prolonging Agents/Lenvatinib

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

MECHANISM OF ACTION: Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of lenvatinib in patients taking other medications that prolong the QT interval may result in additive QT prolongation. QT prolongation may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(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, hypoalbuminemia, bradycardia, female gender, or advanced age.(1,2) 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: Monitor electrocardiograms during concurrent therapy with lenvatinib and agents that prolong the QT interval. In a clinical trial of patients with refractory, progressive thyroid cancer, QT prolongation was reported in 9% of lenvatinib patients. Monitor and correct electrolyte abnormalities in all patients.(1) This is particularly important in lenvatinib patients as diarrhea, nausea, vomiting, and decreased appetite are common side effects which may increase the risk for electrolyte disturbances. Monitor ECG at baseline and at regular intervals. Lenvatinib dose must be withheld if the QTc exceeds 500 msec until QTc resolves to less than 480 msec or baseline. Lenvatinib must be resumed at reduced dose when QTc prolongation resolves to less than 480 msec or to baseline. Dose adjustments below are indication specific and are for patients with normal hepatic and renal function:(1) Dose Modifications in Differentiated Thyroid Cancer(DTC): - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 20 mg once daily - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 14 mg once daily - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose 10 mg once daily Dose Modifications in Renal Cell Cancer (RCC): - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 14 mg once daily - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 10 mg once daily - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose 8 mg once daily Dose Modifications in Hepatocellular Carcinoma (HCC) for Actual weight 60 kg or greater: - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 8 mg once daily - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 4 mg once daily - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose 4 mg every other day Dose Modifications in Hepatocellular Carcinoma (HCC) for Actual weight less than 60 kg: - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 4 mg once daily - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 4 mg every other day - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline and discontinue lenvatinib (1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a clinical trial of patients with refractory, progressive thyroid cancer, QT prolongation was reported in 9% of lenvatinib patients and 2% of placebo patients. The incidence of Grade 3 QT prolongation of > 500 msec was reported in 2% of lenvatinib patients compared with no reports in placebo patients.(1) In contrast, a single lenvatinib dose of 32 mg (1.3 times the recommended daily dose) did not prolong the QT/QTc interval in a thorough QT study performed in healthy subjects.(1) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received lenvatinib, QTc prolongation was identified in 9 (42.9%) with 4 (44.4%) having Grade 1 (QTc 450-480 ms) and 3 (33.3%) having Grade 2 (QTc 480-500 ms). Grade 3 events occurred in 0 (0%) having QTc greater than or equal to 500 ms and 1 (11.1%) having QTc change greater than or equal to 60 ms. Ventricular tachycardia was seen in 1 (11.1%) patient.(3)

Possible Qt Prolonging Agents/Levomepromazine

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

MECHANISM OF ACTION: Levomepromazine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of levomepromazine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade 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 torsade 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, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of levomepromazine states that levomepromazine is not recommended in patients receiving other drugs known to cause QT prolongation.(1) If concurrent therapy is warranted, 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: Case reports of QTc prolongation associated with levomepromazine have been reported.(1,3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)

Possible Qt Prolonging Agents/Milsaperidone

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

MECHANISM OF ACTION: Milsaperidone may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of milsaperidone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, and with concurrent use of inhibitors of CYP3A4 or CYP2D6, which metabolize milsaperidone.(1,2) 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 torsade 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 milsaperidone states that concurrent use of other drugs that are known to prolong the QTc interval should be avoided. If concurrent therapy is warranted, 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. If the QTc interval is consistently above 500 msec, discontinue milsaperidone.(1)

DISCUSSION: Milsaperidone and iloperidone rapidly interconvert in vivo. In a study of 160 patients with psychiatric disorders, coadministration of paroxetine (20 mg daily) and iloperidone (12 mg twice daily) was associated with a mean QTcF increase of 19 msec from baseline, compared with an increase of 9 msec with iloperidone alone.(1) Coadministration of ketoconazole (a CYP3A4 inhibitor) and paroxetine did not increase the effects on iloperidone compared with either agent alone.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Possible Qt Prolonging Agents/Oxaliplatin

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

MECHANISM OF ACTION: Concurrent use of oxaliplatin with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of oxaliplatin with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(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, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Avoid the concurrent use of oxaliplatin in patients with congenital long QT syndrome. ECG monitoring is recommended if oxaliplatin therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Prescribing information for oxaliplatin states post-marketing cases of QT prolongation and ventricular arrhythmias, including fatal Torsades de Pointes, have been reported.(1) Case reports have documented QT prolongation in patients with varying cancer indications for oxaliplatin.(3-6) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(7)

Possible Qt Prolonging Agents/Pacritinib

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

MECHANISM OF ACTION: Pacritinib has been observed to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of pacritinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(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 pacritinib states concurrent use with agents known to prolong the QT interval should be avoided. Avoid the use of pacritinib in patients with a baseline QTc > 480 msec. Correct hypokalemia prior to initiation and during therapy with pacritinib.(1) If patients develop QTc prolongation >500 msec or >60 msec from baseline, hold pacritinib. If QTc prolongation resolves to <=480 msec or to baseline within 1 week, resume pacritinib at the same dose. If time to resolution of the QTc interval takes greater than 1 week to resolve, reduce the pacritinib dose.(1) If concurrent therapy is warranted, 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: In a 24 week clinical study, patients treatment with pacritinib 200 mg twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(1) Pacritinib has been associated with QTc interval prolongation. In clinical trials, patients with QTc prolongation >500 msec occurred in 1.4% of patients in the treatment arm compared to 1% in the control arm. The treatment arm had a greater incidence of an increase in QTc > 60 msec from baseline than the control arm (1.9% vs 1%, respectively). QTc prolongation adverse reactions were higher in the treatment arm than the control group (3.8% vs 2%, respectively).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)

Possible Qt Prolonging Agents/Pimavanserin

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

MECHANISM OF ACTION: Pimavanserin prolongs the QTc interval.(1) Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(2,3)

CLINICAL EFFECTS: The concurrent use of pimavanserin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(2,3)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade 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 torsade 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: Avoid the use of pimavanserin in patients receiving QT prolonging agents.(1) During concomitant therapy with another QT prolonging agent, monitor patients closely for prolongation of the QT interval.(1) Obtain serum calcium, magnesium, and potassium levels and monitoring ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In thorough-QT study, pimavanserin (at twice the therapeutic dose) found that the maximum mean change was 13.5 (16.6) msec. In placebo-controlled effectiveness studies, mean increases of 5-8 msec were observed with normal dosages of 37 mg daily. Sporadic QTcF values of equal to or greater than 500 msec and change from baseline values equal to or greater than 60 msec were observed at this dose as well.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)

Possible Qt Prolonging Agents/Selpercatinib

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

MECHANISM OF ACTION: Selpercatinib prolongs the QTc interval.(1) Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(2,3)

CLINICAL EFFECTS: The concurrent use of selpercatinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(2,3)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade 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 torsade 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: Selpercatinib prolongs the QT interval. An increase in QT interval to > 500 ms was measured in 6% of patients and increase in the QT interval of at least 60 ms over baseline was measured in 15% of patients. Monitor patients at significant risk of developing QT prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes, and TSH at baseline and periodically during treatment. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiation and during treatment. Dose adjustments (1): For grade 3 QT interval prolongation, withhold selpercatinib until recovery to baseline or grade 0 or 1. Resume at a reduced dose. -1st dose reduction: For patients weighing less than 50 kg: 80 mg twice daily. For patients weighing 50 kg or greater: 120 mg twice daily. -2nd dose reduction: For patients weighing less than 50 kg: 40 mg twice daily. For patients weighing 50 kg or greater: 80 mg twice daily. -3rd dose reduction: For patients weighing less than 50 kg: 40 mg once daily. For patients weighing 50 kg or greater: 40 mg twice daily. -For grade 4 QT prolongation, discontinue selpercatinib.

DISCUSSION: The effect of selpercatinib on the QT interval was evaluated in a thorough QT study in healthy subjects. The largest mean increase in QT is predicted to be 10.6 ms (upper 90% confidence interval: 12.1 ms) at the mean steady state maximum concentration (Cmax) observed in patients after administration of 160 mg twice daily. The increase in QT was concentration-dependent. Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)

Possible Qt Prolonging Agents/Vepdegestrant

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

MECHANISM OF ACTION: Vepdegestrant may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of vepdegestrant with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and advanced age.(1,2) 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 torsade 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 vepdegestrant states that concurrent use of other drugs that are known to prolong the QTc interval should be avoided. If concurrent therapy is warranted, monitor ECG when initiating vepdegestrant, during concurrent use, and as clinically indicated. Consider increasing the frequency of ECG monitoring. Do not initiate vepdegestrant in patients with a baseline QTc >470 ms. Withhold vepdegestrant if the QTc is >480 ms or the change from baseline is >60 ms.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Vepdegestrant 200 mg daily increased QTc by 12 ms (upper confidence interval = 15 ms) in patients with ESR1 mutation-positive breast cancer.(1) In VERITAC-2, QTc prolongation occurred in 10% of patients, with 1.6% of patients having Grade 3 events. QTc was >500 ms in 1.6% of patients and QTc increase from baseline of >60 ms occurred in 2.6% of patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Possible Qt Prolonging Agents/Ziftomenib

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

MECHANISM OF ACTION: Ziftomenib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of ziftomenib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade 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 torsade 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 ziftomenib states that the concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating ziftomenib, during concomitant use, and as clinically indicated. More frequent ECG monitoring may be necessary. Do not initiate ziftomenib if baseline QTcF > 480 ms.(1) Perform ECG at least once weekly for the first 4 weeks on treatment, then at least monthly thereafter. If the QTc interval is greater than 500 ms or the change from baseline is greater than 60 ms, withhold ziftomenib therapy.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In clinical trials, QTc interval prolongation was reported as an adverse event in 12% of 112 patients treated with the recommended dosage of ziftomenib. QTc was >500 ms in 9% of patients and the increase from baseline QTcF was >60 ms in 12% of patients. Ziftomenib increased the QTc interval in a concentration-dependent manner. At a dose of 600 mg daily, the largest mean increase in QTc was 7.7 ms (upper bound of confidence interval = 12.6 ms).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Qt Prolonging Agents/Amisulpride

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

MECHANISM OF ACTION: Amisulpride has been shown to prolong the QT interval. Concurrent use with QT prolonging agents may result in additive effects on the QT interval.(1)

CLINICAL EFFECTS: The concurrent use of amisulpride with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(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, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Use caution when using amisulpride concurrently with other agents that can prolong the QT interval. Amisulpride may cause a dose and concentration dependent increase in the QTc interval. When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. ECG monitoring is recommended in patients with pre-existing arrhythmias or cardiac conduction disorders; electrolyte abnormalities; congestive heart failure; or in patients taking medications or with other medical conditions known to prolong the QT interval. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.(2)

DISCUSSION: QT prolongation and torsades de pointes have been reported with amisulpride. In a study in 40 patients with post operative nausea and vomiting, amisulpride increased baseline QTcF by 5 msec after a 2-minute intravenous infusion of 5 mg and by 23.4 msec after an 8-minute intravenous infusion of 40 mg. Based on an exposure-response relationship, it is expected that a 10 mg intravenous infusion over 1 minute may increase the QTcF by 13.4 msec.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Qt Prolonging Agents/Anamorelin

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

MECHANISM OF ACTION: Anamorelin may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of anamorelin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade 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 torsade 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 anamorelin states that the concurrent use of QT prolonging agents should be approached with caution, especially in the early stages (i.e., the first 3 weeks) of drug administration.(1,3) Obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. If abnormalities are found, take appropriate measures, including discontinuing anamorelin.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Anamorelin blocks sodium channels and may suppress cardiac conduction, resulting in prolongation of the QRS width or QT interval. A study of 7 healthy volunteers receiving single-dose anamorelin 400 mg found that 1 patient experienced QRS width prolongation. In 60 healthy adults recieving anamorelin, the maximum difference (upper limit of 95% one-sided confidence interval) in the change from baseline in QTcF interval compared to placebo was 6.16 (7.73) msec in patients on 100 mg and 7.38 (10.31) msec in patients on 300 mg.(1) The Japanese pharmacovigilance database was reviewed to evaluate disproportionality of conduction defects related to anamorelin. Out of 537 cases of adverse reactions, there were 51 cases of conduction defects (36 cases of prolonged QT, 5 cases of prolonged QRS complex, 2 cases of long QT syndrome). When adjusted for concomitant use of QT prolonging agents, the reporting odds ratio (ROR) of anamorelin-related conduction defects was 20.00 (95% CI 14.86-26.91).(3) There have been several case reports of widened QRS complexes following anamorelin exposure, usually accompanied by worsening hepatic function.(4-6) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(7)

Qt Prolonging Agents/Catequentinib

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

MECHANISM OF ACTION: Catequentinib has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of catequentinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade 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 torsade 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 concurrent use of catequentinib with other agents known to prolong the QTc interval should be monitored closely. Monitor ECG and electrolytes regularly (every 3-6 weeks) if catequentinib is administered with concurrent QTc prolonging drugs.(1) If concurrent therapy is warranted, 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: Catequentinib causes QTc prolongation. In clinical studies, QTc prolongation was reported as a very common adverse effect.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)

Qt Prolonging Agents/Escitalopram

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

MECHANISM OF ACTION: Concurrent use of multiple agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of multiple agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(1) 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 torsade 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, and/or renal/hepatic dysfunction).(1)

PATIENT MANAGEMENT: While the US FDA and manufacturer recommend no special precautions when escitalopram is used with QT prolonging agents,(2,3) Health Canada and the Canadian manufacturer of escitalopram discourage the concurrent use of agents known to prolong the QT interval(4,5) and the UK manufacturer states that concurrent use is contraindicated.(6) If concurrent therapy is warranted, 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: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(7) 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.

Qt Prolonging Agents/Etrasimod

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

MECHANISM OF ACTION: Etrasimod is a sphingosine-1-phosphate (S1P) receptor modulator. Initiation of etrasimod has a negative chronotropic effect, which may increase the risk of developing QT prolongation.

CLINICAL EFFECTS: Initiation of etrasimod may result in a transient decrease in heart rate. A mean decrease in heart rate of 7.2 (8.98) beats per minute was seen 2 to 3 hours after the first dose. The first dose has also been associated with heart block. Symptomatic bradycardia has been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsades de pointes.(1)

PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to etrasimod initiation, factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to etrasimod. The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, 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 the 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: Prior to initiation of etrasimod, obtain an ECG to determine if preexisting conduction abnormalities are present.(1) Advice from a cardiologist is recommended in patients with preexisting heart and cerebrovascular conditions, prolonged QTc interval, risk factors for QT prolongation, concurrent therapy with QT prolonging drugs or drugs that slow the heart rate or AV conduction.(1) Monitor blood pressure during treatment.(1) If concurrent therapy is warranted, 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: Initiation of etrasimod may result in a transient decrease in heart rate or transient AV conduction delays.(1) A transient decrease in heart rate was observed during the initial dosing phase of etrasimod and bradyarrhythmic events (AV blocks) were detected at a higher incidence under etrasimod treatment than placebo.(1)

Qt Prolonging Agents/Fingolimod

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

MECHANISM OF ACTION: Fingolimod is a sphingosine 1-phosphate (S1P) receptor modulator. Initiation of fingolimod has a negative chronotropic effect leading to a mean decrease in heart rate of 13 beats per minute (bpm) after the first dose. The first dose has also been associated with heart block.(1-3) Fingolimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis is unknown but may involve the reduction of lymphocyte migration into the central nervous system.(1-3)

CLINICAL EFFECTS: The heart rate lowering effect of fingolimod is biphasic with an initial decrease usually within 6 hours, followed by a second decrease 12 to 24 hours after the first dose. Symptomatic bradycardia and heart block, including third degree block, have been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsades de pointes. There is no consistent signal of increased incidence of QTc outliers, either absolute or change from baseline, associated with fingolimod treatment.(1-3)

PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to fingolimod initiation, factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to fingolimod. The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of the 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).(4)

PATIENT MANAGEMENT: Patients with a baseline QTc interval greater than or equal to 500 milliseconds should not be started on fingolimod. Patients with pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, or a prolonged QTc interval prior to fingolimod initiation should receive cardiologist consultation to evaluate the risks of fingolimod therapy. In all patients, first dose monitoring is recommended to monitor for bradycardia for the first 6 hours. Check blood pressure and pulse hourly. ECG monitoring is recommended prior to dosing and at the end of the observation period. US monitoring recommendations include additional monitoring for the following patients:(1) If heart rate (HR) is less than 45 beats per minute (bpm), the heart rate 6 hours postdose is at the lowest value postdose, or if the ECG shows new onset of second degree or higher AV block at the end of the monitoring period, then monitoring should continue until the finding has resolved. Continuous overnight ECG monitoring is recommended in patients requiring pharmacologic intervention for symptomatic bradycardia, some preexisting heart and cerebrovascular conditions, prolonged QTc before dosing or during 6 hours observation, concurrent therapy with QT prolonging drugs, or concurrent therapy with drugs that slow heart rate or AV conduction. Consult the prescribing information for full monitoring recommendations. United Kingdom recommendations:(3) Obtain a 12-lead ECG prior to initiating fingolimod therapy. Consult a cardiologist for pretreatment risk-benefit assessment if patient has a resting heart rate less than 55 bpm, history of syncope, second degree or greater AV block, sick-sinus syndrome, concurrent therapy with beta-blockers, Class Ia, or Class III antiarrhythmics, heart failure or other significant cardiovascular disease. Perform continuous ECG monitoring, measure blood pressure and heart rate every hour, and perform a 12-lead ECG 6 hours after the first dose. Monitoring should be extended beyond 6 hours if symptomatic bradycardia or new onset of second degree AV block, Mobitz Type II or third degree AV block has occurred at any time during the monitoring period. If heart rate 6 hours after the first dose is less than 40 bpm, has decreased more than 20 bpm compared with baseline, or if a new onset second degree AV block, Mobitz Type I (Wenckebach) persists, then monitoring should also be continued. If fingolimod treatment is discontinued for more than two weeks, the effects on heart rate and conduction could recur. Thus, first dose monitoring precautions should be followed upon reintroduction of fingolimod. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: After the first dose of fingolimod, heart rate decrease may begin within an hour. Decline is usually maximal at approximately 6 hours followed by a second decrease 12 to 24 hours after the first dose. The second dose may further decrease heart rate, but the magnitude of change is smaller than the first dose. With continued, chronic dosing, heart rate gradually returns to baseline in about one month.(1,2) In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at steady-state, when a negative chronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of QTc, with the upper boundary of the 90% confidence interval (CI) of 14.0 msec. The cause of death in a patient who died within 24 hour after taking the first dose of fingolimod was not conclusive; however a link to fingolimod or a drug interaction with fingolimod could not be ruled out.(1)

Qt Prolonging Agents/Galantamine

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

MECHANISM OF ACTION: Galantamine may reduce heart rate by increasing acetylcholine in the heart and increasing vagal tone. Bradycardia has been associated with increased risk of QTc interval prolongation.(1) Concurrent use of galantamine with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(2)

CLINICAL EFFECTS: The use of galantamine in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(2)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age or when receiving concomitant treatment with an inhibitor of CYP3A4.(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 torsade 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 UK manufacturer of galantamine states that it should be used with caution in patients treated with drugs that affect the QTc interval.(2) If concurrent therapy is warranted, monitor ECG more frequently and consider obtaining serum calcium, magnesium, and potassium levels at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Therapeutic doses of galantamine have been reported to cause QTc prolongation in patients.(2) An 85 year old male with dementia was restarted on galantamine 8 mg daily after a 2-week treatment interruption due to a syncopal episode that occurred 3 months previously. During his prior syncopal episode, he was hypotensive and bradycardic, but QTc interval was normal. After restarting galantamine, he was found to be hypotension and bradycardiac again, and QTc interval was significantly prolonged to 503 msec, over 60 msec longer than when he was off galantamine. Galantamine was discontinued and his QTc interval returned to baseline.(4) A 47 year old schizophrenic male experienced prolongation of the QTc interval to 518 msec after galantamine was increased from 8 mg daily to 12 mg daily. Although he was also on quetiapine and metoprolol, he had been stable on his other medications. His QTc interval normalized after galantamine was stopped.(5) The European pharmacovigilance (Eudravigilance) database contains 14 reports of torsades de pointe in patients on galantamine as of October 2019.(1) A pharmacovigilance study based on the FDA Adverse Event Reporting System (FAERS) database found that, of a total of 33,626 cases of TdP/QT prolongation reported between January 2004 and September 2022, 54 cases occurred in patients on galantamine. The disproportionality analysis found a ROR = 5.12, 95% CI (3.92,6.68) and a PRR = 5.11, chi-square = 175.44.(6) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(7)

Qt Prolonging Agents/Mavorixafor

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

MECHANISM OF ACTION: Mavorixafor has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of mavorixafor with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade 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 torsade 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 mavorixafor states that concurrent use of mavorixafor with other agents known to prolong the QTc interval should be approached with caution. ECG monitoring is recommended prior to initiation, during concurrent therapy, and as clinically indicated with other agents known to prolong the QTc interval.(1) If QT prolongation occurs, a dose reduction or discontinuation of mavorixafor may be required.(1) If concurrent therapy is warranted, 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: In a thorough QT study, a dose of mavorixafor 800 mg increased the mean QTc 15.6 msec (upper 90% CI = 19.9 msec). The dose of mavorixafor was 2 times the recommended maximum daily dose.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Qt Prolonging Agents/Osilodrostat

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

MECHANISM OF ACTION: Osilodrostat has been shown to prolong the QT interval. Concurrent use with QT prolonging agents may result in additive effects on the QT interval.(1)

CLINICAL EFFECTS: The concurrent use of osilodrostat with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(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, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Use caution when using osilodrostat concurrently with other agents that can prolong the QT interval and consider more frequent ECG monitoring. A dose-dependent QT interval prolongation was noted in clinical studies. Prior to initiating therapy with osilodrostat, obtain a baseline ECG and monitor for QTc interval changes thereafter. Consider temporary discontinuation of therapy if the QTc interval increases > 480 msec. When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.(2)

DISCUSSION: QTc prolongation has been reported with osilodrostat. In a thorough QT study in 86 healthy patients, osilodrostat increased baseline QTcF by 1.73 msec at a 10 mg dose and 25.38 msec at a 150 mg dose (up to 2.5 times the maximum recommended dosage). The predicted mean placebo-corrected QTcF at the highest recommended dose in clinical practice (30 mg twice daily) was estimated as 5.3 msec.(1) In a clinical study, five patients (4%) were reported to have an event of QT prolongation, three patients (2%) had a QTcF increase of > 60 msec from baseline, and 18 patients (13%) had a new QTcF value of > 450 msec.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Qt Prolonging Agents/Ozanimod

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

MECHANISM OF ACTION: Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator. Initiation of ozanimod has a negative chronotropic effect leading to a mean decrease in heart rate of 13 beats per minute (bpm) after the first dose. The first dose has also been associated with heart block.(1,2) Ozanimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis is unknown but may involve the reduction of lymphocyte migration into the central nervous system.

CLINICAL EFFECTS: The initial heart rate lowering effect of ozanimod usually occurs within 5 hours. With continued up-titration, the maximal heart rate effect of ozanimod occurred on Day 8. Symptomatic bradycardia and heart block, including third degree block, have been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsades de pointes.(1,2)

PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to ozanimod initiation, factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to ozanimod.(1,2) The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, 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 the 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: Prior to initiation of ozanimod, obtain an ECG to determine if preexisting conduction abnormalities are present. Patients with preexisting cardiac conditions, significant QT prolongation (QTc >450 msec in males, >470 msec in females), concurrent Class Ia or Class III antiarrhythmics, or receiving concurrent treatment with a QT prolonging agent at the time ozanimod is initiated or resumed should be referred to a cardiologist.(1) The US recommendations state: Dose titration is recommended with initiation of ozanimod due to transient decrease in heart rate and AV conduction delays.(1) United Kingdom recommendations:(2) Due to the risk of transient decreases in HR with the initiation of ozanimod, first dose, 6-hour monitoring for signs and symptoms of symptomatic bradycardia is recommended in patients with resting HR <55 bpm, second-degree [Mobitz type I] AV block or a history of myocardial infarction or heart failure. Patients should be monitored with hourly pulse and blood pressure measurement during this 6-hour period. An ECG prior to and at the end of this 6-hour period is recommended. Additional monitoring after 6 hours is recommended in patients with: heart rate less than 45 bpm, heart rate at the lowest value post-dose (suggesting that the maximum decrease in HR may not have occurred yet), evidence of a new onset second-degree or higher AV block at the 6-hour post dose ECG, or QTc interval greater than 500 msec. In these cases, appropriate management should be initiated and observation continued until the symptoms/findings have resolved. Instruct patients to report any irregular heartbeat, dizziness, or fainting.(2,3)

DISCUSSION: After the first dose of ozanimod heart rate decline is usually maximal at approximately 5 hours, returning to baseline at 6 hours. With continued, chronic dosing, maximum heart rate effect occurred on day 8.(1,2)

Qt Prolonging Agents/Ponesimod

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

MECHANISM OF ACTION: Ponesimod is a sphingosine 1-phosphate (S1P) receptor 1 modulator. Initiation of ponesimod has a negative chronotropic effect leading to a mean decrease in heart rate of 6 beats per minute (bpm) after the first dose. The first dose has also been associated with heart block.(1)

CLINICAL EFFECTS: After a dose of ponesimod, a decrease in heart rate typically begins within an hour and reaches its nadir within 2-4 hours. The heart rate typically recovers to baseline levels 4-5 hours after administration. All patients recovered from bradycardia. The conduction abnormalities typically were transient, asymptomatic, and resolved within 24 hours. Second- and third-degree AV blocks were not reported. With up-titration after Day 1, the post-dose decrease in heart rate is less pronounced. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsades de pointes.(1,2)

PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to ponesimod initiation, factors associated with QTc prolongation, or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to ponesimod.(1) The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, 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 the 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: Prior to initiation of ponesimod, obtain an ECG to determine if preexisting conduction abnormalities are present. Ponesimod is generally not recommended in patients who are receiving concurrent treatment with a QT prolonging agent, anti-arrhythmic drugs, or drugs that may decrease heart rate. Consultation with a cardiologist is recommended.(1) In patients with heart rate (HR) less than 55 beats per minute (bpm), first- or second-degree AV block, or history of myocardial infarction or heart failure, monitor patients for 4 hours after the first dose for signs and symptoms of bradycardia with a minimum of hourly pulse and blood pressure measurements. Obtain an ECG in these patients prior to dosing and at the end of the 4-hour observation period.(1) Additional US monitoring recommendations include: If HR is less than 45 bpm, the heart rate 4 hours post-dose is at the lowest value post-dose or if the ECG shows new onset of second degree or higher AV block at the end of the monitoring period, then monitoring should continue until the finding has resolved. If patient requires treatment for symptomatic bradycardia, second-degree or higher AV block, or QTc interval greater than or equal to 500 msec, perform continuous overnight ECG monitoring and repeat the first dose monitoring strategy for the second dose of ponesimod. Consult the prescribing information for full monitoring recommendations. If fewer than 4 consecutive doses are missed during titration: resume treatment with the first missed titration dose and resume the titration schedule at that dose and titration day. If fewer than 4 consecutive doses are missed during maintenance: resume treatment with the maintenance dosage. If 4 or more consecutive daily doses are missed during treatment initiation or maintenance treatment, reinitiate Day 1 of the dose titration (new starter pack) and follow first-dose monitoring recommendations. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: After the first dose of ponesimod, heart rate decrease may begin within the first hour. Decline is usually maximal at approximately 4 hours. With continued, chronic dosing, post-dose decrease in heart rate is less pronounced. Heart rate gradually returns to baseline in about 4-5 hours.(1)

Qt Prolonging Agents/Siponimod

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

MECHANISM OF ACTION: Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Initiation of siponimod has a negative chronotropic effect. Siponimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.(1,2)

CLINICAL EFFECTS: The heart rate lowering effect of siponimod starts within an hour, and the Day 1 decline is maximal at approximately 3-4 hours. This leads to a mean decrease in heart rate of 5-6 beats per minute after the first dose. The first dose has also been associated with heart block. With continued up-titration, further heart rate decreases are seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 5-6. Symptomatic bradycardia has been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsades de pointes.(1)

PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to siponimod initiation, factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to siponimod. The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, 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 the 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: Prior to initiation of siponimod, obtain an ECG to determine if preexisting conduction abnormalities are present.(1) Advice from a cardiologist is recommended in patients with preexisting heart and cerebrovascular conditions, prolonged QTc interval before or during the 6 hour observation, risk factors for QT prolongation, concurrent therapy with QT prolonging drugs or drugs that slow the heart rate or AV conduction.(1) In patients with heart rate (HR) less than 55 beats per minute (bpm), first- or second-degree AV block, or history of myocardial infarction or heart failure, first dose monitoring is recommended with hourly pulse and blood pressure to monitor for bradycardia for the first 6 hours. ECG monitoring is recommended prior to dosing and at the end of the observation period.(1) Additional US monitoring recommendations include: If HR is less than 45 bpm, the heart rate 6 hours postdose is at the lowest value postdose or if the ECG shows new onset of second degree or higher AV block at the end of the monitoring period, then monitoring should continue until the finding has resolved. If patient requires treatment for symptomatic bradycardia, second-degree or higher AV block, or QTc interval greater than or equal to 500 msec, perform continuous overnight ECG monitoring. Repeat the first dose monitoring strategy for the second dose of siponimod. If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations. Patient will need to be observed in the doctor's office or other facility for at least 6 hours after the first dose and after reinitiation if treatment is interrupted or discontinued for certain periods. Consult the prescribing information for full monitoring recommendations. United Kingdom recommendations:(3) In certain patients, it is recommended that an electrocardiogram (ECG) is obtained prior to dosing and at the end of the observation period. If post-dose bradyarrhythmia or conduction-related symptoms occur or if ECG 6 hours post-dose shows new onset second-degree or higher AV block or QTc > 500 msec, appropriate management should be initiated and observation continued until the symptoms/findings have resolved. If pharmacological treatment is required, monitoring should be continued overnight and 6-hour monitoring should be repeated after the second dose. During the first 6 days of treatment, if a titration dose is missed on one day, treatment needs to be re-initiated with a new titration pack. If there is a missed dose after day 6 the prescribed dose should be taken at the next scheduled time; the next dose should not be doubled. If maintenance treatment is interrupted for 4 or more consecutive daily doses, siponimod needs to be re-initiated with a new titration pack.(1,2)

DISCUSSION: After the first dose of siponimod, heart rate decrease may begin within an hour. Decline is usually maximal at approximately 3-4 hours. With continued, chronic dosing, heart rate gradually returns to baseline in about 10 days.(1,2) A transient, dose-dependent decrease in heart rate was observed during the initial dosing phase of siponimod, which plateaued at doses greater than or equal to 5 mg, and bradyarrhythmic events (AV blocks and sinus pauses) were detected at a higher incidence under siponimod treatment than placebo. AV blocks and sinus pauses occurred above the recommended dose of 2 mg, with notably higher incidence under non-titrated conditions compared to dose titration conditions.(1)

Qt Prolonging Agents/Tolterodine

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

MECHANISM OF ACTION: Tolterodine has been observed to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: The concurrent use of tolterodine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1,2)

PREDISPOSING FACTORS: Patients who are CYP2D6 poor metabolizers may be at increased risk.(1,2) 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 tolterodine states concurrent use agents known to prolong the QT interval should be used with caution. Consider close observation in patients with a known history of QT prolongation or patients taking antiarrhythmic medications.(1,2) If concurrent therapy is warranted, 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: In a study of the effect of tolterodine immediate release tablets, the effect on the QT interval appeared greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day. Tolterodine 2 mg BID and tolterodine 4 mg BID increased the QTcF by 5.01 msec (0.28-9.74 msec) and 11.84 msec (7.11-16.58 msec), respectively. The change in QT interval was more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers (EMs).(1,2) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)

Qt Prolonging Agents/Triclabendazole

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

MECHANISM OF ACTION: Triclabendazole has been observed to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1) Triclabendazole is partially metabolized by CYP1A2. Ciprofloxacin, propafenone, and vemurafenib are CYP1A2 inhibitors and may inhibit the CYP1A2 mediated metabolism of triclabendazole.

CLINICAL EFFECTS: The concurrent use of triclabendazole with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(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) Hepatic impairment and concurrent use of CYP1A2 inhibitors may raise triclabendazole levels and increase the risk of QT prolongation.(1)

PATIENT MANAGEMENT: The manufacturer of triclabendazole states concurrent use with agents known to prolong the QT interval should be used with caution. Monitor ECG in patients with a history of QTc prolongation, symptoms of long QT interval, electrolyte imbalances, concurrent CYP1A2 inhibitors, or hepatic impairment. If signs of a cardiac arrhythmia develop, stop treatment with triclabendazole and monitor ECG.(1) If concurrent therapy is warranted, 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: In a thorough QT study, a dose-dependent prolongation in the QTc interval was observed with triclabendazole. The largest placebo-corrected mean increase in QTc was 9.2 msec (upper limit of confidence interval (UCI): 12.2 msec) following oral administration of 10 mg/kg triclabendazole twice daily (at the recommended dose), and the largest placebo-corrected mean increase in QTc was 21.7 msec (UCI: 24.7 msec) following oral administration of 10 mg/kg triclabendazole twice daily for 3 days (3 times the approved recommended dosing duration).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)

Qt Prolonging Agents/Tucidinostat

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

MECHANISM OF ACTION: Concurrent use of tucidinostat with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The use of tucidinostat in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade 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 torsade 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: Concurrent use of tucidinostat and other agents that are known to prolong the QTc interval should be used with caution. The manufacturer of tucidinostat recommends monitoring ECG and electrolytes every three weeks.(1) If the QTc interval exceeds 500 ms, tucidinostat should be suspended and the ECG should be monitored more frequently. After the QTc interval prolongation has resolved, tucidinostat may be restarted at a reduced dose.(1) If concurrent therapy is warranted, 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: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)

Qt Prolonging Agents/Zidesamtinib

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

MECHANISM OF ACTION: Zidesamtinib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of zidesamtinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and advanced age.(1,2) 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 torsade 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 zidesamtinib states that concurrent use of other drugs that are known to prolong the QTc interval should be monitored more frequently.(1) If concurrent use is warranted, monitor ECG and electrolytes when initiating zidesamtinib, during concurrent use, and as clinically indicated. Consider increasing the frequency of ECG and electrolyte monitoring. Withhold, then resume at same or reduced dose, or permanently discontinue zidesamtinib based on severity.(1) If QTc prolongation occurs, follow recommended dose modifications: - Grade 2 (QTc interval 481-500 ms): Withhold zidesamtinib until recovery to Grade <= 1 or baseline; correct electrolytes and/or change concomitant medications; and resume at same dose. - Grade 3 (QTc interval >= 501 ms or QTc interval increase of > 60 ms from baseline): Withhold zidesamtinib until recovery to Grade <= 1 or baseline; correct electrolytes and/or change concomitant medications; and resume at reduced dose. - Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia; or signs/symptoms of serious arrhythmia): Permanently discontinue zidesamtinib. Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Zidesamtinib 100 mg once daily increased the QTc by 13 ms (upper confidence interval = 19 ms) in patients with advanced ROS1-positive NSCLC and other advanced ROS1-positive solid tumors.(1) In a pooled safety study, QTc increase >60 ms occurred in 2% of patients and 0.2% of patients had an increase in QTcF > 500 ms.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Selected 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 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 antidepressants metabolized by this pathway. The tricyclic antidepressants, the SSRIs, and the SNRIs are the most sensitive to CYP2D6 inhibition and are addressed in separate monographs. Antidepressants which are metabolized by CYP2D6 but less susceptible to CYP2D6 inhibition are: mianserin, mirtazapine, nefazodone active metabolite (mCPP), and trazodone active metabolite (mCPP).(3)

CLINICAL EFFECTS: Concurrent use of bupropion and an 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 mianserin, mirtazepine, nefazodone, and trazodone.(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 an 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)

PATIENT MANAGEMENT: 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) 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)

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)

Serotonergic Agents That Prolong Qt/Gepirone

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

MECHANISM OF ACTION: Gepirone is a serotonin receptor agonist. Concurrent use with one or more serotonergic agents that prolong the QTc interval may increase serotonin effects. Concurrent use may also result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: Concurrent use of gepirone with other serotonergic agents that prolong the QTc interval may increase the risk of hypertensive crisis and serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1) Additive QTc prolongation may also occur, resulting in potentially life-threatening arrhythmias like torsades de pointes.(1)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2) 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: If concurrent use of gepirone with other serotonergic agents is clinically warranted, counsel the patient on the increased risk of serotonin syndrome and monitor for symptoms. If symptoms of serotonin syndrome develop, discontinue gepirone and/or the other serotonergic agents immediately and initiate supportive measures.(1) Gepirone should be used with caution and ECGs should be monitored more frequently when used with other agents known to prolong the QTc interval.(1) If QTcF is > 450 msec at baseline, do not initiate gepirone. If QTc increases to > 450 msec during treatment, monitor ECGs more frequently and do not increase the dose of gepirone.(1) If concurrent therapy is warranted, 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: Gepirone and its 3'-OH metabolite act as agonists at 5HT1A receptors. Use with other agents that also increase serotonin in the body must be undertaken with caution and monitored closely due to the risk of serotonin syndrome.(1) In a thorough QT study, 100 mg per day of immediate-release gepirone increased the mean QTc 18.4 msec (upper 90% CI = 22.7 msec) on day 1 and 16.1 msec (upper 90% CI = 20.7) on day 7. The dose of gepirone was 2-fold the exposure of the recommended maximum daily dose.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(4)

Serotonergic Agents/Centanafadine

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

MECHANISM OF ACTION: Centanafadine is a norepinephrine, dopamine, and serotonin reuptake inhibitor.(1) Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2)

CLINICAL EFFECTS: Concurrent use of centanafadine with other serotonergic agents may increase the risk of serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1,2)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2)

PATIENT MANAGEMENT: If concurrent use of centanafadine with other serotonergic agents is clinically warranted, counsel the patient on the increased risk of serotonin syndrome and monitor for symptoms. If symptoms of serotonin syndrome develop, discontinue centanafadine and/or the other serotonergic agents immediately and initiate supportive measures.(1)

DISCUSSION: Centanafadine inhibits reuptake of norepinephrine, dopamine, and serotonin.(1)

Trazodone (> 50 Mg)/Meperidine; Tramadol

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

MECHANISM OF ACTION: Tramadol inhibits the reuptake of serotonin.(1,2) Metabolism of trazodone leads to formation of a common active metabolite, m-chlorophenylpiperazine (mCPP) which is an agonist at a variety of serotonin receptors.(3-5) Both tramadol and mCPP are metabolized by CYP2D6.(1,3-5)

CLINICAL EFFECTS: Concurrent administration could increase the risk for serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(6)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of meperidine, tramadol or mCPP would be predicted to increase risk for serotonin toxicity. Concomitant therapy with other agents which increase brain serotonin concentrations may also increase risk.(1-3,6) Renal dysfunction and chronic use of meperidine would be expected to increase the risk for serotonin toxicity due to meperidine. Concomitant treatment with inhibitors of CYP2D6 (e.g. bupropion, cinacalcet, duloxetine, fluoxetine, paroxetine, quinidine, or systemic terbinafine) may also increase mCPP and tramadol concentrations, increasing risk for serotonin toxicity. Patients who are poor metabolizers at CYP2D6 would be expected to have higher tramadol and mCPP concentrations compared with extensive metabolizers.(1,3)

PATIENT MANAGEMENT: Assess patient for predisposing risk factors and monitor accordingly. Manufacturers of meperidine, tramadol and trazodone recommend careful monitoring for signs and symptoms of serotonin syndrome when a metabolic inhibitor or another serotoninergic agent is started, or when the dose of either agent is increased.(1-3)

DISCUSSION: Meperidine, tramadol, and trazodone have each been associated with serotonin syndrome when given concurrently with one or more serotoninergic agents.(1-3) MCPP has been associated with serotonin syndrome when used as a probe of central serotonin function in human investigational studies.(7) CYP3A4 converts trazodone to mCPP which is then converted to an inactive metabolite via CYP2D6.(3-4)

Trazodone (>= 100 Mg)/Possible Qt Prolonging Agents

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

MECHANISM OF ACTION: Concurrent use of trazodone with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: The use of trazodone in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(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.(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 US manufacturer of trazodone states that concurrent use with agents known to prolong the QT interval should be avoided.(1) If concurrent therapy is warranted, 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: Trazodone has been reported to prolong the QT interval.(1) A thorough QT study in 20 subjects evaluated the effects of trazodone at doses of 20 mg, 60 mg and 140 mg. There was no evidence of QTc prolongation at the lowest trazodone dose of 20mg (mean effect on QTc of 4.5 ms 95% CI 3.7-5.3 ms), but at 60 mg and 140 mg, there was a significant effect that exceeds the E14 FDA Guidelines threshold of prolonging the QT/QTc interval by more than 5 ms. The study found a dose-dependent effect on QTc prolongation starting at 60 mg with a mean effect on QTc of 12.3 ms (95% CI 11-13.6 ms) and increasing with a 140 mg dose to a mean effect on QTc of 19.8 ms (95% CI 17.6-22.1).(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)

Trazodone/Fluconazole (<= 150 Mg)

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

MECHANISM OF ACTION: Fluconazole may inhibit the metabolism of trazodone by CYP3A4.(1,2) Trazodone has been shown to prolong the QT interval.(1)

CLINICAL EFFECTS: Concurrent use of fluconazole may result in elevated levels of and adverse effects from trazodone,(1,2) including nausea, dizziness, hypotension, syncope, serotonin syndrome, and cardiac arrhythmias such as QT prolongation or torsades de pointes, which may be life-threatening.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: This interaction may be more severe with larger and/or routine doses of trazodone. 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: A lower dose of trazodone should be considered in patients receiving CYP3A4 inhibitors such as fluconazole (especially at dosages greater than 150 mg).(1,2) If concurrent therapy is warranted, 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. In addition to QT prolongation, 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: Trazodone has been shown to be metabolized by CYP3A4.(1) Fluconazole's inhibition of CYP3A4 is dose dependent, with dosages greater than 150 mg having the highest potential to inhibit CYP3A4.(4)

Trazodone/Selected Ssris; Snris

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

MECHANISM OF ACTION: Selected serotonin or serotonin-norepinephrine reuptake inhibitors (SSRIs or SNRIs) may impair the oxidative hepatic metabolism of trazodone. Trazodone is metabolized by CYP3A4 and its active metabolite meta-chlorophenylpiperazine (m-CPP) is metabolized by CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6. Desvenlafaxine, fluvoxamine, sertraline, and venlafaxine are weak inhibitors of CYP2D6. Fluvoxamine is also a weak inhibitor of CYP3A4.

CLINICAL EFFECTS: Concurrent administration of selected SSRIs or SNRIs with trazodone may result in an increase in serum levels, toxicities (e.g. torsades de pointes), and/or clinical effects of trazodone. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

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.(5) 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).(5)

PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of trazodone at the initiation of concurrent therapy with selected SSRIs or SNRIs. Plasma concentrations of trazodone should be monitored and the dosage adjusted accordingly. If the SSRI or SNRI is discontinued in a patient receiving trazodone, the dosage of trazodone may need to be adjusted. If concurrent therapy is warranted, 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. 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: There have been case reports of serotonin syndrome with trazodone and amitriptyline with lithium, and cyclobenzaprine (structurally related to the TCAs) with duloxetine.(3) The affinity of the different selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and tricyclics for CYP P-450 may vary.

There is no enhanced messaging for this drug.

• Congenital long QT syndrome
• Prolonged QT interval
• Serotonin syndrome
• Torsades de pointes

• 30 day risk period post-myocardial infarction
• Angle-closure glaucoma
• Hypokalemia
• Hypomagnesemia
• Priapism
• Risk of angle-closure glaucoma due to narrow angle of anterior chamber of eye
• Suicidal ideation

• Fibrosis of corpus cavernosum
• Hyponatremia
• Increased risk of bleeding
• Orthostatic hypotension
• Penile angulation
• Peyronie's disease
• SIADH syndrome

There is no enhanced messaging for this drug.

More Frequent

• Hypotension

Less Frequent

• Acute cognitive impairment
• Concentration difficulty
• Hypertension
• Syncope
• Tremor

Rare or Very Rare

• Abnormal hepatic function tests
• Achalasia of esophagus
• Agitation
• Akathisia
• Allergic dermatitis
• Alopecia
• Anemia
• Aphasia
• Apnea
• Appetite changes
• Ataxia
• Bradycardia
• Breast engorgement
• Cerebrovascular accident
• Chest pain
• Chills
• Cholestasis
• Chronic heart failure
• Excitement
• Flatulence
• Hallucinations
• Hematuria
• Hyperhidrosis
• Hypoesthesia
• Hypomania
• Increased urinary frequency
• Jaundice
• Leukopenia
• Libido changes
• Menstrual disorder
• Nasal congestion
• Paresthesia
• Priapism
• Prolonged QT interval
• Secondary angle-closure glaucoma
• Seizure disorder
• Serotonin syndrome
• Skin rash
• Suicidal ideation
• Tachycardia
• Torsades de pointes
• Urinary hesitancy

More Frequent

• Constipation
• Dizziness
• Drowsy
• Dysgeusia
• Fatigue
• Headache disorder
• Nausea
• Vomiting
• Xerostomia

Less Frequent

• Myalgia
• Weight gain

Rare or Very Rare

• Accidental fall
• Anticholinergic toxicity
• Blurred vision
• Diarrhea
• Edema
• Erectile dysfunction
• General weakness
• Muscle fasciculation
• Mydriasis
• Nightmares
• Sialorrhea
• Symptoms of anxiety
• Weight loss

No enhanced messaging available.

No enhanced messaging available.

Trazodone has been shown to be teratogenic in rats and rabbits when given at dosages 15-50 times the maximum human dosage. The drug also caused increased fetal resorption and other adverse fetal effects in rats when given at dosages approximately 30-50 times the suggested maximum human dosage. There are no adequate and controlled studies to date using trazodone in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Because trazodone is distributed into milk, the drug should be used with caution in nursing women.

No enhanced messaging available.