Norpace (disopyramide phosphate)

Dosage of disopyramide phosphate is expressed in terms of disopyramide. Dosage must be carefully adjusted according to individual requirements and response and the general condition and cardiovascular status of the patient. Dosage should be reduced in patients with moderate or severe renal insufficiency, hepatic insufficiency, cardiomyopathy, possible cardiac decompensation, acute myocardial infarction, and in patients weighing less than 50 kg.

The usual adult dosage of disopyramide is 400-800 mg daily, given in divided doses. The usual dosage of disopyramide in adults weighing more than 50 kg is 150 mg every 6 hours as conventional capsules or 300 mg every 12 hours as extended-release capsules. The usual adult dosage of disopyramide in adults weighing less than 50 kg is 100 mg every 6 hours as conventional capsules or 200 mg every 12 hours as extended-release capsules. When rapid control of ventricular arrhythmias is required, 300 mg of disopyramide (200 mg for patients weighing less than 50 kg) may be given initially and followed by 150 mg every 6 hours (as conventional capsules); the extended-release capsules should not be used initially when rapid control of ventricular arrhythmias is necessary. Therapeutic effects are usually attained 0.5-3 hours after administration of a 300-mg loading dose. If there is no therapeutic response and if no toxic effects occur within 6 hours after the initial 300-mg dose, 200-mg doses of the conventional capsules may be given every 6 hours. If there is no response to this dosage in 48 hours, the drug should be discontinued and alternative therapy initiated or the patient should be hospitalized, closely evaluated, and continuously monitored while the dosage of disopyramide is increased to 250 or 300 mg every 6 hours. In a few patients with severe refractory ventricular tachycardia, up to 400 mg every 6 hours has been required. In patients with cardiomyopathy or possible cardiac decompensation, the manufacturers state that an initial loading dose should not be given and an initial dosage of 100 mg every 6 hours should not be exceeded. Dosage should be carefully adjusted while the patient is closely monitored for hypotension and/or congestive heart failure.(See Cautions: Precautions and Contraindications.)

Based on theoretical considerations, the manufacturers suggest that when patients with normal renal function who have been receiving quinidine sulfate or procainamide are changed to disopyramide, the usual dosage of disopyramide (without an initial loading dose) should be initiated 6-12 hours after the last dose of quinidine sulfate or 3-6 hours after the last dose of procainamide. If withdrawal of quinidine or procainamide is likely to produce life-threatening arrhythmias, the patient should be hospitalized and closely monitored. When transferring a patient from conventional disopyramide capsules to the extended-release capsules, the maintenance schedule of the extended-release capsules may be started 6 hours after the last dose of the conventional capsules.

Optimum pediatric dosage of disopyramide has not been established; however, dosage recommendations have been made based on clinical experience. The total daily dose should be given in equally divided doses every 6 hours or at intervals according to individual requirements. Pediatric patients should be hospitalized during the initial treatment period, and dose titration should begin at the lower end of the recommended ranges; plasma drug concentrations and therapeutic response must be carefully monitored. For children unable to swallow the capsules, a suspension may be prepared extemporaneously from the conventional capsules. (See Chemistry and Stability: Stability.) The suggested pediatric dosage of disopyramide is 10-30 mg/kg daily for children younger than 1 year of age, 10-20 mg/kg daily for children 1-4 years of age, 10-15 mg/kg daily for children 4-12 years of age, and 6-15 mg/kg daily for children 12-18 years of age.

Disopyramide has been given IV+ in an initial dose of 1-2 mg/kg over a period of 1-5 minutes followed by a maintenance infusion of 20-40 mg/hour.

In patients with moderately impaired renal function (creatinine clearance greater than 40 mL/minute) or hepatic insufficiency, the usual dosage of disopyramide is 100 mg every 6 hours as conventional capsules or 200 mg every 12 hours as extended-release capsules. For rapid control of a ventricular arrhythmia in these patients, an initial 200-mg dose may be given (as conventional capsules).

In patients with severely impaired renal function (creatinine clearance of 40 mL/minute or less), the usual dosage of disopyramide (as conventional capsules) is 100 mg (with or without an initial 150-mg dose) given at the following approximate intervals depending on the patient's creatinine clearance:

Table 1.

Creatinine Clearance (mL/minute) Dosage Interval 30-40 every 8 h 15-30 every 12 h <15 every 24 h

The extended-release capsules are not recommended for use in patients with a creatinine clearance of 40 mL/minute or less.

Disopyramide phosphate is administered orally. ECG monitoring is recommended during disopyramide therapy, especially when the drug is given to patients with increased risk of adverse effects to the drug such as those with severe heart disease, hypertension, or hepatic or renal disease.

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.

Class I And Iii Antiarrhythmics/Halofantrine

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

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

CLINICAL EFFECTS: Concurrent use of halofantrine and Class I or III antiarrhythmics may pre-dispose patients to development of prolonged QTc interval.(1)

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

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

DISCUSSION: Because concurrent use may pre-dispose patients to prolongation of the QTc interval, the manufacturer of halofantrine states in the contraindications section of the prescribing information that halofantrine should not be used with Class I or III antiarrhythmics unless compelling clinical reasons exist.(1) 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.

Class Ia & Iii Antiarrhythmics/Selected Quinolones

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

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

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

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

PATIENT MANAGEMENT: Concurrent administration of sparfloxacin with Class Ia (disopyramide, moricizine, procainamide, quinidine) or Class III (amiodarone, bretylium, sotalol) antiarrhythmic agents is contraindicated by the manufacturer of sparfloxacin.(1) Concurrent administration of these agents with grepafloxacin is also contraindicated by the manufacturer of grepafloxacin unless appropriate cardiac monitoring can be assured.(2) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: The product information for grepafloxacin states that because prolongation of the QTc interval has been observed in healthy subjects receiving grepafloxacin, the concurrent administration of grepafloxacin with medications known to prolong the QTc interval is contraindicated unless appropriate cardiac monitoring can be assured.(2) Torsades de pointes has been reported in patients receiving sparfloxacin with disopyramide and amiodarone.(1)

Class Ia And Class Iii Antiarrhythmics/Dofetilide

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: Dofetilide 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 dofetilide with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: Renal impairment may increase risk for excessive QTc prolongation as dofetilide is primarily renally eliminated. To prevent increased serum levels and risk for ventricular arrhythmias, dofetilide must be dose adjusted for creatinine clearance < or = to 60 mL/min.(1) The risk of QT prolongation may be increased by reduced creatinine clearance, female gender, larger doses of sotalol, and a history of cardiomegaly or congestive heart failure.(1-2) Risk may also be increased in patients with cardiovascular disease (e.g. myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, 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: Class Ia or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to initiating dofetilide. Dofetilide has been administered to patients previously treated with amiodarone when amiodarone levels were below 0.3 mg/L or amiodarone had been withdrawn for at least 3 months.(1) The manufacturer of propafenone states that Class Ia or Class III antiarrhythmic agents should be withheld for at least 5 half-lives prior to initiating propafenone.(2) If concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Because of the risk of adverse effects, Class Ia or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to initiating dofetilide. Dofetilide has been administered to patients previously treated with amiodarone when amiodarone levels were below 0.3 mg/L or amiodarone had been withdrawn for at least three months.(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) 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.

Class Ia And Iii Antiarrhythmic Agents/Fingolimod

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: 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.(1-4)

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. 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 could not be ruled out.

PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, history of torsades de pointes, congenital long QT syndrome, 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, bradycardia, female gender, advanced age), or concomitant treatment with Class IA or III agents may increase risk for cardiovascular toxicity due to fingolimod. 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).(5)

PATIENT MANAGEMENT: US, Canada and UK manufacturer information states Class Ia or Class III antiarrhythmics are contraindicated and should not be co-administered with fingolimod.(1-4) 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. 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) 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) Antiarrhythmic agents linked to this monograph are disopyramide, procainamide, quinidine, amiodarone, dofetilide, dronedarone, ibutilide and sotalol.

Class Ia And Iii Antiarrhythmics/Ibutilide

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 use of ibutilide with Class IA or III antiarrhythmics may result in additive or synergistic effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of ibutilide with Class IA or III antiarrhythmics may result in life-threatening ventricular 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.(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 manufacturer of ibutilide states that Class IA or III antiarrhythmics should not be used concomitantly with ibutilide or within 4 hours post-infusion.(1) If concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor 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, Class IA and III antiarrhythmics were withheld for 5 half-lives prior to the administration of ibutilide and for 4 hours after.(1) In separate clinical trials, concomitant use of ibutilide with amiodarone resulted in significantly prolonged QTc intervals.(2,3) 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.

Disopyramide/Class Ia And Iii Antiarrhythmics

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: Disopyramide 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 disopyramide 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 may be increased by reduced creatinine clearance, female gender, larger doses of sotalol, and a history of cardiomegaly or congestive heart failure.(1) Risk may also be increased in patients with cardiovascular disease (e.g. myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, 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 Australian manufacturer of disopyramide states that the concurrent use of other antiarrhythmics, such as Class I, II, III, or IV is contraindicated.(1) If concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Because combinations of antiarrhythmics are not well researched and concurrent use may result in unpredictable effects, the Australian manufacturer of disopyramide states that the concurrent use of other antiarrhythmics, such as Class I, II, III, or IV is contraindicated.(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) 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.

Disopyramide/Class Ib, Ii, And Iv Antiarrhythmics

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: Disopyramide has been shown to prolong the QTc interval. Concurrent use with other agents that affect the heart rate and rhythm may result in unpredictable effect on heart rhythm.(1-2)

CLINICAL EFFECTS: The concurrent use of disopyramide with other agents that affect the heart rate and rhythm may result in in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of disopyramide states that concurrent use of disopyramide with antiarrhythmic agents should be reserved for patients with life-threatening arrhythmias who are demonstrably unresponsive to single-agent antiarrhythmic therapy.(3) The Australian manufacturer of disopyramide states that the concurrent use of other antiarrhythmics, such as Class I, II, III, or IV is contraindicated.(1) The US manufacturer of verapamil states that disopyramide should not be administered within 48 hours before or 24 hours after verapamil.(2) The Australian manufacturer of celiprolol states that the concurrent use of antiarrhythmics such as disopyramide is contraindicated during treatment with celiprolol (exception: intensive care).(4) If concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Because combinations of antiarrhythmics are not well researched and concurrent use may result in unpredictable effects, the Australian manufacturer of disopyramide states that the concurrent use of other antiarrhythmics, such as Class I, II, III, or IV is contraindicated.(1)

Disopyramide/Qt Prolonging Agents

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 use of disopyramide and agents known to prolong the QT interval may result in additive or synergistic effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent administration may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.

PREDISPOSING FACTORS: The risk of torsades 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 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 and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The Australian manufacturer of disopyramide states that concurrent use with agents liable to produce torsades de pointes, including tricyclic or tetracyclic antidepressants, erythromycin, vincamine, and sultopride, is contraindicated.(1) If alternatives are not available and concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor 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. 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) 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.

Disopyramide/Strong Cyp3a4 Inhibitors That Prolong Qt

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: Strong CYP3A4 inhibitors that prolong the QTc interval may inhibit the metabolism of disopyramide and result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong the QT interval with disopyramide may result in elevated levels of disopyramide and serious and/or life-threatening effects, including QT prolongation.(1,2)

PREDISPOSING FACTORS: Renal and hepatic impairment may increase risk for excessive QTc prolongation as disopyramide is eliminated renally and hepatically. To prevent increased serum levels and risk for ventricular arrhythmias, disopyramide must be dose adjusted in renal and hepatic insufficiency. 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 US labeling states coadministration of disopyramide with QT prolonging agents is not advised and coadministration of strong CYP3A4 inhibitors that prolong the QT interval with disopyramide should be avoided. If use of the combination is warranted, clinical monitoring is recommended.(1) The Australian manufacturer of disopyramide states that concurrent use with agents liable to produce torsades de pointes is contraindicated.(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: Strong CYP3A4 inhibitors may inhibit the metabolism and increase levels of disopyramide by inhibition of CYP3A4.(1,2) Selected CYP3A4 inhibitors that prolong QT linked to this monograph include: adagrasib, clarithromycin, levoketoconazole and lonafarnib.(4,5)

Disopyramide; Quinidine/Selected Azole Antifungals

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: Fluconazole,(1) itraconazole,(2) ketoconazole,(3) posaconazole,(4,5) and voriconazole (6) may inhibit the metabolism of disopyramide and quinidine by CYP3A4. Fluconazole, posaconazole, and voriconazole may also have additive effects on the QT interval.

CLINICAL EFFECTS: The concurrent use of fluconazole,(1) itraconazole,(2) ketoconazole,(3) posaconazole,(4,5) or voriconazole(6) with disopyramide or quinidine may result in elevated plasma levels of these antiarrhythmics, which may result in potentially serious or life-threatening adverse effects, including QT prolongation. Concurrent use of itraconazole and quinidine may also result in transient or permanent hearing loss.(2)

PREDISPOSING FACTORS: Renal and hepatic impairment decrease elimination of disopyramide and quinidine and may increase risk for excessive QTc prolongation. To prevent increased serum levels and risk for ventricular arrhythmias, disopyramide and quinidine must be dose adjusted in renal and hepatic insufficiency. 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.(7) 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).(7)

PATIENT MANAGEMENT: The manufacturers of fluconazole(1) and posaconazole(4,5) state that administration with agents metabolized by CYP3A4 that are known QT prolonging agents is contraindicated. The manufacturer of itraconazole(2) and ketoconazole(3) state that administration with disopyramide is contraindicated. The manufacturers of fluconazole,(1) itraconazole,(2) ketoconazole,(3) posaconazole,(4,5) and voriconazole(6) state that the concurrent use of quinidine is contraindicated. The US manufacturer of itraconazole states that disopyramide or quinidine should not be administered until at least 2 weeks after itraconazole treatment.(2) If concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Azole antifungals that inhibit CYP3A4 would be expected to increase levels of disopyramide.(1-5) Life threatening reactions have been reported with other CYP3A4 inhibitors such as clarithromycin and erythromycin.(8) Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have been reported in patients taking quinidine in combination with itraconazole and/or other CYP3A4 inhibitors. Transient or permanent hearing loss has been reported with itraconazole use, several of these reports involved concurrent quinidine.(2) Posaconazole has been shown to inhibit CYP3A4.(4) Voriconazole has been shown to increase levels of sirolimus, which is metabolized by the same isoenzyme that quinidine is. Therefore, the manufacturer of voriconazole states that the concurrent use of voriconazole and quinidine is contraindicated.(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.

Qt Prolonging Agents/Anagrelide

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 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 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 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.

Qt Prolonging Agents/Artemether-Lumefantrine

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

MECHANISM OF ACTION: Concurrent use of artemether-lumefantrine and agents known to prolong the QT interval may result in additive or synergistic effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent administration may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.

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.(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 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).(4)

PATIENT MANAGEMENT: The UK manufacturer of artemether-lumefantrine states that the use of artemether-lumefantrine in patients taking drugs that are known to prolong the QTc interval is contraindicated. These agents include class IA and III antiarrhythmics; neuroleptics; antidepressive agents; some macrolides, fluoroquinolones, imidazole and triazole antifungals; terfenadine; astemizole; and cisapride.(1) The US manufacturer of artemether-lumefantrine states that the use of artemether-lumefantrine should be avoided in patients taking drugs that are known to prolong the QTc interval. These agents include class IA and III antiarrhythmics; neuroleptics; antidepressive agents; some macrolides, fluoroquinolones, imidazole and triazole antifungals; terfenadine; astemizole; and cisapride.(2) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: 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/Bepridil

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: Bepridil 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 bepridil with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: Hypokalemia, the use of potassium wasting diuretics, and the presence of antecedent bradycardia may increase the risk of torsades de pointes.(1) 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, 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 inhibitors its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The manufacturer of bepridil states under contraindications that bepridil is contraindicated in patients taking other drugs that prolong the QT interval.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: 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) 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/Dronedarone

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 use of dronedarone and agents known to prolong the QT interval may result in additive or synergistic effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent administration may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.

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, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The US manufacturer of dronedarone states that the use of drugs or herbal products that are known to prolong the QTc interval is contraindicated. These agents include phenothiazine anti-psychotics, tricyclic antidepressants, certain oral macrolide antibiotics, and Class IA and III antiarrhythmics.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: 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) 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/Droperidol

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: Droperidol 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 droperidol with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: Congestive heart failure, bradycardia, use of a diuretic, cardiac hypertrophy, hypokalemia, hypomagnesemia, age over 65 years, alcohol abuse, and the use of agents such as benzodiazepines, volatile anesthetics, and intravenous opiate may predispose patients to the development of prolonged QT syndrome.(1) Risk may also be increased in patients with other cardiovascular diseases (e.g. myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypocalcemia, or female gender.(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 manufacturer of droperidol states under precautions drug interactions that drugs known to have the potential to prolong the QT interval should not be used together with droperidol.(1)

DISCUSSION: 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) 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/Levomethadyl

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: Levomethadyl has been shown to prolong the QTc interval and induce torsade de pointes. 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 levomethadyl with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: Congestive heart failure, bradycardia, diuretic use, cardiac hypertrophy, hypokalemia, or hypomagnesemia may increase the risk of torsade de pointes and/or sudden death.(1) The risk of QT prolongation may also be increased in patients with other cardiovascular diseases (e.g. myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypocalcemia, 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: The manufacturer of levomethadyl states under contraindications that levomethadyl is contraindicated in patients being treated concomitantly with other drug products known to prolong the QT interval.(1)

DISCUSSION: 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) 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/Sertindole

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: Sertindole 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 sertindole 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.(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 manufacturer of sertindole states that sertindole is contraindicated in patients receiving drugs known to prolong the QT interval.(1)

DISCUSSION: 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)

Selected Antiarrhythmics/Pimozide

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 use may possibly result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use may result in prolongation of the QTc interval, which may result in potentially life-threatening arrhythmias.(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: Concurrent therapy with pimozide and Class IA and III antiarrhythmics should be avoided. The manufacturer of pimozide states that concurrent therapy with agents that prolong the QTc interval is contraindicated.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Pimozide has been shown to prolong the QTc interval. Therefore, the manufacturer of pimozide states that concurrent therapy with agents that prolong the QTc interval is contraindicated because of the risk of additive effects on the QTc interval.(1) No other clinical documentation is available. 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.

Selected Antiarrhythmics/Quinidine

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: Amiodarone inhibits quinidine metabolism via CYP3A4, leading to increased serum levels of quinidine.(2) In addition to additive or synergistic effects on the QTc interval, quinidine may inhibit CYP2D6-mediated hydroxylation of propafenone, which results in decreased propafenone clearance.(16,17) Concurrent use may result in additive or synergistic effects on the QT interval.

CLINICAL EFFECTS: Concurrent amiodarone may result in an increase in the pharmacologic effects of quinidine due to elevated serum levels. The QTc interval may be prolonged and result in life-threatening arrhythmias, including torsades de pointes. Concurrent quinidine may result in elevated levels and effects of propafenone.(16,17) Concurrent use of quinidine and other antiarrhythmics may result in additive QT prolongation and torsades de pointes.

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(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 increased 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) The effects of quinidine on propafenone levels may not be clinically significant in poor metabolizers(17) because poor metabolizers have a genetically-determined lack of the isoenzyme inhibited by quinidine.(18)

PATIENT MANAGEMENT: The Australian manufacturer of amiodarone states that concurrent use of agents known to cause torsades de pointes, such as quinidine, is contraindicated.(3) The US manufacturer of amiodarone states that the concurrent use of QT prolonging drugs should be avoided.(4) If concurrent therapy is warranted, patients should be monitored for increased quinidine levels and signs of quinidine toxicity. Cardiac function should also be monitored. The dosage of quinidine may need to be adjusted. The US manufacturer of amiodarone recommends that the dosage of quinidine be reduced by one-third during concurrent amiodarone.(4) One study recommends that the dosage of quinidine be reduced by 30-50% when amiodarone is added to therapy.(2) The Australian manufacturer of disopyramide states that the concurrent use of other antiarrhythmics, such as Class I, II, III, or IV is contraindicated.(11) The manufacturer of dofetilide states that Class I or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to initiating dofetilide. Dofetilide has been administered to patients previously treated with amiodarone when amiodarone levels were below 0.3 mg/L or amiodarone had been withdrawn for at least 3 months.(12) The manufacturer of ibutilide states that Class IA or III antiarrhythmics should not be used concomitantly with ibutilide or within 4 hours post-infusion.(13) The manufacturer of propafenone states that concurrent use of Class IA and III Antiarrhythmics is not recommended and these agents should be withheld for at least 5 half-lives prior to dosing with propafenone.(16) If alternatives are not available and concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In patients receiving concurrent amiodarone and quinidine, elevated serum levels and prolonged QT interval have been reported.(1,5-9) In a study in 11 patients, the addition of amiodarone to quinidine therapy resulted in an increase in quinidine levels by 32% and quinidine toxicity in seven patients. The increase in quinidine levels was seen as early as 24 hours after the addition of amiodarone.(2) Because combinations of antiarrhythmics are not well researched and concurrent use may result in unpredictable effects, the Australian manufacturer of disopyramide states that the concurrent use of other antiarrhythmics, such as quinidine, is contraindicated.(11) Because of the risk of adverse effects, the manufacturer of dofetilide states that Class I or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to initiating dofetilide.(12) In clinical trials, Class IA and III antiarrhythmics were withheld for 5 half-lives prior to the administration of ibutilide and for 4 hours after.(13) In separate clinical trials, concomitant use of ibutilide with amiodarone resulted in significantly prolonged QTc intervals.(14,15) In a study in 11 patients with frequent ventricular arrhythmias who had not responded to treatment with quinidine sulfate alone, the addition of propafenone resulted in a significantly greater mean suppression suppression of baseline premature ventricular contractions (PVCs) than quinidine alone. Patients on propafenone alone required a higher dose to achieve significant suppression of PVCs when compared to concurrent quinidine and propafenone. It was not determined if this suppression was a result of changes in the propafenone plasma concentration or a synergistic effect of the two antiarrhythmics.(19) In another study in seven extensive metabolizer prototypes, the addition quinidine to propafenone resulted in a more than 2-fold increase in the steady-state propafenone plasma concentration, a decrease in the 5-hydroxypropafenone concentration and a reduction in the oral clearance of propafenone. In the same study, two patients who were found to be poor metabolizer phenotypes showed no change in the plasma concentrations of propafenone or its active metabolite with concomitant quinidine administration.(17) Quinidine, at a low dose, may improve efficacy of propafenone by inhibition of CYP P-450-2D6 isozyme. Propafenone 300 mg to 450 mg/day was administered to 60 patients with history of paroxysmal atrial fibrillation for a period of eight weeks resulting in 62% symptomatically controlled. Nineteen refractory patients were randomized in a double-blind fashion to receive either a higher dose of propafenone (450 to 675 mg/d) or standard propafenone dose plus low-dose quinidine (150 mg/d). After the eight week study period, serum levels recorded propafenone levels at 259 and 336 mg/d, respectively, not found to be significantly different. However, the higher dose of propafenone resulted in greater gastrointestinal side effects compared to the addition of low-dose quinidine combination.(20) 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.

Selected Antiarrhythmics/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 coadministered with ritonavir acts as a strong CYP3A4 inhibitor and may decrease the metabolism of some antiarrhythmics. Concurrent use of saquinavir/ritonavir and some antiarrhythmics may result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: Concurrent use of saquinavir/ritonavir with amiodarone, bepridil, disopyramide, flecainide, propafenone, or quinidine may result in elevated levels of and adverse events from (including life-threatening reactions such as QT prolongation or torsades de pointes) the antiarrhythmics.(1,2)

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

PATIENT MANAGEMENT: The US manufacturer of saquinavir mesylate states that the antiarrhythmics amiodarone, bepridil, disopyramide, flecainide, propafenone, and quinidine are contraindicated in patients receiving saquinavir/ritonavir.(1) If concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: The US manufacturer of saquinavir mesylate states that the antiarrhythmics amiodarone, bepridil, disopyramide, flecainide, propafenone, and quinidine are contraindicated in patients receiving saquinavir/ritonavir.(1)

Selected Class Ia & Iii Antiarrhythmics/Cisapride

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

MECHANISM OF ACTION: Concurrent administration of cisapride and Class IA or III antiarrhythmics may result in additive effects on the QT interval.(1)

CLINICAL EFFECTS: Concurrent administration of cisapride and Class IA or III antiarrhythmics may result in prolongation of the QT interval, which may result in potentially life-threatening arrhythmias.(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.(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 US manufacturer of cisapride states that cisapride should not be concomitantly administered with agents known to prolong the QT interval such as the Class IA and Class III antiarrhythmics.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: The manufacturer of cisapride states that QT prolongation, torsades de pointes (sometimes with syncope), cardiac arrest, and sudden death have been reported in patients who were not taking agents known to increase cisapride levels. Some of these patients were taking agents known to prolong the QT interval, such as the Class IA and Class III antiarrhythmics.(1) Class I antiarrhythmics known to prolong the QT interval are disopyramide, encainide, flecainide, procainamide, propafenone, and quinidine. Class III antiarrhythmics known to prolong the QT interval are amiodarone and sotalol. In clinical studies, gastric emptying significantly increased with the combination disopyramide (100mg t.i.d.) and cisapride (2.5mg t.i.d.), which resulted in a two-fold increase in the absorption rate constant of disopyramide compared to disopyramide monotherapy. In addition, the lag time of disopyramide decreased and was two-fold shorter.(2) 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.

Selected Class Ia And Iii Antiarrhythmics/Propafenone

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 use of propafenone with other Class IA or III antiarrhythmics may result in additive or synergistic effects on the QTc interval.(1) In addition to additive or synergistic effects on the QTc interval, concurrent amiodarone and propafenone may affect conduction and repolarization.(1)

CLINICAL EFFECTS: Concurrent use of propafenone with other Class IA and III antiarrhythmics may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias. In addition to these effects, concurrent amiodarone may affect conduction and repolarization.(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 increased 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 propafenone states that concurrent use of Class IA and III Antiarrhythmics is not recommended and these agents should be withheld for at least 5 half-lives prior to dosing with propafenone.(1) If alternatives are not available and concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Two studies evaluated the safety of adding ibutilide to propafenone for cardioversion. Although positive clinical results were observed, ten patients reported significant bradycardia and one patient experienced torsades de pointes.(4,5) A study assessed the use of propafenone in patients with amiodarone-resistant ventricular tachycardia. Two cases reported suppressed ventricular tachycardia after the addition of propafenone to amiodarone. Four cases reported worsening of spontaneous tachycardia with combined administration, and one case degenerated to ventricular fibrillation. The combination may be useful but is often associated with undesirable, significant side-effects. The combination may be limited to patients without severely depressed left ventricular function and a reduced probability of inducing ventricular tachycardia.(6)

Selected Qt Prolonging Agents/Ziprasidone

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: Ziprasidone 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 ziprasidone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: Bradycardia, hypokalemia, hypomagnesemia, and the presence of congenital prolongation of the QT interval may increase the risk of torsades de pointes and/or sudden death.(1) The risk of QT prolongation or torsade de pointes may also be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes), hypocalcemia, 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: 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, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: 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)

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

Anticholinergics That Prolong Qt/Clozapine

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

MECHANISM OF ACTION: Concurrent use of clozapine with anticholinergic agents that prolong the QTc interval may result in additive effects on the QTc interval and increased risk of anticholinergic toxicity.(1) In particular, the anticholinergic agents may compound the anticholinergic and anti-serotonergic effects of clozapine to inhibit gastrointestinal (GI) smooth muscle contraction, resulting in decreased peristalsis.(1-6)

CLINICAL EFFECTS: The use of clozapine in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1) Concurrent use of clozapine with anticholinergic agents may increase the risk of constipation (common) and serious bowel complications (uncommon), including complete bowel obstruction, fecal impaction, paralytic ileus and intestinal ischemia or infarction.(1-6)

PREDISPOSING FACTORS: The risk 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.(7) 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).(7) The risk for serious bowel complications is higher with increasing age and in patients on multiple anticholinergic agents.(5)

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

DISCUSSION: Treatment with clozapine has been associated with QT prolongation as well as ventricular arrhythmia, Torsades de Pointes, cardiac arrest, and sudden death.(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.(8) In a prospective cohort study of 26,720 schizophrenic patients in the Danish Central Psychiatric Research Registry, the odds ratio (OR) for ileus was 1.99 with clozapine and 1.48 with anticholinergics. The OR for fatal ileus was 6.73 with clozapine and 5.88 with anticholinergics. Use of anticholinergics with 1st generation antipsychotics (FGA) increased the risk of ileus compare to FGA alone, but this analysis was not done with clozapine.(5) A retrospective cohort study of 24,970 schizophrenic patients from the Taiwanese National Health Insurance Research Database found that the hazard ratio (HR) for clozapine-induced constipation increased from 1.64 when clozapine is used alone, to 2.15 when used concomitantly with anticholinergics. However, there was no significant difference in the HR for ileus when clozapine is used with and without anticholinergics (1.95 and 2.02, respectively).(6) In the French Pharmacovigilance Database, 7 of 38 cases of antipsychotic-associated ischemic colitis or intestinal necrosis involved clozapine, and 5 of these cases involved use of concomitant anticholinergic agents. Three patients died, one of whom was on concomitant anticholinergics.(3) In a case series, 4 of 9 cases of fatal clozapine-associated GI dysfunction involved concurrent anticholinergic agents.(4)

Anticholinergics/Solid Oral Potassium Capsules

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

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

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

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

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

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

Anticholinergics/Solid Oral Potassium Tablets

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

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

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

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

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

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

Anticholinergics; Opioids/Eluxadoline

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Class I & Class Iii Antiarrhythmics/Vernakalant

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

MECHANISM OF ACTION: Concurrent administration of vernakalant and Class I or Class III antiarrhythmics may result in additive effects.

CLINICAL EFFECTS: The concurrent administration of vernakalant with Class I or Class III antiarrhythmics may result in additive effects on the heart. Concurrent use of Class I antiarrhythmics may increase the risk of atrial flutter.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of vernakalant states that intravenous Class I or Class III antiarrhythmic agents should not be used within 4 hours before or after vernakalant administration. Use of vernakalant in patients who have received intravenous Class I or Class III antiarrhythmic agents in the previous 4-24 hours cannot be recommended.(1) The manufacturer of vernakalant states that the use of vernakalant in patients receiving oral Class I or Class III antiarrhythmic agents should be approached with caution. Resumption or initiation of oral Class I or Class III antiarrhythmic agents may be considered 2 hours after completion of vernakalant administration.(1)

DISCUSSION: Because of the risk of adverse effects, the manufacturer of vernakalant states that intravenous Class I or Class III antiarrhythmic agents should not be used within 4 hours before or after vernakalant administration. Resumption or initiation of oral Class I or Class III antiarrhythmic agents may be considered 2 hours after completion of vernakalant administration.(1)

Class Ia & Iii Antiarrhythmics/Eliglustat

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

MECHANISM OF ACTION: Concurrent use of eliglustat and Class IA or III antiarrhythmics may result in additive effects on the PR, QRS and QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of eliglustat and Class IA or III antiarrhythmics may result in QTc prolongation and life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: If the patient has hepatic impairment, eliglustat metabolism can be inhibited and result in increased levels and increased 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, advanced age, use of multiple medications, and/or in patients who are taking strong CYP3A4 inhibitors.(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: Systemic exposure to eliglustat is highly variable depending upon use of concurrent CYP2D6 and/or CYP3A4 inhibitors and the patient's CYP2D6 metabolizer status. For example, - Eliglustat maximum concentration (Cmax) and area-under-curve (AUC) increased 7.0-fold and 8.4-fold respectively in CYP2D6 extensive metabolizers (EM) treated with paroxetine 30 mg daily. - In simulated models, concomitant use of both a strong CYP3A4 inhibitor (e.g. ketoconazole) and a strong CYP2D6 inhibitor (e.g. paroxetine) may increase eliglustat Cmax and AUC 16.7-fold and 24-fold respectively in CYP2D6 EMs. Because high systemic concentrations of eliglustat prolong PR, QRS and QTc intervals and because systemic exposure to eliglustat in a particular individual may be very high, the use of eliglustat is not recommended in patients maintained on Class IA or III antiarrhythmics.(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: Eliglustat has been shown to prolong the PR, QRS and QTc interval in a dose dependent manner.(1)

Class Ia & Iii Antiarrhythmics/Telithromycin

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

MECHANISM OF ACTION: Telithromycin may prolong the QT interval.(1) Telithromycin may affect the absorption of sotalol.(1)

CLINICAL EFFECTS: Concurrent administration of telithromycin with a Class IA or III antiarrhythmic may result in prolongation of the QTc interval, which may result in potentially life-threatening arrhythmias.(1) Levels of sotalol may be reduced.(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 US manufacturer of telithromycin states that telithromycin should be avoided in patients taking Class IA or III antiarrhythmics.(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: Telithromycin may prolong the QT interval. Concurrent administration with a Class IA or III antiarrhythmic may result in prolongation of the QTc interval, which may result in potentially life-threatening arrhythmias, and should be avoided.(1) Telithromycin has been shown to decrease the maximum concentration (Cmax) and area-under-curve (AUC) of sotalol by 34% and 20%, respectively.(1)

Disopyramide/Ombitasvir-Paritaprevir-Ritonavir

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

MECHANISM OF ACTION: Ombitasvir-paritaprevir-ritonavir may inhibit the metabolism of disopyramide at CYP3A4.(1-3)

CLINICAL EFFECTS: Serum disopyramide concentrations may be increased, leading to cardiac arrhythmias including QT prolongation or torsades de pointes.

PREDISPOSING FACTORS: Renal and hepatic impairment may increase risk for excessive QTc prolongation as disopyramide is eliminated renally and hepatically. To prevent increased serum levels and risk for ventricular arrhythmias, disopyramide must be dose adjusted in renal and hepatic insufficiency.(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) 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: Patients receiving concurrent therapy with disopyramide and ombitasvir-paritaprevir-ritonavir should be monitored for changes in cardiac status. The dosage of disopyramide 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.

DISCUSSION: There have been case reports of life-threatening cardiac arrhythmias when other CYP3A4 inhibitors, clarithromycin and erythromycin, were added to disopyramide.(3)

Disopyramide/Possible 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 disopyramide and agents known to prolong the QT interval may result in additive or synergistic effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent administration may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.

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 Australian manufacturer of disopyramide states that concurrent use with agents liable to produce torsades de pointes, including tricyclic or tetracyclic antidepressants, erythromycin, vincamine, and sultopride, is contraindicated.(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 been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(3) 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.

Disopyramide/Selected Macrolides

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

MECHANISM OF ACTION: Macrolide antibiotics may inhibit the metabolism of disopyramide at CYP3A4.(1-6)

CLINICAL EFFECTS: Serum disopyramide concentrations may be increased, leading to cardiac arrhythmias including QT prolongation or torsades de pointes.

PREDISPOSING FACTORS: Renal and hepatic impairment may increase risk for excessive QTc prolongation as disopyramide is eliminated renally and hepatically. To prevent increased serum levels and risk for ventricular arrhythmias, disopyramide must be dose adjusted in renal and hepatic insufficiency. 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: Patients receiving concurrent therapy with disopyramide and a macrolide antibiotic that inhibits CYP3A4 should be monitored for changes in cardiac status. The dosage of disopyramide 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.

DISCUSSION: There have been three reports of life-threatening cardiac arrhythmias and one report of severe hypoglycemia and prolonged QTc interval when clarithromycin was added to disopyramide therapy.(1-3,7) There have been two reports of life-threatening cardiac arrhythmias when erythromycin was added to disopyramide.(4) The patients had been well controlled on disopyramide alone. In the cases of cardiac arrhythmias, increased disopyramide concentrations, prolonged QT interval and ventricular tachycardia were observed when the macrolide was added to their treatment. Erythromycin(5) and troleandomycin(6) have been shown to inhibit disopyramide metabolism in vitro. Azithromycin has been shown not to inhibit CYP3A4.(8)

Disopyramide/Selected Strong Cyp3a4 Inhibitor;Protease Inhib

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

MECHANISM OF ACTION: Strong CYP3A4 inhibitors and protease inhibitors may inhibit the metabolism of disopyramide by inhibition of CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors and protease inhibitors with disopyramide may result in elevated levels of disopyramide and serious and/or life-threatening effects, including QT prolongation.(1,2)

PREDISPOSING FACTORS: Renal and hepatic impairment may increase risk for excessive QTc prolongation as disopyramide is eliminated renally and hepatically. To prevent increased serum levels and risk for ventricular arrhythmias, disopyramide must be dose adjusted in renal and hepatic insufficiency. 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: Coadministration of strong CYP3A4 inhibitors and protease inhibitors with disopyramide should be avoided. If use of the combination is warranted, clinical monitoring is recommended.(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: Strong CYP3A4 inhibitors and protease inhibitors may inhibit the metabolism and increase levels of disopyramide by inhibition of CYP3A4.(1,2) Selected CYP3A4 inhibitors linked to this monograph include: atazanavir, boceprevir, darunavir, ensitrelvir, fosamprenavir, idelalisib, indinavir, josamycin, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, relacorilant, telaprevir, tipranavir, and tucatinib.(4,5)

Disopyramide; Ranolazine/Mavacamten

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

MECHANISM OF ACTION: Mavacamten has been associated with left ventricular systolic dysfunction and worsening heart failure symptoms in patients with obstructive hypertrophic cardiomyopathy. Concurrent use with disopyramide and ranolazine may have additive negative inotropic effects.(1)

CLINICAL EFFECTS: The concurrent use of mavacamten with other agents that have negative inotropic effects may result in left ventricular systolic dysfunction and worsening heart failure symptoms.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of mavacamten states that the concurrent use with disopyramide or ranolazine should be avoided.(1)

DISCUSSION: Concurrent use of mavacamten with disopyramide or ranolazine has not been studied. Patients on monotherapy with disopyramide or ranolazine were excluded from clinical trials.(1)

Qt Prolonging Agents/Dordaviprone

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

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)

Qt Prolonging Agents/Encorafenib

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

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

CLINICAL EFFECTS: The concurrent use of encorafenib 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 encorafenib with medications that prolong the QT interval.(1) Recommended dosage modifications for encorafenib and QTc prolongation adverse reactions include: - QTcF greater than 500 ms and less than or equal to 60 ms increase from baseline: Withhold encorafenib until QTcF less than or equal to 500 ms. Resume at reduced dose. If more than one recurrence, permanently discontinue encorafenib. - QTcF greater than 500 ms and greater than 60 ms increase from baseline: Permanently discontinue encorafenib.(1) See prescribing information for additional information regarding dose reductions.(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: Encorafenib has been associated with a dose-dependent QTc interval prolongation. Following administration of encorafenib in combination with binimetinib, the largest mean (90% CI) QTcF change from baseline was 18 ms (14-22 ms), based on central tendency analysis.(1) Following administration of encorafenib in combination with cetuximab and mFOLFOX6, an increase of QTcF >500 ms was measured in 4% (9/226) of patients. Following administration of encorafenib with cetuximab and FOLFIRI, an increase of QTcF >500 ms was measured in 1.5% (1/65) 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)

Qt Prolonging Agents/Entrectinib

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

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

CLINICAL EFFECTS: The concurrent use of entrectinib 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 entrectinib with medications that prolong the QT interval.(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. If QTc prolongation develops: ---Monitor and supplement electrolytes as clinically indicated ---Review and adjust concomitant QT prolonging medications ---Interrupt entrectinib therapy for QTc interval greater than 500 ms. ---Follow labeling recommendations regarding restarting entrectinib.(1) If torsade de pointes, polymorphic ventricular tachycardia, and/or signs/symptoms of serious arrhythmia occur, permanently discontinue entrectinib.(1)

DISCUSSION: In clinical trials, 3.1% of patients with at least one post-baseline ECG experienced QTcF prolongation of greater than 60 msec after starting entrectinib..(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/Fexinidazole

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

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)

Qt Prolonging Agents/Gadofosveset

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

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)

Qt Prolonging Agents/Gepotidacin

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

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)

Qt Prolonging Agents/Givinostat

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

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)

Qt Prolonging Agents/Glasdegib

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

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

CLINICAL EFFECTS: The concurrent use of glasdegib 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 glasdegib with medications that prolong the QT interval.(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. If QTc prolongation develops: ---Monitor and supplement electrolytes as clinically indicated ---Review and adjust concomitant QT prolonging medications ---Interrupt glasdegib therapy for QTc interval greater than 500 ms. ---Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation ---Follow labeling recommendations regarding restarting glasdegib.(1)

DISCUSSION: In a randomized, single-dose, double-blind, 4-way cross-over, placebo- and open-label moxifloxacin-controlled study in 36 healthy subjects, the largest placebo and baseline-adjusted QTc interval change was 8 msec (90% CI: 6-10 msec) with a single 150 mg dose of glasdegib (The 150 mg single dose was used to achieve therapeutic plasma concentrations). With two-fold therapeutic plasma concentrations (achieved with a 300 mg single dose), the QTc change was 13 msec (90% CI: 11-16 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/Hydroxyzine

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

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

CLINICAL EFFECTS: The concurrent use of hydroxyzine 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) Doses of hydroxyzine greater than 100 mg/day may also increase the risk.(1,2)

PATIENT MANAGEMENT: Concurrent use of hydroxyzine with agents known to prolong the QT interval is contraindicated in Canada(1,2) and the UK.(3) The US manufacturer states that concurrent use should be approached with caution.(4) 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 vitro data indicates that hydroxyzine blocks the hERG channel, which results in the potential risk of QT interval prolongation.(6) In a placebo controlled, non-thorough QT study, 10 patients in the placebo group (n=152) had a change in QT interval from baseline between 30 ms and 60 ms and one patient presented a change from baseline higher than 60 ms. In the hydroxyzine group (n=148), 14 subjects had a change in QT interval from baseline between 30 and 60 ms and were considered to have a potential risk factor for risk of QT interval prolongation and TdP due to relevant medical history, concomitant medication potentially associated with the induction of prolongation of QT interval, and/or polymedication.(6) Health Canada reviewed 61 cases of QT interval prolongation or torsades de pointes with hydroxyzine. In a majority of cases, patients had additional risk factors for QT prolongation. Three reports provided enough data for a more detailed review. Hydroxyzine was found to be either "possible" or "probably" contribution to QT prolongation/torsades in these reports.(1) The European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) reviewed 190 case reports found in a search of "torsade de pointes/QT prolongation with hydroxyzine". Forty-two non-fatality cases were subdivided into torsades (n=16), QT prolongation (n=21), and ventricular tachycardia (n=5). All included risk factors for QT interval prolongation and TdP (cardiac disorders, hypokalemia, long QT syndrome, bradycardia, concomitant drugs which are known to prolong the QT interval). Dosages ranged from <= 100 mg/day (n=10), > 100 mg/day to <=300 mg/day (n=4), > 300 mg/day (n=8), overdosages (n=11), and premedication (n=9). Twenty-one cases involving fatalities had at least one risk factor for QT prolongation. The PRAC concluded that post-marketing cases of QT interval prolongation, TdP and ventricular tachycardia confirm the findings of the hERG studies suggesting that hydroxyzine blocks hERG channels. No difference in the risk of QT interval prolongation could be observed based on the indication, age of the subject, or dose.(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/Inotuzumab Ozogamicin

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

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

CLINICAL EFFECTS: The concurrent use of inotuzumab ozogamicin 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: When possible, discontinue QT prolonging agents prior to therapy with inotuzumab ozogamicin or use alternative agents during inotuzumab ozogamicin therapy.(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.(1) Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.(1)

DISCUSSION: Inotuzumab ozogamicin was shown to prolong the QT interval in clinical trials. In the INO-VATE trial, 3% (4/162) of patients experienced an increase in QTc equal to or greater than 60 msec. No patients has QTc values greater than 500 msec. Grade 2 QT prolongation was reported in 1% (2/164) patients. There were no reports of Grade 3 QT prolongation or Torsade de Pointes.(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/Ivabradine

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

MECHANISM OF ACTION: QT prolongation may be exacerbated by ivabradine-induced reduction in heart rate.(1)

CLINICAL EFFECTS: Concurrent use of ivabradine and agents known to prolong the QT interval may exacerbate QT prolongation.(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.(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, AU, and Canadian manufacturer of ivabradine states that concurrent use with cardiovascular and non-cardiovascular QT prolonging agents should be avoided.(1,4,5) The Canadian manufacturer states that if concurrent therapy is deemed necessary, close cardiac monitoring (12-lead ECG) is required. Depending on the ECG results, ivabradine dosing may need to be decreased or stopped.(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: 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)

Qt Prolonging Agents/Ivosidenib

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

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

CLINICAL EFFECTS: The concurrent use of ivosidenib 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 ivosidenib with medications that prolong the QT interval.(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. If QTc prolongation develops: ---Monitor and supplement electrolytes as clinically indicated ---Review and adjust concomitant QT prolonging medications ---Interrupt ivosidenib therapy ---Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation ---Follow labeling recommendations regarding restarting ivosidenib.(1)

DISCUSSION: In clinical trials of ivosidenib, 9% of patients experienced a QTc interval greater than 500 msec and 14% of patients had an increased from baseline QTc interval of greater than 60 msec. Patients with a baseline QTc of equal to or greater than 450 msec without pre-existing bundle branch block, or with a history of long QT syndrome were excluded from this trial.(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/Lefamulin

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

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

CLINICAL EFFECTS: The concurrent use of lefamulin 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 lefamulin with medications that prolong the QT interval.(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.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a thorough QT study, intravenous lefamulin increased the QTcF 13.6 msec (90% CI = 15.5 msec) and oral lefamulin increased the QTcF by 9.3 msec (90% CI = 10.9 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/Levomepromazine

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

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)

Qt Prolonging Agents/Lofexidine

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

MECHANISM OF ACTION: Lofexidine 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.(1,2)

CLINICAL EFFECTS: Concurrent use of lofexidine and agents known to prolong the QT interval may exacerbate QT prolongation.(1,2)

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,(3) renal impairment, and/or hepatic impairment.(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).(3)

PATIENT MANAGEMENT: The UK manufacturer of lofexidine states that concurrent use of lofexidine and QT prolonging agents should be avoided.(1) The US manufacturer states that ECGs should be monitored in patients receiving concurrent therapy with lofexidine and agents that are known to prolong the QT interval.(2) 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: In a study of healthy volunteers, lofexidine 1.44 mg to 1.8 mg had a change from baseline in QTc of 14.4 msec and 13.6 msec, respectively.(2) In a dose response study, lofexidine had a mean QTc prolongation of 7.3 msec and 9.3 msec at doses of 2.16 mg/day and 2.88 mg/day, respectively.(2) 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)

Qt Prolonging Agents/Macimorelin

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

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

CLINICAL EFFECTS: The concurrent use of macimorelin 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 macimorelin with medications that prolong the QT interval.(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: In a thorough QT study in 60 healthy subjects, a supra-therapeutic dose of macimorelin (2mg/kg, 4 times the recommended dosage) produced a mean change in QTc of 9.6 msec (upper 95% CI of 11.4 msec). Similar effects were seen in a single-ascending dose study which examined dosages of 1.5 mg/kg, 1 mg/kg, and 2 mg/kg, suggesting an absence of dose-dependent changes.(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/Osimertinib

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

MECHANISM OF ACTION: Osimertinib 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 osimertinib 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: Osimertinib prolongs the QT interval. Premarket clinical trials excluded patients with a baseline QTc > or = 470 msec. In these trials 11 patients (2.7%) had increase in QTc greater than 60 msec.(1) Manufacturer recommendations: when feasible, avoid concurrent administrations of osimertinib with drugs known to prolong the QTc interval. Conduct baseline and periodic monitoring with ECGs in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities (e.g. serum calcium, magnesium, and potassium), or those taking medications known to prolong the QT interval.(1) Dose adjustments (1): - If QTc is greater than 500 msec on at least 2 separate ECGs, withhold osimertinib until QTc is < 481 msec or recovery to baseline (if baseline QTc was greater than or equal to 481 msec), then resume osimertinib at 40 mg per day. - For QTc prolongation with signs or symptoms of life threatening arrhythmia, permanently discontinue osimertinib. 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: 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 osimertinib, QTc prolongation was identified in 4 (25%) with 1 (25%) having Grade 1 (QTc 450-480 ms) and 1 (25%) having Grade 2 (QTc 480-500 ms). Grade 3 events occurred in 1 (25%) having QTc greater than or equal to 500 ms and 1 (25%) having QTc change greater than or equal to 60 ms. No patients had ventricular tachycardia, sudden cardiac death, or TdP.(4) In clinical studies of 1813 patients treated with osimertinib monotherapy, 1.1% of patients were found to have a QTc interval greater than 500 ms and 4.3% of patients had an increase from baseline QTc > 60 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.(2)

Qt Prolonging Agents/Pacritinib

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

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)

Qt Prolonging Agents/Pimavanserin

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

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)

Qt Prolonging Agents/Ribociclib

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

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

CLINICAL EFFECTS: The concurrent use of ribociclib 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 concurrent use of ribociclib with agents known to prolong the QT interval.(1) If concurrent therapy is deemed medically necessary, monitor patients closely. Obtain serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities at the beginning of each ribociclib cycle. Monitor ECG at baseline, Day 14 of the first cycle, at the beginning of the second cycle, and as necessary. If a prolonged QTc is noted, refer to ribociclib prescribing information for current dose modification and management instructions. Ribociclib may need to be interrupted, reduced, or discontinued.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Ribociclib has been shown to prolong the QTc interval in a concentration-dependent manner. At steady state, the mean increase in QTc interval exceeded 20 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/Selpercatinib

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

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)

Qt Prolonging Agents/Toremifene

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

MECHANISM OF ACTION: Toremifene has been shown to prolong the QTc interval in a dose-related and concentration-related manner.(1) Concurrent use of toremifene and agents known to prolong the QT interval may result in additive or synergistic effects on the QTc interval.(1,2)

CLINICAL EFFECTS: Concurrent administration may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1,2)

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, 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 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).(4)

PATIENT MANAGEMENT: The US manufacturer of toremifene states that concurrent use should be avoided. If treatment with an agent known to prolong the QT interval is required, toremifene therapy should be interrupted. If it is not possible to interrupt toremifene therapy, patients should be closely monitored. Electrocardiograms (ECGs) should be obtained.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. The UK manufacturer of toremifene states that the use of other drugs that are known to prolong the QTc interval is contraindicated. These agents include class IA and III antiarrhythmics, astemizole, bepridil, cisapride, diphemanil, erythromycin IV, halofantrine, haloperidol, mizolastine, moxifloxacin, pentamidine, phenothiazines, pimozide, sertindole, terfenadine, and vincamine IV.(2)

DISCUSSION: 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/Trazodone (>= 100 Mg)

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)

Qt Prolonging Agents/Ziftomenib

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

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/Zuclopenthixol

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

MECHANISM OF ACTION: Zuclopenthixol prolongs the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1) Zuclopenthixol is partially metabolized by CYP2D6. Some QT prolonging agents such as quinidine are also CYP2D6 inhibitors and may inhibit metabolism of zuclopenthixol.

CLINICAL EFFECTS: The concurrent use of zuclopenthixol with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1) CYP2D6 inhibitors such as quinidine may increase zuclopenthixol concentrations resulting in zuclopenthixol toxicity.

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, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The UK manufacturer of zuclopenthixol states that the concurrent administration of other drugs that are known to prolong the QTc 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: 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)

Selected Antiarrhythmics/Elvitegravir-Cobicistat

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

MECHANISM OF ACTION: Cobicistat may inhibit the metabolism of amiodarone, disopyramide, flecainide, propafenone, and quinidine.(1,2)

CLINICAL EFFECTS: Concurrent use of cobicistat and amiodarone, disopyramide, flecainide, propafenone, or quinidine may result in elevated levels of these antiarrhythmics and serious and/or life-threatening effects including QT prolongation or 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.(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 concurrent use of cobicistat and amiodarone, disopyramide, flecainide, propafenone, or quinidine should be used with caution and clinical monitoring is recommended with concomitant use.(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: Cobicistat may inhibit the metabolism and increase levels of amiodarone, disopyramide, flecainide, propafenone, or quinidine.(1,2) Selected antiarrhythmics linked to this monograph include: ajmaline, amiodarone, bepridil, disopyramide, flecainide, propafenone, and quinidine.

Selected Antiarrhythmics/Quinupristin-Dalfopr; Pristinamycin

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

MECHANISM OF ACTION: Quinupristin-dalfopristin and pristinamycin may inhibit the metabolism of amiodarone, disopyramide, and quinidine at CYP3A4.(1)

CLINICAL EFFECTS: The concurrent administration of quinupristin-dalfopristin or pristinamycin with amiodarone, disopyramide, or quinidine may result in elevated levels of these agents, which may result in prolongation of the QTc interval and possibly life-threatening arrhythmias.(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 quinupristin-dalfopristin states that the concurrent administration of quinupristin-dalfopristin with agents that are known to be metabolized by CYP3A4 and to prolong the QTc interval, such as amiodarone, disopyramide, and quinidine, 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: Quinupristin-dalfopristin has been shown to inhibit CYP3A4. Because of the risk that elevated levels of agents that are known to prolong the QTc interval may result in potentially life-threatening arrhythmias, the manufacturer of quinupristin-dalfopristin states that the concurrent administration of quinupristin-dalfopristin with such agents that are also metabolized by CYP3A4 should be avoided.(1) Pristinamycin has been shown to inhibit CYP3A4.(3)

Selected Class Ia & Iii Antiarrhythmics/Selected Quinolones

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

MECHANISM OF ACTION: Unknown. Possibly additive or synergistic effects on the QTc interval.(1-7) Proposed mechanisms for this interaction may stem from quinolone inhibition of hepatic cytochromes and/or competitive inhibition of renal elimination via active tubular secretion.(2-7) Norfloxacin is a moderate CYP3A4 inhibitor. Amiodarone, disopyramide, and dronedarone are CYP3A4 substrates.

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

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

PATIENT MANAGEMENT: The manufacturers of gatifloxacin,(2) gemifloxacin,(3) lomefloxacin,(4), norfloxacin(5) and ofloxacin(6) state that these agents should be avoided in patients receiving Class IA and III antiarrhythmic agents. 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: Gatifloxacin,(2) gemifloxacin,(3) lomefloxacin,(4), norfloxacin(5) and ofloxacin(6) have the potential to prolong the QTc interval. Torsades de pointes has been reported during post-marketing surveillance in patients receiving lomefloxacin.(4) A pharmacokinetic and pharmacodynamic study evaluated the interaction between ofloxacin and procainamide. Nine healthy volunteers randomly received one dose of procainamide 1 G, including or excluding pretreatment with ofloxacin (400 mg b.i.d. for 5 doses). A 12-point EKG monitored for any pharmacodynamic abnormalities and blood urine samples evaluated for pharmacokinetic variations. The AUC and Cmax for procainamide were increased by 27% and 21% with clearance diminished by 22%.(7)

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

Class Ia & Iii Antiarrhythmics/Sunitinib

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

MECHANISM OF ACTION: Concurrent use of sunitinib and Class IA or III antiarrhythmics may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of sunitinib and Class IA or III antiarrhythmics may result in QTc prolongation and 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, advanced age, use of multiple medications, and/or in patients who are taking strong CYP P-450-3A4 inhibitors.(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: Use sunitinib with caution in patients maintained on Class IA or III antiarrhythmics.(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: Sunitinib has been shown to prolong the QT interval in a dose dependent manner. Torsade de Pointes has been observed in less than 0.1% of patients receiving sunitinib.(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 sunitinib, QTc prolongation was identified in 26 (19.4%) with 16 (61.5%) having Grade 1 (QTc 450-480 ms) and 6 (23.1%) having Grade 2 (QTc 480-500 ms). Grade 3 events occurred in 1 (3.8%) having QTc greater than or equal to 500 ms and 1 (3.8%) having QTc change greater than or equal to 60 ms. Ventricular tachycardia was seen in 1 (3.8%) of patients and 1 (3.8%) patient experienced sudden cardiac death.(3)

Class Ia & Iii Antiarrhythmics/Tolterodine

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

MECHANISM OF ACTION: Concurrent use of tolterodine and Class IA or III antiarrhythmics may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of tolterodine and Class IA or III antiarrhythmics may result in QTc prolongation and 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, congential long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, and/or patients who are poor CYP P-450-2D6 metabolizers.(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: Use tolterodine with caution in patients maintained on Class IA or III antiarrhythmics.(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: The effects of tolterodine on the QTc interval were studied in 45 healthy subjects. Effects were compared to moxifloxacin, a known QTc prolonging agent. Tolterodine's effect on the QTc interval correlated with tolterodine plasma concentration. There was a greater increase in QTc in patients who were CYP P-450-2D6 poor metabolizers. There has been no associated with tolterodine and torsades in the international post-marketing experience of Detrol or Detrol LA.(1)

Disopyramide/Selected Hydantoins

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

MECHANISM OF ACTION: The hepatic metabolism of disopyramide may be increased.

CLINICAL EFFECTS: The pharmacologic effects of disopyramide may be decreased while anticholinergic side effects associated with the metabolite of disopyramide may occur.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor serum disopyramide concentrations when starting or stopping phenytoin. Adjust the dose of disopyramide accordingly.

DISCUSSION: Administration of phenytoin to the therapeutic regimen of patients receiving disopyramide has been reported to produce a decrease in plasma disopyramide concentration, half-life and area under the serum concentration-time curve. Disopyramide concentration increases after discontinuing phenytoin. Coinciding with the decrease in disopyramide levels is an increase in the concentration of the mono-N-dealkyldisopyramide metabolite. The metabolite possess anticholinergic activity. Anticholinergic effects have been reported during concurrent administration of disopyramide and phenytoin.

Disopyramide; Mexiletine; Propafenone/Rifamycins

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

MECHANISM OF ACTION: Rifampin and other rifamycins may increase the hepatic metabolism of disopyramide,(1-2) mexiletine(3) and propafenone(4-6).

CLINICAL EFFECTS: Concurrent use of rifampin may result in decreased levels and effectiveness of disopyramide,(2) mexiletine(3) and propafenone(4-6).

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patient's cardiac function and serum disopyramide, mexiletine or propafenone levels. Adjust the dosage accordingly.

DISCUSSION: Coadministration of mexiletine and rifampin have been reported to decrease the elimination half-life and increase the nonrenal clearance of mexiletine.(3) In a study in six elderly subjects, pretreatment with rifampin (600 mg daily for 9 days) decreased the bioavailability of a single dose of oral propafenone (300 mg) by 86%. Maximum QRS prolongation after oral propafenone was decreased by 50%. There were no significant effects on intravenous propafenone.(5) In a study in six extensive CYP2D6 metabolizers and six poor CYP2D6 metabolizers, pretreatment with rifampin (600 mg daily for 9 days) decreased the bioavailability of a single dose of oral propafenone by 67% and by 41% in extensive and poor metabolizers, respectively. Maximum QRS prolongation after oral propafenone decreased by 38% and by 40% in extensive and poor metabolizers, respectively. There were no effects on intravenous propafenone.(6) During concomitant administration of disopyramide and rifampin to patients with tuberculosis, serum disopyramide concentrations decreased by approximately 50% while the concentration of an active metabolite of disopyramide increased.(1) Concurrent administration of disopyramide and rifampin to a 62-year-old patient produced subtherapeutic disopyramide levels and a failure in correcting the patient's arrhythmia. Five days after stopping rifampin, disopyramide levels increased and the arrhythmia was abolished.(2) Rifamycins linked to this monograph are rifabutin, rifampin and rifapentine.

Disopyramide; Propafenone/Strong Cyp3a4 Inducers

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

MECHANISM OF ACTION: Disopyramide and propafenone are partially metabolized by CYP3A4. Strong CYP3A4 inducers may increase the hepatic metabolism of disopyramide and propafenone(1-2).

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of disopyramide and propafenone(1-2).

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Monitor patient's cardiac function and serum disopyramide or propafenone levels. Adjust the dosage accordingly.(1)

DISCUSSION: In a study of 8 smokers and 8 non-smokers, phenobarbital (100 mg daily for 21 days) decreased single-dose disopyramide area-under-curve (AUC) and half life by 35%, and increased metabolic clearance by 120% in all subjects.(3) During concomitant administration of disopyramide and rifampin to patients with tuberculosis, serum disopyramide concentrations decreased by approximately 50% while the concentration of an active metabolite of disopyramide increased.(4) Concurrent administration of disopyramide and rifampin to a 62-year-old patient produced subtherapeutic disopyramide levels and a failure in correcting the patient's arrhythmia. Five days after stopping rifampin, disopyramide levels increased and the arrhythmia was abolished.(5) In a study in six elderly subjects, pretreatment with rifampin (600 mg daily for 9 days) decreased the bioavailability of a single dose of oral propafenone (300 mg) by 86%. Maximum QRS prolongation after oral propafenone was decreased by 50%. There were no significant effects on intravenous propafenone.(6) In a study in six extensive CYP2D6 metabolizers and six poor CYP2D6 metabolizers, pretreatment with rifampin (600 mg daily for 9 days) decreased the bioavailability of a single dose of oral propafenone by 67% and by 41% in extensive and poor metabolizers, respectively. Maximum QRS prolongation after oral propafenone decreased by 38% and by 40% in extensive and poor metabolizers, respectively. There were no effects on intravenous propafenone.(7) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, and St. John's wort.

Qt Prolonging Agents/Efavirenz

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

MECHANISM OF ACTION: Efavirenz 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 efavirenz 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) CYP2B6 genotype may also increase the risk of this interaction. Patients who are most susceptible to this interaction are patients who are CYP2B6 poor metabolizers with CYP2B6 *6/*6 allele.(3)

PATIENT MANAGEMENT: The US manufacturer of efavirenz states alternatives should be considered when concurrent administration with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes. Limited information is available on the potential pharmacodynamic interaction between efavirenz and drugs that prolong the QT interval; however, QT prolongation has been observed with efavirenz.(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: A thorough QT study was conducted in the general population in 120 healthy subjects receiving efavirenz 600 mg daily. Time-matched differences in QTc with efavirenz compared to placebo was evaluated on day 11, at 6 hours post dose. The mean change in QTc was 5.2 msec and no change in QTc was greater than 10 msec.(4) In addition to the thorough QT study, the effect of efavirenz on the QTc interval was evaluated in 58 healthy subjects based on CYP2B6 genotype. CYP2B6 polymorphism was evaluated for each patient and results were the following: 65% with *1/*1 or *1/*4 allele (wild-type metabolizers), 26% with *1/*6 allele (intermediate metabolizers) and 9% with *6/*6 allele (slow metabolizers). Subjects with 2 copies of the CYP2B6*6 allele had significantly higher efavirenz exposure at steady-state (p<0.05). At steady-state concentrations of efavirenz, patients with CYP2B6 *1/*1 or *1/*6 alleles had no change in the QTc interval (p>0.05). However, patients with CYP2B6 *6/*6 allele had an increase in QTc mean +/- SD from 406 +/- 16.4 to 423 +/- 11.8 msec (p=0.02).(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.(5)

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/Gilteritinib

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

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

CLINICAL EFFECTS: The concurrent use of gilteritinib 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.(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 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).(1)

PATIENT MANAGEMENT: 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. Prior to initiation of therapy with gilteritinib, obtain baseline ECG and on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. If QTc prolongation develops: ---Monitor and supplement electrolytes as clinically indicated ---Review and adjust concomitant QT prolonging medications For a QTc interval greater than 500 msec: ---Interrupt gilteritinib therapy ---Resume gilteritinib therapy at 80 mg when the QTc interval returns to within 30 msec of baseline or <= 480 msec. For QTc interval increased by > 30 msec on ECG on Day 8 of cycle 1: ---Confirm with ECG on Day 9 ---If confirmed, consider dose reduction to 80 mg.(2)

DISCUSSION: In the gilteritinib clinical trial, 1.4% of patients developed a QTc interval greater than 500 msec and 7% of patients had an increase QTc greater than 60 msec.(2) 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/Pitolisant

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

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

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

PREDISPOSING FACTORS: Patients who are CYP2D6 poor metabolizers or on concurrent use with CYP2D6 inhibitors are at increased risk for higher systemic exposure to pitolisant and may be at increased risk of QT prolongation.(1) 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: 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: In two dedicated QT prolongation studies, supra-therapeutic doses of pitolisant at 3-6 times the therapeutic dose (108-216 mg) were seen to cause mild to moderate QTc prolongation (10-13 ms). A study in patients who were CYP2D6 poor metabolizers had higher systemic exposure up to 3-fold compared to CYP2D6 extensive metabolizers.(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/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/Trazodone (< 100 Mg)

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)

Sodium Channel Blocker; Potassium Channel Blocker/Lacosamide

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

MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (sodium channel blockers and potassium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers and potassium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1)

DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) A case report of a 49 year old male with refractory complex partial and generalized seizures described the development of ventricular tachycardia four months after addition of lacosamide 400 mg/day to the existing regimen of carbamazepine, lamotrigine, clonazepam, and valproate. The patient's ECG showed first-degree AV block, posterior left fascicular block, and severe widening of the QRS complex, all of which resolved upon discontinuation of lacosamide.(2)

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• Acute decompensated heart failure
• Cardiogenic shock
• Congenital long QT syndrome
• Prolonged QT interval

• Angle-closure glaucoma
• Benign prostatic hyperplasia
• Cardiomyopathy
• Child-pugh class A hepatic impairment
• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Complete atrioventricular block
• Disease of liver
• Hyperkalemia
• Hypokalemia
• Hypotension
• Increased intraocular pressure after ocular procedure
• Myasthenia gravis
• Second degree atrioventricular heart block
• Urinary retention

• Atrial fibrillation
• Atrial flutter
• Chronic heart failure
• Hypoglycemic disorder
• Myocarditis

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More Frequent

• Dysuria

Less Frequent

• Acute cognitive impairment
• Body fluid retention
• Chest pain
• Chronic heart failure
• Hypotension
• Muscle weakness

Rare or Very Rare

• Aggravated glaucoma
• Agranulocytosis
• Depression
• Hypoglycemic disorder
• Jaundice
• Prolonged QT interval
• Torsades de pointes

Less Frequent

• Abdominal pain with cramps
• Abnormal sexual function
• Anorexia
• Anticholinergic toxicity
• Blurred vision
• Constipation
• Decreased sweating
• Erectile dysfunction
• Flatulence
• Increased urinary frequency
• Xerostomia

Rare or Very Rare

• Accidental fall

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In studies in rats, disopyramide dosages of 250 mg/kg daily (20 times the usual daily human dosage) have been associated with decreased numbers of implantation sites and decreased growth and survival of pups; this dosage also was associated with reduced weight gain and food consumption in the dams. In rabbits, disopyramide dosages of 60 mg/kg daily (5 or more times the usual daily human dosage) was associated with increased resorption rates; effects on implantation, pup growth, and survival were not evaluated. There are no adequate and controlled studies to date using disopyramide phosphate in pregnant women, and experience with the drug during pregnancy is limited. The possibility of fetal harm cannot be excluded. Disopyramide has been reported to stimulate contractions of the pregnant uterus. There has been one reported case of premature initiation of uterine contractions during the eighth month of pregnancy beginning 1 hour after administration of 300 mg of disopyramide and continuing for 24 hours until disopyramide was discontinued. Disopyramide phosphate should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. It is not known whether use of the drug during labor or delivery could have any immediate or delayed adverse effects on the mother or fetus, affect the duration of labor, or increase the likelihood of forceps delivery or other obstetric intervention.

Disopyramide is distributed into milk. Because of the potential for serious adverse effects in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

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