DOFETILIDE (dofetilide)

There are 25 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
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 unpredictable and/or additive effects, including 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.	NUEDEXTA, QUINIDINE GLUCONATE, QUINIDINE SULFATE
Pimozide/Selected 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: 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.	PIMOZIDE
Dofetilide/Verapamil 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 is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. Verapamil is believed to inhibit the cation transport system and thus may inhibit the active tubular secretion of dofetilide.(1) CLINICAL EFFECTS: The concurrent administration of dofetilide with verapamil may result in elevated levels and increased effects of dofetilide, including torsades de pointes.(1,2) 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 or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) PATIENT MANAGEMENT: The manufacturer of dofetilide states that the concurrent administration of dofetilide with verapamil is contraindicated. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting verapamil.(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: The concurrent administration of dofetilide and verapamil resulted in an increase in dofetilide peak plasma levels by 42%. Concurrent administration was also associated with a higher occurrence of torsades de pointes.(1) A study in twelve healthy subjects examined the effects of combination therapy with verapamil and dofetilide. Though no clinically adverse effects were observed, concurrent use of both drugs increased plasma concentration of dofetilide by 43%.(2)	TRANDOLAPRIL-VERAPAMIL ER, VERAPAMIL ER, VERAPAMIL ER PM, VERAPAMIL HCL, VERAPAMIL SR
Dofetilide/MATE Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The active tubular secretion of dofetilide is inhibited by renal cation transport inhibitors.(1) CLINICAL EFFECTS: The concurrent administration of dofetilide with renal cation transport inhibitors may result in elevated levels and increased effects of dofetilide including QT prolongation or 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 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 dofetilide states that the concurrent administration of dofetilide with renal cation transport inhibitors is contraindicated. The manufacturer suggests that agents that have no effect on dofetilide plasma levels, such as aluminum and magnesium hydroxide antacids, omeprazole, or ranitidine, be used as alternatives to cimetidine. If dofetilide is to be discontinued, a washout of at least 2 days is recommendation prior to starting cimetidine.(1) DISCUSSION: Dofetilide is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. Cimetidine is believed to inhibit the cation transport system.(1) The concurrent administration of dofetilide (500 mcg twice daily) with cimetidine (400 mg twice daily) resulted in an increase in dofetilide plasma levels by 58%. The concurrent administration of dofetilide (500 mcg single dose) with cimetidine (100 mg twice daily) resulted in an increase in dofetilide plasma levels by 13%.(1) Therefore, the manufacturer of dofetilide states that the concurrent administration of dofetilide and cimetidine is contraindicated. The manufacturer suggests that agents that have no effect on dofetilide plasma levels, such as aluminum and magnesium hydroxide antacids, omeprazole, or ranitidine, be used as alternatives to cimetidine.(1) MATE renal transport inhibitors include: cimetidine, pyrimethamine, risdiplam, and vandetanib.(3)	CAPRELSA, CIMETIDINE, DARAPRIM, EVRYSDI, PYRIMETHAMINE
Dofetilide/Trimethoprim SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The active tubular secretion of dofetilide is inhibited by trimethoprim.(1) CLINICAL EFFECTS: The concurrent administration of dofetilide with trimethoprim may result in elevated levels and increased effects of dofetilide, including QT prolongation or 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 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 dofetilide states that the concurrent administration of dofetilide with trimethoprim (alone or in combination with sulfamethoxazole) is contraindicated. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting trimethoprim.(1) DISCUSSION: Dofetilide is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. Trimethoprim is believed to inhibit the cation transport system. The concurrent administration of dofetilide (500 mcg twice daily) with trimethoprim-sulfamethoxazole (160 mg-800 mg twice daily) for four days resulted in an increase in dofetilide area-under-curve (AUC) and maximum concentration (Cmax) by 93% and 103%, respectively.(1) Therefore, the manufacturer of dofetilide states that the concurrent administration of dofetilide and trimethoprim is contraindicated.(1)	BACTRIM, BACTRIM DS, PRIMSOL, SULFAMETHOXAZOLE-TRIMETHOPRIM, SULFATRIM, TRIMETHOPRIM, TRIMETHOPRIM MICRONIZED
Dofetilide/Itraconazole; Ketoconazole(Oral) 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: Although dofetilide is primarily eliminated unchanged in the urine, a portion is metabolized via CYP3A4.(1) Systemic ketoconazole inhibits active renal tubular secretion of dofetilide via the cation transport system.(1) Itraconazole and ketoconazole are both strong inhibitors of CYP3A4.(2) Dofetilide is a Class III antiarrhythmic agent which must be initiated in the hospital due to the risk for serious ventricular arrhythmias including torsades de pointes. There is a linear relationship between dofetilide plasma concentration and QT prolongation.(1) CLINICAL EFFECTS: The concurrent administration of dofetilide with itraconazole(3) or ketoconazole(4) may result in elevated levels and increased effects of dofetilide, including prolongation of the QT interval and torsades de pointes. 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 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, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5) PATIENT MANAGEMENT: The concurrent use of dofetilide with either itraconazole(3) or ketoconazole(1,4) is contraindicated. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting azole therapy.(1) The concurrent use of dofetilide with itraconazole is contraindicated during and two weeks after itraconazole treatment.(3) 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 concurrent administration of dofetilide (500 mcg twice daily) with ketoconazole (400 mg daily) for seven days resulted in increases in the dofetilide maximum concentration (Cmax) and area-under-curve (AUC) by 53% and 41%, respectively, in males and by 97% and 69%, respectively, in females.(1)	ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KETOCONAZOLE, SPORANOX, TOLSURA
Dofetilide/Prochlorperazine SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The active tubular secretion of dofetilide may be inhibited by prochlorperazine.(1) CLINICAL EFFECTS: The concurrent administration of dofetilide with prochlorperazine may result in elevated levels and increased effects of dofetilide, including QT prolongation or 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 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 dofetilide states that prochlorperazine should not be used in patients on dofetilide. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting prochlorperazine.(1) DISCUSSION: Dofetilide is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. Prochlorperazine is believed to inhibit the cation transport system. Other agents that inhibit this system, including cimetidine, ketoconazole, trimethoprim, and verapamil, have been shown to increase dofetilide levels. Therefore, the manufacturer of dofetilide states that prochlorperazine should not be used in patients on dofetilide.(1)	COMPAZINE, COMPRO, PROCHLORPERAZINE, PROCHLORPERAZINE EDISYLATE, PROCHLORPERAZINE MALEATE
Dofetilide/Megestrol SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The active tubular secretion of dofetilide may be inhibited by megestrol.(1) CLINICAL EFFECTS: The concurrent administration of dofetilide with megestrol may result in elevated levels and increased effects of dofetilide, including QT prolongation or 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 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 dofetilide states that megestrol should not be used in patients on dofetilide. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting megestrol.(1) DISCUSSION: Dofetilide is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. Megestrol is believed to inhibit the cation transport system. Other agents that inhibit this system, including cimetidine, ketoconazole, trimethoprim, and verapamil, have been shown to increase dofetilide levels. Therefore, the manufacturer of dofetilide states that megestrol should not be used in patients on dofetilide.(1)	MEGESTROL ACETATE
Dofetilide/Class Ia And Class 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: 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.	AMIODARONE HCL, AMIODARONE HCL-D5W, BETAPACE, BETAPACE AF, DISOPYRAMIDE PHOSPHATE, FLECAINIDE ACETATE, MULTAQ, NEXTERONE, NORPACE, NORPACE CR, PACERONE, PROCAINAMIDE HCL, PROPAFENONE HCL, PROPAFENONE HCL ER, SOTALOL, SOTALOL AF, SOTALOL HCL, SOTYLIZE
Ziprasidone/Selected 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: Dofetilide, quinidine, sotalol and ziprasidone have been shown to prolong the QTc interval. The concurrent use of ziprasidone with these agents may result in additive effects on the QTc interval.(1) CLINICAL EFFECTS: The concurrent use of ziprasidone with dofetilide, quinidine, or sotalol may result in additive prolongation of the QTc interval and 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: The manufacturer of ziprasidone states under contraindications that ziprasidone should not be used with other drugs that prolong the QTc interval, including dofetilide, quinidine, or sotalol.(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: Ziprasidone has been shown to prolong the QTc interval in a dose-related fashion. Therefore, the manufacturer of ziprasidone states under contraindications that ziprasidone should not be used with other drugs that prolong the QTc interval, including dofetilide, quinidine, or sotalol.(1)	GEODON, ZIPRASIDONE HCL, ZIPRASIDONE MESYLATE
Dofetilide/Thiazide Diuretics 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: Thiazide diuretics may decrease the excretion of dofetilide and may decrease potassium levels.(1) CLINICAL EFFECTS: Concurrent use of dofetilide with a thiazide diuretic may result in elevated levels and clinical effects of dofetilide, as well as prolongation of the QT interval.(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 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, and 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 dofetilide states that the concurrent use of dofetilide with hydrochlorothiazide, alone or in combination with triamterene, is contraindicated.(1) Other thiazides should also be considered contraindicated as well. If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: In a study, hydrochlorothiazide (50 mg daily) alone or hydrochlorothiazide/triamterene (50 mg/100 mg daily) was administered with dofetilide (500 mcg twice daily) for 5 days following 2 days of diuretic use at half-dose. In patients receiving hydrochlorothiazide alone, the area-under-curve (AUC) and maximum concentration (Cmax) of dofetilide increased by 27% and by 21%, respectively. The pharmacodynamic effects of dofetilide increased by 197% (QTc increase over time) and by 95% (maximum QTc increase). In patients on combination hydrochlorothiazide/triamterene, dofetilide AUC and Cmax increased by 30% and by 16%, respectively. The pharmacodynamic effects of dofetilide increased by 190% (QTc increase over time) and by 84% (maximum QTc increase).(1) Dofetilide clearance was 16% lower in patients receiving thiazide diuretics.(1)	ACCURETIC, AMILORIDE-HYDROCHLOROTHIAZIDE, AMLODIPINE-VALSARTAN-HCTZ, ATACAND HCT, ATENOLOL-CHLORTHALIDONE, AVALIDE, BENAZEPRIL-HYDROCHLOROTHIAZIDE, BENICAR HCT, BISOPROLOL-HYDROCHLOROTHIAZIDE, CANDESARTAN-HYDROCHLOROTHIAZID, CAPTOPRIL-HYDROCHLOROTHIAZIDE, CHLOROTHIAZIDE, CHLOROTHIAZIDE SODIUM, CHLORTHALIDONE, DIOVAN HCT, DIURIL, EDARBYCLOR, ENALAPRIL-HYDROCHLOROTHIAZIDE, EXFORGE HCT, FOSINOPRIL-HYDROCHLOROTHIAZIDE, HEMICLOR, HYDROCHLOROTHIAZIDE, HYZAAR, INDAPAMIDE, INZIRQO, IRBESARTAN-HYDROCHLOROTHIAZIDE, LISINOPRIL-HYDROCHLOROTHIAZIDE, LOSARTAN-HYDROCHLOROTHIAZIDE, LOTENSIN HCT, METHYLDOPA-HYDROCHLOROTHIAZIDE, METOLAZONE, METOPROLOL-HYDROCHLOROTHIAZIDE, MICARDIS HCT, OLMESARTAN-AMLODIPINE-HCTZ, OLMESARTAN-HYDROCHLOROTHIAZIDE, PROPRANOLOL-HYDROCHLOROTHIAZID, QUINAPRIL-HYDROCHLOROTHIAZIDE, SPIRONOLACTONE-HCTZ, TELMISARTAN-HYDROCHLOROTHIAZID, TENORETIC 100, TENORETIC 50, THALITONE, TRIAMTERENE-HYDROCHLOROTHIAZID, TRIBENZOR, TRICHLORMETHIAZIDE, VALSARTAN-HYDROCHLOROTHIAZIDE, VASERETIC, ZESTORETIC
Droperidol/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: 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.	DROPERIDOL
Ibutilide/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: 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.	CORVERT, IBUTILIDE FUMARATE
Artemether-Lumefantrine/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 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)	COARTEM
Fingolimod/Class IA and III Antiarrhythmic 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: 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.	FINGOLIMOD, GILENYA, TASCENSO ODT
Dofetilide/Dolutegravir 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: Dolutegravir may inhibit the elimination of dofetilide by the renal organic cation transporter (OCT2).(1) CLINICAL EFFECTS: Concurrent use of dolutegravir may result in elevated levels of dofetilide.(1) Dofetilide has been shown to prolong the QTc interval in a dose-dependent fashion. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes(TdP).(2) 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 or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) PATIENT MANAGEMENT: Concurrent use of dofetilide and dolutegravir is contraindicated. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting dolutegravir.(1,2) 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: Dolutegravir has been shown to inhibit OCT2 in vitro and in vivo and is expected to inhibit the excretion of dofetilide.(1)	DOVATO, JULUCA, TIVICAY, TIVICAY PD, TRIUMEQ, TRIUMEQ PD
Anagrelide/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 anagrelide with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1) 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) 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: The US manufacturer of anagrelide states that anagrelide should not be used in patients taking medications known to 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: 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.(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.	AGRYLIN, ANAGRELIDE HCL
Dofetilide/Lamotrigine SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The active tubular secretion via organic cationic transporter 2 (OCT2) of dofetilide may be inhibited by lamotrigine.(1,2) CLINICAL EFFECTS: The concurrent administration of dofetilide with lamotrigine may result in elevated levels and increased effects of dofetilide including QT prolongation or torsades de pointes.(1,2) 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 or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) PATIENT MANAGEMENT: The manufacturer of dofetilide states that the concurrent administration of dofetilide with known inhibitors of the renal cation transport system should not be used. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting lamotrigine.(1) The manufacturer of lamotrigine states the concurrent administration of lamotrigine with organic cationic transporter 2 (OCT2) substrates with a narrow therapeutic index, such as dofetilide, is not recommended.(2) DISCUSSION: Dofetilide is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. Lamotrigine is believed to inhibit the cation transport system (OCT2).(1,2)	LAMICTAL, LAMICTAL (BLUE), LAMICTAL (GREEN), LAMICTAL (ORANGE), LAMICTAL ODT, LAMICTAL ODT (BLUE), LAMICTAL ODT (GREEN), LAMICTAL ODT (ORANGE), LAMICTAL XR, LAMICTAL XR (BLUE), LAMICTAL XR (GREEN), LAMICTAL XR (ORANGE), LAMOTRIGINE, LAMOTRIGINE (BLUE), LAMOTRIGINE (GREEN), LAMOTRIGINE (ORANGE), LAMOTRIGINE ER, LAMOTRIGINE ODT, LAMOTRIGINE ODT (BLUE), LAMOTRIGINE ODT (GREEN), LAMOTRIGINE ODT (ORANGE), SUBVENITE, SUBVENITE (BLUE), SUBVENITE (GREEN), SUBVENITE (ORANGE)
Dofetilide/Bictegravir 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 is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. Bictegravir is believed to inhibit the cation transport system (OCT2) and thus may inhibit the active tubular secretion of dofetilide.(1) CLINICAL EFFECTS: The concurrent administration of dofetilide with bictegravir may result in elevated levels and increased effects of dofetilide, 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 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 bictegravir states that the concurrent administration of dofetilide with bictegravir is contraindicated. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting bictegravir.(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: The concurrent administration of dofetilide and bictegravir is expected to increase dofetilide plasma concentrations. Bictegravir is an inhibitor of organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1) in vitro.(1)	BIKTARVY
Dofetilide/Tafenoquine SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The active tubular secretion via organic cationic transporter 2 (OCT2) of dofetilide may be inhibited by tafenoquine.(1) CLINICAL EFFECTS: The concurrent administration of dofetilide with tafenoquine may result in elevated levels and increased effects of dofetilide 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 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 dofetilide states that the concurrent administration of dofetilide with known inhibitors of the renal cation transport system should not be used. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting tafenoquine.(1) The manufacturer of tafenoquine states the concurrent administration of tafenoquine with organic cationic transporter 2 (OCT2) substrates, such as dofetilide, should be avoided. If coadministration cannot be avoided, monitor for drug-related toxicities.(3) DISCUSSION: Dofetilide is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. Tafenoquine is believed to inhibit the cation transport system (OCT2).(1,3)	ARAKODA, KRINTAFEL
Dofetilide/OCT2 Inhibitors 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: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of dofetilide by OCT2 in the kidneys.(1) CLINICAL EFFECTS: Concurrent use of OCT2 inhibitors may result in increased levels of and toxicities of dofetilide, including potentially life-threatening cardiac arrhythmias, like torsades de pointes (TdP).(1-3) PREDISPOSING FACTORS: Risk factors for QT prolongation include: cardiovascular disease (e.g. heart failure, recent myocardial infarction, history of torsades de pointes, congenital long QT syndrome), female sex, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and concurrent use of agents known to cause QT prolongation.(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) 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) PATIENT MANAGEMENT: The manufacturer of dofetilide states that all renal cation transport inhibitors are contraindicated. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting OCT2 inhibitors.(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: Dofetilide is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. The concurrent administration of dofetilide (500 mcg twice daily) with cimetidine (an OCT2 inhibitor)(400 mg twice daily) resulted in an increase in dofetilide plasma levels by 58%. The concurrent administration of dofetilide (500 mcg single dose) with cimetidine (100 mg twice daily) resulted in an increase in dofetilide plasma levels by 13%.(1) In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(3) In a study, trilaciclib increased the area-under-curve (AUC) and maximum concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by approximately 65% and 81%, respectively. Renal clearance of metformin was decreased by 37%. Trilaciclib did not cause significant changes in the pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(4) OCT2 inhibitors linked to this monograph include: abemaciclib, arimoclomol, givinostat, isavuconazole, trilaciclib, tucatinib, and vimseltinib. (5)	COSELA, CRESEMBA, DUVYZAT, MIPLYFFA, ROMVIMZA, TUKYSA, VERZENIO
CYP3A4 Substrates that Prolong QT/Posaconazole 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: Posaconazole is a strong inhibitor of CYP3A4 and may inhibit the metabolism of CYP3A4 substrates. Use of posaconazole with agents that prolong the QTc interval may result in an additive effect on the QTc interval.(1,2) CLINICAL EFFECTS: Concurrent administration may result in elevated levels of the CYP3A4 substrate and/or prolongation of the QTc interval, which may result in 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.(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 posaconazole states that the concurrent use of agents that prolong the QTc interval that are metabolized by CYP3A4 is contraindicated.(1) The UK manufacturer of posaconazole states that CYP3A4 substrates that are known to prolong the QTc interval must not be coadministered.(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: Posaconazole has been shown to inhibit CYP3A4. Elevated levels of CYP3A4 substrates that are known to prolong the QTc interval may have an additive effect on the QTc interval.(1,2) CYP3A4 substrates that prolong the QTc interval and that are linked to this monograph include: aclarubicin, adagrasib, amiodarone, artemether-lumefantrine, bepridil, clarithromycin, dofetilide, erythromycin, fexinidazole, levomethadyl, lonafarnib, mobocertinib, quizartinib, revumenib, savolitinib, and telithromycin.	NOXAFIL, POSACONAZOLE
Dofetilide/Levoketoconazole 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: Levoketoconazole may inhibit the elimination of dofetilide by the renal organic cation transporter (OCT2) and Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys.(1,2) CLINICAL EFFECTS: Concurrent use of levoketoconazole may result in elevated levels of dofetilide.(1) Dofetilide and levoketoconazole have been shown to prolong the QTc interval in a dose-dependent fashion.(1,2) Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(2) 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 or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) PATIENT MANAGEMENT: Concurrent use of dofetilide and levoketoconazole is contraindicated. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting levoketoconazole.(1,2) 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: Levoketoconazole has been shown to inhibit OCT2 and MATE in vitro and in vivo and is expected to inhibit the excretion of dofetilide.(1)	RECORLEV
Dofetilide/Cephalexin 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 is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. Cephalexin may inhibit the excretion of dofetilide by the renal cation transport system.(1) CLINICAL EFFECTS: Concurrent use of dofetilide with cephalexin may result in increased levels of and toxicities of dofetilide, including potentially life-threatening cardiac arrhythmias, like torsades de pointes (TdP).(1,2) PREDISPOSING FACTORS: Risk factors for QT prolongation include: cardiovascular disease (e.g. heart failure, recent myocardial infarction, history of torsades de pointes, congenital long QT syndrome), female sex, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and concurrent use of agents known to cause QT prolongation.(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) 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) PATIENT MANAGEMENT: The manufacturer of dofetilide states that all renal cation transport inhibitors are contraindicated.(1) If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting cephalexin.(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: While the combination of dofetilide and cephalexin has not been studied, clinical data is available for the combination of dofetilide with other renal transport inhibitors, and for cephalexin with other renal transport substrates. In a study, cephalexin 500 mg with metformin 500 mg increased the mean metformin concentration maximum (Cmax) and area-under-curve (AUC) by an average of 34% and 24%, respectively, and metformin mean renal clearance decreased by 14%. Metformin is a MATE and OCT2 substrate.(3) Dofetilide is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. The concurrent administration of dofetilide (500 mcg twice daily) with cimetidine (a MATE and OCT2 inhibitor)(400 mg twice daily) resulted in an increase in dofetilide plasma levels by 58%. The concurrent administration of dofetilide (500 mcg single dose) with cimetidine (100 mg twice daily) resulted in an increase in dofetilide plasma levels by 13%.(1)	CEPHALEXIN
Dofetilide/OCT2 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: Agents that inhibit the organic cation transporter 2 (OCT2) that prolong the QT interval may inhibit the excretion of dofetilide by OCT2 in the kidneys and result in additive risk of QT prolongation.(1) CLINICAL EFFECTS: Concurrent use of OCT2 inhibitors that prolong QT may result in increased levels of and toxicities of dofetilide, including additive potentially life-threatening cardiac arrhythmias, like torsades de pointes (TdP).(1-3) PREDISPOSING FACTORS: Risk factors for QT prolongation include: cardiovascular disease (e.g. heart failure, recent myocardial infarction, history of torsades de pointes, congenital long QT syndrome), female sex, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and concurrent use of agents known to cause QT prolongation.(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) 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) PATIENT MANAGEMENT: The manufacturer of dofetilide states that all renal cation transport inhibitors are contraindicated. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting OCT2 inhibitors.(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: Dofetilide is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. The concurrent administration of dofetilide (500 mcg twice daily) with cimetidine (an OCT2 inhibitor)(400 mg twice daily) resulted in an increase in dofetilide plasma levels by 58%. The concurrent administration of dofetilide (500 mcg single dose) with cimetidine (100 mg twice daily) resulted in an increase in dofetilide plasma levels by 13%.(1) OCT2 inhibitors that prolong QT include: ranolazine.(3)	ASPRUZYO SPRINKLE, RANOLAZINE ER

Drug contraindication overview.

Congenital or acquired long QT syndromes; baseline QT or QTc interval exceeding 440 msec (500 msec in patients with ventricular conduction abnormalities). Severe renal impairment (calculated creatinine clearance below 20 mL/minute). Concomitant use of verapamil or cation transport system inhibitors (e.g., cimetidine, ketoconazole, megestrol, prochlorperazine, trimethoprim (alone or in combination with sulfamethoxazole)).

Concomitant use of hydrochlorothiazide (alone or in combination with triamterene). (See Drug Interactions.) Known hypersensitivity to dofetilide.

Adverse reaction overview.

Adverse effects occurring in 2% or more of patients receiving dofetilide and more frequently than placebo include headache, chest pain, dizziness, respiratory tract infection, dyspnea, nausea, flu syndrome, insomnia, accidental injury, back pain, medical, surgical, or other health service procedure, diarrhea, rash, and abdominal pain.

Safety and efficacy not established in children younger than 18 years of age.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None