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    Anti-arrhythmics, Class III

    BOXED WARNING

    Requires a specialized care setting, requires an experienced clinician

    Administration of dofetilide requires a specialized care setting; treatment with dofetilide may be started only in patients placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic (ECG) monitoring, and cardiac resuscitation. Dofetilide therapy requires an experienced clinician trained in the management of serious ventricular arrhythmias.

    DEA CLASS

    Rx

    DESCRIPTION

    Class III antiarrhythmic; converts and maintains NSR in AFIB/Flutter; reserved for highly symptomatic patients; proarrhythmic (torsade de pointes); selectively blocks potassium channels; prolongs QT, APD, and ERP; does not affect ventricular conduction time; has negative chronotropy; lacks negative inotropy; renally eliminated; numerous drug interactions.

    COMMON BRAND NAMES

    Tikosyn

    HOW SUPPLIED

    Dofetilide/Tikosyn Oral Cap: 125mcg, 250mcg, 500mcg

    DOSAGE & INDICATIONS

    For use in the conversion of atrial fibrillation/atrial flutter to normal sinus rhythm; or, for maintenance therapy of patients with highly symptomatic atrial fibrillation/atrial flutter of 1 week or more duration.
    NOTE: Patients with atrial fibrillation (AF) should be anticoagulated according to usual medical practice prior to electrical or pharmacological cardioversion. Anticoagulant therapy may be continued after cardioversion according to medical guidelines for the treatment of patients with AF.
    NOTE: Dofetilide is not effective in patients with paroxysmal atrial fibrillation.
    For maintenance therapy of atrial fibrillation/atrial flutter after hospital discharge.
    Oral dosage
    Adults

    Continue dosage at discharge as from initial dosage titration. Individualize dosage based on renal function and QTc, which should be re-evaluated every 3 months or as medically warranted. If the QTc exceeds 500 milliseconds (or 550 msec in patients with ventricular conduction abnormalities) at any time, dofetilide therapy should be discontinued. Such patients should be carefully monitored until QTc returns to baseline levels. If renal function deteriorates, adjust the dose as described in the dosage guidelines for patients with renal impairment.

    Oral dosage
    Adults

    Individualize dosage based on renal function and QTc in a monitored facility. Refer to the step-by-step procedure above for determining the initial dosage of dofetilide. Based an individualized assessment of the patient's other medical conditions and concurrent drug therapy, the prescriber may elect to initiate dofetilide at a lower dose than recommended. If patients do not convert to normal sinus rhythm (NSR) within 24 hours of initiating dofetilide, electrical conversion should be considered. Patients should be monitored by continuous ECG for 3 or more days, or 12 hours or more after successful pharmacological or electrical conversion to NSR, whichever is greater. Clinical practice guidelines include dofetilide as an option for pharmacological cardioversion of atrial fibrillation or atrial flutter as long as no contraindications to therapy exist.

    MAXIMUM DOSAGE

    Adults

    1000 mcg/day PO.

    Elderly

    1000 mcg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment is needed for patients with mild to moderate hepatic impairment. Dofetilide should be used with caution in patients with severe hepatic impairment; data are lacking in this population.

    Renal Impairment

    NOTE: Dosage adjustments based on determinations of renal function are critically important. The manufacturer recommends using actual body weight in the Cockcroft-Gault equation to calculate creatinine clearance.
    CrCl > 60 mL/min: the initial dose is 500 mcg dofetilide PO twice daily.
    CrCl 40—60 mL/min: the initial dose is 250 mcg dofetilide PO twice daily.
    CrCl 20—39 mL/min: the initial dose is 125 mcg dofetilide PO twice daily.
    CrCl < 20 mL/min: dofetilide is contraindicated.
     
    Intermittent hemodialysis
    Not applicable; dofetilide is contraindicated in patients with severe renal impairment (CrCl < 20 mL/min). It is not known if hemodialysis removes dofetilide from plasma.

    ADMINISTRATION

     
     
    WARNING: DOSING OF DOFETILIDE MUST BE DONE VERY CAREFULLY. DOFETILIDE CAN CAUSE SERIOUS CARDIAC ARRHYTHMIAS, PARTICULARLY, VENTRICULAR TACHYCARDIA OF THE TORSADES DE POINTES TYPE. ECG AND RENAL FUNCTION MUST BE ASSESSED PRIOR TO BEGINNING THERAPY. CLINICIANS WHO ARE UNFAMILIAR WITH THE USE OF THIS DRUG SHOULD READ THE FOLLOWING NOTES.
     
    NOTE: To minimize the risk of proarrhythmias, patients initiated or re-initiated on dofetilide should be placed for 3 or more days in a monitored facility with the capacity to monitor continuous ECG and CrCl and perform cardiac resuscitation. Hypokalemia should be corrected before initiation of therapy.
     
    NOTE: Patients with atrial fibrillation should be anticoagulated prior to electrical or pharmacological cardioversion. Anticoagulant therapy may be continued after cardioversion for the treatment of patients with atrial fibrillation.

    Oral Administration

    Administer with or without food.

    STORAGE

    Tikosyn:
    - Avoid excessive humidity
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Dofetilide is contraindicated in patients with a history of hypersensitivity to dofetilide.

    Requires a specialized care setting, requires an experienced clinician

    Administration of dofetilide requires a specialized care setting; treatment with dofetilide may be started only in patients placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic (ECG) monitoring, and cardiac resuscitation. Dofetilide therapy requires an experienced clinician trained in the management of serious ventricular arrhythmias.

    Apheresis, cardiomyopathy, celiac disease, females, fever, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE), torsade de pointes

    Dofetilide is contraindicated in patients with congenital long QT syndrome, acquired QT prolongation syndromes, or history of torsade de pointes (TdP). Dofetilide, a Class III antiarrhythmic, is proarrhythmic and may induce or worsen cardiac arrhythmias. Dofetilide is associated with a well-established risk of QT prolongation and TdP. Do not use dofetilide in patients with a baseline QT interval or QTc greater than 440 milliseconds (500 milliseconds in patients with ventricular conduction abnormalities). QT prolongation is directly related to dofetilide dose and plasma concentration. Factors which increase dofetilide plasma concentrations, such as reduced creatinine clearance or certain drug interactions, will increase the risk of QT prolongation and associated arrhythmias. Using dofetilide in conjunction with other drugs that prolong the QT interval has not been studied and is generally not recommended due to the potential risk for ventricular tachycardia, including TdP and monomorphic ventricular tachycardia. The risk of TdP can be reduced by avoiding excessive plasma dofetilide concentrations through adjustment of the initial dose according to creatinine clearance, avoidance of potential drug interactions, and by ECG monitoring of the QT interval. Use dofetilide with caution in patients with conditions that may increase the risk of QT prolongation including heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. People 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. Hypomagnesemia, hypokalemia, or hypocalcemia may increase the risk of QT prolongation. Maintain potassium concentrations within the normal range prior to and during the administration of dofetilide. During clinical trials, potassium concentrations were generally maintained between 3.6 and 4 mEq/L. Correct any electrolyte imbalances prior to initiation of therapy. Females may be at increased risk for QT prolongation; as with other drugs that cause TdP, dofetilide was associated with a greater risk of TdP in females than in males. During the dofetilide clinical development program (32% were females in placebo-controlled trials), the risk of TdP in females was approximately 3 times that in males. However, the incidence of ventricular arrhythmias other than TdP was similar in female patients receiving dofetilide and patients receiving placebo. Although no study specifically investigated this risk, in post-trial analyses there was no increase in mortality observed in females receiving dofetilide vs. placebo. In contrast to increased mortality documented with d-sotalol (pure class III antiarrhythmic, devoid of beta-blocking properties) in high-risk post-MI patients, dofetilide has been shown to have a neutral effect on the mortality from arrhythmias post-MI and in severe congestive heart failure.

    Dialysis, renal disease, renal failure, renal impairment

    Dofetilide is contraindicated in patients with renal failure or severe renal impairment as defined by a creatinine clearance (CrCl) less than 20 mL/min. Total clearance of dofetilide is decreased and plasma concentration is increased in proportion to the decline in creatinine clearance associated with renal disease. Because increases in the QT interval and the risk of ventricular arrhythmias are directly related to plasma concentrations of dofetilide, it is critical that the dose of dofetilide be adjusted based on calculated CrCl. Patients undergoing hemodialysis (dialysis) were not included in clinical studies. It is not known whether hemodialysis removes dofetilide from plasma. Clinicians should also evaluate any concomitant drug therapy for the potential to decrease the renal elimination of dofetilide.

    Hepatic disease

    In clinical trials, there was no clinically significant alteration in the pharmacokinetics of dofetilide in volunteers with mild to moderate hepatic impairment (Child-Pugh class A and B). After adjustment for creatinine clearance, no additional dose adjustment is required for patients with mild or moderate hepatic disease. Dofetilide should be used with caution in patients with severe hepatic impairment; data are lacking in this population.

    AV block, bradycardia, sick sinus syndrome

    Use dofetilide with caution in patients with conditions that may increase the risk of QT prolongation including AV block and bradycardia. Animal and human studies have not shown adverse effects of dofetilide on cardiac conduction velocity. No effect on AV nodal conduction following dofetilide was noted in normal volunteers and in patients with 1st degree AV block. There are no data on the use of dofetilide in patients with bradycardia (heart rate less than 50 bpm). Patients with sick sinus syndrome or with 2nd or 3rd degree AV block were not included in Phase III clinical trials unless a functioning pacemaker was present. Dofetilide has been used safely in conjunction with pacemakers in clinical trials.

    Pregnancy

    No adequate and well-controlled studies have been conducted in pregnant women, and it is unknown if use of dofetilide during pregnancy increases the risk for adverse maternal or fetal outcomes. Dofetilide should only be administered to pregnant women when the benefits to the mother justify the potential fetal risks. Animal studies using oral dofetilide revealed evidence of a variety of adverse effects, including effects on in utero growth and survival when administered during organogenesis at doses of 2 mg/kg/day or more. The "no observed adverse effect dose" in both rat and mouse species was 0.5 mg/kg/day; the mean dofetilide exposure (AUC) at this dose in the rat and mouse are estimated to be about equal to the maximum likely human AUC and about half the likely human AUC, respectively.[28221]

    Breast-feeding

    It is not known whether dofetilide is excreted into breast milk. Women should be advised to avoid breast-feeding an infant while taking dofetilide.

    Children, infants

    The safety and effectiveness of dofetilide in pediatric patients (adolescents, children or infants) less than 18 years of age have not been established.

    Geriatric

    During clinical studies of dofetilide, 46% of patients were older adults (65 to 89 years old). No overall differences in safety, the effect on QTc interval, or effectiveness were observed between geriatric and younger adult patients. However, since geriatric patients are more likely to have decreased renal function, care must be taken in dose selection for dofetilide.[28221] In general, geriatric patients may be at increased risk for QT prolongation. According to the Beers Criteria, there is an increased risk of QT prolongation and torsade de pointes with dofetilide use in older adults when the creatinine clearance (CrCl) is less than 60 mL/minute. The Beers panel recommends a dose reduction if the CrCl is 20 to 59 mL/minute and avoidance of the drug if the CrCl is less than 20 mL/minute; follow dose reduction guidance in the product label.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; monitor patients receiving antiarrhythmic drugs for efficacy and adverse effects. Antiarrhythmics can have serious adverse effects (e.g., changes in mental function, appetite, behavior, heart function, or falls) in older individuals.[60742]

    ADVERSE REACTIONS

    Severe

    torsade de pointes / Rapid / 0.3-3.3
    ventricular tachycardia / Early / 2.6-3.3
    bradycardia / Rapid / 0-2.0
    cardiac arrest / Early / 0-2.0
    myocardial infarction / Delayed / 0-2.0
    stroke / Early / 0-2.0
    angioedema / Rapid / 0-2.0
    AV block / Early / 0.4-1.5
    ventricular fibrillation / Early / 0.3-0.4
    arrhythmia exacerbation / Early / Incidence not known
    muscle paralysis / Delayed / Incidence not known

    Moderate

    chest pain (unspecified) / Early / 10.0-10.0
    dyspnea / Early / 6.0-6.0
    edema / Delayed / 0-2.0
    migraine / Early / 0-2.0
    elevated hepatic enzymes / Delayed / 0-2.0
    angina / Early / 2.0
    peripheral edema / Delayed / 2.0
    palpitations / Early / 2.0
    hypertension / Early / 2.0
    QT prolongation / Rapid / Incidence not known

    Mild

    headache / Early / 11.0-11.0
    dizziness / Early / 8.0-8.0
    infection / Delayed / 0-7.0
    nausea / Early / 5.0-5.0
    insomnia / Early / 4.0-4.0
    influenza / Delayed / 4.0-4.0
    diarrhea / Early / 3.0-3.0
    abdominal pain / Early / 3.0-3.0
    rash / Early / 3.0-3.0
    back pain / Delayed / 3.0-3.0
    syncope / Early / 0-2.0
    cough / Delayed / 0-2.0
    asthenia / Delayed / 2.0
    anxiety / Delayed / 2.0
    arthralgia / Delayed / 2.0
    diaphoresis / Early / 2.0
    paresthesias / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Contraindicated) Concurrent use of dolutegravir with dofetilide is contraindicated due of the potential for serious and life-threatening adverse events, such as QT prolongation and torsade de pointes (TdP). Dolutegravir inhibits the renal organic cation transporter OCT2, dofetilide is eliminated via this transporter. If coadministered, the plasma concentration of dofetilide may increase. (Moderate) Drugs that are actively secreted via cationic secretion, such as lamivudine, should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion.
    Abacavir; Lamivudine, 3TC: (Moderate) Drugs that are actively secreted via cationic secretion, such as lamivudine, should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion.
    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Drugs that are actively secreted via cationic secretion, such as lamivudine, should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion.
    Abarelix: (Contraindicated) Since abarelix can cause QT prolongation, abarelix should be used cautiously, if at all, with other drugs that are associated with QT prolongation, including dofetilide.
    Aclidinium; Formoterol: (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Adefovir: (Moderate) Adefovir is eliminated renally by a combination of glomerular filtration and active tubular secretion; coadministration of adefovir dipivoxil with drugs that reduce renal function or compete for active tubular secretion, such as dofetilide, may decrease adefovir elimination by competing for common renal tubular transport systems, therefore increasing serum concentrations of either adefovir and/or these coadministered drugs.
    Albuterol: (Minor) Coadministration of dofetilide and short-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol; Ipratropium: (Minor) Coadministration of dofetilide and short-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Alfuzosin: (Major) Coadministration of dofetilide and alfuzosin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Alfuzosin may prolong the QT interval in a dose-dependent manner.
    Aliskiren; Amlodipine: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with amlodipine is necessary. Amlodipine is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with amlodipine is necessary. Amlodipine is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Alogliptin; Metformin: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
    Amiloride: (Major) Drugs that are actively secreted via cationic tubular secretion, such as amiloride, should be co-administered with caution with dofetilide since they could increase dofetilide plasma concentrations via potential competition for renal cationic secretion. Increased dofetilide plasma concentrations may be associated with proarrhythmias.
    Amiloride; Hydrochlorothiazide, HCTZ: (Major) Drugs that are actively secreted via cationic tubular secretion, such as amiloride, should be co-administered with caution with dofetilide since they could increase dofetilide plasma concentrations via potential competition for renal cationic secretion. Increased dofetilide plasma concentrations may be associated with proarrhythmias.
    Amiodarone: (Major) Coadministration of dofetilide and amiodarone is not recommended as concurrent use may increase the risk of QT prolongation. Class III antiarrhythmic agents, such as amiodarone, should be withheld for at least 3 half-lives prior to initiating dofetilide therapy. Both dofetilide and amiodarone are associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. In clinical trials, dofetilide was administered to patients previously treated with oral amiodarone only if serum amiodarone concentrations were below 0.3 mg/L or amiodarone had been withdrawn for at least three months.
    Amisulpride: (Major) Coadministration of dofetilide and amisulpride is not recommended as concurrent use may increase the risk of QT prolongation. Monitor ECGs for QT prolongation if concomitant use is unavoidable. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Amisulpride causes dose- and concentration- dependent QT prolongation.
    Amitriptyline: (Minor) Coadministration of dofetilide and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amitriptyline; Chlordiazepoxide: (Minor) Coadministration of dofetilide and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amlodipine: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with amlodipine is necessary. Amlodipine is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with amlodipine is necessary. Amlodipine is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Amlodipine; Benazepril: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with amlodipine is necessary. Amlodipine is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Amlodipine; Celecoxib: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with amlodipine is necessary. Amlodipine is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with amlodipine is necessary. Amlodipine is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with amlodipine is necessary. Amlodipine is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Amlodipine; Olmesartan: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with amlodipine is necessary. Amlodipine is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Amlodipine; Telmisartan: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with amlodipine is necessary. Amlodipine is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Amlodipine; Valsartan: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with amlodipine is necessary. Amlodipine is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Coadministration of dofetilide and clarithromycin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and TdP.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Coadministration of dofetilide and clarithromycin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and TdP.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Major) Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting drugs, such as amphotericin B, increasing the potential for dofetilide-induced torsade de pointes. Potassium levels should be within the normal range prior and during administration of dofetilide.
    Amphotericin B lipid complex (ABLC): (Major) Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting drugs, such as amphotericin B, increasing the potential for dofetilide-induced torsade de pointes. Potassium levels should be within the normal range prior and during administration of dofetilide.
    Amphotericin B liposomal (LAmB): (Major) Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting drugs, such as amphotericin B, increasing the potential for dofetilide-induced torsade de pointes. Potassium levels should be within the normal range prior and during administration of dofetilide.
    Amphotericin B: (Major) Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting drugs, such as amphotericin B, increasing the potential for dofetilide-induced torsade de pointes. Potassium levels should be within the normal range prior and during administration of dofetilide.
    Amprenavir: (Contraindicated) Amprenavir may inhibit the metabolism of medications that are metabolized via CYP3A4. Although drug interaction studies have not been conducted, the serum concentrations of dofetilide may be increased with concomitant administration of amprenavir.
    Anagrelide: (Major) Coadministration of dofetilide and anagrelide is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. TdP and ventricular tachycardia have been reported during postmarketing use of anagrelide.
    Apomorphine: (Major) Coadministration of dofetilide and apomorphine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
    Aprepitant, Fosaprepitant: (Major) Use caution if dofetilide and aprepitant, fosaprepitant are used concurrently and monitor for an increase in dofetilide-related adverse effects, including QT prolongation and torsade de pointes (TdP), for several days after administration of a multi-day aprepitant regimen. In vitro, dofetilide is a CYP3A4 substrate, although it has low affinity for this isoenzyme. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of dofetilide. Erythromycin, a potent CYP3A4 inhibitor, significantly increases dofetilide plasma concentrations. The AUC of a single dose of another CYP3A4 substrate, midazolam, increased by 2.3-fold on day 1 and by 3.3-fold on day 5 when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Arformoterol: (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Aripiprazole: (Major) Coadministration of dofetilide and aripiprazole is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
    Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide and dofetilide due to the potential for additive QT prolongation; discontinue or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP.
    Artemether; Lumefantrine: (Major) Avoid coadministration of artemether; lumefantrine with dofetilide due to the potential for additive QT prolongation. Consider ECG monitoring if dofetilide must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Articaine; Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Asenapine: (Major) Coadministration of dofetilide and asenapine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Asenapine has been associated with QT prolongation.
    Atazanavir: (Major) Coadministration of CYP3A4 inhibitors, such as atazanavir, with dofetilide may decrease the metabolism of dofetilide, thereby increasing the potential for QT prolongation. Dofetilide is a Class III antiarrhythmic agent that has a well-established risk of QT prolongation and torsade de pointes (TdP). Plasma dofetilide concentrations are correlated with the risk of drug-induced proarrhythmias.
    Atazanavir; Cobicistat: (Major) Coadministration of CYP3A4 inhibitors, such as atazanavir, with dofetilide may decrease the metabolism of dofetilide, thereby increasing the potential for QT prolongation. Dofetilide is a Class III antiarrhythmic agent that has a well-established risk of QT prolongation and torsade de pointes (TdP). Plasma dofetilide concentrations are correlated with the risk of drug-induced proarrhythmias.
    Atomoxetine: (Major) Coadministration of dofetilide and atomoxetine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
    Azelastine; Fluticasone: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Azithromycin: (Major) Avoid coadministration of azithromycin with dofetilide due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP.
    Beclomethasone: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Bedaquiline: (Major) Coadministration of dofetilide and bedaquiline is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECGs during treatment. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 milliseconds. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Bedaquiline also prolongs the QT interval.
    Berotralstat: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with berotralstat is necessary as concurrent use may increase dofetilide exposure. Dofetilide is a minor CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Betamethasone: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Bicalutamide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with bicalutamide is necessary as concurrent use may increase dofetilide exposure. bicalutamide is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Concomitant use of bictegravir and dofetilide is contraindicated due to the potential for increased dofetilide plasma concentrations and risk of serious and/or life-threatening events. Dofetilide is a substrate of OCT2 and MATE1; bictegravir is an inhibitor of these drug transporters. (Moderate) Use caution when administering dofetilide concurrently with emtricitabine as both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Coadministration of dofetilide and metronidazole is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Coadministration of dofetilide and metronidazole is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bosentan: (Moderate) Theoretically, bosentan can induce the hepatic metabolism of dofetilide via CYP3A4 isoenzymes. The clinical significance of this interaction is unknown.
    Bretylium: (Major) Withdraw bretylium at least 3 half-lives before starting dofetilide therapy.
    Budesonide: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Budesonide; Formoterol: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide. (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Budesonide; Glycopyrrolate; Formoterol: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide. (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Bupivacaine; Lidocaine: (Contraindicated) Concurrent exposure of systemic lidocaine with dofetilide could increase the risk of dofetilide-induced proarrhythmias. Before switching from lidocaine to dofetilide therapy, lidocaine generally should be withheld for at least three half-lives prior to initiating dofetilide. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP).
    Buprenorphine: (Major) Coadministration of dofetilide and buprenorphine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Buprenorphine has been associated with QT prolongation and has a possible risk of TdP.
    Buprenorphine; Naloxone: (Major) Coadministration of dofetilide and buprenorphine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Buprenorphine has been associated with QT prolongation and has a possible risk of TdP.
    Cabotegravir; Rilpivirine: (Major) Coadministration of dofetilide and rilpivirine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Canagliflozin; Metformin: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
    Cardiac glycosides: (Major) Dofetilide does not affect the pharmacokinetics of digoxin; however, the concomitant administration of digoxin with dofetilide is associated with a higher occurrence of torsade de pointes.
    Ceritinib: (Major) Avoid coadministration of ceritinib with dofetilide due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Dofetilide is a CYP3A4 substrate that is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Ceritinib is a strong CYP3A4 inhibitor that is also associated with concentration-dependent QT prolongation.
    Chloroquine: (Major) Avoid coadministration of chloroquine with dofetilide due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP.
    Chlorpromazine: (Major) Coadministration of dofetilide and chlorpromazine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP.
    Ciclesonide: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Cimetidine: (Contraindicated) Cimetidine is an inhibitor of renal cationic tubular secretion and is contraindicated with dofetilide due to the potential for increased plasma dofetilide concentrations and associated proarrhythmias. Cimetidine (400 mg PO twice daily) coadministered with dofetilide (500 mcg PO twice daily) for 7 days increased dofetilide plasma levels by 58%. Cimetidine, at over-the-counter doses of 100 mg PO twice daily, results in a 13% increase in dofetilide plasma concentrations following a single 500 mcg oral dose. Omeprazole, ranitidine, or antacids (aluminum and magnesium hydroxides) may be used as anti-ulcer therapy alternatives to cimetidine; these agents did not alter dofetilide pharmacokinetics.
    Ciprofloxacin: (Major) Coadministration of dofetilide and ciprofloxacin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Rare cases of QT prolongation and TdP have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Contraindicated) Coadministration of cisapride with dofetilide is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP.
    Citalopram: (Major) Coadministration of dofetilide and citalopram is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Citalopram causes dose-dependent QT interval prolongation.
    Clarithromycin: (Major) Coadministration of dofetilide and clarithromycin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and TdP.
    Clofazimine: (Major) Coadministration of dofetilide and clofazimine is not recommended as concurrent use may increase the risk of QT prolongation. Monitor ECGs for QT prolongation if concomitant use is unavoidable. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients receiving clofazimine in combination with QT prolonging medications.
    Clomipramine: (Minor) Coadministration of dofetilide and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clozapine: (Major) Coadministration of dofetilide and clozapine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
    Codeine; Phenylephrine; Promethazine: (Major) Coadministration of dofetilide and promethazine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Codeine; Promethazine: (Major) Coadministration of dofetilide and promethazine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Conivaptan: (Major) Hypokalemia may occur with administration of potassium-depleting drugs such as conivaptan, increasing the potential for dofetilide-induced torsade de pointes. Conivaptan has been associated with hypokalemia (9.8%). Potassium levels should be within the normal range prior and during administration of dofetilide. Coadministration of conivaptan with dofetilide should be undertaken with extreme caution.
    Corticosteroids: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Cortisone: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Crizotinib: (Major) Avoid coadministration of crizotinib with dofetilide due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Danazol: (Major) Danazol could significantly inhibit the CYP3A4 metabolism of dofetilide. The resultant increase in serum dofetilide concentrations could increase the risk of torsade de pointes.
    Dapagliflozin; Metformin: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
    Darunavir: (Major) Coadministration of CYP3A4 inhibitors, such as darunavir, with dofetilide may decrease the metabolism of dofetilide, thereby increasing the potential for QT prolongation. Dofetilide is a Class III antiarrhythmic agent that has a well-established risk of QT prolongation and torsade de pointes (TdP). Plasma dofetilide concentrations are correlated with the risk of drug-induced proarrhythmias.
    Darunavir; Cobicistat: (Major) Coadministration of CYP3A4 inhibitors, such as darunavir, with dofetilide may decrease the metabolism of dofetilide, thereby increasing the potential for QT prolongation. Dofetilide is a Class III antiarrhythmic agent that has a well-established risk of QT prolongation and torsade de pointes (TdP). Plasma dofetilide concentrations are correlated with the risk of drug-induced proarrhythmias.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of CYP3A4 inhibitors, such as darunavir, with dofetilide may decrease the metabolism of dofetilide, thereby increasing the potential for QT prolongation. Dofetilide is a Class III antiarrhythmic agent that has a well-established risk of QT prolongation and torsade de pointes (TdP). Plasma dofetilide concentrations are correlated with the risk of drug-induced proarrhythmias. (Moderate) Use caution when administering dofetilide concurrently with emtricitabine as both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concomitant use of dofetilide and ritonavir may increase the risk of QT prolongation and torsade de pointes (TdP) due to increased dofetilide exposure. Dofetilide is metabolized to a small degree by CYP3A4; ritonavir is a potent inhibitor of CYP3A4.
    Dasatinib: (Major) Coadministration of dofetilide and dasatinib is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
    Deflazacort: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Degarelix: (Major) Coadministration of dofetilide and degarelix is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval.
    Delavirdine: (Contraindicated) Avoid concurrent use of dofetilide with delavirdine. Delavirdine may theoretically inhibit the CYP3A4 metabolism of dofetilide, resulting in elevated dofetilide plasma concentrations. Dofetilide plasma concentrations are correlated with the risk of drug-induced proarrhythmias.
    Desflurane: (Major) Coadministration of dofetilide and halogenated anesthetics is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Halogenated anesthetics can prolong the QT interval.
    Desipramine: (Minor) Coadministration of dofetilide and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Deutetrabenazine: (Major) Coadministration of dofetilide and deutetrabenazine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
    Dexamethasone: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Dextromethorphan; Promethazine: (Major) Coadministration of dofetilide and promethazine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Dextromethorphan; Quinidine: (Contraindicated) Coadministration of dofetilide and quinidine is contraindicated as concurrent use may increase the risk QT prolongation and torsades de pointes (TdP). Class I antiarrhythmic agents, such as quinidine, should be withheld for at least 3 half-lives prior to initiating dofetilide therapy. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Quinidine administration is associated with QT prolongation and TdP.
    Diltiazem: (Major) Diltiazem should be used with caution with dofetilide since it may increase dofetilide plasma concentrations via inhibition of CYP3A4 metabolism. This interaction may increase the potential for dofetilide-induced proarrhythmias.
    Disopyramide: (Major) Coadministration of dofetilide and disopyramide is not recommended as concurrent use may increase the risk of QT prolongation. Class I antiarrhythmic agents, such as disopyramide, should be withheld for at least 3 half-lives prior to initiating dofetilide therapy. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Disopyramide administration is associated with QT prolongation and TdP.
    Dolasetron: (Major) Coadministration of dofetilide and dolasetron is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir: (Contraindicated) Concurrent use of dolutegravir with dofetilide is contraindicated due of the potential for serious and life-threatening adverse events, such as QT prolongation and torsade de pointes (TdP). Dolutegravir inhibits the renal organic cation transporter OCT2, dofetilide is eliminated via this transporter. If coadministered, the plasma concentration of dofetilide may increase.
    Dolutegravir; Lamivudine: (Contraindicated) Concurrent use of dolutegravir with dofetilide is contraindicated due of the potential for serious and life-threatening adverse events, such as QT prolongation and torsade de pointes (TdP). Dolutegravir inhibits the renal organic cation transporter OCT2, dofetilide is eliminated via this transporter. If coadministered, the plasma concentration of dofetilide may increase. (Moderate) Drugs that are actively secreted via cationic secretion, such as lamivudine, should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion.
    Dolutegravir; Rilpivirine: (Contraindicated) Concurrent use of dolutegravir with dofetilide is contraindicated due of the potential for serious and life-threatening adverse events, such as QT prolongation and torsade de pointes (TdP). Dolutegravir inhibits the renal organic cation transporter OCT2, dofetilide is eliminated via this transporter. If coadministered, the plasma concentration of dofetilide may increase. (Major) Coadministration of dofetilide and rilpivirine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Donepezil: (Major) Coadministration of dofetilide and donepezil is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Donepezil; Memantine: (Major) Coadministration of dofetilide and donepezil is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. (Major) Drugs that are actively secreted via cationic secretion (e.g., memantine) should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion. Competition for renal elimination may increase plasma concentrations of dofetilide and increase the risk of pro-arrhythmias.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Major) Dofetilide should be co-administered with tenofovir, PMPA with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of dofetilide is recommended. (Moderate) Drugs that are actively secreted via cationic secretion, such as lamivudine, should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion.
    Doxepin: (Minor) Coadministration of dofetilide and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Dronedarone: (Contraindicated) Concurrent use of dronedarone and dofetilide is contraindicated. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce TdP and is contraindicated.
    Droperidol: (Major) Coadministration of dofetilide and droperidol is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Droperidol administration is associated with an established risk for QT prolongation and TdP. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.
    Duvelisib: (Major) Monitor for an increase in dofetilide-related adverse effects, including QT prolongation and torsade de pointes (TdP), if coadministered with duvelisib. Coadministration may increase the exposure of dofetilide. Dofetilide is a CYP3A substrate; duvelisib is a moderate CYP3A inhibitor.
    Efavirenz: (Major) Coadministration of dofetilide and efavirenz is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). QTc prolongation has been observed with the use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Coadministration of dofetilide and efavirenz is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). QTc prolongation has been observed with the use of efavirenz. (Major) Dofetilide should be co-administered with tenofovir, PMPA with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of dofetilide is recommended. (Moderate) Use caution when administering dofetilide concurrently with emtricitabine as both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of dofetilide and efavirenz is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). QTc prolongation has been observed with the use of efavirenz. (Major) Dofetilide should be co-administered with tenofovir, PMPA with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of dofetilide is recommended. (Moderate) Drugs that are actively secreted via cationic secretion, such as lamivudine, should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion.
    Eliglustat: (Major) Coadministration of dofetilide and eliglustat is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Use caution when administering dofetilide concurrently with emtricitabine as both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Dofetilide should be co-administered with tenofovir, PMPA with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of dofetilide is recommended. (Moderate) Use caution when administering dofetilide concurrently with emtricitabine as both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia.
    Empagliflozin; Linagliptin; Metformin: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
    Empagliflozin; Metformin: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
    Emtricitabine: (Moderate) Use caution when administering dofetilide concurrently with emtricitabine as both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Coadministration of dofetilide and rilpivirine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. (Moderate) Use caution when administering dofetilide concurrently with emtricitabine as both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Coadministration of dofetilide and rilpivirine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. (Major) Dofetilide should be co-administered with tenofovir, PMPA with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of dofetilide is recommended. (Moderate) Use caution when administering dofetilide concurrently with emtricitabine as both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Use caution when administering dofetilide concurrently with emtricitabine as both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia.
    Emtricitabine; Tenofovir disoproxil fumarate: (Major) Dofetilide should be co-administered with tenofovir, PMPA with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of dofetilide is recommended. (Moderate) Use caution when administering dofetilide concurrently with emtricitabine as both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia.
    Encainide: (Contraindicated) Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Before switching from another antiarrhythmic drug to dofetilide therapy, antiarrhythmics generally should be withheld for at least three half-lives prior to initiating dofetilide. According to the manufacturer, Class I (disopyramide, encainide, flecainide, lidocaine, mexiletine, moricizine, procainamide, propafenone, quinidine, and tocainide) and Class III (e.g., amiodarone, bretylium, ibutilide, and sotalol) antiarrhythmic agents are associated with QT prolongation and ventricular arrhythmias and concurrent exposure with dofetilide could increase the risk of dofetilide-induced proarrhythmias.
    Encorafenib: (Major) Avoid coadministration of encorafenib and dofetilide due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Enflurane: (Major) Coadministration of dofetilide and halogenated anesthetics is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Halogenated anesthetics can prolong the QT interval.
    Entecavir: (Major) In the manufacturers package label for dofetilide, administration of drugs that are excreted via renal tubular secretion should be used very cautiously, if at all, with dofetilide. Entecavir is also excreted via renal tubular excretion.
    Entrectinib: (Major) Avoid coadministration of entrectinib with dofetilide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Erdafitinib: (Contraindicated) Coadministration of dofetilide with erdafitinib is contraindicated due to the risk of increased dofetilide exposure which may be associated with QT prolongation. Dofetilide is eliminated in the kidney by cationic secretion. Erdafitinib is an inhibitor of the renal uptake transporter organic cation transporter 2 (OCT2).
    Eribulin: (Major) Coadministration of dofetilide and eribulin is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Eribulin has been associated with QT prolongation.
    Ertugliflozin; Metformin: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
    Erythromycin: (Major) Coadministration of dofetilide and erythromycin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Erythromycin is associated with QT prolongation and TdP. In addition, erythromycin may theoretically increase plasma concentrations of dofetilide via inhibition of CYP3A4. Higher antiarrhythmic plasma concentrations increase the potential risk of QT prolongation, TdP, or other proarrhythmias.
    Erythromycin; Sulfisoxazole: (Major) Coadministration of dofetilide and erythromycin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Erythromycin is associated with QT prolongation and TdP. In addition, erythromycin may theoretically increase plasma concentrations of dofetilide via inhibition of CYP3A4. Higher antiarrhythmic plasma concentrations increase the potential risk of QT prolongation, TdP, or other proarrhythmias.
    Escitalopram: (Major) Coadministration of dofetilide and escitalopram is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Escitalopram has been associated with a risk of QT prolongation and TdP.
    Everolimus: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with everolimus is necessary. Everolimus is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Ezogabine: (Major) Coadministration of dofetilide and ezogabine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Ezogabine has been associated with QT prolongation.
    Fedratinib: (Moderate) Monitor for an increase in dofetilide-related adverse effects, including QT prolongation and torsade de pointes (TdP), if coadministered with fedratinib. Coadministration may increase the exposure of dofetilide. Dofetilide is a CYP3A substrate; fedratinib is a moderate CYP3A inhibitor.
    Fingolimod: (Contraindicated) Fingolimod is contraindicated in patients requiring treatment with dofetilide, a Class III antiarrhythmic. Fingolimod treatment results in decreased heart rate and may prolong the QT interval. Dofetilide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Flecainide: (Major) Coadministration of dofetilide and flecainide is not recommended as concurrent use may increase the risk of QT prolongation. Class I antiarrhythmic agents, such as flecainide, should be withheld for at least 3 half-lives prior to initiating dofetilide therapy. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Contraindicated) Coadministration of dofetilide and fluconazole is contraindicated as concurrent use may increase the risk of QT prolongation and torsade de pointes (TdP). Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Fluconazole has been associated with QT prolongation and rare cases of TdP. Additionally, fluconazole is also an inhibitor of CYP3A4, which could increase dofetilide exposure, further increasing the risk of cardiac events.
    Fludrocortisone: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Flunisolide: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Fluoxetine: (Major) Coadministration of dofetilide and fluoxetine is not recommended as concurrent use may increase the risk of QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. The use of dofetilide with other drugs that prolong the QT interval has not been studied and is not recommended.
    Fluoxetine; Olanzapine: (Major) Coadministration of dofetilide and fluoxetine is not recommended as concurrent use may increase the risk of QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. The use of dofetilide with other drugs that prolong the QT interval has not been studied and is not recommended. (Major) Coadministration of dofetilide and olanzapine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Fluphenazine: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as dofetilide.
    Fluticasone: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Fluticasone; Salmeterol: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide. (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide. (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Vilanterol: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide. (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluvoxamine: (Major) Coadministration of dofetilide and fluvoxamine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have also been reported during fluvoxamine postmarketing use. Additionally, fluvoxamine is also an inhibitor of CYP3A4, which could increase dofetilide exposure, further increasing the risk of cardiac events.
    Formoterol: (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Formoterol; Mometasone: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide. (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fosamprenavir: (Major) Coadministration of CYP3A4 inhibitors, such as fosamprenavir, with dofetilide may decrease the metabolism of dofetilide, thereby increasing the potential for QT prolongation. Dofetilide is a Class III antiarrhythmic agent that has a well-established risk of QT prolongation and torsade de pointes (TdP). Plasma dofetilide concentrations are correlated with the risk of drug-induced proarrhythmias.
    Foscarnet: (Major) Coadministration of dofetilide and foscarnet is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Both QT prolongation and TdP have been reported during postmarketing use of foscarnet.
    Fostamatinib: (Moderate) Monitor for dofetilide toxicities that may require dofetilide dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a CYP3A4 substrate may increase the concentration of the CYP3A4 substrate. The active metabolite of fostamatinib, R406, is a CYP3A4 inhibitor; dofetilide is a substrate for CYP3A4. Coadministration of fostamatinib with a sensitive CYP3A4 substrate increased the substrate AUC by 64% and Cmax by 113%.
    Fostemsavir: (Major) Coadministration of dofetilide and fostemsavir is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, 4 times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
    Gemifloxacin: (Major) Coadministration of dofetilide and gemifloxacin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Coadministration of dofetilide and gemtuzumab is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
    Gilteritinib: (Major) Coadministration of dofetilide and gilteritinib is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Gilteritinib has been associated with QT prolongation.
    Glasdegib: (Major) Avoid coadministration of glasdegib with dofetilide due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Glipizide; Metformin: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
    Glyburide; Metformin: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
    Glycopyrrolate; Formoterol: (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Goserelin: (Major) Coadministration of dofetilide and goserelin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval.
    Granisetron: (Major) Coadministration of dofetilide and granisetron is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Granisetron has been associated with QT prolongation.
    Grapefruit juice: (Major) Clinicians should be aware that food interactions with dofetilide are possible. Grapefruit juice inhibits the cytochrome P-450 3A4 isozyme in the gut wall. Grapefruit juice contains furanocoumarins that are metabolized by CYP3A4 to reactive intermediates. These intermediates form a covalent bond to the active site of the CYP3A4 enzyme, causing irreversible inactivation (mechanism-based inhibition). Consequently, CYP3A4 activity in the gut wall is inhibited until de novo synthesis returns the enzyme to its previous level. According to the manufacturer of dofetilide, caution should be used when coadministering with grapefruit juice. Elderly patients have the greatest possibility of ingesting grapefruit and interacting medications and are the most vulnerable to the adverse clinical consequences.
    Halogenated Anesthetics: (Major) Coadministration of dofetilide and halogenated anesthetics is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Halogenated anesthetics can prolong the QT interval.
    Haloperidol: (Major) Coadministration of dofetilide and haloperidol is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Halothane: (Major) Coadministration of dofetilide and halogenated anesthetics is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Halogenated anesthetics can prolong the QT interval.
    Histrelin: (Major) Coadministration of dofetilide and histrelin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Hydrochlorothiazide, HCTZ; Triamterene: (Major) Drugs that are actively secreted via cationic tubular secretion, such as triamterene, should be co-administered with caution with dofetilide since they could increase dofetilide plasma concentrations via potential competition for renal cationic secretion. Increased dofetilide plasma concentrations may be associated with proarrhythmias.
    Hydrocortisone: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Hydroxychloroquine: (Major) Avoid coadministration of dofetilide and hydroxychloroquine due to the risk of increased QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Hydroxychloroquine also prolongs the QT interval.
    Hydroxyzine: (Major) Coadministration of dofetilide and hydroxyzine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP.
    Ibutilide: (Major) Coadministration of dofetilide and ibutilide is not recommended as concurrent use may increase the risk of QT prolongation. Class III antiarrhythmic agents, such as ibutilide, should be withheld for at least 3 half-lives prior to initiating dofetilide therapy. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Ibutilide administration can cause QT prolongation and TdP; proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Iloperidone: (Major) Coadministration of dofetilide and iloperidone is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Iloperidone has been associated with QT prolongation.
    Imatinib: (Major) Imatinib could significantly inhibit the CYP3A4 metabolism of dofetilide. The resultant increase in serum dofetilide concentrations could increase the risk of torsade de pointes.
    Imipramine: (Minor) Coadministration of dofetilide and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Indacaterol: (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indapamide: (Major) Indapamide may induce hypokalemia, increasing the potential for proarrhythmic effects (e.g., torsade de pointes) of dofetilide. Potassium levels should be within the normal range prior and during administration of these agents. In the absence of electrolyte imbalances, these agents can be used together safely.
    Indinavir: (Major) Coadministration of CYP3A4 inhibitors, such as indinavir, with dofetilide may decrease the metabolism of dofetilide, thereby increasing the potential for QT prolongation. Dofetilide is a Class III antiarrhythmic agent that has a well-established risk of QT prolongation and torsade de pointes (TdP). Plasma dofetilide concentrations are correlated with the risk of drug-induced proarrhythmias.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab with dofetilide due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs and electrolytes prior to the start of treatment and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP.
    Isavuconazonium: (Contraindicated) Concurrent use of isavuconazonium with dofetilide is contraindicated due to the potential for increased dofetilide exposure resulting in serious and life-threatening adverse events, such as QT prolongation and torsade de pointes (TdP). Isavuconazonium inhibits the renal organic cation transporter OCT2, and dofetilide is eliminated via this transporter.
    Isoflurane: (Major) Coadministration of dofetilide and halogenated anesthetics is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Halogenated anesthetics can prolong the QT interval.
    Isoniazid, INH: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with isoniazid is necessary. Isoniazid is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with isoniazid is necessary. Isoniazid is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Isoniazid, INH; Rifampin: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with isoniazid is necessary. Isoniazid is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Istradefylline: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with istradefylline 40 mg daily is necessary. Istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Itraconazole: (Contraindicated) Use of dofetilide during and for 2 weeks after discontinuation of itraconazole treatment is contraindicated due to the potential elevated dofetilide concentrations and QT prolongation. Serious cardiovascular events including EKG changes (i.e., QT prolongation), cardiac arrhythmias, including ventricular arrhythmias and torsade de pointes, cardiac arrest, and sudden death may occur when these drugs are administered together. Itraconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation. Dofetilide is a CYP3A4 substrate that is associated with QT prolongation and torsade de pointes (TdP).
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with dofetilide due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Ketoconazole: (Contraindicated) Concurrent use of dofetilide with ketoconazole is contraindicated due to the risk of serious cardiovascular events. Ketoconazole co-administered with dofetilide for 7 days has been shown to increase dofetilide Cmax by 53% in males and 97% in females, and increase dofetilide AUC by 41% in males and 69% in females. This interaction is proposed to occur primarily by inhibition of cationic renal tubular secretion of dofetilide by ketoconazole, however, inhibition of CYP 3A4 metabolism may also contribute.
    Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction, such as Class III antiarrhythmics, because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
    Lamivudine, 3TC: (Moderate) Drugs that are actively secreted via cationic secretion, such as lamivudine, should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion.
    Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Drugs that are actively secreted via cationic secretion, such as lamivudine, should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Dofetilide should be co-administered with tenofovir, PMPA with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of dofetilide is recommended. (Moderate) Drugs that are actively secreted via cationic secretion, such as lamivudine, should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion.
    Lamotrigine: (Major) Coadministration of lamotrigine and dofetilide is not recommended. Coadministration may decrease dofetilide clearance, resulting in increased plasma concentrations and the potential for serious adverse events, including QT prolongation and cardiac arrhythmias. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and dofetilide is excreted via this route.
    Lapatinib: (Major) Coadministration of dofetilide and lapatinib is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Larotrectinib: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with larotrectinib is necessary. larotrectinib is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Lefamulin: (Major) Avoid coadministration of lefamulin with dofetilide as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP.
    Lenvatinib: (Major) Coadministration of dofetilide and lenvatinib is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Prolongation of the QT interval has been reported with lenvatinib therapy.
    Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of dofetilide may occur if given with letermovir; monitor patient closely for dofetilide-related adverse events. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Dofetilide is metabolized to a small degree by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
    Leuprolide: (Major) Coadministration of dofetilide and leuprolide is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Major) Coadministration of dofetilide and leuprolide is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
    Levalbuterol: (Minor) Coadministration of dofetilide and short-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Levamlodipine: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with amlodipine is necessary. Amlodipine is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Levofloxacin: (Major) Coadministration of dofetilide and levofloxacin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Levofloxacin has been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Lidocaine: (Contraindicated) Concurrent exposure of systemic lidocaine with dofetilide could increase the risk of dofetilide-induced proarrhythmias. Before switching from lidocaine to dofetilide therapy, lidocaine generally should be withheld for at least three half-lives prior to initiating dofetilide. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP).
    Lidocaine; Prilocaine: (Contraindicated) Concurrent exposure of systemic lidocaine with dofetilide could increase the risk of dofetilide-induced proarrhythmias. Before switching from lidocaine to dofetilide therapy, lidocaine generally should be withheld for at least three half-lives prior to initiating dofetilide. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP).
    Linagliptin; Metformin: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
    Lithium: (Major) Coadministration of dofetilide and lithium is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Lithium has been associated with QT prolongation.
    Lofexidine: (Major) Coadministration of dofetilide and lofexidine is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval.
    Lonafarnib: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with lonafarnib is necessary as concurrent use may increase dofetilide exposure. Dofetilide is a minor CYP3A4 substrate and lonarfarnib is a strong CYP3A4 inhibitor; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmias (torsade de pointes).
    Long-acting beta-agonists: (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Loop diuretics: (Major) Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting drugs such as loop diuretics increasing the potential for dofetilide-induced torsade de pointes. Potassium levels should be within the normal range prior and during administration of dofetilide.
    Loperamide: (Major) Coadministration of dofetilide and loperamide is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest.
    Loperamide; Simethicone: (Major) Coadministration of dofetilide and loperamide is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with dofetilide due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). (Moderate) Concomitant use of dofetilide and ritonavir may increase the risk of QT prolongation and torsade de pointes (TdP) due to increased dofetilide exposure. Dofetilide is metabolized to a small degree by CYP3A4; ritonavir is a potent inhibitor of CYP3A4.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as dofetilide. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Maprotiline: (Major) Coadministration of dofetilide and maprotiline is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Mefloquine: (Major) Coadministration of dofetilide and mefloquine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
    Megestrol: (Contraindicated) All inhibitors of renal cationic secretion, including megestrol, are contraindicated with dofetilide. In a population pharmacokinetic analysis of plasma dofetilide concentrations, the mean clearance of dofetilide was 15% lower in patients receiving inhibitors of tubular organic cation transport.
    Memantine: (Major) Drugs that are actively secreted via cationic secretion (e.g., memantine) should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion. Competition for renal elimination may increase plasma concentrations of dofetilide and increase the risk of pro-arrhythmias.
    Meperidine; Promethazine: (Major) Coadministration of dofetilide and promethazine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Metaproterenol: (Minor) Coadministration of dofetilide and short-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Metformin: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
    Metformin; Pioglitazone: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
    Metformin; Repaglinide: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
    Metformin; Rosiglitazone: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
    Metformin; Saxagliptin: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
    Metformin; Sitagliptin: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
    Methadone: (Major) Coadministration of dofetilide and methadone is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Methadone is considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Methylprednisolone: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Metronidazole: (Major) Coadministration of dofetilide and metronidazole is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Potential QT prolongation has been reported in limited case reports with metronidazole.
    Mexiletine: (Contraindicated) Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Before switching from another antiarrhythmic drug to dofetilide therapy, antiarrhythmics generally should be withheld for at least three half-lives prior to initiating dofetilide. According to the manufacturer, Class I (disopyramide, encainide, flecainide, lidocaine, mexiletine, moricizine, procainamide, propafenone, quinidine, and tocainide) antiarrhythmic agents are associated with QT prolongation and ventricular arrhythmias and concurrent exposure with dofetilide could increase the risk of dofetilide-induced proarrhythmias.
    Midostaurin: (Major) Coadministration of dofetilide and midostaurin is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, consider interval assessments of QT by EKG. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). QT prolongation was reported in patients who received midostaurin in clinical trials.
    Mifepristone: (Major) Coadministration of dofetilide and mifepristone is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Mifepristone is associated with dose-related prolongation of the QT interval. Additionally, dofetilide is metabolized to a small extent by CYP3A4, and inhibitors of CYP3A4, such as mifepristone, could increase systemic dofetilide exposure, further increasing the risk for QT prolongation.
    Mirtazapine: (Major) Coadministration of dofetilide and mirtazapine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Mirtazapine has been associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Mometasone: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Moricizine: (Contraindicated) In general, combination therapy with Class IC and Class III antiarrhythmics has been reported to increase the risk of proarrhythmias. Before switching from moricizine to dofetilide therapy, moricizine generally should be withheld for at least three half-lives prior to initiating dofetilide. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Class I antiarrhythmic agents are contraindicated with dofetilide, and may increase the risk of dofetilide-induced proarrhythmias.
    Moxifloxacin: (Major) Coadministration of dofetilide and moxifloxacin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Quinolones have been associated with a risk of QT prolongation. Although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nefazodone: (Major) Nefazodone may reduce the metabolism of dofetilide via CYP3A4 inhibition. This interaction may result in increased dofetilide plasma concentrations and risk for QTc prolongation.
    Nelfinavir: (Major) Coadministration of CYP3A4 inhibitors, such as nelfinavir, with dofetilide may decrease the metabolism of dofetilide, thereby increasing the potential for QT prolongation. Dofetilide is a Class III antiarrhythmic agent that has a well-established risk of QT prolongation and torsade de pointes (TdP). Plasma dofetilide concentrations are correlated with the risk of drug-induced proarrhythmias.
    Nevirapine: (Minor) Coadministration of dofetilide with inducers of CYP3A4, such as nevirapine, may increase the metabolism of dofetilide.
    Nicardipine: (Moderate) Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including doeftilide.
    Nilotinib: (Major) Coadministration of dofetilide and nilotinib is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
    Norfloxacin: (Contraindicated) Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, torsade de pointes has been reported during post-marketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Because of the potential for TdP, use of dofetilide with norfloxacin is contraindicated.
    Nortriptyline: (Minor) Coadministration of dofetilide and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Octreotide: (Major) Coadministration of dofetilide and octreotide is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Major) Coadministration of dofetilide and ofloxacin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Major) Coadministration of dofetilide and olanzapine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olodaterol: (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concomitant use of dofetilide and ritonavir may increase the risk of QT prolongation and torsade de pointes (TdP) due to increased dofetilide exposure. Dofetilide is metabolized to a small degree by CYP3A4; ritonavir is a potent inhibitor of CYP3A4.
    Ondansetron: (Major) Coadministration of dofetilide and ondansetron is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP.
    Osilodrostat: (Major) Coadministration of dofetilide and osilodrostat is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Osilodrostat is associated with dose-dependent QT prolongation.
    Osimertinib: (Major) Avoid coadministration of dofetilide with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Oxaliplatin: (Major) Coadministration of dofetilide and oxaliplatin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). QT prolongation and ventricular arrhythmias including fatal TdP have been reported with oxaliplatin use in postmarketing experience.
    Ozanimod: (Major) In general, do not initiate ozanimod in patients taking dofetilide due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP.
    Palbociclib: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Paliperidone: (Major) Coadministration of dofetilide and paliperidone is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose.
    Panobinostat: (Major) Coadministration of dofetilide and panobinostat is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation has been reported with panobinostat.
    Pasireotide: (Major) Coadministration of dofetilide and pasireotide is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Coadministration of dofetilide and pazopanib is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, closely monitor the patient for QT interval prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Pazopanib has been reported to prolong the QT interval.
    Pentamidine: (Major) Coadministration of dofetilide and pentamidine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of Systemic pentamidine has been associated with QT prolongation.
    Perindopril; Amlodipine: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with amlodipine is necessary. Amlodipine is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Perphenazine: (Minor) Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as dofetilide.
    Perphenazine; Amitriptyline: (Minor) Coadministration of dofetilide and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). (Minor) Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as dofetilide.
    Phenylephrine; Promethazine: (Major) Coadministration of dofetilide and promethazine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Pimavanserin: (Major) Coadministration of dofetilide and pimavanserin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of Pimavanserin prolongs the QT interval.
    Pimozide: (Contraindicated) Coadministration of pimozide with dofetilide is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Both drugs are associated with a well-established risk of QT prolongation and TdP.
    Pirbuterol: (Minor) Coadministration of dofetilide and short-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Pitolisant: (Major) Coadministration of dofetilide and pitolisant is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Pitolisant also prolongs the QT interval.
    Posaconazole: (Contraindicated) The concurrent use of posaconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as dofetilide, is contraindicated. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Posaconazole has also been associated with QT prolongation and TdP.
    Prednisolone: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Prednisone: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Prilocaine; Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Primaquine: (Major) Coadministration of dofetilide and primaquine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Primaquine has been associated with QT prolongation.
    Procainamide: (Contraindicated) Coadministration of dofetilide and procainamide is contraindicated as concurrent use may increase the risk of QT prolongation and torsade de pointes (TdP). Class I antiarrhythmic agents, such as procainamide, should be withheld for at least 3 half-lives prior to initiating dofetilide therapy. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Procainamide is also associated with a well-established risk of QT prolongation and TdP.
    Prochlorperazine: (Contraindicated) Coadministration of dofetilide and prochlorperazine is contraindicated as concurrent use may increase the risk QT prolongation and torsades de pointes (TdP). Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Prochlorperazine is associated with a possible risk for QT prolongation. Additionally, prochlorperazine is an inhibitor of the renal cation transport system which may result in increased dofetilide exposure, further increasing the risk of cardiac-related adverse effects.
    Promethazine: (Major) Coadministration of dofetilide and promethazine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Propafenone: (Major) Coadministration of dofetilide and propafenone is not recommended as concurrent use may increase the risk of QT prolongation. Class I antiarrhythmic agents, such as propafenone, should be withheld for at least 3 half-lives prior to initiating dofetilide therapy. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Protriptyline: (Minor) Coadministration of dofetilide and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Quetiapine: (Major) Coadministration of dofetilide and quetiapine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances.
    Quinidine: (Contraindicated) Coadministration of dofetilide and quinidine is contraindicated as concurrent use may increase the risk QT prolongation and torsades de pointes (TdP). Class I antiarrhythmic agents, such as quinidine, should be withheld for at least 3 half-lives prior to initiating dofetilide therapy. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Quinidine administration is associated with QT prolongation and TdP.
    Quinine: (Contraindicated) Coadministration of dofetilide and quinine is contraindicated as concurrent use may increase the risk QT prolongation and torsades de pointes (TdP). Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Quinine has been associated with QT prolongation and rare cases of TdP.
    Ranolazine: (Major) Coadministration of dofetilide and ranolazine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
    Relugolix: (Major) Coadministration of dofetilide and relugolix is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
    Ribociclib: (Major) Coadministration of dofetilide and ribociclib is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption.
    Ribociclib; Letrozole: (Major) Coadministration of dofetilide and ribociclib is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption.
    Rilpivirine: (Major) Coadministration of dofetilide and rilpivirine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Risperidone: (Major) Coadministration of dofetilide and risperidone is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting.
    Ritonavir: (Moderate) Concomitant use of dofetilide and ritonavir may increase the risk of QT prolongation and torsade de pointes (TdP) due to increased dofetilide exposure. Dofetilide is metabolized to a small degree by CYP3A4; ritonavir is a potent inhibitor of CYP3A4.
    Romidepsin: (Major) Coadministration of dofetilide and romidepsin is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor electrolytes and ECGs at baseline and periodically during treatment. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Romidepsin has been reported to prolong the QT interval.
    Rucaparib: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with rucaparib is necessary. Rucaparib is a weak CYP3A4 inhibitor and dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Salmeterol: (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Saquinavir: (Contraindicated) Coadministration of saquinavir boosted with ritonavir with dofetilide is contraindicated as concurrent use may increase dofetilide exposure and risk of QT prolongation. Saquinavir boosted with ritonavir is strong CYP3A4 inhibitor that increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Dofetilide, a Class III antiarrhythmic agent, is a CYP3A4 substrate that is associated with a well-established risk of QT prolongation and TdP.
    Selpercatinib: (Major) Coadministration of dofetilide and selpercatinib is not recommended as concurrent use may increase the risk of QT prolongation. Monitor ECGs more frequently for QT prolongation if coadministration is necessary. Dofetilide exposure may be increased. Dofetilide, a Class III antiarrhythmic agent, is a CYP3A4 substrate that is associated with a well-established risk of QT prolongation and TdP. Selpercatinib is a weak CYP3A4 inhibitor that is associated with concentration-dependent QT prolongation.
    Sertraline: (Major) Coadministration of dofetilide and sertraline is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, use caution and monitor patients for signs and symptoms of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although sertralines FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Sevoflurane: (Major) Coadministration of dofetilide and halogenated anesthetics is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Halogenated anesthetics can prolong the QT interval.
    Short-acting beta-agonists: (Minor) Coadministration of dofetilide and short-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Siponimod: (Major) Coadministration of dofetilide and siponimod is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, consult a cardiologist regarding appropriate monitoring. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Siponimod therapy prolonged the QT interval at recommended doses in a clinical study.
    Solifenacin: (Major) Coadministration of dofetilide and solifenacin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Solifenacin has been associated with dose-dependent prolongation of the QT interval. TdP has been reported with postmarketing use, although causality was not determined.
    Sorafenib: (Major) Coadministration of dofetilide and sorafenib is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Sorafenib is associated with QTc prolongation.
    Sotalol: (Major) Coadministration of dofetilide and sotalol is not recommended as concurrent use may increase the risk of QT prolongation. Class III antiarrhythmic agents, such as sotalol, should be withheld for at least 3 half-lives prior to initiating dofetilide therapy. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Sotalol administration is associated with QT prolongation and torsade de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    St. John's Wort, Hypericum perforatum: (Major) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system, including CYP3A4, Co-administration of St. John's wort could decrease the efficacy of some medications metabolized by CYP3A4, such as dofetilide. Clinicians should observe patients closely if St. John's wort is used.
    Streptogramins: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with dalfopristin; quinupristin is necessary. Dalfopristin; quinupristin is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Contraindicated) Concomitant use of dofetilide with trimethoprim is contraindicated due to increased plasma concentrations of dofetilide, which may cause serious ventricular arrhythmias associated with QT prolongation, including torsade de pointes (TdP). Trimethoprim is an inhibitor of the renal cation transport system and decreases the active tubular secretion of dofetilide. The combination of trimethoprim 160 mg and 800 mg sulfamethoxazole co-administered twice daily with dofetilide 500 mcg for 4 days has been shown to increase dofetilide AUC by 93% and Cmax by 103%.
    Sunitinib: (Major) Coadministration of dofetilide and sunitinib is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Sunitinib can prolong the QT interval.
    Tacrolimus: (Major) Coadministration of dofetilide and tacrolimus is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG and electrolytes periodically during treatment. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Tacrolimus may prolong the QT interval and cause TdP.
    Tafenoquine: (Contraindicated) Coadministration of dofetilide and tafenoquine is contraindicated due to the potential for increased dofetilide concentrations and arrhythmias (QT prolongation and torsade de pointes). The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like dofetilide, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Dofetilide is eliminated by cationic renal secretion, and tafenoquine may interfere with the renal elimination of dofetilide.
    Tamoxifen: (Major) Coadministration of dofetilide and tamoxifen is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Telavancin: (Major) Coadministration of dofetilide and telavancin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Telavancin has been associated with QT prolongation.
    Telithromycin: (Major) Coadministration of dofetilide and telithromycin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Telithromycin is also associated with QT prolongation and TdP.
    Tenofovir Alafenamide: (Major) Dofetilide should be co-administered with tenofovir alafenamide with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of dofetilide is recommended.
    Tenofovir, PMPA: (Major) Dofetilide should be co-administered with tenofovir, PMPA with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of dofetilide is recommended.
    Terbutaline: (Minor) Coadministration of dofetilide and short-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tetrabenazine: (Major) Coadministration of dofetilide and tetrabenazine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Tetrabenazine causes a small increase in the corrected QT interval (QTc).
    Thiazide diuretics: (Contraindicated) Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting drugs such as loop diuretics and thiazide diuretics, increasing the potential for dofetilide-induced torsade de pointes. Additionally, in patients treated with either hydrochlorothiazide 50 mg or hydrochlorothiazide/triamterene 50 mg/100 mg daily in combination with dofetilide 500 mcg twice daily for 5 days, dofetilide AUC and Cmax concentrations increased by 27% and 21%, respectively, for the hydrochlorothiazide alone group and by 30% and 16%, respectively, for the hydrochlorothiazide/triamterene group. Furthermore, a 197% and 190% QTc increase over time was seen in the hydrochlorothiazide and hydrochlorothiazide/triamterene groups, respectively. Based on these findings, the manufacturer of dofetilide contraindicates the concomitant use of hydrochlorothiazide (alone or in combination with other drugs such as triamterene); these findings can be explained both by an increase in the plasma concentration of dofetilide and a reduction in the serum potassium concentration. In a population pharmacokinetic analysis of plasma dofetilide concentrations, the mean dofetilide clearance of dofetilide was 16% lower in patients on thiazide diuretics. It is prudent to avoid the use of any thiazide diuretic in combination with dofetilide.
    Thioridazine: (Contraindicated) Coadministration of thioridazine with dofetilide is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Both drugs are associated with a well-established risk of QT prolongation and TdP.
    Tiotropium; Olodaterol: (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tipranavir: (Major) Coadministration of CYP3A4 inhibitors, such as tipranavir, with dofetilide may decrease the metabolism of dofetilide, thereby increasing the potential for QT prolongation. Dofetilide is a Class III antiarrhythmic agent that has a well-established risk of QT prolongation and torsade de pointes (TdP). Plasma dofetilide concentrations are correlated with the risk of drug-induced proarrhythmias.
    Tocainide: (Contraindicated) Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Before switching from another antiarrhythmic drug to dofetilide therapy, antiarrhythmics generally should be withheld for at least three half-lives prior to initiating dofetilide. According to the manufacturer, Class I (disopyramide, encainide, flecainide, lidocaine, mexiletine, moricizine, procainamide, propafenone, quinidine, and tocainide) and Class III (e.g., amiodarone, bretylium, ibutilide, and sotalol) antiarrhythmic agents are associated with QT prolongation and ventricular arrhythmias and concurrent exposure with dofetilide could increase the risk of dofetilide-induced proarrhythmias.
    Tolterodine: (Major) Coadministration of dofetilide and tolterodine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Toremifene: (Major) Coadministration of dofetilide and toremifene is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, closely monitor ECGs for QT prolongation and monitor electrolytes. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Trandolapril; Verapamil: (Contraindicated) The concomitant use of verapamil (CYP3A4 inhibitor) and dofetilide is contraindicated. Coadministration of dofetilide with verapamil increased dofetilide peak plasma concentrations by 42%, although the overall exposure to dofetilide was not significantly increased. Concurrent use of verapamil and dofetilide was also associated with a higher occurrence of torsade de pointes in dofetilide clinical trials.
    Trazodone: (Major) Coadministration of dofetilide and trazodone is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP.
    Triamcinolone: (Major) Corticosteroids can cause increases in blood pressure, sodium and water retention, and hypokalemia, predisposing patients to interactions with certain other medications. Corticosteroid-induced hypokalemia could also enhance the proarrhythmic effects of dofetilide.
    Triamterene: (Major) Drugs that are actively secreted via cationic tubular secretion, such as triamterene, should be co-administered with caution with dofetilide since they could increase dofetilide plasma concentrations via potential competition for renal cationic secretion. Increased dofetilide plasma concentrations may be associated with proarrhythmias.
    Triclabendazole: (Major) Coadministration of dofetilide and triclabendazole is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECGs during treatment. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Transient prolongation of the mean QTc interval was noted on the ECG recordings in dogs administered triclabendazole.
    Tricyclic antidepressants: (Minor) Coadministration of dofetilide and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Trifluoperazine: (Minor) Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation such as dofetilide.
    Trilaciclib: (Contraindicated) Concomitant use of dofetilide and trilaciclib is contraindicated. This combination may increase dofetilide exposure and the risk of dofetilide-related adverse effects including drug-induced QT prolongation and torsade de pointes (TdP). Dofetilide is an OCT2 substrate; trilaciclib is an OCT2 inhibitor.
    Trimethoprim: (Contraindicated) Concomitant use of dofetilide with trimethoprim is contraindicated due to increased plasma concentrations of dofetilide, which may cause serious ventricular arrhythmias associated with QT prolongation, including torsade de pointes (TdP). Trimethoprim is an inhibitor of the renal cation transport system and decreases the active tubular secretion of dofetilide. The combination of trimethoprim 160 mg and 800 mg sulfamethoxazole co-administered twice daily with dofetilide 500 mcg for 4 days has been shown to increase dofetilide AUC by 93% and Cmax by 103%.
    Trimipramine: (Minor) Coadministration of dofetilide and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Triptorelin: (Major) Coadministration of dofetilide and triptorelin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval.
    Trospium: (Major) Drugs that are actively secreted via cationic secretion (e.g., trospium) should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion.
    Tucatinib: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with tucatinib is necessary as concurrent use may increase dofetilide exposure. Tucatinib is a strong CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Umeclidinium; Vilanterol: (Moderate) Coadministration of dofetilide and long-acting beta-agonists may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Vandetanib: (Major) Coadministration of dofetilide and vandetanib is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib.
    Vardenafil: (Major) Coadministration of dofetilide and vardenafil is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Vemurafenib: (Major) Coadministration of dofetilide and vemurafenib is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Vemurafenib has been associated with QT prolongation.
    Venlafaxine: (Major) Coadministration of dofetilide and venlafaxine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has been reported with postmarketing use.
    Verapamil: (Contraindicated) The concomitant use of verapamil (CYP3A4 inhibitor) and dofetilide is contraindicated. Coadministration of dofetilide with verapamil increased dofetilide peak plasma concentrations by 42%, although the overall exposure to dofetilide was not significantly increased. Concurrent use of verapamil and dofetilide was also associated with a higher occurrence of torsade de pointes in dofetilide clinical trials.
    Voclosporin: (Major) Concomitant use of dofetilide and voclosporin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Voclosporin has been associated with QT prolongation with supratherapeutic doses.
    Voriconazole: (Major) Coadministration of dofetilide and voriconazole is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Voriconazole has been associated with QT prolongation and rare cases of TdP.
    Vorinostat: (Major) Coadministration of dofetilide and vorinostat is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Vorinostat therapy is associated with a risk of QT prolongation.
    Voxelotor: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with voxelotor is necessary as concurrent use may increase dofetilide exposure. Voxelotor is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Zafirlukast: (Major) Zafirlukast, a CYP 3A4 inhibitor, may increase plasma dofetilide concentrations with potential for dofetilide toxicity.
    Ziprasidone: (Contraindicated) Concomitant use of ziprasidone and class III antiarrhythmics, such as dofetilide, is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Class III antiarrhythmics are associated with a well-established risk of QT prolongation and TdP.

    PREGNANCY AND LACTATION

    Pregnancy

    No adequate and well-controlled studies have been conducted in pregnant women, and it is unknown if use of dofetilide during pregnancy increases the risk for adverse maternal or fetal outcomes. Dofetilide should only be administered to pregnant women when the benefits to the mother justify the potential fetal risks. Animal studies using oral dofetilide revealed evidence of a variety of adverse effects, including effects on in utero growth and survival when administered during organogenesis at doses of 2 mg/kg/day or more. The "no observed adverse effect dose" in both rat and mouse species was 0.5 mg/kg/day; the mean dofetilide exposure (AUC) at this dose in the rat and mouse are estimated to be about equal to the maximum likely human AUC and about half the likely human AUC, respectively.[28221]

    It is not known whether dofetilide is excreted into breast milk. Women should be advised to avoid breast-feeding an infant while taking dofetilide.

    MECHANISM OF ACTION

    Dofetilide is an antiarrhythmic drug with Vaughn Williams Class III (cardiac action potential duration prolonging) properties. The specific mechanism of action is selective blockade of the cardiac ion channel which carries the rapid component of the delayed rectifier potassium current; dofetilide does not block the other repolarizing potassium currents. Due to selective and potent blockade of potassium channels, dofetilide prolongs ventricular refractoriness (i.e., widens the QT interval); prolongs the action potential duration; prolongs the effective refractory period; and does not affect ventricular conduction time. Doefetilide does not affect calcium channels. At clinically relevant concentrations, dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors. Dofetilide increases the monophasic action potential duration in a predictable, concentration-dependent manner, primarily due to delayed repolarization. This effect, and the related increase in effective refractory period, is observed in the atria and ventricles in electrophysiology studies. The increase in QT interval observed on the ECG is a result of prolongation of both effective and functional refractory periods in the His-Purkinje system and the ventricles.
     
    Dofetilide did not influence cardiac conduction velocity and sinus node function in a variety of studies in patients with or without structural heart disease. This is consistent with a lack of effect of dofetilide on the PR interval and QRS width in patients with pre-existing heart block and/or sick sinus syndrome.
     
    Dofetilide terminates induced re-entrant tachyarrhythmias (e.g. atrial fibrillation/flutter and ventricular tachycardia) and prevents their re-induction. Dofetilide does not increase the electrical energy required to convert electrically-induced ventricular fibrillation, and it significantly reduces the defibrillation threshold in patients with ventricular tachycardia and ventricular fibrillation undergoing implantation of a cardioverter-defibrillator device.
     
    In hemodynamic studies, dofetilide had no effect on cardiac output, cardiac index, stroke volume index, or systemic vascular resistance in patients with ventricular tachycardia, mild to moderate congestive heart failure or angina and either normal or low left ventricular ejection fraction. There was no evidence of a negative inotropic effect related to dofetilide therapy in patients with atrial fibrillation. There was no increase in heart failure in patients with significant left ventricular dysfunction. Generally, dofetilide does not affect blood pressure; however it may reduce heart rate by about 4-6 beats per minute.

    PHARMACOKINETICS

    Dofetilide is administered orally. The terminal half-life is approximately 10 hours, and steady state plasma concentrations are attained within 2 to 3 days. Plasma protein binding is 60% to 70%, and is independent of plasma concentration and renal function. The volume of distribution is about 3 L/kg. Metabolites are formed by N-dealkylation and N-oxidation. There are no quantifiable metabolites circulating in plasma, but five metabolites have been identified in the urine. In vitro studies with human hepatic microsomes show that dofetilide is metabolized to some extent by CYP3A4, although it has a low affinity for this isoenzyme. Approximately 80% of a single dose is excreted in urine, of which approximately 80% is excreted as unchanged dofetilide and the remaining 20% consists of inactive or minimally active metabolites. Renal elimination involves both glomerular filtration as well as active tubular secretion via the cation transport system, a process that can be inhibited by cimetidine and ketoconazole. Use is contraindicated for renal cation transport inhibitors.
     
    Affected cytochrome P450 isoenzymes: CYP3A4
    Dofetilide is a substrate of CYP3A4, although it has a low affinity for this enzyme. Erythromycin, a potent CYP3A4 inhibitor, significantly increases dofetilide plasma concentrations. Dofetilide does not inhibit CYP3A4 or other cytochrome P450 isoenzymes. 

    Oral Route

    The oral bioavailability of dofetilide is greater than 90% with maximal plasma concentrations occurring in about 2 to 3 hours in fasted patients. The oral bioavailability is unaffected by food or antacids. Dofetilide plasma concentrations are linearly related to drug dosage.