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    Anti-arrhythmics, Class I-C

    BOXED WARNING

    Alcoholism, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, mortality, myocardial infarction, QT prolongation, thyroid disease

    Propafenone is a Class IC antiarrhythmic which has proarrhythmic properties; cardiac arrhythmias may be induced or exacerbated. Propafenone increases the QT interval, but largely due to prolongation of the QRS interval. QT prolongation and torsade de pointes (TdP) have occurred during propafenone therapy. Therefore, propafenone should be avoided when possible in patients with congenital or acquired long QT syndrome or in patients with a history of TdP. The use of propafenone in conjunction with other drugs that prolong the QT interval has not been studied and is not recommended by the manufacturer due to potential risk for ventricular tachycardia, including TdP and monomorphic ventricular tachycardia. Further, use propafenone with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation. The CAST trial, a randomized double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias, demonstrated an excessive rate of mortality or non-fatal cardiac arrest in patients treated with encainide or flecainide (7.7%) compared to placebo (3%). The enrolled patients had a history of myocardial infarction (more than 6 days but less than 2 years); the average duration of antiarrhythmic therapy was 10 months. The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) or other antiarrhythmics is uncertain. The manufacturer for propafenone advises that it is prudent to consider Class 1C antiarrhythmics to have significant risks in patients with structural heart disease. Given the lack of evidence for improved survival, the use of propafenone or other antiarrhythmic agents should generally be avoided in patients with non-life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant symptoms or signs which are not life-threatening.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral class IC antiarrhythmic; used to suppress life-threatening ventricular arrhythmias; mechanism similar to encainide and flecainide; possesses beta-blocking activity; proarrhythmic; should be initiated in the hospital to allow for appropriate ECG monitoring.

    COMMON BRAND NAMES

    Rythmol, Rythmol SR

    HOW SUPPLIED

    Propafenone/Propafenone Hydrochloride/Rythmol Oral Tab: 150mg, 225mg, 300mg
    Propafenone/Propafenone Hydrochloride/Rythmol SR Oral Cap ER: 225mg, 325mg, 425mg

    DOSAGE & INDICATIONS

    For the treatment of sustained ventricular tachycardia that is deemed to be life-threatening.
    NOTE: Dosage should be initiated in the hospital setting.
    Oral dosage (immediate-release tablets):
    Adults

    Initially, 150 mg PO every 8 hours. Dosage may be increased, if necessary, after 3 to 4 days to 225 mg PO every 8 hours. Max dosage: 300 mg PO every 8 hours.

    Geriatric

    See adult dosage; however, increase dosage more gradually during initial treatment.

    For the conversion to† and/or maintenance of sinus rhythm in patients with supraventricular arrhythmias in patients without structural heart disease.
    For the maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation or atrial flutter associated with disabling symptoms.
    Oral dosage (immediate-release tablets)
    Adults

    Initially, 150 mg PO every 8 hours. Increase dosage after intervals of 3 to 4 days or more to 225 mg PO every 8 hours, and if necessary, to 300 mg PO every 8 hours. The safety and efficacy of doses more than 900 mg/day have not been established. Consider dose reduction in patients with significant QRS widening or second or third AV block. Clinical practice guidelines recommend propafenone to maintain sinus rhythm in patients with atrial fibrillation without structural heart disease. Avoid use in patients with heart failure and/or left ventricular dysfunction.

    Oral dosage (extended-release capsules)
    Adults

    Initially, 225 mg PO every 12 hours. Increase dosage at intervals of 5 days or more to 325 mg PO every 12 hours, and if necessary, to 425 mg PO every 12 hours. Consider dose reduction in patients with significant QRS widening or second or third AV block. Clinical practice guidelines recommend propafenone to maintain sinus rhythm in patients with atrial fibrillation without structural heart disease. Avoid use in patients with heart failure and/or left ventricular dysfunction.

    For paroxysmal supraventricular tachycardia (PSVT) prophylaxis in patients with AV reentrant tachycardias, including patients with Wolff-Parkinson-White (WPW) syndrome†.
    Oral dosage (immediate-release tablets)
    Adults

    Data are very limited. In one study of 10 patients with WPW, a dosage of 300 mg PO every 8 hours for 48 hours was used to abolish retrograde conduction through the accessory pathway in 6 of 9 patients in whom it was present during control. In another study with a mean follow-up period of 7 +/- 3.5 months, 4 of 10 patients with WPW became asymptomatic on the starting dose of 300 mg PO every 8 hours, while the other 6 patients required doses up to 900 mg PO every 8 hours.

    Children†

    Initially, 8 to 10 mg/kg/day PO in 3 divided doses. Increase by 2 to 3 mg/kg/day every 2 to 3 days, as needed, up to 15 mg/kg/day PO in 3 divided doses. The average dosage required is about 13 to 16 mg/kg/day. Alternatively, an initial dose of 100 to 200 mg/m2/day PO in 3 divided doses can be used. This dose should be increased, as needed, by 100 mg/m2/day every 3 days to a maximum of 600 mg/m2/day PO in 3 divided doses. The average required dose is usually 300 to 380 mg/m2/day.

    Infants†

    Initially, 100 to 200 mg/m2/day PO in 3 divided doses for 3 days or more. This dose may be increased by 100 mg/m2/day every 3 days, if needed, to a maximum of 600 mg/m2/day PO in 3 divided doses. The average dosage is 300 to 500 mg/m2/day.

    For conversion to† sinus rhythm in patients with recent-onset atrial fibrillation.
    Oral dosage (immediate-release tablets)
    Adults

    450 to 600 mg PO as a single dose. Clinical practice guidelines recommend propafenone for pharmacological cardioversion of atrial fibrillation or atrial flutter, if no contraindications exist. Propafenone is also recommended in combination with a beta blocker or nondihydropyridine calcium channel blocker to terminate atrial fibrillation out of the hospital once observed to be safe in a monitored setting. Administer beta blocker or nondihydropyridine calcium channel blocker 30 minutes or more before flecainide. Avoid use in patients with coronary artery disease.

    MAXIMUM DOSAGE

    Adults

    900 mg/day PO immediate-release tablets (Rythmol); 850 mg/day PO extended-release capsules (Rythmol SR).

    Elderly

    900 mg/day PO immediate-release tablets (Rythmol); 850 mg/day PO extended-release capsules (Rythmol SR).

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established; however, doses up to 600 mg/m2/day PO immediate-release tablets have been used off-label for WPW.

    Infants

    Safety and efficacy have not been established; however, doses up to 600 mg/m2/day PO immediate-release tablets have been used off-label for WPW.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Give approximately 20—30% of the normal oral dosage for immediate-release tablets (see Dosage). Severe liver dysfunction increases propafenone bioavailability to approximately 70% compared to 3—40% for normal hepatic function. Although specific guidelines are not available, the manufacturer recommends consideration of dosage reduction for the extended-release capsules (Rythmol SR) in patients with hepatic impairment.

    Renal Impairment

    No dosage adjustment appears to be needed.
     
    Intermittent hemodialysis:
    No dosage adjustment is needed following hemodialysis. Hemodialysis does not appear to significantly affect propafenone clearance.

    ADMINISTRATION

    NOTE: The relative bioavailability of Rythmol SR 325 mg PO twice daily approximates that of immediate-release propafenone 150 mg PO three times daily.

    Oral Administration

    Immediate-release tablets: May be taken with or without food.
    Extended-release capsules (Rythmol SR): May be taken with or without food. The capsules should not be crushed or divided.

    STORAGE

    Rythmol:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Rythmol SR:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    AV block, bradycardia, cardiogenic shock, electrolyte imbalance, heart failure, hyperkalemia, hypotension, sick sinus syndrome

    Propafenone is contraindicated in patients with preexisting second- or third-degree AV block or sick sinus syndrome in the absence of an artificial pacemaker. Propafenone is also contraindicated in patients with bradycardia and marked hypotension. Although propafenone's effects on normal sinus node function are negligible, risk-benefit must be considered when using the drug in patients with preexisting sick sinus syndrome because it can cause sinus bradycardia, sinus pause, or sinus arrest in such patients. Propafenone can increase endocardial pacing thresholds, so it is not recommended for use in patients with nonprogrammable pacemakers unless pacing rescue is available. Propafenone exhibits a mild to moderate negative inotropic effect and can cause or worsen congestive heart failure; these effects occur particularly in patients with cardiomyopathy, preexisting severe heart failure, or left ventricular dysfunction. Due to its potential negative inotropic effects, the risk of further depression of myocardial contractility due to the beta-adrenergic blocking activity, and the increased risk of arrhythmogenicity, propafenone is contraindicated in patients with congestive heart failure, cardiogenic shock, or manifest electrolyte imbalance and should not be used in patients with myocardial dysfunction. Any electrolyte imbalance, such as hyperkalemia, should be corrected before beginning therapy with propafenone.

    Alcoholism, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, mortality, myocardial infarction, QT prolongation, thyroid disease

    Propafenone is a Class IC antiarrhythmic which has proarrhythmic properties; cardiac arrhythmias may be induced or exacerbated. Propafenone increases the QT interval, but largely due to prolongation of the QRS interval. QT prolongation and torsade de pointes (TdP) have occurred during propafenone therapy. Therefore, propafenone should be avoided when possible in patients with congenital or acquired long QT syndrome or in patients with a history of TdP. The use of propafenone in conjunction with other drugs that prolong the QT interval has not been studied and is not recommended by the manufacturer due to potential risk for ventricular tachycardia, including TdP and monomorphic ventricular tachycardia. Further, use propafenone with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation. The CAST trial, a randomized double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias, demonstrated an excessive rate of mortality or non-fatal cardiac arrest in patients treated with encainide or flecainide (7.7%) compared to placebo (3%). The enrolled patients had a history of myocardial infarction (more than 6 days but less than 2 years); the average duration of antiarrhythmic therapy was 10 months. The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) or other antiarrhythmics is uncertain. The manufacturer for propafenone advises that it is prudent to consider Class 1C antiarrhythmics to have significant risks in patients with structural heart disease. Given the lack of evidence for improved survival, the use of propafenone or other antiarrhythmic agents should generally be avoided in patients with non-life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant symptoms or signs which are not life-threatening.

    Brugada syndrome

    Propafenone is contraindicated in patients with known Brugada syndrome. Additionally, exposure to propafenone may unmask Brugada syndrome. After initiating therapy with propafenone, perform an ECG and discontinue propafenone if changes suggestive of Brugada syndrome are present.

    Renal failure, renal impairment

    Approximately 50% of propafenone metabolites are excreted in the urine following administration of propafenone hydrochloride. In patients with renal impairment or renal failure, monitor for signs of overdosage.

    Hepatic disease

    Propafenone is highly metabolized by the liver and should, therefore, be administered cautiously to patients with hepatic disease. Severe liver dysfunction increases propafenone bioavailability to approximately 70% compared to 3 to 40% for patients with normal liver function. Dosage reduction is recommended. Increased bioavailability of propafenone in these patients may result in excessive accumulation. Closely monitor therapy in patients with hepatic dysfunction to assess efficacy and toxicity. Medications that inhibit hepatic enzymes CYP2D6 or CYP3A4 can be expected to cause increased plasma levels of propafenone and an increased potential for excess pharmacologic effects. Avoid the simultaneous use of propafenone with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.

    Acute bronchospasm, asthma, chronic obstructive pulmonary disease (COPD)

    Although propafenone is much less potent than propranolol as a beta-adrenergic blocker, propafenone is contraindicated in patients with bronchospastic disorders, including asthma or acute bronchospasm. Use with caution in patients with chronic bronchitis and emphysema, if a bronchospastic component exists to the chronic obstructive pulmonary disease (COPD), to avoid precipitating acute bronchospasm.

    Myasthenia gravis

    Exacerbation of myasthenia gravis has been reported during propafenone therapy.

    Systemic lupus erythematosus (SLE)

    Positive ANA titers have been reported in patients receiving propafenone. They have been reversible upon cessation of treatment and may disappear even in the face of continued propafenone therapy. These laboratory findings were not usually associated with clinical symptoms. One published case of drug-induced systemic lupus erythematosus (SLE), with positive rechallenge, has been reported; the SLE resolved completely upon discontinuation of therapy. Carefully evaluate patients who develop an abnormal ANA test and, if persistent or worsening elevation of ANA titers is detected, consider discontinuing therapy.

    Neonates, pregnancy

    There are no studies of propafenone in human pregnancy. Available data from published case reports and postmarketing experience with propafenone use in pregnancy have not identified any drug-associated risks of miscarriage, birth defects, or adverse maternal or fetal outcomes. Untreated arrhythmias during pregnancy may pose a risk to the mother and fetus. The incidence of ventricular tachycardia is increased and may be more symptomatic during pregnancy. Breakthrough arrhythmias may also occur; therapeutic propafenone concentrations may be difficult to maintain during pregnancy. Propafenone and its metabolite cross the placenta. Monitor fetuses and neonates exposed to propafenone for signs and symptoms of arrhythmia during and after maternal treatment. Monitor patients treated with propafenone continuously for arrhythmias during labor and delivery; the risk of arrhythmias may increase.[28287]

    Breast-feeding

    Propafenone and its active metabolite are present in human milk, but concentrations are likely to be low. There are no data on the effects of propafenone on the breast-fed infant or the effects on milk production. Consider the benefits of breast-feeding along with the mother's clinical need for propafenone and any potential adverse effects on the breast-fed infant from propafenone or the underlying maternal condition.[28287] Previous American Academy of Pediatrics (AAP) guidelines had not evaluated propafenone; however, the AAP considered flecainide, another class IC antiarrhythmic, to be usually compatible with breast-feeding.[27500]

    Infertility

    Propafenone may temporarily induce male-mediated infertility via reductions in sperm count. Evaluation of the effects of short-term administration of propafenone on spermatogenesis in healthy males (n = 11) suggested that propafenone produced a reversible, short-term drop (within normal range) in sperm count. Reversible decreases in spermatogenesis have been demonstrated in monkeys, dogs, and rabbits after high-dose intravenous administration of propafenone.[28287]

    Geriatric

    Geriatric patients maybe at increased risk for QT prolongation from drugs such as propafenone. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities. The OBRA guidelines caution that antiarrhythmics can have serious adverse effects (e.g., impairment of mental function, appetite, behavior, heart function, or falls) in older individuals.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 0-1.0
    agranulocytosis / Delayed / 0-1.0
    nephrotic syndrome / Delayed / 0-1.0
    seizures / Delayed / 0.3-0.3
    AV block / Early / 1.0
    atrial flutter / Early / 2.0
    bradycardia / Rapid / 2.0
    heart failure / Delayed / 2.0
    arrhythmia exacerbation / Early / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    asystole / Rapid / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    cardiac arrest / Early / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    hypertensive crisis / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    pericarditis / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    GI obstruction / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    apnea / Delayed / Incidence not known
    coma / Early / Incidence not known
    ocular hemorrhage / Delayed / Incidence not known
    pleural effusion / Delayed / Incidence not known
    muscle paralysis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    oliguria / Early / Incidence not known

    Moderate

    constipation / Delayed / 8.0-8.0
    blurred vision / Early / 3.0-3.0
    ataxia / Delayed / 2.0-2.0
    hot flashes / Early / 0-1.0
    hepatitis / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    cholestasis / Delayed / 0-1.0
    confusion / Early / 0-1.0
    psychosis / Early / 0-1.0
    mania / Early / 0-1.0
    memory impairment / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    anemia / Delayed / 0-1.0
    leukopenia / Delayed / 0-1.0
    impotence (erectile dysfunction) / Delayed / 0-1.0
    hypotension / Rapid / 2.0
    angina / Early / 2.0
    dyspnea / Early / 5.0
    edema / Delayed / 5.0
    palpitations / Early / 2.0
    bundle-branch block / Early / 2.0
    chest pain (unspecified) / Early / 5.0
    depression / Delayed / 2.0
    hematuria / Delayed / 2.0
    QT prolongation / Rapid / Incidence not known
    hematoma / Early / Incidence not known
    hypertension / Early / Incidence not known
    hepatomegaly / Delayed / Incidence not known
    dehydration / Delayed / Incidence not known
    melena / Delayed / Incidence not known
    dysphagia / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    oral ulceration / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    amnesia / Delayed / Incidence not known
    hypertonia / Delayed / Incidence not known
    ocular inflammation / Early / Incidence not known
    hemoptysis / Delayed / Incidence not known
    erythema / Early / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    urinary retention / Early / Incidence not known
    dysuria / Early / Incidence not known
    pyuria / Delayed / Incidence not known
    urinary incontinence / Early / Incidence not known
    glycosuria / Early / Incidence not known
    gout / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known
    hyperlipidemia / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    infertility / Delayed / Incidence not known

    Mild

    dysgeusia / Early / 14.0-14.0
    nausea / Early / 11.0-11.0
    vomiting / Early / 11.0-11.0
    dizziness / Early / 9.0-9.0
    fatigue / Early / 6.0-6.0
    headache / Early / 6.0-6.0
    weakness / Early / 3.0-3.0
    anorexia / Delayed / 2.0-2.0
    flushing / Rapid / 0-1.0
    vertigo / Early / 0-1.0
    tinnitus / Delayed / 0-1.0
    paresthesias / Delayed / 0-1.0
    ocular irritation / Rapid / 0-1.0
    muscle cramps / Delayed / 0-1.0
    pruritus / Rapid / 0-1.0
    alopecia / Delayed / 0-1.0
    ecchymosis / Delayed / 0-1.0
    purpura / Delayed / 0-1.0
    flatulence / Early / 2.0
    abdominal pain / Early / 1.0
    diarrhea / Early / 2.0
    xerostomia / Early / 2.0
    dyspepsia / Early / 1.0
    drowsiness / Early / 2.0
    tremor / Early / 2.0
    anxiety / Delayed / 5.0
    infection / Delayed / 5.0
    influenza / Delayed / 5.0
    pallor / Early / Incidence not known
    gastroesophageal reflux / Delayed / Incidence not known
    eructation / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    weight gain / Delayed / Incidence not known
    halitosis / Early / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    syncope / Early / Incidence not known
    libido decrease / Delayed / Incidence not known
    emotional lability / Early / Incidence not known
    nightmares / Early / Incidence not known
    insomnia / Early / Incidence not known
    malaise / Early / Incidence not known
    ptosis / Delayed / Incidence not known
    miosis / Early / Incidence not known
    rhinitis / Early / Incidence not known
    epistaxis / Delayed / Incidence not known
    cough / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    petechiae / Delayed / Incidence not known
    xerosis / Delayed / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    rash / Early / Incidence not known
    fever / Early / Incidence not known
    nocturia / Early / Incidence not known
    increased urinary frequency / Early / Incidence not known
    spermatogenesis inhibition / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Severe) Since abarelix can cause QT prolongation, abarelix should be used cautiously, if at all, with other drugs that are associated with QT prolongation including propafenone.
    Acebutolol: (Major) Pharmacologically, beta-blockers, like acebutolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with propafenone may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of propafenone could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Propafenone is a moderate inhibitor of CYP2D6.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
    Acetaminophen; Dextromethorphan: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Acetaminophen; Dextromethorphan; Doxylamine: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Acetaminophen; Oxycodone: (Moderate) Oxycodone is metabolized in part by cytochrome P450 2D6 to oxymorphone, which represents < 15% of the total administered dose. Potent inhibitors of CYP2D6, such as propafenone, may potentially increase the effects of oxycodone; however, such blockade has not been shown to be of clinical significance during oxycodone treatment. Clinicians should be aware of this possible interaction.
    Acetaminophen; Propoxyphene: (Major) Class IC antiarrhythmics are significantly metabolized by CYP2D6. Caution is recommended when administering class IC antiarrhythmics with propoxyphene, a CYP2D6 inhibitor. Monitor clinical response, and adjust antiarrhythmic dosage if necessary.
    Acetaminophen; Tramadol: (Moderate) As propafenone is a moderate CYP2D6 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Decreased analgesia might occur. Inhibition of either CYP2D6 and/or CYP3A4 is also expected to reduce the metabolic clearance of tramadol and may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Afatinib: (Moderate) If the concomitant use of propafenone and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of propafenone. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Albuterol: (Minor) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Albuterol; Ipratropium: (Minor) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Alfuzosin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with alfuzosin. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Based on electrophysiology studies performed by the manufacturer, alfuzosin also has a slight QT prolonging effect. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg.
    Amiodarone: (Major) The use of propafenone with other antiarrhythmics has not been well-studied. Class III antiarrhythmics are associated with QT prolongation and ventricular arrhythmias, including torsades de pointes (TdP). The concurrent use of amiodarone with propafenone is not recommended by the manufacturer, In addition to potential for additive effects on cardiac conduction and repolarization, amiodarone is a CYP2D6 inhibitor and may inhibit the metabolism of propafenone (CYP2D6 substrate). In general, combination therapy with Class III and Class IC antiarrhythmics has been reported to increase the risk of proarrhythmias. In one pediatric trial, combined therapy with amiodarone and propafenone resulted in electrocardiographic abnormalities. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Minor) Tricyclic antidepressants (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). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are 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 TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
    Amitriptyline; Chlordiazepoxide: (Minor) Tricyclic antidepressants (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). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are 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 TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
    Amoxapine: (Major) Because most cyclic antidepressants are partially metabolized by CYP2D6, caution is advisable during co-administration of amoxapine and potent CYP2D6 inhibitors such as quinidine. Elevated plasma concentrations of amoxapine may result in more pronounced anticholinergic effects and the risk of seizures may be increased. Anti-arrhythmics that are less potent inhibitors of CYP2D6, such as propafenone, may similarly interact with amoxapine. CYP2D6 substrates including flecainide may compete with amoxapine for the same metabolic pathway.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with propafenone. Clarithromycin is associated with an established risk for QT prolongation and TdP. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with propafenone. Clarithromycin is associated with an established risk for QT prolongation and TdP. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Amprenavir: (Severe) Propafenone should be used with caution with drugs that inhibit CYP3A4, such as antiretroviral protease inhibitors, which could decrease the hepatic metabolism of propafenone. Coadministration of amprenavir, boosted with ritonavir, and propafenone is contraindicated.
    Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include propafenone.
    Apomorphine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with apomorphine. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Limited data indicate that QT prolongation is also possible with apomorphine administration. The change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines; however, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended.
    Aprepitant, Fosaprepitant: (Major) Use caution if propafenone and aprepitant, fosaprepitant are used concurrently and monitor for an increase in propafenone-related adverse effects for several days after administration of a multi-day aprepitant regimen. Propafenone is a CYP3A4 substrate. 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 propafenone. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. 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) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Aripiprazole: (Major) Because both propafenone and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, because aripiprazole is partially metabolized by CYP2D6 and propafenone is a CYP2D6 inhibitor, patients should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor.
    Arsenic Trioxide: (Major) Concurrent use of arsenic trioxide and propafenone should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If possible, propafenone should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. TdP and complete atrioventricular block have been reported. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor and propafenone is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased propafenone concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as propafenone, should be avoided. Consider ECG monitoring if propafenone must be used with or after artemether; lumefantrine treatment.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer, asenapine should be avoided in combination with other agents also known to have this effect (e.g., propafenone). Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with propafenone may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of propafenone could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Propafenone is a moderate inhibitor of CYP2D6.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
    Aspirin, ASA; Oxycodone: (Moderate) Oxycodone is metabolized in part by cytochrome P450 2D6 to oxymorphone, which represents < 15% of the total administered dose. Potent inhibitors of CYP2D6, such as propafenone, may potentially increase the effects of oxycodone; however, such blockade has not been shown to be of clinical significance during oxycodone treatment. Clinicians should be aware of this possible interaction.
    Atazanavir: (Major) Avoid coadministration of atazanavir and propafenone when possible. Caution should be used in patients receiving atazanavir concurrently with drugs metabolized via CYP3A4 and known to cause QT prolongation. Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of propafenone and an increased potential for QT prolongation or other adverse effects. Serious and/or life-threatening drug interactions could potentially occur between atazanavir and propafenone.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of atazanavir and propafenone when possible. Caution should be used in patients receiving atazanavir concurrently with drugs metabolized via CYP3A4 and known to cause QT prolongation. Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of propafenone and an increased potential for QT prolongation or other adverse effects. Serious and/or life-threatening drug interactions could potentially occur between atazanavir and propafenone. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of propafenone with cobicistat. Propafenone is a substrate for CYP3A4 and a substrate and inhibitor of CYP2D6; cobicistat is a substrate and inhibitor of both these enzymes. Concurrent use may result in elevated propafenone plasma concentration.
    Atenolol: (Major) Pharmacologically, beta-blockers, like atenolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Atenolol; Chlorthalidone: (Major) Pharmacologically, beta-blockers, like atenolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Both atomoxetine and propafenone are considered drugs with a possible risk of torsade de pointes (TdP); therefore, the combination should be used cautiously and with close monitoring. In addition, because atomoxetine is primarily metabolized by CYP2D6, concurrent use of CYP2D6 inhibitors such as propafenone may theoretically increase the risk of atomoxetine-induced adverse effects. Monitor for adverse effects, such as dizziness, drowsiness, nervousness, insomnia, and cardiac effects (e.g., hypertension, increased pulse rate, QT prolongation).
    Azithromycin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with azithromycin. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Azithromycin has been associated with cases of QT prolongation and TdP, reported during the postmarketing period.
    Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with propafenone. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Propafenone is a Class IC antiarrhythmic which also increases the QT interval, but largely due to prolongation of the QRS interval.
    Bendroflumethiazide; Nadolol: (Major) Pharmacologically, beta-blockers, like nadolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Bepridil: (Severe) Patients receiving other drugs which have the potential for QT prolongation, such as propafenone, have an increased risk of developing proarrhythmias during bepridil therapy.
    Betaxolol: (Major) Pharmacologically, beta-blockers, like betaxolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving propafenone. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving propafenone. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; propafenone inhibits P-gp.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include propafenone.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include propafenone.
    Bisoprolol: (Major) Pharmacologically, beta-blockers, like bisoprolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) Pharmacologically, beta-blockers, like bisoprolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Boceprevir: (Major) Close clinical monitoring is advised when administering propafenone with boceprevir due to an increased potential for serious and/or life-threatening propafenone-related adverse events. If propafenone dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of propafenone. Propafenone is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Additionally, propafenone is an inhibitor of P-glycoprotein (P-gp), an efflux transporter partially responsible for the metabolism of boceprevir. When used in combination, the plasma concentrations of both medications may be elevated.
    Bretylium: (Severe) The use of bretylium in conjunction with drugs associated with QT prolongation, such as propafenone, should be avoided due to the potential risk for ventricular tachycardia, including torsade de pointes.
    Brimonidine; Timolol: (Major) Pharmacologically, beta-blockers, like timolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Budesonide; Formoterol: (Moderate) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Bupivacaine; Lidocaine: (Major) There is limited experience with the use of propafenone with Class IB antiarrhythmics. No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients. However, the concomitant use of propafenone and lidocaine has been reported to increase the risks of central nervous system side effects of lidocaine. When propafenone is coadministered, the dose of lidocaine should be titrated to the desired therapeutic effects.
    Buprenorphine: (Major) Buprenorphine should be used cautiously and with close monitoring with propafenone. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If these drugs are used together, consider the potential for additive effects on the QT interval.
    Buprenorphine; Naloxone: (Major) Buprenorphine should be used cautiously and with close monitoring with propafenone. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If these drugs are used together, consider the potential for additive effects on the QT interval.
    Bupropion: (Major) Bupropion is an inhibitor of CYP2D6. Concentrations of medications metabolized by CYP2D6, such as propafenone, may be increased if bupropion is added. Dosage reductions of propafenone may be needed.
    Bupropion; Naltrexone: (Major) Bupropion is an inhibitor of CYP2D6. Concentrations of medications metabolized by CYP2D6, such as propafenone, may be increased if bupropion is added. Dosage reductions of propafenone may be needed.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Carvedilol: (Major) Pharmacologically, beta-blockers, like carvedilol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Ceritinib: (Major) Avoid coadministration of ceritinib with propafenone due to increased propafenone exposure, especially if the patient is a poor CYP2D6 metabolizer or is also taking a CYP2D6 inhibitor. Additive QT prolongation may also occur. If coadministration is unavoidable, monitor for propafenone-related adverse reactions. Periodically monitor electrolytes and ECGs; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib is a CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. Propafenone is primarily metabolized by CYP3A4 and is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Cevimeline: (Moderate) Cevimeline is metabolized by cytochrome P450 3A4 and CYP2D6. Concurrent administration of inhibitors of these enzymes, such as propafenone, may lead to increased cevimeline plasma concentrations.
    Chloroquine: (Major) Coadminister chloroquine with other drugs known to prolong the QT interval, such as propafenone, with caution. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
    Chlorpheniramine; Dextromethorphan: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with propafenone may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of propafenone could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Propafenone is a moderate inhibitor of CYP2D6.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with propafenone may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of propafenone could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Propafenone is a moderate inhibitor of CYP2D6.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Chlorpromazine: (Major) Concurrent use of chlorpromazine and propafenone should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Chlorpromazine is associated with an established risk of QT prolongation and TdP; case reports have included patients receiving therapeutic doses of chlorpromazine. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Cimetidine: (Moderate) Cimetidine is a potent inhibitor of many of the isoenzymes of the hepatic CYP450 oxidative enzyme system and has been shown to increase propafenone serum concentrations by 24%. Close clinical monitoring may be necessary during coadministration of cimetidine with interacting drugs.
    Cinacalcet: (Major) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering cinacalcet with other CYP2D6 substrates that have a narrow therapeutic range or where large increases in serum concentrations may be associated with significant adverse reactions. Patients should be monitored for toxicity if cinacalcet is administered with strong CYP2D6 substrates. Other affected CYP2D6 substrates may include propafenone.
    Ciprofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with ciprofloxacin. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Ciprofloxacin is associated with a possible risk for QT prolongation and TdP.
    Cisapride: (Severe) Concurrent use of propafenone and cisapride 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. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Citalopram: (Major) Concurrent use of citalopram and propafenone should be avoided. If concurrent therapy is considered essential, ECG monitoring is recommended. Citalopram is associated with a dose-dependent QT prolongation. Propafenone is a Class IC antiarrhythmic which increases the QT interval, largely due to prolongation of the QRS interval. The use of propafenone in conjunction with other drugs that prolong the QT interval has not been studied and is not recommended by the manufacturer due to potential risk for ventricular tachycardia, including torsade de pointes (TdP) and monomorphic ventricular tachycardia. Some SSRIs may inhibit CYP2D6, and can result in increased concentrations of drugs metabolized by this pathway including propafenone, with potential to increase the risk of drug toxicity. Citalopram mildly inhibit the hepatic CYP2D6 isoenzyme.
    Clarithromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with propafenone. Clarithromycin is associated with an established risk for QT prolongation and TdP. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Clobazam: (Moderate) A dosage reduction of CYP2D6 substrates, such as propafenone, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. If these agents are used in combination, it is advisable to monitor the patient for propafenone-related adverse reactions.
    Clomipramine: (Minor) Tricyclic antidepressants (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). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are 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 TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
    Clozapine: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation such as propafenone. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. In addition, propafenone is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary.
    Cobicistat: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of propafenone with cobicistat. Propafenone is a substrate for CYP3A4 and a substrate and inhibitor of CYP2D6; cobicistat is a substrate and inhibitor of both these enzymes. Concurrent use may result in elevated propafenone plasma concentration.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of propafenone with cobicistat. Propafenone is a substrate for CYP3A4 and a substrate and inhibitor of CYP2D6; cobicistat is a substrate and inhibitor of both these enzymes. Concurrent use may result in elevated propafenone plasma concentration.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of propafenone with cobicistat. Propafenone is a substrate for CYP3A4 and a substrate and inhibitor of CYP2D6; cobicistat is a substrate and inhibitor of both these enzymes. Concurrent use may result in elevated propafenone plasma concentration. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as propafenone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Cobimetinib: (Minor) If concurrent use of cobimetinib and propafenone is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and propafenone is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
    Codeine: (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
    Codeine; Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include propafenone. (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
    Codeine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include propafenone. (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
    Colchicine: (Major) Coadministration of colchicine and propafenone should be avoided due to the potential for serious and life-threatening toxicity. Colchicine is a substrate of P-glycoprotein (P-gp) and propafenone is an inhibitor of P-gp; increased concentrations of colchicine are expected with concurrent use. Colchicine accumulation may be greater in patients with renal or hepatic impairment; therefore the manufacturer of Colcrys contraindicates the use of colchicine and P-gp inhibitors in this population. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine either by reducing the daily dose or reducing the dose frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations for coadministration with P-gp inhibitors are provided by the manufacturer of Colcrys.
    Colesevelam: (Moderate) Colesevelam may decrease the bioavailability of propafenone if coadministered. To minimize potential for interactions, consider administering oral antiarrhythmics such as propafenone at least 1 hour before or at least 4 hours after colesevelam.
    Crizotinib: (Major) Avoid coadministration of crizotinib with propafenone 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 has been associated with concentration-dependent QT prolongation. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with propafenone, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like propafenone in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with propafenone, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dacomitinib: (Moderate) Monitor for increased toxicity of propafenone if coadministered with dacomitinib. Coadministration may increase serum concentrations of propafenone. Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity. Propafenone is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor. Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous. Therefore, avoid simultaneous use of propafenone with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.
    Dalfopristin; Quinupristin: (Moderate) Coadministration of propafenone with dalfopristin; quinupristin may result in elevated propafenone plasma concentrations. If these drugs are used together, closely monitor for signs of propafenone-related adverse events. Propafenone is a substrate of CYP3A; dalfopristin; quinupristin is a weak CYP3A inhibitor.
    Darifenacin: (Moderate) Monitor for increased toxicity of propafenone if coadministered with darifenacin. Coadministration may increase serum concentrations of propafenone. Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity. Propafenone is a CYP2D6 substrate; darifenacin is a moderate CYP2D6 inhibitor. Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous. Therefore, avoid simultaneous use of propafenone with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.
    Darunavir: (Major) Coadministration of darunavir with propafenone should be done with extreme caution. Therapeutic monitoring of antiarrhythmic concentrations is recommended. Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme should be expected with concurrent use.
    Darunavir; Cobicistat: (Major) Coadministration of darunavir with propafenone should be done with extreme caution. Therapeutic monitoring of antiarrhythmic concentrations is recommended. Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme should be expected with concurrent use. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of propafenone with cobicistat. Propafenone is a substrate for CYP3A4 and a substrate and inhibitor of CYP2D6; cobicistat is a substrate and inhibitor of both these enzymes. Concurrent use may result in elevated propafenone plasma concentration.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of darunavir with propafenone should be done with extreme caution. Therapeutic monitoring of antiarrhythmic concentrations is recommended. Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme should be expected with concurrent use. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of propafenone with cobicistat. Propafenone is a substrate for CYP3A4 and a substrate and inhibitor of CYP2D6; cobicistat is a substrate and inhibitor of both these enzymes. Concurrent use may result in elevated propafenone plasma concentration.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) The manufacturer of ombitasvir; paritaprevir; ritonavir recommends caution and therapeutic drug monitoring (when available) if administered concurrently with propafenone. However, since one of the components of the 3-drug combination is ritonavir, use of these drugs together is contraindicated. Both ritonavir and propafenone are associated with QT prolongation; concomitant use increases the risk for developing Torsade de Pointes (TdP). In addition, ritonavir is a potent CYP3A4 inhibitor, an enzyme partially responsible for the metabolism of propafenone. If administered together, serum concentration of propafenone may increase. (Major) Coadministration of HIV treatment doses of ritonavir and propafenone is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. However, propafenone and ritonavir may be coadministered with caution to patients receiving ritonavir as a boosting agent. Ritonavir inhibits both CYP3A4 and CYP2D6. Drugs that inhibit both pathways are expected to increase propafenone serum concentrations.
    Dasatinib: (Major) Monitor for evidence of QT prolongation during concurrent use of dasatinib and propafenone. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Degarelix: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with degarelix. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Degarelix may also cause QT prolongation.
    Delavirdine: (Major) Caution is recommended when administering propafenone with delavirdine. Delavirdine is a CYP2D6 inhibitor and propafenone is significantly metabolized by this enzyme. Concurrent use may result in elevated propafenone plasma concentrations. Propafenone exhibits a narrow therapeutic range and large increases in serum concentrations may be associated with severe cardiovascular adverse reactions.
    Desipramine: (Minor) Tricyclic antidepressants (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). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are 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 TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
    Deutetrabenazine: (Major) For patients taking a deutetrabenazine dosage more than 24 mg/day with propafenone, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Propafenone is a Class IC antiarrhythmic that increases the QT interval, but largely due to prolongation of the QRS interval.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Dextromethorphan: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Dextromethorphan; Guaifenesin: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Dextromethorphan; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include propafenone. (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Dextromethorphan; Quinidine: (Severe) Class IA antiarrhythmics are associated with QT prolongation and ventricular arrhythmias including torsades de pointes (TdP), and concurrent use with propafenone is not recommended by the manufacturer. Before switching from another antiarrhythmic drug to propafenone therapy, Class IA antiarrhythmics and Class III antiarrhythmics generally should be withheld for at least five half-lives prior to initiating propafenone. Quinidine is a CYP2D6 inhibitor with potential to inhibit propafenone metabolism, and coadministration is contraindicated. Small doses of quinidine completely inhibit the CYP2D6 hydroxylation metabolic pathway, with the result that extensive metabolizers become poor metabolizers. Coadministration with quinidine markedly decreases propafenone clearance in extensive metabolizers, and increases plasma propafenone concentrations by 2 to 3-fold at steady-state. Steady-state plasma concentrations increased more than 2-fold for propafenone, and decreased 50% for 5-OH-propafenone. (Minor) In vitro studies support that propafenone inhibits CYP2D6. Therefore, propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme, including dextromethorphan.
    Digoxin: (Major) Propafenone reduces the clearance of digoxin and may lead to digoxin toxicity. Increases in digoxin serum concentrations may occur in over 80% of patients when propafenone is added to the regimen. Concomitant use of propafenone and digoxin has been reported to increase the steady-state AUC of orally administered digoxin by 60 to 270%, and decrease digoxin clearance by 31 to 67%. When propafenone is coadministered with intravenous (IV) digoxin, the serum concentration of digoxin is increased by 28%. Although the exact mechanism for this interaction has not been established, several mechanisms have been proposed including reduced distribution volume and nonrenal clearance of digoxin, as well as potential inhibition of P-glycoprotein renal tubular transport of digoxin. Measure serum digoxin concentrations before initiating propafenone. Reduce digoxin concentrations by decreasing the oral digoxin dose by approximately 30 to 50%, decreasing the IV digoxin dose by 15 to 30%, or by modifying the dosing frequency and continue monitoring.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with propafenone may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of propafenone could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Propafenone is a moderate inhibitor of CYP2D6.
    Diltiazem: (Major) Coadministration of propafenone with diltiazem has the potential to cause additive decreases in AV conduction and/or negative inotropic effects. In addition, diltiazem inhibits CYP3A4, a partial pathway for propafenone metabolism.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Disopyramide: (Major) Class IA antiarrhythmics are associated with QT prolongation and ventricular arrhythmias including torsades de pointes (TdP), and concurrent use with propafenone is not recommended by the manufacturer. Before switching from another antiarrhythmic drug to propafenone therapy, Class IA antiarrhythmics and Class III antiarrhythmics generally should be withheld for at least five half-lives prior to initiating propafenone.
    Dofetilide: (Severe) 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, propafenone antiarrhythmic agents is associated with QT prolongation and ventricular arrhythmias and concurrent exposure with dofetilide could increase the risk of dofetilide-induced proarrhythmias.
    Dolasetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), dolasetron and propafenone should be used together cautiously. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Propafenone is a Class IC antiarrhythmic, which increases the QT interval, but largely due to prolongation of the QRS interval. Coadministration may increase the risk of QT prolongation.
    Dolutegravir; Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with propafenone. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Propafenone has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, propafenone inhibits CYP2D6, one of the isoenzymes involved in the metabolism of donepezil. In theory, co-administration of propafenone and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Propafenone has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, propafenone inhibits CYP2D6, one of the isoenzymes involved in the metabolism of donepezil. In theory, co-administration of propafenone and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as propafenone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Dorzolamide; Timolol: (Major) Pharmacologically, beta-blockers, like timolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Doxepin: (Minor) Tricyclic antidepressants (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). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are 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 TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
    Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, such as propafenone, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy.
    Doxorubicin: (Major) Avoid coadministration of propafenone with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Propafenone is a CYP2D6 and P-gp inhibitor and doxorubicin is a CYP2D6 and P-gp substrate. Concurrent use of CYP2D6 and/or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Dronedarone: (Severe) Concomitant use of dronedarone and propafenone is contraindicated. Dronedarone is an inhibitor of CYP2D6 and CYP3A. Propafenone is a substrate for CYP2D6 and CYP3A4. Coadministration of dronedarone and propafeone may result in increased plasma concentrations of propafenone. In addition, propafenone has been established to have a causal association with QT prolongation and Torsade 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.
    Droperidol: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering droperidol with propafenone. Droperidol is associated with an established risk for QT prolongation and TdP. In December 2001, the FDA issued a black box warning regarding the use of droperidol and its association with QT prolongation and potential for cardiac arrhythmias based on post-marketing surveillance data. According to the revised 2001 labeling for droperidol, any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Propafenone, a Class IC antiarrhythmic, increases the QT interval, but largely due to prolongation of the QRS interval.
    Drospirenone; Ethinyl Estradiol: (Moderate) Drugs that inhibit CYP1A2, such as ethinyl estradiol, can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Drugs that inhibit CYP1A2, such as ethinyl estradiol, can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals.
    Dutasteride; Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP2D6 inhibitor such as propafenone. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP2D6 inhibitor resulted in increases in tamsulosin exposure; interactions with moderate CYP2D6 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Duvelisib: (Moderate) Monitor for increased toxicity of propafenone if coadministered with duvelisib. Coadministration may increase the exposure of propafenone. Propafenone is a CYP3A4 substrate; duvelisib is a moderate CYP3A4 inhibitor.
    Edoxaban: (Moderate) Coadministration of edoxaban and propafenone may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of propafenone; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Efavirenz: (Major) Although data are limited, coadministration of efavirenz and propafenone may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. In addition, efavirenz is an inducer of CYP3A4; propafenone concentrations may be decreased with coadministration.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Although data are limited, coadministration of efavirenz and propafenone may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. In addition, efavirenz is an inducer of CYP3A4; propafenone concentrations may be decreased with coadministration. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as propafenone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Although data are limited, coadministration of efavirenz and propafenone may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. In addition, efavirenz is an inducer of CYP3A4; propafenone concentrations may be decreased with coadministration. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as propafenone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Elbasvir; Grazoprevir: (Moderate) Administering propafenone with elbasvir; grazoprevir may result in elevated propafenone plasma concentrations. Propafenone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Major) Coadministration of propafenone and eliglustat may result in a complex drug interaction that increases the risk of QT prolongation and cardiac arrhythmias; coadministration must be approached with extreme caution and careful patient selection. Coadministration of eliglustat with both propafenone and a CYP3A inhibitor is contraindicated. In extensive or intermediate CYP2D6 metabolizers (EMs or IMs), coadministration requires dosage reduction of eliglustat to 84 mg PO once daily. In addition, consider reducing the dosage of propafenone and titrate to clinical effect with careful monitoring. Coadministration can increase plasma concentrations of either or both drugs. Propafenone is a CYP2D6 substrate and moderate CYP2D6 inhibitor that can increase the QT interval. Eliglustat is a CYP2D6 inhibitor and a substrate of CYP2D6 and CYP3A that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with propafenone. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with propafenone. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as propafenone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as propafenone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Encorafenib: (Major) Avoid coadministration of encorafenib and propafenone due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Eribulin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with eribulin. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Eribulin has been associated with QT prolongation. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Erythromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with propafenone. Erythromycin is associated with prolongation of the QT interval and TdP. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval. In addition, erythromycin may theoretically increase plasma concentrations of propafenone via inhibition of CYP3A4. Higher propafenone plasma concentrations increases the potential risk of QT prolongation, TdP or other proarrhythmias.
    Erythromycin; Sulfisoxazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with propafenone. Erythromycin is associated with prolongation of the QT interval and TdP. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval. In addition, erythromycin may theoretically increase plasma concentrations of propafenone via inhibition of CYP3A4. Higher propafenone plasma concentrations increases the potential risk of QT prolongation, TdP or other proarrhythmias.
    Escitalopram: (Major) Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as propafeone, should be done with caution and close monitoring. In addition, escitalopram modestly inhibits the hepatic CYP2D6 isoenzyme. This can result in increased concentrations of drugs metabolized via the same pathway, including some antiarrhythmics like propafenone.
    Esmolol: (Major) Pharmacologically, beta-blockers, like esmolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Ethinyl Estradiol: (Moderate) Drugs that inhibit CYP1A2, such as ethinyl estradiol, can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals.
    Ethinyl Estradiol; Desogestrel: (Moderate) Drugs that inhibit CYP1A2, such as ethinyl estradiol, can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Drugs that inhibit CYP1A2, such as ethinyl estradiol, can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Drugs that inhibit CYP1A2, such as ethinyl estradiol, can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Drugs that inhibit CYP1A2, such as ethinyl estradiol, can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Drugs that inhibit CYP1A2, such as ethinyl estradiol, can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Drugs that inhibit CYP1A2, such as ethinyl estradiol, can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Drugs that inhibit CYP1A2, such as ethinyl estradiol, can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Drugs that inhibit CYP1A2, such as ethinyl estradiol, can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Drugs that inhibit CYP1A2, such as ethinyl estradiol, can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals.
    Ethinyl Estradiol; Norethindrone: (Moderate) Drugs that inhibit CYP1A2, such as ethinyl estradiol, can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Drugs that inhibit CYP1A2, such as ethinyl estradiol, can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals.
    Ethinyl Estradiol; Norgestimate: (Moderate) Drugs that inhibit CYP1A2, such as ethinyl estradiol, can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals.
    Ethinyl Estradiol; Norgestrel: (Moderate) Drugs that inhibit CYP1A2, such as ethinyl estradiol, can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals.
    Etoposide, VP-16: (Major) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with propafenone. Propafenone is an inhibitor of P-glycoprotein (P-gp) and etoposide, VP-16 is a P-gp substrate. Coadministration may increase etoposide concentrations.
    Etravirine: (Major) Etravirine is an inducer of CYP3A4; propafenone concentrations may be decreased with coadministration. Coadminister these drugs with caution. It is recommended to monitor propafenone concentrations when possible.
    Everolimus: (Major) Avoid coadministration of propafenone with everolimus due to the risk of increased exposure to both drugs. Everolimus is a weak CYP3A4 inhibitor and a CYP2D6 inhibitor, as well as a P-glycoprotein (P-gp) substrate. Propafenone is a CYP3A4 and CYP2D6 substrate, in addition to being a P-gp inhibitor. The combination of CYP3A4 and CYP2D6 inhibition may significantly increase propafenone concentrations, increasing the risk of proarrhythmia and other adverse events, while P-gp inhibition increases everolimus exposure.
    Ezogabine: (Major) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with propafenone include ezogabine.
    Fingolimod: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering fingolimod with propafenone. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Propafenone, a Class IC antiarrhythmic, increases the QT interval, but largely due to prolongation of the QRS interval.
    Flecainide: (Major) Coadministration of propafenone with flecainide may represent duplicate therapy and increases the potential for QT prolongation and torsade de pointes (TdP). Both flecainide and propafenone are Class IC antiarrhythmics which increases the QT interval largely due to prolongation of the QRS interval. In addition, propafenone is a CYP2D6 substrate/inhibitor, and flecainide is significantly metabolized by CYP2D6. The coadministration may result in increased flecainide plasma concentrations and an increased risk of QT prolongation.
    Fluconazole: (Severe) Due to the risk of life-threatening arrhythmias such as torsade de pointes (TdP), coadministration of fluconazole with drugs that both prolong the QT interval and are CYP3A4 substrates, like propafenone, is contraindicated. Fluconazole has been associated with QT prolongation and rare cases of TdP. Additonally, fluconazole is an inhibitor of CYP3A4. Coadministration may result in elevated plasma concentrations of propafenone, causing an increased risk for adverse events such as QT prolongation.
    Fluoxetine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Propafenone is associated with a possible risk of QT prolongation and TdP. In addition, fluoxetine is a potent CYP2D6 inhibitor, and increased concentrations of antiarrhythmic drugs metabolized via the same pathway, including propafenone, can occur. Concomitant administration of propafenone and fluoxetine in extensive metabolizers increases the S-propafenone Cmax and AUC by 39% and 50%, and the R-propafenone Cmax and AUC by 71% and 50%. Increased plasma antiarrhythmic drug concentrations may increase the risk of proarrhythmias.
    Fluoxetine; Olanzapine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Propafenone is associated with a possible risk of QT prolongation and TdP. In addition, fluoxetine is a potent CYP2D6 inhibitor, and increased concentrations of antiarrhythmic drugs metabolized via the same pathway, including propafenone, can occur. Concomitant administration of propafenone and fluoxetine in extensive metabolizers increases the S-propafenone Cmax and AUC by 39% and 50%, and the R-propafenone Cmax and AUC by 71% and 50%. Increased plasma antiarrhythmic drug concentrations may increase the risk of proarrhythmias. (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with olanzapine. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Fluphenazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering fluphenazine with propafenone. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Fluticasone; Salmeterol: (Moderate) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Vilanterol: (Moderate) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and propafenone. Propafenone is a Class IC antiarrhythmic that increases the QT interval largely due to prolongation of the QRS interval. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
    Formoterol: (Moderate) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Formoterol; Mometasone: (Moderate) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fosamprenavir: (Major) Caution is advised when administering propafenone with fosamprenavir; if fosamprenavir is boosted with ritonavir, use is contraindicated. Propafenone is significantly metabolized by CYP2D6 and partially metabolized by CYP3A4. When administering with drugs that inhibit CYP3A4, such as fosamprenavir, the serum concentrations of propafenone may increase. Use of propafenone with drugs that inhibit CYP2D6, such as ritonavir, causes large increases in propafenone serum concentrations which may be associated with serious and/or life threatening adverse reaction, including cardiac arrhythmia.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as propafenone. Foscarnet has been associated with postmarketing reports of both 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. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with propafenone is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and propafenone is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Gemifloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with gemifloxacin. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; 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) Use gemtuzumab ozogamicin and propafenone together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Propafenone is a class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Ginger, Zingiber officinale: (Minor) In vitro studies have demonstrated the positive inotropic effects of certain gingerol constituents of ginger; but it is unclear if whole ginger root exhibits these effects clinically in humans. It is theoretically possible that excessive doses of ginger could affect the action of antiarrhythmics; however, no clinical data are available.
    Glasdegib: (Major) Avoid coadministration of glasdegib with propafenone 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. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and propafenone as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp); propafenone is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and propafenone as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); propafenone is a P-gp inhibitor.
    Glycopyrrolate; Formoterol: (Moderate) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Goserelin: (Major) Propafenone should be used cautiously and with close monitoring with goserelin. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Granisetron: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering granisetron with propafenone. Granisetron has been associated with QT prolongation. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Grapefruit juice: (Major) Drugs that inhibit CYP1A2 and CYP3A4 can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2 or CYP3A4, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals. Grapefruit juice is a CYP 3A4 inhibitor.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Halofantrine: (Severe) Halofantrine is considered to have a well-established risk for QT prolongation and torsades de pointes and should be avoided in patients receiving drugs which may induce QT prolongation including propafenone.
    Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with propafenone. Halogenated anesthetics can prolong the QT interval. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Haloperidol: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with haloperidol. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. QT prolongation and TdP have also 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. In addition, haloperidol is a substrate for CYP2D6 and propafenone is a CYP2D6 substrate/inhibitor. Mild to moderate increases in haloperidol plasma concentrations may occur during concurrent use.
    Hawthorn, Crataegus laevigata: (Major) It would be prudent to avoid use of Hawthorn, Crataegus laevigata (also known as C. oxycantha) during therapy with antiarrhythmic agents whenever possible, due to the possibility of additive effects on cardiac conduction and the known effects of antiarrhythmic drugs on the heart. Following hawthorn administration to guinea pigs, the cardiac action potential duration was increased and the refractory period was prolonged. Hawthorn may also lower peripheral vascular resistance. Hawthorn could potentially interact with antiarrhythmics that have similar actions to hawthorn on cardiac electrophysiology. Use extreme caution with class IC antiarrhythmics, due to the potential for QT prolongation. However, no human clinical data are available. Patients should be advised to only use hawthorn with these antiarrhythmic agents after discussion with their prescriber. If co-use is advised, patients should receive periodic blood pressure and heart rate monitoring.
    Histrelin: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and propafenone is necessary; correct any electrolyte abnormalities. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Major) Pharmacologically, beta-blockers, like metoprolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Propafenone a CYP2D6 inhibitor, has been shown to increase the plasma concentrations and prolong the elimination half-life of metoprolol, with potential for adverse effects. Dosages of metoprolol may need to be reduced when used concomitantly with propafenone.
    Hydrochlorothiazide, HCTZ; Propranolol: (Major) Pharmacologically, beta-blockers, like propranolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Additionally, propafenone, a CYP2D6 inhibitor, appears to inhibit the metabolism of propranolol. Coadministration of propafenone with propranolol increases the plasma concentrations and prolongs the elimination half-life of propranolol; these affects were associated with a 15% decrease in diastolic blood pressure. Patients should be monitored closely and a reduction in the dosage of propranolol may be indicated.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and propafenone. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include propafenone.
    Ibuprofen; Oxycodone: (Moderate) Oxycodone is metabolized in part by cytochrome P450 2D6 to oxymorphone, which represents < 15% of the total administered dose. Potent inhibitors of CYP2D6, such as propafenone, may potentially increase the effects of oxycodone; however, such blockade has not been shown to be of clinical significance during oxycodone treatment. Clinicians should be aware of this possible interaction.
    Ibutilide: (Major) Although concurrent use of propafenone with Class III agents is not recommended by the manufacturer, one study showed efficacy benefits with the use of ibutilide in 71 patients receiving long-term treatment with Class IC agents (n=46 propafenone; n=25 flecainide) for atrial fibrillation or atrial flutter. The majority of patients had normal left ventricular systolic function (91.5%). Conversion of atrial fibrillation was achieved in 23 of 48 patients (47.9%) receiving ibutilide, while conversion of atrial flutter occurred in 17 of 23 patients (73.9%) studied. Ibutilide resulted in a small increase in the QTc interval (from 442 +/- 61 ms to 462 +/- 59 ms). Two patients developed proarrhythmias, non-sustained polymorphous ventricular tachycardia and sustained torsade de pointes (TdP), which were successfully treated. Administration of ibutilide to patients who have received flecainide should be done with great caution, and under controlled settings, with emergency equipment available. In general, continuous ECG monitoring is recommended during administration and for at least 4 hours following ibutilide infusions or until the QT interval corrected for heart rate (QTc) has returned to baseline.
    Idelalisib: (Severe) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with propafenone, a CYP3A substrate, as propafenone toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Major) Concurrent use of iloperidone and propafenone should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Iloperidone has been associated with QT prolongation; however, TdP has not been reported. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Imatinib: (Major) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering imatinib with CYP2D6 substrates that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions including propafenone.
    Imipramine: (Minor) Tricyclic antidepressants (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). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are 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 TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
    Indacaterol: (Moderate) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indacaterol; Glycopyrrolate: (Moderate) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indinavir: (Major) Propafenone should be used with caution with drugs that inhibit CYP3A4, such as antiretroviral protease inhibitors, which could decrease the hepatic metabolism of propafenone.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with propafenone due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Irinotecan Liposomal: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with propafenone is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Irinotecan: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with propafenone is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor. Concomitant use may increase irinotecan exposure.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with propafenone may result in increased serum concentrations of propafenone. Propafenone is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Rifampin may reduce the bioavailability of oral propafenone via induction of propafenone metabolism. Rifampin induces Phase I and Phase II metabolism of propafenone, increasing drug clearance via N-dealkylation and glucuronidation pathways by over 4-fold, but does not appear to induce hydroxylation of propafenone. The extent of reduction in propafenone mean bioavailability is greater in extensive metabolizers of propafenone (reduced from 30% to 10%), although bioavailability is also significantly reduced in poor metabolizers (81% to 48%). The manufacturer reports that concomitant administration of rifampin and propafenone in extensive metabolizers decreases the plasma concentrations of propafenone by 67%, with a corresponding decrease of 5OH-propafenone by 65%. The concentrations of norpropafenone is increased by 30%. In poor metabolizers, there is 50% decrease in propafenone plasma concentrations, and increased the AUC and Cmax of norpropafenone by 74 and 20%, respectively. Urinary excretion of propafenone and its metabolites decreased significantly. Similar results were noted in elderly patients; both the AUC and Cmax propafenone decreased by 84%, with a corresponding decrease in AUC and Cmax of 5OH-propafenone by 69 and 57%. When propafenone is coadministered with rifamycins which induce hepatic metabolism (e.g., rifampin, rifabutin, rifapentine), monitor therapeutic response and adjust dosage as needed to attain antiarrhythmic efficacy endpoints.
    Isoniazid, INH; Rifampin: (Major) Rifampin may reduce the bioavailability of oral propafenone via induction of propafenone metabolism. Rifampin induces Phase I and Phase II metabolism of propafenone, increasing drug clearance via N-dealkylation and glucuronidation pathways by over 4-fold, but does not appear to induce hydroxylation of propafenone. The extent of reduction in propafenone mean bioavailability is greater in extensive metabolizers of propafenone (reduced from 30% to 10%), although bioavailability is also significantly reduced in poor metabolizers (81% to 48%). The manufacturer reports that concomitant administration of rifampin and propafenone in extensive metabolizers decreases the plasma concentrations of propafenone by 67%, with a corresponding decrease of 5OH-propafenone by 65%. The concentrations of norpropafenone is increased by 30%. In poor metabolizers, there is 50% decrease in propafenone plasma concentrations, and increased the AUC and Cmax of norpropafenone by 74 and 20%, respectively. Urinary excretion of propafenone and its metabolites decreased significantly. Similar results were noted in elderly patients; both the AUC and Cmax propafenone decreased by 84%, with a corresponding decrease in AUC and Cmax of 5OH-propafenone by 69 and 57%. When propafenone is coadministered with rifamycins which induce hepatic metabolism (e.g., rifampin, rifabutin, rifapentine), monitor therapeutic response and adjust dosage as needed to attain antiarrhythmic efficacy endpoints.
    Itraconazole: (Major) Use caution during coadministration of itraconazole and propafenone due to the potential for additive effects on the QT interval and increased exposure to propafenone. Both propafenone and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with propafenone (a CYP3A4 substrate) may result in elevated propafenone plasma concentrations and an increased risk for adverse events, including QT prolongation. It may be prudent to avoid use of propafenone for up to 2 weeks after discontinuing itraconazole, unless benefits of treatment outweigh the potential risk for side effects. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with propafenone 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. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Ixabepilone: (Minor) Propafenone is an inhibitor of P-glycoprotein (Pgp). Ixabepilone is a Pgp substrate, and concomitant use of ixabepilone with a Pgp inhibitor may cause an increase in ixabepilone concentrations. Caution is recommended if ixabepilone is coadministered with a Pgp inhibitor.
    Ketoconazole: (Major) Use caution during coadministration of propafenone and ketoconazole due to the potential for additive effects on the QT interval and increased exposure to propafenone. Both propafenone and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with propafenone (a CYP3A4 substrate) may result in elevated propafenone plasma concentrations and an increased risk for adverse events, including QT prolongation.
    Labetalol: (Major) Pharmacologically, beta-blockers, like labetalol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction, such as Class IC 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; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as propafenone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Lapatinib: (Major) Propafenone is a P-glycoprotein inhibitor, and lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1); concurrent administration with a P-glycoprotein inhibitor is likely to cause elevated serum lapatinib concentrations, and caution is recommended. Also, lapatinib and propafenone may prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking other drugs that lead to QT prolongation. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval..
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with propafenone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Propafenone is a Class IC antiarrhythmic which increases the QT interval, largely due to prolongation of the QRS interval.
    Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of propafenone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Propafenone is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Leuprolide: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include propafenone.
    Leuprolide; Norethindrone: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include propafenone.
    Levalbuterol: (Minor) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Levofloxacin: (Major) Concurrent use of propafenone and levofloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Additionally, rare cases of TdP have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. Propafenone is a Class IC antiarrhythmic which also increases the QT interval, but largely due to prolongation of the QRS interval.
    Levomethadyl: (Severe) Levomethadyl is associated with an established risk of QT prolongation and/or torsades de pointes and is contraindicated in combination with other agents that may prolong the QT interval, such as propafenone.
    Lidocaine: (Major) There is limited experience with the use of propafenone with Class IB antiarrhythmics. No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients. However, the concomitant use of propafenone and lidocaine has been reported to increase the risks of central nervous system side effects of lidocaine. When propafenone is coadministered, the dose of lidocaine should be titrated to the desired therapeutic effects.
    Lithium: (Major) Lithium should be used cautiously and with close monitoring with propafenone. Lithium has been associated with QT prolongation. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Lofexidine: (Major) Monitor ECG for QT prolongation and monitor for bradycardia during concurrent use of lofexidine and propafenone. Lofexidine may prolong the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Lomefloxacin: (Major) Lomefloxacin has been associated with QT prolongation and infrequent cases of arrhythmia. Other medications which may prolong the QT interval, such as propafenone, should be used cautiously when given concurrently with lomefloxacin.
    Long-acting beta-agonists: (Moderate) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Loperamide: (Major) Loperamide should be used cautiously and with close monitoring with propafenone. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Coadministration may further increase the risk for QT prolongation and torsade de pointes (TdP). In addition, the plasma concentrations of loperamide, a CYP2D6 and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with propafenone, a potent CYP2D6 and P-gp inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Loperamide; Simethicone: (Major) Loperamide should be used cautiously and with close monitoring with propafenone. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Coadministration may further increase the risk for QT prolongation and torsade de pointes (TdP). In addition, the plasma concentrations of loperamide, a CYP2D6 and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with propafenone, a potent CYP2D6 and P-gp inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Lopinavir; Ritonavir: (Major) Coadministration of HIV treatment doses of ritonavir and propafenone is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. However, propafenone and ritonavir may be coadministered with caution to patients receiving ritonavir as a boosting agent. Ritonavir inhibits both CYP3A4 and CYP2D6. Drugs that inhibit both pathways are expected to increase propafenone serum concentrations. (Major) Coadministration of lopinavir; ritonavir and propafenone may result in increased exposure to propafenone and increased risk of QT prolongation. Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2; lopinavir; ritonavir is an inhibitor of CYP3A. Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity. In addition, both propafenone and lopinavir; ritonavir have been associated with QT prolongation. Coadministration may result in additive QT prolongation. Close monitoring is advised if these drugs are administered together.
    Luliconazole: (Moderate) The manufacturer of propafenone warns that it should be used with caution with drugs that inhibit CYP1A2 and CYP3A4, which could theoretically reduce metabolism of propafenone to N-depropylpropafenone. N-depropylpropafenone is formed via dual metabolic pathways (CYP1A2 and/or CYP3A4). Drugs that inhibit CYP1A2 and CYP3A4 can be expected to increase the serum concentrations of propafenone. When propafenone is coadministered with inhibitors of CYP1A2 or CYP3A4, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP3A4 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of propafenone by decreasing its systemic exposure; if used together, monitor therapeutic response and adjust the propafenone dosage as needed to attain antiarrhythmic efficacy endpoints. Proprafenone is partially metabolized by CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of propafenone by decreasing its systemic exposure; if used together, monitor therapeutic response and adjust the propafenone dosage as needed to attain antiarrhythmic efficacy endpoints. Proprafenone is partially metabolized by CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as propafenone. 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. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Maprotiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with maprotiline. The need to coadminister these drugs should be done with a careful assessment of risk versus benefit; consider alternative therapy. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Maprotiline has also 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. Additionally, propafenone may inhibit the CYP2D6 metabolism of maprotiline.
    Maraviroc: (Moderate) Use caution and careful monitoring with the coadministration of maraviroc and propafenone as increased maraviroc concentrations may occur. Maraviroc is a substrate of P-glycoprotein (P-gp); propafenone is an inhibitor of P-gp. The effects of P-gp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
    Mefloquine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with mefloquine. There is evidence that the use of halofantrine after mefloquine causes significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation; however due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval, such as propafenone. In addition, mefloquine is metabolized by P-glycoprotein (P-gp) and propafenone is a P-gp inhibitor. Coadministration may increase mefloquine systemic exposure and further increasing the risk for QT prolongation.
    Meperidine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include propafenone.
    Mesoridazine: (Severe) Propafenone increases the QT interval and the use of propafenone in conjunction with other drugs that prolong the QT interval, such as mesoridazine, has not been studied and is not recommended by the manufacturer due to potential risk for ventricular tachycardia, including torsade de pointes and monomorphic ventricular tachycardia.
    Metaproterenol: (Minor) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Methadone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with methadone. The need to coadminister these drugs should be done with a careful assessment of treatment risks versus benefits. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Methadone is also considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). In addition, methadone is a substrate for CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Propafenone inhibits CYP2D6 and P-gp. Concurrent use may result in increased serum concentrations of methadone.
    Methamphetamine: (Minor) Propafenone inhibits CYP2D6. Propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme. Caution is recommended when administering propafenone with other CYP2D6 substrates, such as methamphetamine, that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions.
    Metoprolol: (Major) Pharmacologically, beta-blockers, like metoprolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Propafenone a CYP2D6 inhibitor, has been shown to increase the plasma concentrations and prolong the elimination half-life of metoprolol, with potential for adverse effects. Dosages of metoprolol may need to be reduced when used concomitantly with propafenone.
    Metronidazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include propafenone.
    Mexiletine: (Moderate) The concomitant use of mexiletine with other antiarrhythmics can lead to additive pharmacodynamic, electrophysiologic, and/or toxic effects of the drug combination compared with either agent alone.
    Midostaurin: (Major) The concomitant use of midostaurin and propafenone may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. QT prolongation and torsade de pointes have occurred during propafenone therapy.
    Mifepristone: (Major) Propafenone should be used cautiously and with close monitoring with mifepristone. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Mifepristone has been associated with dose-dependent prolongation of the QT interval. There is no experience with high exposure or concomitant use with other QT prolonging drugs. To minimize the risk of QT prolongation, the lowest effective dose should always be used.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as propafenone may be increased when administered with mirabegron. This is especially true for patients who are also CYP2D6 poor metabolizers (PMs). Therefore, appropriate monitoring and dose adjustment may be necessary.
    Mirtazapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and propafenone. Coadminister with caution. Propafenone is a Class IC antiarrhythmic that increases the QT interval largely due to prolongation of the QRS interval. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Moxifloxacin: (Major) Concurrent use of propafenone and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Propafenone, a Class IC antiarrhythmic, increases the QT interval, but largely due to prolongation of the QRS interval. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
    Nadolol: (Major) Pharmacologically, beta-blockers, like nadolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Nefazodone: (Moderate) Nefazodone is a CYP3A4 inhibitors which theoretically may decrease the hepatic metabolism of propafenone.
    Nelfinavir: (Major) Propafenone should be used with caution with drugs that inhibit CYP3A4, such as antiretroviral protease inhibitors, which could decrease the hepatic metabolism of propafenone.
    Nicardipine: (Moderate) Certain calcium-channel blockers, such as nicardipine, inhibit CYP3A4, a partial pathway for propafenone metabolism.
    Nifedipine: (Major) Because both propafenone and nifedipine have negative inotropic properties, additive effects are possible especially in patients with abnormal ventricular function. It may be prudent to monitor patients closely if nifedipine is used with other drugs that are negative inotropes such as propafenone.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib and propafenone; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Norfloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with norfloxacin. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Quinolones have also been associated with QT prolongation and TdP. For norfloxacin specifically, extremely rare cases of TdP were reported during post-marketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nortriptyline: (Minor) Tricyclic antidepressants (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). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are 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 TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as propafenone. Therapeutic monitoring is recommended with coadministration.
    Octreotide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with octreotide. 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. Propafenone, a Class IC antiarrhythmic, increases the QT interval largely due to prolongation of the QRS interval.
    Ofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with ofloxacin. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Some quinolones, including ofloxacin, have also been associated with QT prolongation. Additionally, post-marketing surveillance for ofloxacin has identified very rare cases of TdP.
    Olanzapine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with olanzapine. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Olodaterol: (Moderate) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) The manufacturer of ombitasvir; paritaprevir; ritonavir recommends caution and therapeutic drug monitoring (when available) if administered concurrently with propafenone. However, since one of the components of the 3-drug combination is ritonavir, use of these drugs together is contraindicated. Both ritonavir and propafenone are associated with QT prolongation; concomitant use increases the risk for developing Torsade de Pointes (TdP). In addition, ritonavir is a potent CYP3A4 inhibitor, an enzyme partially responsible for the metabolism of propafenone. If administered together, serum concentration of propafenone may increase. (Major) Coadministration of HIV treatment doses of ritonavir and propafenone is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. However, propafenone and ritonavir may be coadministered with caution to patients receiving ritonavir as a boosting agent. Ritonavir inhibits both CYP3A4 and CYP2D6. Drugs that inhibit both pathways are expected to increase propafenone serum concentrations.
    Ondansetron: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with ondansetron. If these drugs must be coadministered, ECG monitoring is recommended. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Ondansetron has also been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001).
    Oritavancin: (Moderate) Propafenone is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Plasma concentrations and efficacy of propafenone may be reduced if these drugs are administered concurrently.
    Orlistat: (Major) Orlistat may limit the fraction of propafenone available for absorption. In post-marketing reports, abrupt cessation of orlistat in patients stabilized on propafenone therapy has resulted in severe adverse events including convulsions, AV block and acute circulatory failure.
    Osimertinib: (Major) Avoid coadministration of propafenone 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 of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Propafenone is a Class IC antiarrhythmic which increases the QT interval, largely due to prolongation of the QRS interval.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of propafenone with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Oxycodone: (Moderate) Oxycodone is metabolized in part by cytochrome P450 2D6 to oxymorphone, which represents < 15% of the total administered dose. Potent inhibitors of CYP2D6, such as propafenone, may potentially increase the effects of oxycodone; however, such blockade has not been shown to be of clinical significance during oxycodone treatment. Clinicians should be aware of this possible interaction.
    Paliperidone: (Major) Concurrent use of paliperidone and propafenone should be avoided if possible due to an increased risk for QT prolongation and torsade de pointes (TdP). If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Panobinostat: (Major) The co-administration of panobinostat with propafenone is not recommended; QT prolongation has been reported with both of these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of propafenone toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and propafenone is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
    Paroxetine: (Major) Paroxetine impairs metabolism of the cytochrome P-450 isoenzyme CYP2D6 pathway at therapeutic doses. Although no clinical data are available, paroxetine should be used cautiously in patients receiving type IC antiarrhythmics and mexiletine since these antiarrhythmics are metabolized by this isozyme. Inhibition of CYP2D6 can result in increased concentrations of Class IC antiarrhythmics which may increase the risk of side effects or proarrhythmia.
    Pasireotide: (Major) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Cautious use of pasireotide and drugs that prolong the QT interval is needed, as coadministration may have additive effects on the prolongation of the QT interval.
    Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib and propafenone have been reported to prolong the QT interval. If pazopanib and propafenone must be continued, closely monitor the patient for QT interval prolongation. In addition, pazopanib is a weak inhibitor of CYP3A4 and a substrate for P-glycoprotein (P-gp). Propafenone is a substrate for CYP3A4 and an inhibitor of P-gp. Concurrent administration of propafenone and pazopanib may result in increased pazopanib concentrations and/or increased propafenone concentrations. Use caution when concurrent administration of propafenone and pazopanib is necessary.
    Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to propafenone if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while propafenone is a CYP2D6 substrate.
    Penbutolol: (Major) Pharmacologically, beta-blockers, like penbutolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Pentamidine: (Major) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with propafenone include pentamidine. Pentamidine has been associated with QT prolongation and may also cause electrolyte disturbances, such as hypokalemia, hypomagnesemia, and hypocalcemia which may increase the risk for cardiac arrhythmia. Monitor heart rate and serum electrolytes closely.
    Perphenazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering perphenazine with propafenone. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Perphenazine; Amitriptyline: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering perphenazine with propafenone. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval. (Minor) Tricyclic antidepressants (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). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are 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 TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
    Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include propafenone.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Coadministration may increase the risk for QT prolongation.
    Pimozide: (Severe) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of propafenone with pimozide is contraindicated.
    Pindolol: (Major) Pharmacologically, beta-blockers, like pindolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Pirbuterol: (Minor) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Posaconazole: (Severe) Concurrent use of posaconazole and propafenone is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of propafenone. Further, propafenone is an inhibitor of the drug efflux protein, P-glycoprotein, for which posaconazole is a substrate and an inhibitor. This complex interaction may ultimately result in altered plasma concentrations of both posaconazole and propafenone. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as propafenone.
    Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include propafenone.
    Procainamide: (Major) Procainamide is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Class IC antiarrhythmic agents, such as propafenone, have proarrhythmic properties, and may have additive electrophysiologic effects with procainamide; use concomitantly with caution. The manufacturer of propafenone recommends against the use of propafenone with Class 1A agents such as procainamide.
    Prochlorperazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with prochlorperazine. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Phenothiazines, such as prochlorperazine, have been reported to prolong the QT interval. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include propafenone.
    Propoxyphene: (Major) Class IC antiarrhythmics are significantly metabolized by CYP2D6. Caution is recommended when administering class IC antiarrhythmics with propoxyphene, a CYP2D6 inhibitor. Monitor clinical response, and adjust antiarrhythmic dosage if necessary.
    Propranolol: (Major) Pharmacologically, beta-blockers, like propranolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Additionally, propafenone, a CYP2D6 inhibitor, appears to inhibit the metabolism of propranolol. Coadministration of propafenone with propranolol increases the plasma concentrations and prolongs the elimination half-life of propranolol; these affects were associated with a 15% decrease in diastolic blood pressure. Patients should be monitored closely and a reduction in the dosage of propranolol may be indicated.
    Protriptyline: (Minor) Tricyclic antidepressants (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). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are 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 TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
    Quetiapine: (Major) Concurrent use of quetiapine and propafenone should be avoided due to an increased risk for 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. Propafenone is a Class IC antiarrhythmic which also increases the QT interval, but largely due to prolongation of the QRS interval.
    Quinidine: (Severe) Class IA antiarrhythmics are associated with QT prolongation and ventricular arrhythmias including torsades de pointes (TdP), and concurrent use with propafenone is not recommended by the manufacturer. Before switching from another antiarrhythmic drug to propafenone therapy, Class IA antiarrhythmics and Class III antiarrhythmics generally should be withheld for at least five half-lives prior to initiating propafenone. Quinidine is a CYP2D6 inhibitor with potential to inhibit propafenone metabolism, and coadministration is contraindicated. Small doses of quinidine completely inhibit the CYP2D6 hydroxylation metabolic pathway, with the result that extensive metabolizers become poor metabolizers. Coadministration with quinidine markedly decreases propafenone clearance in extensive metabolizers, and increases plasma propafenone concentrations by 2 to 3-fold at steady-state. Steady-state plasma concentrations increased more than 2-fold for propafenone, and decreased 50% for 5-OH-propafenone.
    Quinine: (Major) Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP). In addition, quinine is an inhibitor of both CYP3A4 and CYP2D6. Avoid concurrent use of quinine with other drugs that prolong the QT and are CYP3A4/CYP2D6 substrates. such as propafenone, which also may prolong the QT interval. Coadministration may result in an elevated plasma concentrations, as quinine inhibits CYP2D6 and may increase concentrations of drugs metabolized by this enzyme, such as propafenone. Also, quinine is a substrate of P-glycoprotein (P-gp) and propafenone is a P-gp inhibitor; therefore, quinine concentrations could be increased with coadministration. Caution is recommended. Monitor patients for increased side effects, such as fast, irregular heartbeat, if these drugs must be used together. Consider alternative therapy to quinine if possible.
    Ranolazine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with ranolazine. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. In addition, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Coadministration of ranolazine with inhibitors of CYP2D6, such as propafenone, may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects.
    Ribociclib: (Major) Avoid coadministration of ribociclib with propafenone due to an increased risk for QT prolongation. Systemic exposure of propafenone may also be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Propafenone is a CYP3A4 substrate and Class IC antiarrhythmic that increases the QT interval, but largely due to prolongation of the QRS interval. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with propafenone due to an increased risk for QT prolongation. Systemic exposure of propafenone may also be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Propafenone is a CYP3A4 substrate and Class IC antiarrhythmic that increases the QT interval, but largely due to prolongation of the QRS interval. Concomitant use may increase the risk for QT prolongation.
    Rifabutin: (Moderate) Rifabutin is an inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of propafenone.
    Rifampin: (Major) Rifampin may reduce the bioavailability of oral propafenone via induction of propafenone metabolism. Rifampin induces Phase I and Phase II metabolism of propafenone, increasing drug clearance via N-dealkylation and glucuronidation pathways by over 4-fold, but does not appear to induce hydroxylation of propafenone. The extent of reduction in propafenone mean bioavailability is greater in extensive metabolizers of propafenone (reduced from 30% to 10%), although bioavailability is also significantly reduced in poor metabolizers (81% to 48%). The manufacturer reports that concomitant administration of rifampin and propafenone in extensive metabolizers decreases the plasma concentrations of propafenone by 67%, with a corresponding decrease of 5OH-propafenone by 65%. The concentrations of norpropafenone is increased by 30%. In poor metabolizers, there is 50% decrease in propafenone plasma concentrations, and increased the AUC and Cmax of norpropafenone by 74 and 20%, respectively. Urinary excretion of propafenone and its metabolites decreased significantly. Similar results were noted in elderly patients; both the AUC and Cmax propafenone decreased by 84%, with a corresponding decrease in AUC and Cmax of 5OH-propafenone by 69 and 57%. When propafenone is coadministered with rifamycins which induce hepatic metabolism (e.g., rifampin, rifabutin, rifapentine), monitor therapeutic response and adjust dosage as needed to attain antiarrhythmic efficacy endpoints.
    Rifapentine: (Moderate) Rifapentine may reduce the bioavailability of oral propafenone via induction of propafenone metabolism. The extent of reduction in propafenone mean bioavailability is greater in extensive metabolizers of propafenone, although bioavailability is also significantly reduced in poor metabolizers.
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and propafenone, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with propafenone. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Risperidone: (Major) Both risperidone and propafenone are associated with a risk for QT prolongation and torsade de pointes (TdP); therefore, caution is advised during concurrent use. If coadministration is required and the patient has risk factors for cardiac disease or arrhythmias, close monitoring is recommended.
    Ritonavir: (Major) Coadministration of HIV treatment doses of ritonavir and propafenone is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. However, propafenone and ritonavir may be coadministered with caution to patients receiving ritonavir as a boosting agent. Ritonavir inhibits both CYP3A4 and CYP2D6. Drugs that inhibit both pathways are expected to increase propafenone serum concentrations.
    Rivaroxaban: (Minor) Coadministration of rivaroxaban and propafenone may result in increases in rivaroxaban exposure and may increase bleeding risk. Propafenone is an inhibitor of P-gp, and rivaroxaban is a substrate of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Rolapitant: (Major) Monitor for propafenone-related adverse effects, including QT prolongation, if coadministered with rolapitant. Increased exposure to propafenone may occur . Propafenone is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Romidepsin: (Major) Romidepsin is a substrate for P-glycoprotein (P-gp). Propafenone is an inhibitor of P-gp. Concurrent administration of romidepsin with an inhibitor of P-gp may cause an increase in systemic romidepsin concentrations. In addition, romidepsin has been reported to prolong the QT interval. Propafenone may also prolong the QT interval. If romidepsin and propafenone must be continued, closely monitor the patient for QT interval prolongation.
    Rucaparib: (Moderate) Monitor for an increase in propafenone-related adverse reactions including cardiac arrhythmias and increased beta-blocking activity if coadministration with rucaparib is necessary. Propafenone is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Concomitant use may increase plasma concentrations of propafenone.
    Salmeterol: (Moderate) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Saquinavir: (Severe) Concurrent use of propafenone and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Saquinavir boosted with ritonavir is an inhibitor of CYP3A4 and CYP2D6, two enzymes responsible for the metabolism of propafenone. These drugs used together may result in large increases in propafenone serum concentrations, which could cause fatal cardiac arrhythmias. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as propafenone.
    Sertraline: (Major) Because both sertraline and Class IC Antiarrhythmics are associated with a possible risk of QT prolongation and Torsade de Pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, sertraline is a mild to moderate inhibitor of CYP2D6, and inhibition of CYP2D6 can result in increased concentrations of antiarrhythmic drugs metabolized via the same pathway, including flecainide and propafenone.
    Short-acting beta-agonists: (Minor) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Simeprevir: (Moderate) Coadministration of propafenone with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in propafenone plasma concentrations. If these drugs are administered together, monitoring of propafenone plasma concentrations (if available) is recommended.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with propafenone. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); propafenone is an inhibitor of P-gp.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with propafenone. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); propafenone is an inhibitor of P-gp.
    Solifenacin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering solifenacin with propafenone. Solifenacin has been associated with dose-dependent prolongation of the QT interval; TdP has been reported during post-marketing use, although causality was not determined. Propafenone, a Class IC antiarrhythmic, also increases the QT interval largely due to prolongation of the QRS interval.
    Sorafenib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of sorafenib with propafenone is necessary; correct any electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib has been associated with QT prolongation. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Sotalol: (Major) Concurrent use of propafenone and Class III agents is not recommended. Propafenone and sotalol are both associated with QT prolongation. The effects of concomitant administration of antiarrhythmics can be synergistic, additive, or antagonistic, and adverse cardiac effects can be additive. There is limited experience when using class 1C antiarrhythmics in combination with sotalol, a Class III antiarrhythmic. Pharmacologically, sotalol cause AV nodal conduction depression and additive effects are possible when used in combination with class 1C antiarrhythmic drugs such as propafenone. Patients should be monitored closely if class IC antiarrhythmic drugs are used in combination with sotalol, and the dose should be adjusted according to clinical response. Before switching from another antiarrhythmic drug to propafenone therapy, Class III antiarrhythmics generally should be withheld for at least five half-lives prior to initiating propafenone.
    Sparfloxacin: (Severe) Sparfloxacin is associated with an established risk for QT prolongation and torsades de pointes and is contraindicated in patients receiving other drugs that can cause QT prolongation including propafenone.
    St. John's Wort, Hypericum perforatum: (Major) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system and co-administration of St. John's wort could decrease the efficacy of some medications metabolized by these enzymes including propafenone. Clinicians should observe patients closely if St. John's wort is added to propafenone.
    Streptogramins: (Moderate) Coadministration of propafenone with dalfopristin; quinupristin may result in elevated propafenone plasma concentrations. If these drugs are used together, closely monitor for signs of propafenone-related adverse events. Propafenone is a substrate of CYP3A; dalfopristin; quinupristin is a weak CYP3A inhibitor.
    Sunitinib: (Major) Monitor patients for QT prolongation if coadministration of propafenone with sunitinib is necessary. Sunitinib can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points (TdP). Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Tacrine: (Moderate) Tacrine is a CYP1A2 inhibitors which theoretically may decrease the hepatic metabolism of propafenone.
    Tacrolimus: (Major) Concurrent use of tacrolimus and propafenone should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Tacrolimus prolongs the QT interval. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval. In addition, both drugs are metabolized by CYP3A4. Although the manufacturer recommends dose adjustment and close monitoring when tacrolimus is coadminsitered with other drugs that prolong the QT interval and are substrates or inhibitors of CYP3A4, it may be prudent to avoid coadministration as the risk of TdP may be increased.
    Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with propafenone is necessary. Talazoparib is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%.
    Tamoxifen: (Major) Use caution if coadministration of propafenone with tamoxifen is necessary due to the risk of QT prolongation. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP2D6 inhibitor such as propafenone. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP2D6 inhibitor resulted in increases in tamsulosin exposure; interactions with moderate CYP2D6 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Telaprevir: (Major) Close clinical monitoring is advised when administering propafenone with telaprevir due to an increased potential for serious and/or life-threatening propafenone-related adverse events. If propafenone dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of propafenone. Propafenone is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Additionally, propafenone is an inhibitor of P-glycoprotein (P-gp), an efflux transporter partially responsible for the metabolism of telaprevir. When used in combination, the plasma concentrations of both medications may be elevated.
    Telavancin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telavancin with propafenone. Telavancin has been associated with QT prolongation. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Telithromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telithromycin with propafenone. Telithromycin is associated with QT prolongation and TdP. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval. Additionally, telithromycin is a strong inhibitor of CYP3A4 and may affect the CYP3A4 metabolism of propafenone. This could potentially result in increased plasma concentrations of propafenone.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and propafenone is necessary, as the systemic exposure of propafenone may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of propafenone as well as an increase in adverse reactions related to telotristat ethyl. Consider increasing the dose of propafenone if necessary. Propafenone is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and propafenone is a P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with propafenone is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Tenofovir, PMPA: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as propafenone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Terbinafine: (Major) Class IC antiarrhythmics are metabolized by CYP2D6 isoenzymes. Caution is recommended when administering them with CYP2D6 inhibitors, such as terbinafine; Class IC antiarrhythmics exhibit a narrow therapeutic range and large increases in serum concentrations may be associated with severe adverse reactions.
    Terbutaline: (Minor) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Teriflunomide: (Moderate) As teriflunomide is a weak inducer of CYP1A2, exposure to propafenone, a CYP1A2 substrate, may be reduced. Caution should be exercised with concurrent use. Patients should be monitored for loss of antiarrhythmic effect if teriflunomide therapy is initiated. Conversely, propafenone doses may need adjustment if teriflunomide treatment is discontinued.
    Tetrabenazine: (Major) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc, such as propafenone.
    Theophylline, Aminophylline: (Moderate) Although limited data are available, it appears that propafenone may affect theophylline clearance. In several patients, theophylline concentrations increased after the addition of propafenone and in at least one patient, symptoms of theophylline toxicity were suspected. Until more data are available, lower doses of theophylline should be considered in patients receiving propafenone.
    Thioridazine: (Severe) Thioridazine is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Thioridazine is considered contraindicated for use along with propafenone which, when combined with thioridazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension.
    Thiothixene: (Major) Propafenone prolongs the QT interval. Combined use with thiothixene could lead to additive orthostatic hypotension and/or prolonged QT syndrome and torsade de pointes. If concomitant use unavoidable, use together with caution and close monitoring.
    Ticagrelor: (Moderate) Coadministration of ticagrelor and propafenone may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Timolol: (Major) Pharmacologically, beta-blockers, like timolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Tiotropium; Olodaterol: (Moderate) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Tipranavir: (Severe) Coadminsitration of tipranavir with propafenone is contraindicated due to the potential for serious and/or life-threatening cardiac arrhythmias. Tipranavir inhibits the CYP3A4 metabolism of propafenone resulting in elevated propafenone plasma concentrations.
    Tizanidine: (Major) Avoid concomitant use of tizanidine and propafenone as increased serum concentrations of tizanidine may occur. If use together is necessary, initiate tizanidine with the 2 mg dose and increase daily in 2 to 4 mg increments based on clinical response. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occurs. Tizanidine is a CYP1A2 substrate and propafenone is a CYP1A2 inhibitor.
    Tolterodine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with propafenone. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Tolvaptan: (Major) Tolvaptan is a substrate for P-gp. Propafenone is an inhibitor of P-gp. Coadministration may result in increased exposure of tolvaptan; a reduction in the dose of tolvaptan may be required.
    Topotecan: (Major) Avoid coadministration of propafenone with oral topotecan due to increased topotecan exposure; propafenone may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and propafenone is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Toremifene: (Major) Avoid coadministration of propafenone with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Tramadol: (Moderate) As propafenone is a moderate CYP2D6 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Decreased analgesia might occur. Inhibition of either CYP2D6 and/or CYP3A4 is also expected to reduce the metabolic clearance of tramadol and may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Trandolapril; Verapamil: (Major) Coadministration of propafenone with verapamil has the potential to cause additive decreases in AV conduction and/or negative inotropic effects. In addition, certain calcium-channel blockers, such as verapamil, inhibit CYP3A4, a partial pathway for propafenone metabolism.
    Trazodone: (Major) Avoid coadministration of trazodone and propafenone. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP. Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. In addition, in vitro studies support that propafenone inhibits CYP2D6. Coadministration of propafenone with trazodone, a CYP2D6 substrate, may theoretically increase concentrations of trazodone.
    Tricyclic antidepressants: (Minor) Tricyclic antidepressants (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). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are 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 TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
    Trifluoperazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with trifluoperazine. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Trifluoperazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Trimipramine: (Minor) Tricyclic antidepressants (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). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are 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 TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
    Triptorelin: (Major) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with triptorelin include propafenone.
    Umeclidinium; Vilanterol: (Moderate) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with propafenone include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Vandetanib: (Major) Avoid coadministration of vandetanib with propafenone due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, 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. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Vardenafil: (Major) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed. The effect of vardenafil on the QT interval should be considered when prescribing the drug. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with vardenafil include propafenone. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as propafenone, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, propafenone is a substrate of CYP 1A2, 2D6, and 3A4 and is an inhibitor of P-glycoprotein (P-gp). Vemurafenib is an inhibitor of CYP1A2, a weak inhibitor of CYP2D6, a substrate/inducer of CYP3A4, and a substrate/inhibitor of P-glycoprotein (P-gp) . Concentrations of both propafenone and vemurafenib may be altered with concomitant use.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with propafenone due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of propafenone. Venetoclax is a P-glycoprotein (P-gp) substrate; propafenone is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Venlafaxine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with venlafaxine. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Venlafaxine is also associated with a possible risk of QT prolongation; TdP has been reported with post-marketing use. In addition, an elderly women exhibited psychosis 2 weeks after an increase in her dose of venlafaxine from 225 to 300 mg/day and initiation of propafenone at 600 mg/day. Upon evaluation it was found that her serum concentrations of venlafaxine had increased > 6-fold. Although the mechanism of this interaction has not been described, it is possible that strong inhibition of CYP2D6 by propafenone led to elevated serum concentrations of venlafaxine, a CYP2D6 substrate. Additionally, propafenone is also a substrate for CYP2D6, and competitive inhibition may have played a role. Serum concentrations of venlafaxine and the clinical response to therapy should be monitored if adding propafenone to the regimen.
    Verapamil: (Major) Coadministration of propafenone with verapamil has the potential to cause additive decreases in AV conduction and/or negative inotropic effects. In addition, certain calcium-channel blockers, such as verapamil, inhibit CYP3A4, a partial pathway for propafenone metabolism.
    Vinblastine: (Minor) Propafenone is an inhibitor of the efflux transporter P-glycoprotein. Vinblastine is a P-glycoprotein substrate. Increased concentrations of vinblastine are likely if it is coadministered with propafenone; exercise caution.
    Vincristine Liposomal: (Major) Propafenone inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Vincristine: (Major) Propafenone inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Voriconazole: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as propafenone. Both drugs are associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a strong CYP3A4 inhibitor) with propafenone (a CYP3A4 substrate) may result in elevated propafenone plasma concentrations and an increased risk for adverse events, including QT prolongation. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
    Vorinostat: (Major) Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Vorinostat therapy is associated with a risk of QT prolongation and should be used cautiously with propafenone.
    Warfarin: (Major) Concomitant use of propafenone and warfarin results in a significant increase in warfarin plasma levels by 39%, with an increase in prothrombin time of about 25%. Warfarin dosages should be adjusted as needed to attain appropriate INR goals for the individual patient.
    Zafirlukast: (Moderate) In vitro data indicate that zafirlukast inhibits CYP3A4 at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, especially those drugs, like propafenone, with narrow therapeutic ranges.
    Zileuton: (Moderate) Zileuton is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of propafenone.
    Ziprasidone: (Major) Concomitant use of ziprasidone and propafenone should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.

    PREGNANCY AND LACTATION

    Pregnancy

    Propafenone and its active metabolite are present in human milk, but concentrations are likely to be low. There are no data on the effects of propafenone on the breast-fed infant or the effects on milk production. Consider the benefits of breast-feeding along with the mother's clinical need for propafenone and any potential adverse effects on the breast-fed infant from propafenone or the underlying maternal condition.[28287] Previous American Academy of Pediatrics (AAP) guidelines had not evaluated propafenone; however, the AAP considered flecainide, another class IC antiarrhythmic, to be usually compatible with breast-feeding.[27500]

    MECHANISM OF ACTION

    Mechanism of Action: Similar to encainide and flecainide, propafenone inhibits the fast sodium channels of the myocardial cell membrane, thereby increasing the recovery period after repolarization. Propafenone can inhibit extracellular calcium influx but only at high doses. Beta-adrenergic blocking properties of propafenone are approximately 1/40th that of propranolol and local anesthetic activity is roughly equivalent to that of procaine. Although it is a relatively weak beta-receptor antagonist, plasma concentrations for propafenone are 50 times higher than for the beta-blockers, and, as a result, beta-blockade can be seen clinically. Propafenone decreases conduction velocity, automaticity, and excitability of atrioventricular internodal tissue, and it increases the action potential duration in AV nodal tissue. The drug also slows intracardiac conduction velocity and prolongs the effective refractory period of the accessory pathways.

    PHARMACOKINETICS

    Propafenone is administered orally. Following absorption propafenone is approximately 85 to 97% protein-bound, primarily to alpha-1-glycoprotein. The extensive metabolism of the drug is saturable, dose-dependent, acetylator phenotype-dependent, primarily dependent on CYP2D6 isoenzyme activity, and generates active metabolites. These properties contribute to the large inter-subject variability observed in propafenone and metabolite plasma concentrations; propafenone dosage should be monitored closely and the dosage individualized to achieve clinical goals. Extensive metabolizers (> 90% of patients) convert propafenone into 2 active metabolites (5-hydroxypropafenone and N-depropylpropafenone) that have antiarrhythmic properties comparable to the parent compound. Both active metabolites are usually present in plasma concentrations < 20% of propafenone following administration of the immediate-release formulation. Mean exposure to the 5-hydroxypropafenone metabolite is about 20 to 25% higher after the extended-release capsule vs. the immediate-release tablet. Nine other metabolites have been identified in man, most in trace amounts. Propafenone is metabolized to 5-hydroxypropafenone by CYP2D6. Propafenone is metabolized to N-depropylpropafenone by CYP3A4 and CYP1A2. In vitro and in vivo studies have shown that the R-isomer of propafenone is cleared faster than the S-isomer via the 5-hydroxylation pathway (CYP2D6), which is a saturable pathway responsible for the nonlinear elimination of propafenone. This results in a higher ratio of S-propafenone during steady state. Less than 1% is renally excreted as unchanged drug. Approximately 38% of propafenone's metabolites are excreted in the urine, while the remaining metabolites (58%) are excreted in the feces. The half-life of the drug in extensive metabolizers is 2 to 10 hours, while the half-life in poor metabolizers is 10 to 32 hours.
     
    Affected cytochrome P450 enzymes and drug transporters: CYP1A2, CYP2D6, CYP3A4, and P-glycoprotein
    Propafenone is metabolized primarily by CYP2D6, and to a lesser extent by CYP3A4 and CYP1A2. In vitro studies support that propafenone inhibits CYP2D6 enzymes.Propafenone also is an inhibitor of P-glycoprotein.

    Oral Route

    Propafenone immediate-release is almost completely absorbed, but due to significant first-pass metabolism, has dose-dependent bioavailability (3.4% with 150 mg tablet; 10.6% with 300 mg tablet). Following administration of extended-release propafenone capsules (Rythmol SR), peak plasma concentrations are reached within 3 and 8 hours. Since prolonged drug release results in an increase in the overall first pass metabolism of propafenone in extensive metabolizers (> 90% of patients), higher doses of the extended-release product are required to obtain similar drug exposure to the immediate-release formulation. The relative bioavailability of extended-release propafenone 325 mg PO twice daily approximates that of immediate-release propafenone 150 mg PO 3 times daily. Although single dose studies have shown increased propafenone bioavailability with food, a multiple dose study did not show significant differences in the bioavailability of Rythmol or Rythmol SR when administered with food.