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  • CLASSES

    Anti-arrhythmics, Miscellaneous

    BOXED WARNING

    Heart failure, hypovolemia

    Dronedarone is contraindicated in patients with NYHA Class IV heart failure or symptomatic heart failure with recent decompensation requiring hospitalization; use in these populations doubles the risk of death. Marked increase in serum creatinine, pre-renal azotemia, and acute renal failure, often in patients with heart failure or hypovolemia, have been associated with use of dronedarone. Heart failure may increase the risk of prolonging the QT interval. Furthermore, new onset or worsening heart failure has been reported during post-marketing use of dronedarone. Increased rates of heart failure were seen in a placebo-controlled study involving patients with permanent AF with normal left ventricular function and no history of symptomatic heart failure as well as those with a history of heart failure or left ventricular dysfunction. Advise patients to consult their healthcare provider if they develop signs or symptoms of heart failure (e.g., weight gain, edema, increasing shortness of breath). Discontinue dronedarone if heart failure develops or worsens and requires hospitalization.

    Atrial fibrillation

    Dronedarone is contraindicated in patients with permanent atrial fibrillation (AF) in whom normal sinus rhythm will not or cannot be restored; dronedarone doubles the risk of death and heart failure events in patients with permanent AF. Data from the PALLAS trial found patients with permanent atrial fibrillation who were treated with dronedarone experienced increases in cardiovascular death (mainly arrhythmic), cerebrovascular accident (particularly in the first 2 weeks of therapy), and heart failure hospitalizations when compared with patients receiving placebo. Dronedarone is only approved for use in patients in sinus rhythm with a history of paroxysmal or persistent AF. Patients treated with dronedarone should undergo cardiac monitoring at least every 3 months. Discontinue dronedarone or cardiovert (if clinically indicated) patients who are in atrial fibrillation. Dronedarone should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy.

    DEA CLASS

    Rx

    DESCRIPTION

    Antiarrhythmic agent similar in efficacy to amiodarone
    Used to reduce hospitalization risk for AF in patients in sinus rhythm with history of paroxysmal or persistent AF
    Contraindicated in certain patients with heart failure or permanent AF

    COMMON BRAND NAMES

    Multaq

    HOW SUPPLIED

    Multaq Oral Tab: 400mg

    DOSAGE & INDICATIONS

    For reduction in the risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation.
    NOTE: Dronedarone is contraindicated in patients with permanent atrial fibrillation who will not or cannot be cardioverted to normal sinus rhythm. The use of dronedarone in these patients has resulted in increases in death, stroke, and heart failure hospitalizations when compared to placebo.
    Oral dosage

    NOTE: Discontinue Class I or III antiarrhythmics (e.g., amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) or drugs that are strong CYP3A4 inhibitors (e.g., ketoconazole) prior to initiating dronedarone therapy.

    Adults

    400 mg PO twice daily. Clinical practice guidelines recommend dronedarone to maintain sinus rhythm in patients with atrial fibrillation. Avoid use in patients with New York Hear Association (NYHA) class III and IV heart failure or in patients who have had an episode of decompensated heart failure in the past 4 weeks.

    MAXIMUM DOSAGE

    Adults

    800 mg/day PO.

    Geriatric

    800 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild to moderate impairment: Dosage adjustments are not needed; in moderate impairment, limited data are available.
    Severe impairment: Use is contraindicated.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Administer twice daily with the morning and evening meals.
    The appropriate MedGuide should be dispensed with each prescription and refill.

    STORAGE

    Multaq :
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Dronedarone is metabolized primarily by CYP3A and is contraindicated with the concomitant use of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, ritonavir). Concurrent use of strong CYP3A inhibitors can lead to a marked increase in dronedarone concentrations.

    Heart failure, hypovolemia

    Dronedarone is contraindicated in patients with NYHA Class IV heart failure or symptomatic heart failure with recent decompensation requiring hospitalization; use in these populations doubles the risk of death. Marked increase in serum creatinine, pre-renal azotemia, and acute renal failure, often in patients with heart failure or hypovolemia, have been associated with use of dronedarone. Heart failure may increase the risk of prolonging the QT interval. Furthermore, new onset or worsening heart failure has been reported during post-marketing use of dronedarone. Increased rates of heart failure were seen in a placebo-controlled study involving patients with permanent AF with normal left ventricular function and no history of symptomatic heart failure as well as those with a history of heart failure or left ventricular dysfunction. Advise patients to consult their healthcare provider if they develop signs or symptoms of heart failure (e.g., weight gain, edema, increasing shortness of breath). Discontinue dronedarone if heart failure develops or worsens and requires hospitalization.

    Atrial fibrillation

    Dronedarone is contraindicated in patients with permanent atrial fibrillation (AF) in whom normal sinus rhythm will not or cannot be restored; dronedarone doubles the risk of death and heart failure events in patients with permanent AF. Data from the PALLAS trial found patients with permanent atrial fibrillation who were treated with dronedarone experienced increases in cardiovascular death (mainly arrhythmic), cerebrovascular accident (particularly in the first 2 weeks of therapy), and heart failure hospitalizations when compared with patients receiving placebo. Dronedarone is only approved for use in patients in sinus rhythm with a history of paroxysmal or persistent AF. Patients treated with dronedarone should undergo cardiac monitoring at least every 3 months. Discontinue dronedarone or cardiovert (if clinically indicated) patients who are in atrial fibrillation. Dronedarone should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy.

    Amiodarone-induced liver toxicity, hepatic disease

    Dronedarone use is contraindicated in patients with severe hepatic disease; there are no clinical data in this population. Dronedarone is also contraindicated in patients with a history of amiodarone-induced liver toxicity. Dronedarone is extensively metabolized by the liver. Although pharmacokinetic data are altered in patients with moderate hepatic impairment, there is little clinical experience in this patient population. No dosage adjustment is necessary in patients with moderate hepatic impairment.

    Amiodarone-induced lung toxicity

    Dronedarone is contraindicated in patients with a history of amiodarone-induced lung toxicity. Pulmonary toxicity, including cases of interstitial lung disease, has been reported in patients treated with dronedarone in the post-marketing setting.

    Electrolyte imbalance, hypocalcemia, hypokalemia, hypomagnesemia

    Use dronedarone cautiously in patients with an uncorrected electrolyte imbalance (i.e., hypokalemia, hypomagnesemia, hypocalcemia) as it may increase the risk of prolonging the QT interval and could potentially decrease the efficacy of dronedarone. Furthermore, use caution when coadministering dronedarone with medications known to cause electrolyte imbalances, including potassium-depleting diuretics. The serum potassium concentration should be maintained within the normal range prior to and during dronedarone administration.

    Apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, females, fever, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypothermia, hypothyroidism, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sick sinus syndrome, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE), torsade de pointes

    Dronedarone has caused symptomatic bradycardia and is contraindicated in patients with bradycardia less than 50 beats per minute. Dronedarone is also contraindicated in patients with advanced AV block (second or third degree) or sick sinus syndrome, except when used in conjunction with a pacemaker. Additionally, it has been associated with moderate QT prolongation (average of approximately 10 milliseconds) and should not be used in patients with acquired or congenital long QT syndrome or a history of torsade de pointes (TdP). Dronedarone is contraindicated in patients with a QTc Bazett interval of 500 milliseconds or longer or a PR interval above 280 milliseconds. Furthermore, it is contraindicated in patients taking other medications known to prolong the QT interval, as concurrent use could increase the risk of developing QT prolongation or TdP. Use dronedarone with caution in patients with conditions that may increase the risk of QT prolongation including heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

    Asian patients

    Use caution when administering dronedarone to Asian patients. Pharmacokinetic studies show Asian males (Japanese) have an approximate 2-fold higher dronedarone exposure than White males.

    Geriatric

    In the clinical trials of dronedarone, 4,500 patients were 65 years of age or older and 2,000 of those were 75 years of age and older. Systemic exposure is 23% higher in geriatric patients compared to adults under 65 years of age; however, no differences in safety or efficacy were observed between geriatric patients compared to the general study population. Geriatric patients may be at increased risk for QT prolongation from drugs such as dronedarone. According to the Beers Criteria, worse outcomes have been reported in patients taking dronedarone who have permanent atrial fibrillation or severe or recently decompensated heart failure; therefore, the drug should be avoided in geriatric patients with these conditions. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents 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.

    Children, infants, neonates

    Safety and effectiveness of dronedarone have not been established in neonates, infants, children or adolescents less than 18 years of age.

    Pregnancy

    Dronedarone is classified as FDA pregnancy risk category X and is contraindicated in women who are or may become pregnant. Dronedarone may cause fetal harm when administered to pregnant women. It was found to be teratogenic to rats at the maximum recommended human dose and to rabbits at half the maximum recommended human dose. Teratogenic effects found in rats include cranioschisis, cleft palate, incomplete evagination of pineal body, brachygnathia, partially fused carotid arteries, truncus arteriosus, abnormal lobation of the liver, partially duplicated inferior vena cava, brachydactyly, ectrodactylia, syndactylia, and anterior and/or posterior club feet. Teratogenic effects seen in rabbits included anomalous ribcage and vertebrae and pelvic asymmetry. Premenopausal females who have not undergone a hysterectomy or oophorectomy must use effective contraception and be counseled regarding appropriate contraceptive choices while using dronedarone. If the patient becomes pregnant while taking dronedarone, the physician and patient need to discuss the risk to the pregnancy and the potential hazard to the fetus.

    Breast-feeding

    According to the manufacturer, it is unknown whether dronedarone is excreted into human breast milk. It is excreted into the milk of lactating rats. Because of the potential for serious adverse reactions in breast-feeding infants from dronedarone, a decision should be made to discontinue nursing or discontinue dronedarone, taking into account the importance of the drug to the mother. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 2.0-3.5
    heart failure / Delayed / 2.7-2.7
    stroke / Early / 1.4-1.4
    atrial flutter / Early / 0-1.0
    torsade de pointes / Rapid / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    coagulopathy / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatic encephalopathy / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    vasculitis / Delayed / Incidence not known
    azotemia / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known

    Moderate

    QT prolongation / Rapid / 28.0-28.0
    hypothyroidism / Delayed / 0.8-0.8
    jaundice / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    hypomagnesemia / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known

    Mild

    diarrhea / Early / 9.0-9.2
    asthenia / Delayed / 7.0-7.0
    vomiting / Early / 2.0-6.0
    nausea / Early / 5.0-6.0
    maculopapular rash / Early / 5.0-5.0
    pruritus / Rapid / 5.0-5.0
    rash / Early / 5.0-5.0
    abdominal pain / Early / 4.0-4.0
    dyspepsia / Early / 2.0-2.0
    photosensitivity / Delayed / 0-1.0
    dysgeusia / Early / 0-1.0
    weakness / Early / Incidence not known

    DRUG INTERACTIONS

    Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with dronedarone is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
    Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with dronedarone. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Acebutolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with dronedarone may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of dronedarone could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If dronedarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Acetaminophen; Chlorpheniramine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution. (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution. (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution. (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with dronedarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of dronedarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If dronedarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Acetaminophen; Dextromethorphan: (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Diphenhydramine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Diphenhydramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. If dronedarone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like dronedarone can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If dronedarone is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Afatinib: (Moderate) If the concomitant use of dronedarone 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 dronedarone. 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 dronedarone 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.
    Aldesleukin, IL-2: (Moderate) Dronedarone is metabolized by CYP3A. Aldesleukin, IL-2 is an inhibitor CYP3A4. Repeated doses of ketoconazole, a strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. Concomitant use of dronedarone with aldesleukin, IL-2 may also increase dronedarone concentrations. No data exist regarding the appropriate dose adjustment needed to allow safe administration of dronedarone with CYP3A4 inhibitors; therefore, use caution when coadministering dronedarone with CYP3A4 inhibitors such as aldesleukin, IL-2.
    Alfentanil: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Alfentanil is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Alfuzosin: (Contraindicated) Concurrent use of dronedarone and alfuzosin is contraindicated. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated. Based on electrophysiology studies performed by the manufacturer, alfuzosin has a slight effect to prolong the QT interval. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg.
    Aliskiren: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Aliskiren is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Aliskiren; Amlodipine: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Aliskiren is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution. (Moderate) Monitor for evidence of hypotension and edema if amlodipine is coadministered with dronedarone; an amlodipine dose adjustment may be necessary due to increased amlodipine exposure. Dronedarone is a moderate CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Aliskiren is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution. (Moderate) Monitor for evidence of hypotension and edema if amlodipine is coadministered with dronedarone; an amlodipine dose adjustment may be necessary due to increased amlodipine exposure. Dronedarone is a moderate CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Aliskiren is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Aliskiren; Valsartan: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Aliskiren is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Alprazolam: (Major) Avoid coadministration of alprazolam and dronedarone due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with dronedarone, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased alprazolam exposure by 1.6- to 1.98-fold.
    Amiodarone: (Contraindicated) Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amisulpride: (Contraindicated) Coadministration of dronedarone with amisulpride is contraindicated due to the risk of additive 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. Amisulpride causes dose- and concentration- dependent QT prolongation.
    Amitriptyline: (Contraindicated) Coadministration of dronedarone and tricyclic antidepressants is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Tricyclic antidepressants (TCAs) have pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). 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.
    Amlodipine: (Moderate) Monitor for evidence of hypotension and edema if amlodipine is coadministered with dronedarone; an amlodipine dose adjustment may be necessary due to increased amlodipine exposure. Dronedarone is a moderate CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate.
    Amlodipine; Atorvastatin: (Moderate) Dronedarone is metabolized by CYP3A and is an inhibitor of CYP3A, CYP2D6, and P-gp. Atorvastatin is a substrate for CYP3A4 and P-gp. Monitor for signs and symptoms of myopathy in patients receiving dronedarone concurrently with atorvastatin. (Moderate) Monitor for evidence of hypotension and edema if amlodipine is coadministered with dronedarone; an amlodipine dose adjustment may be necessary due to increased amlodipine exposure. Dronedarone is a moderate CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate.
    Amlodipine; Benazepril: (Moderate) Monitor for evidence of hypotension and edema if amlodipine is coadministered with dronedarone; an amlodipine dose adjustment may be necessary due to increased amlodipine exposure. Dronedarone is a moderate CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate.
    Amlodipine; Celecoxib: (Moderate) Monitor for evidence of hypotension and edema if amlodipine is coadministered with dronedarone; an amlodipine dose adjustment may be necessary due to increased amlodipine exposure. Dronedarone is a moderate CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate.
    Amlodipine; Olmesartan: (Moderate) Monitor for evidence of hypotension and edema if amlodipine is coadministered with dronedarone; an amlodipine dose adjustment may be necessary due to increased amlodipine exposure. Dronedarone is a moderate CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate.
    Amlodipine; Valsartan: (Moderate) Monitor for evidence of hypotension and edema if amlodipine is coadministered with dronedarone; an amlodipine dose adjustment may be necessary due to increased amlodipine exposure. Dronedarone is a moderate CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for evidence of hypotension and edema if amlodipine is coadministered with dronedarone; an amlodipine dose adjustment may be necessary due to increased amlodipine exposure. Dronedarone is a moderate CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate.
    Amoxicillin; Clarithromycin; Omeprazole: (Contraindicated) Concomitant use of dronedarone with clarithromycin is contraindicated. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Omeprazole is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Anagrelide: (Contraindicated) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated.
    Apalutamide: (Major) Avoid coadministration of dronedarone with apalutamide due to decreased dronedarone exposure. Dronedarone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased dronedarone exposure by 80%.
    Apixaban: (Moderate) Use apixaban and dronedarone together with caution in patients with significant renal dysfunction as risk of bleeding may be increased. Dronedarone is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with another moderate CYP3A4 and P-gp inhibitor. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased.
    Apomorphine: (Contraindicated) The concomitant use of dronedarone with other drugs that prolong the QTc may induce torsade de pointes (TdP) and is contraindicated. Dronedarone 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. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
    Aprepitant, Fosaprepitant: (Moderate) Avoid the concomitant use of dronedarone with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; increased dronedarone exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in dronedarone- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Dronedarone is a moderate CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Dronedarone is also 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 dronedarone. 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.
    Aripiprazole: (Contraindicated) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated.
    Arsenic Trioxide: (Contraindicated) Coadministration of dronedarone and arsenic trioxide is contraindicated. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated. QT prolongation should be expected with the administration of arsenic trioxide. TdP and complete atrioventricular block have been reported.
    Artemether; Lumefantrine: (Contraindicated) Concomitant use of dronedarone and artemether; lumefantrine is contraindicated. Dronedarone is an inhibitor CYP3A. Artemether and lumefantrine are both substrates of CYP3A4. Coadministration of dronedarone and artemether; lumefantrine may result in elevated plasma concentrations of artemether; lumefantrine. In addition, artemether; lumefantrine has been established to have a possible risk of QT prolongation and Torsade de Pointes (TdP). Dronedarone is associated with a dose-related increase in the QTc interval. 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.
    Articaine; Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Asenapine: (Contraindicated) Concurrent use of dronedarone and asenapine is contraindicated. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated. Asenapine has been associated with QT prolongation.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with dronedarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of dronedarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If dronedarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with dronedarone may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of dronedarone could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If dronedarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with dronedarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of dronedarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If dronedarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Aspirin, ASA; Omeprazole: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Omeprazole is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. If dronedarone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like dronedarone can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If dronedarone is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Atazanavir: (Moderate) Concomitant use of dronedarone with atazanavir may increase dronedarone concentrations. Coadministration with atazanavir; cobicistat is contraindicated. Dronedarone is metabolized by CYP3A. Atazanavir is an inhibitor CYP3A4. No data exist regarding the appropriate dose adjustment needed to allow safe administration of dronedarone with CYP3A4 inhibitors; therefore, use caution when coadministering dronedarone with CYP3A4 inhibitors such as atazanavir.
    Atazanavir; Cobicistat: (Contraindicated) Coadministration of cobicistat with dronedarone is contraindicated due to the potential for elevated dronedarone concentrations. Dronedarone is a CYP3A4 inhibitor/substrate and a CYP2D6 inhibitor. Cobicistat is an inhibitor/substrate of both CYP3A4 and CYP2D6. (Moderate) Concomitant use of dronedarone with atazanavir may increase dronedarone concentrations. Coadministration with atazanavir; cobicistat is contraindicated. Dronedarone is metabolized by CYP3A. Atazanavir is an inhibitor CYP3A4. No data exist regarding the appropriate dose adjustment needed to allow safe administration of dronedarone with CYP3A4 inhibitors; therefore, use caution when coadministering dronedarone with CYP3A4 inhibitors such as atazanavir.
    Atenolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Atenolol; Chlorthalidone: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Atomoxetine: (Contraindicated) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. 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. Because of the potential for TdP, use of atomoxetine with dronedarone is contraindicated.
    Atorvastatin: (Moderate) Dronedarone is metabolized by CYP3A and is an inhibitor of CYP3A, CYP2D6, and P-gp. Atorvastatin is a substrate for CYP3A4 and P-gp. Monitor for signs and symptoms of myopathy in patients receiving dronedarone concurrently with atorvastatin.
    Atorvastatin; Ezetimibe: (Moderate) Dronedarone is metabolized by CYP3A and is an inhibitor of CYP3A, CYP2D6, and P-gp. Atorvastatin is a substrate for CYP3A4 and P-gp. Monitor for signs and symptoms of myopathy in patients receiving dronedarone concurrently with atorvastatin.
    Avanafil: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including dronedarone, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Avapritinib: (Major) Avoid coadministration of avapritinib with dronedarone due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
    Azithromycin: (Contraindicated) Coadministration of dronedarone and azithromycin is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). There have been case reports of QT prolongation and TdP with the use of azithromycin in post-marketing reports. 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.
    Barbiturates: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Barbiturates induce CYP3A4. Coadministration of CYP3A4 inducers, such as barbiturates, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
    Bedaquiline: (Contraindicated) Due to the potential for torsade de pointes (TdP), concurrent use of dofetilide with bedaquiline is contraindicated. Prolongation of the QT interval is known to occur with both drugs, and concurrent use may result in additive QT prolongation.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Ergotamine is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Bendroflumethiazide; Nadolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with dronedarone may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of dronedarone in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If dronedarone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Dronedarone is an inhibitor of CYP3A4 and CYP2D6.
    Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking dronedarone and monitor for an increase in dronedarone-related adverse effects. Concomitant use may increase berotralstat and dronedarone exposure and the risk of adverse effects related to both drugs. Berotralstat is a P-gp substrate and moderate CYP3A4 inhibitor; dronedarone is a CYP3A4 substrate and P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%.
    Beta-adrenergic blockers: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Betaxolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving dronedarone. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving dronedarone. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; dronedarone inhibits P-gp.
    Bexarotene: (Major) The concomitant use of dronedarone and bexarotene should be avoided. Coadministration of CYP3A4 inducers, such as bexarotene, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy. Dronedarone is metabolized by CYP3A. Bexarotene induces CYP3A4.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Contraindicated) Avoid concomitant use of metronidazole and dronedarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Contraindicated) Avoid concomitant use of metronidazole and dronedarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Bisoprolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering dronedarone with boceprevir due to an increased potential for dronedarone-related adverse events. If dronedarone 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 pathways of dronedarone and boceprevir. Both dronedarone and boceprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4. Additionally, dronedarone is an inhibitor of the drug efflux transporter P-glycoprotein (PGP); boceprevir is partially metabolized by this efflux protein. When used in combination, the plasma concentrations of both medications may be elevated.
    Bosentan: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A and is an inhibitor of CYP3A. Bosentan induces and is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, such as bosentan, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy; plasma concentrations of bosentan may also be increased.
    Brexpiprazole: (Major) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Dronedarone is a moderate inhibitor of both CYP3A4 and CYP2D6. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. A reduction of the brexpiprazole dose to 25% of the usual dose is also recommended in patients who are poor metabolizers of CYP2D6 and are receiving a moderate CYP3A4 inhibitor.
    Brigatinib: (Major) Avoid coadministration of brigatinib with dronedarone if possible due to increased plasma exposure of brigatinib; a decrease in dronedarone concentrations may also occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of dronedarone, resume the brigatinib dose that was tolerated prior to initiation of dronedarone. Brigatinib is a CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%. Dronedarone is also a sensitive CYP3A4 substrate. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates.
    Brimonidine; Timolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of dronedarone. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; dronedarone is a moderate inhibitor of CYP3A4. Administration of bromocriptine with a moderate inhibitor of CYP3A4 increased the bromocriptine mean AUC and Cmax by 3.7-fold and 4.6-fold, respectively.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Budesonide: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A; drondarone also inhibits P-gp. Budesonide is a substrate for CYP3A4 and P-gp. The concomitant administration of dronedarone with CYP3A4 and P-gp substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Budesonide; Formoterol: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A; drondarone also inhibits P-gp. Budesonide is a substrate for CYP3A4 and P-gp. The concomitant administration of dronedarone with CYP3A4 and P-gp substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A; drondarone also inhibits P-gp. Budesonide is a substrate for CYP3A4 and P-gp. The concomitant administration of dronedarone with CYP3A4 and P-gp substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Bupivacaine; Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and dronedarone may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; dronedarone inhibits CYP3A4.
    Bupivacaine; Meloxicam: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Meloxicam is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Buprenorphine: (Contraindicated) 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. Because buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP), coadministration is contraindicated.
    Buprenorphine; Naloxone: (Contraindicated) 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. Because buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP), coadministration is contraindicated.
    Buspirone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Buspirone is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with dronedarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of dronedarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If dronedarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Cabotegravir; Rilpivirine: (Contraindicated) Concurrent use of dronedarone and rilpivirine is contraindicated. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. 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.
    Carbamazepine: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Carbamazepine induces CYP3A4. Coadministration of CYP3A4 inducers, such as carbamazepine, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
    Carbetapentane; Chlorpheniramine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Diphenhydramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Cariprazine: (Moderate) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Dronedarone is a moderate inhibitor of CYP3A4 and may reduce the hepatic metabolism of CYP3A4 substrates, although the impact of moderate CYP3A4 inhibitors on cariprazine metabolism has not been studied. Monitoring for adverse effects, such as CNS effects and extrapyramidal symptoms, is advisable during coadministration.
    Carteolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Carvedilol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Celecoxib; Tramadol: (Moderate) Dronedarone is metabolized by CYP3A and is an inhibitor of CYP2D6 and CYP3A. Tramadol is a substrate for CYP2D6 and CYP3A4. The concomitant administration of dronedarone with CYP2D6 and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Ceritinib: (Contraindicated) The concomitant use of dronedarone with ceritinib is contraindicated due to the risk of QT prolongation and torsade de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval; the increase is approximately 10 msec at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 msec at doses of 1,600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, such as ceritinib, coadministration of such drugs may result in additive QT prolongation. Additionally, dronedarone is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Chloramphenicol: (Moderate) Dronedarone is metabolized by CYP3A. Chloramphenicol is an inhibitor CYP3A4. No data exist regarding the appropriate dose adjustment needed to allow safe administration of dronedarone with CYP3A4 inhibitors; therefore, use caution when coadministering dronedarone with CYP3A4 inhibitors such as chloramphenicol.
    Chlordiazepoxide; Amitriptyline: (Contraindicated) Coadministration of dronedarone and tricyclic antidepressants is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Tricyclic antidepressants (TCAs) have pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). 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.
    Chloroquine: (Contraindicated) Coadministration of chloroquine with dronedarone is contraindicated due to the increased risk of QT prolongation. 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 1,600 mg twice daily. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses.
    Chlorpheniramine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with dronedarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of dronedarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If dronedarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Chlorpheniramine; Dextromethorphan: (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution. (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution. (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution. (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with dronedarone may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of dronedarone could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If dronedarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with dronedarone may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of dronedarone could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If dronedarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Chlorpheniramine; Phenylephrine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Chlorpromazine: (Contraindicated) Concomitant use of dronedarone and chlorpromazine is contraindicated. Dronedarone is an inhibitor of CYP2D6. Chlorpromazine is a substrate for CYP2D6. Coadministration of dronedarone and chlorpromazine may result in elevated plasma concentrations of chlorpromazine. In addition, chlorpromazine 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 and is contraindicated.
    Cilostazol: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Cilostazol is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Cimetidine: (Moderate) Dronedarone is metabolized by CYP3A. Cimetidine is an inhibitor CYP3A4. Concomitant use of dronedarone with cimetidine may also increase dronedarone concentrations. No data exist regarding the appropriate dose adjustment needed to allow safe administration of dronedarone with CYP3A4 inhibitors; therefore, use caution when coadministering dronedarone with CYP3A4 inhibitors such as cimetidine.
    Cinacalcet: (Moderate) Dronedarone is metabolized by CYP3A and is an inhibitor of CYP2D6 and CYP3A. Cinacalcet is a substrate for CYP2D6 and CYP3A4. The concomitant administration of dronedarone with CYP2D6 and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Ciprofloxacin: (Contraindicated) Concurrent use of dronedarone and ciprofloxacin is contraindicated. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc, such as ciprofloxacin, may induce Torsade de Pointes (TdP) and is contraindicated.
    Cisapride: (Contraindicated) Concomitant use of dronedarone and cisapride is contraindicated. QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce TdP and is contraindicated.
    Citalopram: (Contraindicated) Concurrent use of citalopram and dronedarone is contraindicated. Citalopram causes dose-dependent QT interval prolongation. 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.
    Clarithromycin: (Contraindicated) Concomitant use of dronedarone with clarithromycin is contraindicated. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Clofazimine: (Contraindicated) Coadministration of dronedarone with clofazimine is contraindicated due to the risk of additive 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. QT prolongation and TdP have been reported in patients receiving clofazimine in combination with QT prolonging medications.
    Clomipramine: (Contraindicated) Coadministration of dronedarone and tricyclic antidepressants is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Tricyclic antidepressants (TCAs) have pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). 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.
    Clonazepam: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Clonazepam is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Clozapine: (Contraindicated) Concomitant use of dronedarone and clozapine is contraindicated. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death and dronedarone is associated with dose-related increases in the QTc interval. 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; concomitant use is contraindicated. In addition, dronedarone is an inhibitor of CYP2D6 and CYP3A, two of the isoenzymes responsible for the metabolism of clozapine. Coadministration of dronedarone and clozapine may result in elevated plasma concentrations of clozapine, which may potentially increase the risk of life-threatening arrhythmias or other adverse effects. According to the manufacturer of clozapine, concomitant use of clozapine and substrates or inhibitors of CYP2D6 may require lower doses of either drug.
    Cobicistat: (Contraindicated) Coadministration of cobicistat with dronedarone is contraindicated due to the potential for elevated dronedarone concentrations. Dronedarone is a CYP3A4 inhibitor/substrate and a CYP2D6 inhibitor. Cobicistat is an inhibitor/substrate of both CYP3A4 and CYP2D6.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with chronic dronedarone therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of dronedarone is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of dronedarone, resume cobimetinib at the previous dose. Use an alternative to dronedarone in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; dronedarone is a moderate inhibitor of CYP3A and a weak P-gp inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
    Codeine: (Moderate) Concomitant use of codeine with dronedarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of dronedarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If dronedarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with dronedarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of dronedarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If dronedarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with dronedarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of dronedarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If dronedarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Codeine; Phenylephrine; Promethazine: (Contraindicated) Dronedarone administration is associated with a dose-related increase in the QTc interval. Promethazine carries a possible risk of QT prolongation. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated. (Moderate) Concomitant use of codeine with dronedarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of dronedarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If dronedarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Codeine; Promethazine: (Contraindicated) Dronedarone administration is associated with a dose-related increase in the QTc interval. Promethazine carries a possible risk of QT prolongation. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated. (Moderate) Concomitant use of codeine with dronedarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of dronedarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If dronedarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and dronedarone in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Dronedarone can inhibit colchicine's metabolism via P-glycoprotein (P-gp) and CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken a moderate CYP3A4 inhibitor like dronedarone in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg twice daily or 0.6 mg once daily or if the original dose is 0.6 mg once daily, decrease the dose to 0.3 mg once daily; for treatment of gout flares, give 1.2 mg as a single dose and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed 1.2 mg/day.
    Conivaptan: (Moderate) Monitor for increased toxicity of dronedarone during coadministration of conivaptan as concomitant use may increase the exposure of dronedarone. Dronedarone is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Crizotinib: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of crizotinib with dronedarone is contraindicated. 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. Crizotinib has also been associated with concentration-dependent QT prolongation. 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.
    Cyclosporine: (Contraindicated) The concomitant use of dronedarone and cyclosporine is contraindicated. Dronedarone is metabolized by CYP3A and is an inhibitor of CYP3A and P-gp. Cyclosporine is a substrate and strong inhibitor of CYP3A4 and is a substrate for P-gp. Repeated doses of ketoconazole, also a strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. No data exist regarding the safe administration of dronedarone with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. Also, the effects of dronedarone on the pharmacokinetics of cyclosporine have not been described, although an increase in cyclosporine serum concentrations is possible.
    Dabigatran: (Major) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with dronedarone, 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 dronedarone in patients with CrCl less than 50 mL/minute. When used in patients with non-valvular atrial fibrillation, avoid the coadministration of dabigatran and dronedarone in patients with severe renal impairment (CrCl less than 30 mL/minute), and reduce the dabigatran dose to 75 mg twice daily when dronedarone and dabigatran are coadministered in patients with moderate renal impairment (CrCl 30 to 50 mL/min). Simultaneous administration of dabigatran and dronedarone (administered once or twice daily) increases exposure to dabigatran by 70 to 140% compared to dabigatran alone. The increase in exposure is only 30 to 60% higher compared to dabigatran alone when dronedarone is administered 2 hours after dabigatran. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dabrafenib: (Major) The concomitant use of dabrafenib and dronedarone may lead to decreased dronedarone concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of dronedarone efficacy. Dabrafenib is a moderate CYP3A4 inducer and dronedarone is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 65%.
    Daclatasvir: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with dronedarone, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Danazol: (Moderate) Dronedarone and danazol should be coadministered with caution. Dronedarone is metabolized by CYP3A. Danazol is an inhibitor of CYP3A4. Concomitant use of dronedarone with danazol may increase dronedarone concentrations.
    Dapagliflozin; Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and dronedarone are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as dronedarone.
    Dapsone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Dapsone is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Darifenacin: (Moderate) Dronedarone is metabolized by CYP3A and is an inhibitor of CYP2D6 and CYP3A. Darifenacin is a substrate for CYP2D6 and CYP3A4. The concomitant administration of dronedarone with CYP2D6 and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Darunavir: (Contraindicated) Coadministration of darunavir with dronedarone is contraindicated due to the potential for elevated dronedarone concentrations and the potential for serious and/or life threatening reactions, such as cardiac arrhythmias. Dronedarone is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4.
    Darunavir; Cobicistat: (Contraindicated) Coadministration of cobicistat with dronedarone is contraindicated due to the potential for elevated dronedarone concentrations. Dronedarone is a CYP3A4 inhibitor/substrate and a CYP2D6 inhibitor. Cobicistat is an inhibitor/substrate of both CYP3A4 and CYP2D6. (Contraindicated) Coadministration of darunavir with dronedarone is contraindicated due to the potential for elevated dronedarone concentrations and the potential for serious and/or life threatening reactions, such as cardiac arrhythmias. Dronedarone is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Coadministration of cobicistat with dronedarone is contraindicated due to the potential for elevated dronedarone concentrations. Dronedarone is a CYP3A4 inhibitor/substrate and a CYP2D6 inhibitor. Cobicistat is an inhibitor/substrate of both CYP3A4 and CYP2D6. (Contraindicated) Coadministration of darunavir with dronedarone is contraindicated due to the potential for elevated dronedarone concentrations and the potential for serious and/or life threatening reactions, such as cardiac arrhythmias. Dronedarone is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) The concomitant use of dronedarone and dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Dronedarone use is contraindicated with other drugs that prolong the QTc and may induce Torsade de Pointes (TdP), such as ritonavir. Furthermore, no data exist for the safe administration of dronedarone (CYP3A substrate/moderate inhibitor) with strong CYP3A4 inhibitors, such as ritonavir, and concomitant use is contraindicated. Elevated concentrations of each drug can be expected, followed by further risk of serious adverse reactions. Dronedarone is also a P-glycoprotein (P-gp) inhibitor. Ritonavir, paritaprevir, and dasabuvir are CYP3A and P-gp substrates; ombitasvir is also a P-gp substrate. (Contraindicated) The concomitant use of dronedarone and ritonavir is contraindicated. Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ritonavir is a strong inhibitor of CYP3A4, is an inducer of CYP3A, and is a substrate of CYP3A and P-gp. Repeated doses of ketoconazole, also a strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. Furthermore, coadministration of dronedarone and ritonavir may, theoretically, result in decreased concentrations of dronedarone due to CYP3A induction by ritonavir; the net effect on dronedarone plasma concentrations is not known. However, no data exist regarding the safe administration of dronedarone with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. Also, the effects of dronedarone on the pharmacokinetics of ritonavir have not been described, although an increase in ritonavir serum concentrations is possible.
    Dasatinib: (Contraindicated) Concomitant use of dronedarone and dasatinib is contraindicated. In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). 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.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with dronedarone. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; dronedarone is a moderate inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
    Degarelix: (Contraindicated) Because of the potential for torsade des pointes (TdP), the use of degarelix with dronedarone is contraindicated. 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. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
    Delavirdine: (Contraindicated) The concomitant use of dronedarone and delavirdine is contraindicated. Coadministration of dronedarone with strong CYP3A4 inhibitors significantly increases dronedarone exposure and the risk of adverse events. Dronedarone is metabolized by CYP3A and is a moderate inhibitor of CYP3A. Delavirdine is a strong inhibitor of CYP3A4 and is a CYP3A substrate. The effects of dronedarone on the pharmacokinetics of delavirdine have not been described, although an increase in delavirdine serum concentrations is possible.
    Desipramine: (Contraindicated) Coadministration of dronedarone and tricyclic antidepressants is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Tricyclic antidepressants (TCAs) have pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). 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.
    Desogestrel; Ethinyl Estradiol: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE.
    Deutetrabenazine: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of deutetrabenazine with dronedarone is contraindicated. 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 1,600 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. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
    Dexamethasone: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A and is an inhibitor of CYP3A and P-gp. Dexamethasone induces CYP3A4 and is a substrate for CYP3A4 and P-gp. Coadministration of CYP3A4 inducers, such as dexamethasone, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy; the plasma concentrations of dexamethasone may also be increased.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan: (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Diphenhydramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution. (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Guaifenesin: (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Quinidine: (Contraindicated) Concurrent use of dronedarone and quinidine is contraindicated. Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Diazepam: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Diazepam is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Diclofenac: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Diclofenac is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Diclofenac; Misoprostol: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Diclofenac is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Digoxin: (Major) Dronedarone is an inhibitor of P-glycoprotein (P-gp). Digoxin is a substrate for P-gp. In clinical trials, the coadministration of dronedarone and digoxin resulted in an increase in the exposure of digoxin by 2.5-fold, with a subsequent increase in gastrointestinal adverse effects. Furthermore, digoxin can potentiate the electrophysiologic effects of dronedarone (e.g., decreased AV node conduction). In clinical trials, sudden death was more common in patients receiving combined therapy with dronedarone and digoxin than in patients on either therapy alone. It is unclear if combination therapy contributed to this increase or if this was related to the presence of advanced heart disease. According to the manufacturer of dronedarone, concurrent administration of dronedarone and digoxin should be avoided. However, if coadministration is unavoidable, a 50% reduction in the digoxin dose is recommended. The manufacturer of digoxin recommends measuring serum digoxin concentrations before initiating dronedarone and reducing digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency; continue monitoring.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with dronedarone may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of dronedarone could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If dronedarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Dihydroergotamine: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Dihydroergotamine is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Diltiazem: (Major) If coadministered with dronedarone, initiate diltiazem at a low dose and increase only after ECG verification of good tolerability. Both diltiazem and dronedarone are substrates and moderate CYP3A4 inhibitors; increased exposure to both drugs may occur. Additionally, the conduction effects of dronedarone may be potentiated by concurrent use of calcium channel blockers with depressant effects on the sinus and AV nodes.
    Diphenhydramine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Diphenhydramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Dronedarone is an inhibitor of CYP2D6. Diphenhydramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Diphenhydramine; Ibuprofen: (Moderate) Dronedarone is an inhibitor of CYP2D6. Diphenhydramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Diphenhydramine; Naproxen: (Moderate) Dronedarone is an inhibitor of CYP2D6. Diphenhydramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Diphenhydramine; Phenylephrine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Diphenhydramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Disopyramide: (Contraindicated) Concurrent use of dronedarone and disopyramide is contraindicated. Disopyramide administration is associated with QT prolongation and torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Disulfiram: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Disulfiram is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Docetaxel: (Major) Docetaxel is a substrate for CYP3A4 and P-gp and dronedarone is metabolized by and is an inhibitor of CYP3A; dronedarone also inhibits P-gp. The concomitant administration of dronedarone with CYP3A4 and P-gp substrates may result in increased exposure of the substrate; concomitant use of these agents should be used with extreme caution and possibly avoided in elderly patients. Fatal pan mucositis was reported in an elderly patient who was receiving docetaxel for metastatic prostate cancer and dronedarone to control atrial fibrillation in a case report. This 79-year-old man presented to the hospital with grade 4 mucositis and febrile neutropenia following his third cycle of docetaxel after receiving dronedarone for appoximately 6 weeks. Despite neutrophil recovery, he experienced skin and cutaneous lesion deterioration, grade 4 stomatitis, necrotic conjunctivitis, and grade 4 keratitis; no infectious etiology for mucositis was identified. A docetaxel level of 2.4 ng/ml was detected 14 days after the last infusion; this detectable docetaxel level was unexpected. The patient subsequently died of ICU-acquired sepsis. Consider using an alternate antiarrhythmic agent in patients receiving docetaxel. Following a risk/benefit analysis, if docetaxel is administered in a patient who also requires dronedarone, monitor patient for signs of severe stomatitis/mucositis or cutaneous reactions and other serious side effects associated with docetaxel (eg, paresthesias/dysesthesias, asthenia, febrile neutropenia, infection).
    Dofetilide: (Contraindicated) Concurrent use of dronedarone and dofetilide is contraindicated. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce TdP and is contraindicated.
    Dolasetron: (Contraindicated) Concomitant use of dronedarone and dolasetron is contraindicated. Dronedarone is an inhibitor of CYP2D6 and CYP3A. Dolasetron is a substrate for CYP2D6 and CYP3A4. Coadministration of dronedarone and dolasetron may result in elevated plasma concentrations of dolasetron. In addition, dolasetron has been established to have a possible risk of QT prolongation and Torsade de Pointes (TdP). Dronedarone is associated with dose-related increases in the QTc interval. Dolasetron has also been associated with a dose-dependant prolongation in the PR interval on an electrocardiogram. 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; concomitant use is contraindicated.
    Dolutegravir; Rilpivirine: (Contraindicated) Concurrent use of dronedarone and rilpivirine is contraindicated. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. 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.
    Donepezil: (Contraindicated) The concomitant use of dronedarone with other drugs that prolong the QTc may induce torsade de pointes (TdP) and is contraindicated. 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. 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.
    Donepezil; Memantine: (Contraindicated) The concomitant use of dronedarone with other drugs that prolong the QTc may induce torsade de pointes (TdP) and is contraindicated. 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. 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.
    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 dronedarone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Dorzolamide; Timolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Doxepin: (Contraindicated) Coadministration of dronedarone and tricyclic antidepressants is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Tricyclic antidepressants (TCAs) have pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). 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.
    Doxorubicin Liposomal: (Major) Avoid coadministration of dronedarone with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Dronedarone is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4, CYP2D6, and P-gp. Concurrent use of CYP3A4, CYP2D6, or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Doxorubicin: (Major) Avoid coadministration of dronedarone with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Dronedarone is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4, CYP2D6, and P-gp. Concurrent use of CYP3A4, CYP2D6, or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Dronabinol: (Major) Use caution if coadministration of dronabinol with dronedarone is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; dronedarone is a moderate inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Droperidol: (Contraindicated) Concomitant use of dronedarone and droperidol is contraindicated. Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (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. 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.
    Drospirenone; Ethinyl Estradiol: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE.
    Dutasteride; Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of dronedarone. Tamsulosin is extensively metabolized by CYP2D6 and CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Therefore, concomitant use with drugs that inhibit both CYP2D6 and CYP3A4, such as dronedarone, should be avoided.
    Duvelisib: (Moderate) Monitor for increased toxicity of duvelisib and dronedarone during coadministration. Coadministration may increase the exposure of both drugs. Duvelisib is a substrate and moderate inhibitor of CYP3A; dronedarone is a sensitive substrate and moderate inhibitor of CYP3A.
    Edoxaban: (Moderate) Coadministration of edoxaban and dronedarone may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and dronedarone is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of dronedarone; 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: (Contraindicated) 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. Efavirenz has also been associated with QT prolongation. Because of the potential for QT prolongation and TdP, use of efavirenz with dronedarone is contraindicated.
    Efavirenz; Emtricitabine; Tenofovir: (Contraindicated) 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. Efavirenz has also been associated with QT prolongation. Because of the potential for QT prolongation and TdP, use of efavirenz with dronedarone is contraindicated. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as dronedarone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Contraindicated) 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. Efavirenz has also been associated with QT prolongation. Because of the potential for QT prolongation and TdP, use of efavirenz with dronedarone is contraindicated. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as dronedarone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with dronedarone may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Dronedarone is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
    Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with dronedarone. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A4, and dronedarone is a moderate CYP3A4 inhibitor. Coadministration of other moderate CYP3A4 inhibitors increased the eletriptan AUC by 2 to 4-fold.
    Elexacaftor; tezacaftor; ivacaftor: (Major) Adjust the elexacaftor; tezacaftor; ivacaftor dosing schedule when coadministered with dronedarone; coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 2 elexacaftor; tezacaftor; ivacaftor combination tablets every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., elexacaftor; tezacaftor; ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Elexacaftor, tezacaftor, and ivacaftor are CYP3A4 substrates (ivacaftor is a sensitive CYP3A4 substrate); dronedarone is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased ivacaftor exposure by 3-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2-fold, respectively. (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with dronedarone; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); dronedarone is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If dronedarone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Eliglustat: (Contraindicated) Coadministration of dronedarone and eliglustat is contraindicated. Dronedarone is a moderate CYP2D6 and CYP3A inhibitor associated with a dose-related increase in the QTc interval; its use is contraindicated with other drugs that prolong the QT interval. Eliglustat is a CYP2D6 and CYP3A substrate that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Coadministration of dronedarone and eliglustat may result in additive effects on the QT interval and signficantly increased plasma concentrations eliglustat, further increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Coadministration of cobicistat with dronedarone is contraindicated due to the potential for elevated dronedarone concentrations. Dronedarone is a CYP3A4 inhibitor/substrate and a CYP2D6 inhibitor. Cobicistat is an inhibitor/substrate of both CYP3A4 and CYP2D6.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Coadministration of cobicistat with dronedarone is contraindicated due to the potential for elevated dronedarone concentrations. Dronedarone is a CYP3A4 inhibitor/substrate and a CYP2D6 inhibitor. Cobicistat is an inhibitor/substrate of both CYP3A4 and CYP2D6. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as dronedarone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Contraindicated) Concurrent use of dronedarone and rilpivirine is contraindicated. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. 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.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Contraindicated) Concurrent use of dronedarone and rilpivirine is contraindicated. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. 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. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as dronedarone. 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 dronedarone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Enalapril; Felodipine: (Moderate) Concurrent use of felodipine and dronedarone should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor. Concurrent use of another moderate CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 2.5-fold and 2-fold, respectively.
    Encorafenib: (Contraindicated) Coadministration of encorafenib with dronedarone is contraindicated due to QT prolongation. Encorafenib is associated with dose-dependent QT interval prolongation. 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.
    Entrectinib: (Contraindicated) Coadministration of dronedarone with entrectinib is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Entrectinib has been associated with QT prolongation. 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 1,600 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.
    Enzalutamide: (Major) Avoid coadministration of dronedarone with enzalutamide due to decreased dronedarone exposure. Dronedarone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased dronedarone exposure by 80%.
    Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Dronedarone is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Ergotamine: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Ergotamine is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Ergotamine; Caffeine: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Ergotamine is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Eribulin: (Contraindicated) Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated. Contraindicated drugs inclue dronedarone.
    Erythromycin: (Contraindicated) Concomitant use of dronedarone and erythromycin is contraindicated. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Erythromycin; Sulfisoxazole: (Contraindicated) Concomitant use of dronedarone and erythromycin is contraindicated. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Escitalopram: (Contraindicated) Because of the potential for QT prolongation and torsade de pointes (TdP), use of dronedarone with escitalopram is contraindicated.
    Eslicarbazepine: (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as dronedarone, may result in decreased serum concentrations of the substrate. The concomitant use of dronedarone and CYP3A4 inducers should be avoided.
    Esmolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Esomeprazole: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Esomeprazole is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Estazolam: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Estazolam is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Eszopiclone: (Moderate) Patients should be advised of the potential for next-day psychomotor and/or memory impairment during co-administration of eszopiclone and CYP3A4 inhibitors, such as dronedarone. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Ethinyl Estradiol: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE.
    Ethinyl Estradiol; Norgestrel: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE.
    Ethosuximide: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Ethosuximide is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE.
    Etonogestrel: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as dronedarone may increase the serum concentration of etonogestrel.
    Etonogestrel; Ethinyl Estradiol: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE. (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as dronedarone may increase the serum concentration of etonogestrel.
    Etravirine: (Major) Dronedarone is metabolized by CYP3A and should not be coadministered with CYP3A4 inducers, such as etravirine. Concurrent use may result in reduced dronedarone plasma concentration and treatment effectiveness.
    Everolimus: (Major) Coadministration of everolimus with dronedarone requires a dose reduction for some indications and close monitoring for others. For patients with oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the initial dose of everolimus to 2.5 mg PO once daily; the dose may be increased to 5 mg PO once daily if the 2.5 mg dose is tolerated. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, reduce the daily dose of everolimus by 50%, changing to every-other-day dosing if the reduced dose is lower than the lowest available strength; assess the everolimus whole blood trough concentration 2 weeks after initiation of dronedarone and adjust the dose as necessary to remain in the recommended therapeutic range. Also monitor everolimus whole blood trough concentrations for patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Dronedarone is a moderate CYP3A4 and a P-gp inhibitor. Coadministration with other moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    Ezetimibe; Simvastatin: (Major) Do not exceed a simvastatin dose of 10 mg/day in patients taking dronedarone due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on dronedarone, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of dronedarone and simvastatin against the potential risks. Dronedarone increases the simvastatin exposure by approximately 4-fold.
    Ezogabine: (Contraindicated) Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated. Contraindicated drugs include: ezogabine.
    Fedratinib: (Moderate) Monitor for increased toxicity of dronedarone during coadministration. Coadministration may increase the exposure of dronedarone. Fedratinib is a moderate inhibitor of CYP3A; dronedarone is a sensitive substrate of CYP3A.
    Felodipine: (Moderate) Concurrent use of felodipine and dronedarone should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor. Concurrent use of another moderate CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 2.5-fold and 2-fold, respectively.
    Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. If dronedarone is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like dronedarone can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If dronedarone is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
    Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or dronedarone; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia.
    Fingolimod: (Contraindicated) Concurrent administration of fingolimod and dronedarone is contraindicated. Fingolimod may prolong the QT interval and is contraindicated for use by patients with a baseline QTc interval >= 500 msec. 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.
    Flecainide: (Contraindicated) The concomitant use of dronedarone and flecainide is contraindicated. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsades de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. 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.
    Flibanserin: (Contraindicated) The concomitant use of flibanserin and moderate CYP3A4 inhibitors, such as dronedarone, is contraindicated. Moderate CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a moderate CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a moderate CYP3A4 inhibitor following flibanserin use, start the moderate CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
    Fluconazole: (Contraindicated) Concurrent use of dronedarone and fluconazole is contraindicated. Fluconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Fluoxetine: (Contraindicated) QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Dronedarone administration is associated with a dose-related increase in the QTc interval. The concomitant use of dronedarone with fluoxetine may induce TdP and is contraindicated.
    Fluphenazine: (Contraindicated) Concurrent use of dronedarone and fluphenazine is contraindicated. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation and/or 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.
    Flurazepam: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Flurazepam is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Flutamide: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A and is an inhibitor of CYP3A. Flutamide induces and is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, such as flutamide, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy; plasma concentrations of flutamide may also be increased.
    Fluvoxamine: (Contraindicated) Because of the potential for torsade de pointes (TdP), concurrent use of dronedarone and fluvoxamine is contraindicated. Dronedarone is associated with a dose-related increase in the QTc interval. The increase in QTc is about 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. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, dronedarone is metabolized by CYP3A and fluvoxamine is a moderate inhibitor of CYP3A4. Concomitant use of dronedarone with fluvoxamine may increase dronedarone concentrations.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with dronedarone. Dronedarone is an inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with dronedarone, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Fosamprenavir: (Major) The concomitant use of dronedarone and moderate CYP3A4 inhibitors and inducers should be avoided. Dronedarone is metabolized by CYP3A and inhibits P-gp. Fosamprenavir is a moderate inhibitor and inducer of CYP3A4 and is a substrate for P-gp. Coadministration of CYP3A4 inhibitors with dronedarone may cause a marked increased in dronedarone concentrations; however, coadministration with CYP3A4 inducers may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy. Further, the effects of dronedarone on the pharmacokinetics of fosamprenavir have not been described, although an increase in fosamprenavir serum concentrations is possible.
    Foscarnet: (Contraindicated) 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. Because of the potential for TdP, use of foscarnet with dronedarone is contraindicated.
    Fosphenytoin: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Fosphenytoin induces CYP3A4. Coadministration of CYP3A4 inducers, such as fosphenytoin, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
    Fostamatinib: (Moderate) Monitor for dronedarone toxicities that may require dronedarone dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a CYP3A4 substrate may increase the concentration of the CYP3A4 substrate. The active metabolite of fostamatinib, R406, is a CYP3A4 inhibitor; dronedarone is a substrate for CYP3A4. Coadministration of fostamatinib with a sensitive CYP3A4 substrate increased the substrate AUC by 64% and Cmax by 113%.
    Fostemsavir: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of fostemsavir with dronedarone is contraindicated. 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. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, 4 times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
    Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with dronedarone 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 dronedarone 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: (Contraindicated) Concurrent use of gemifloxacin and dronedarone is contraindicated. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5-10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated.
    Gemtuzumab Ozogamicin: (Contraindicated) Coadministration of gemtuzumab ozogamicin with dronedarone is contraindicated due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). Although QT interval prolongation has not been reported with gemtuzumab ozogamicin, it has been reported with other drugs that contain calicheamicin. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds (msec) at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 msec 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.
    Gilteritinib: (Contraindicated) Use of gilteritinib with dronedarone is contraindicated because of the potential for torsade de pointes (TdP). Gilteritinib has been associated with QT prolongation. Dronedarone 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 1,600 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.
    Glasdegib: (Contraindicated) Coadministration of glasdegib and dronedarone is contraindicated due to the potential for additive QT prolongation and torsade de pointes (TdP). Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and dronedarone as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp); dronedarone is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and dronedarone as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); dronedarone is an inhibitor of P-gp.
    Goserelin: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of goserelin with dronedarone is contraindicated. 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 1,600 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. Androgen deprivation therapy (e.g., goserelin) is known to prolong the QT interval.
    Granisetron: (Contraindicated) Concurrent use of granisetron and dronedarone is contraindicated. Granisetron has been associated with QT prolongation. According to the manufacturer, use of granisetron in patients concurrently treated with drugs known to prolong the QT interval and/or are arrhythmogenic, may result in clinical consequences. 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.
    Grapefruit juice: (Moderate) Concomitant use of dronedarone and grapefruit juice should be avoided. Dronedarone is metabolized by CYP3A. Grapefruit juice is a moderate inhibitor of CYP3A4. The concomitant administration of dronedarone and grapefruit juice results in an increase in dronedarone exposure by 3-fold and increase in dronedarone Cmax of 2.5-fold. No data exist regarding the appropriate dose adjustment needed to allow safe administration of dronedarone and grapefruit juice.
    Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guanfacine: (Major) Dronedarone may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon dronedarone discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and dronedarone is a moderate CYP3A4 inhibitor.
    Halogenated Anesthetics: (Contraindicated) Concurrent use of halogenated anesthetics and dronedarone is contraindicated. Halogenated anesthetics prolong the QT interval. 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.
    Haloperidol: (Contraindicated) The concomitant use of dronedarone and haloperidol is contraindicated. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. 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.
    Histrelin: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of histrelin with dronedarone is contraindicated. 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 1,600 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. Androgen deprivation therapy (e.g., histrelin) is known to prolong the QT interval.
    Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydroxychloroquine: (Contraindicated) Coadministration of dronedarone and hydroxychloroquine is contraindicated due to the risk of increased QT prolongation. Hydroxychloroquine prolongs the QT interval. 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.
    Hydroxyzine: (Contraindicated) Coadministration of dronedarone with hydroxyzine is contraindicated due to the risk of additive 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. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP.
    Ibrutinib: (Major) If coadministered with dronedarone, reduce the ibrutinib dose to 280 mg/day PO for the treatment of B-cell malignancies. Resume ibrutinib at the previous dose if dronedarone is discontinued. Initiate ibrutinib at the recommended dose of 420 mg/day PO for the treatment of chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); interruption of ibrutinib therapy or a dose reduction may be necessary in patients who develop severe toxicity. Ibrutinib is a CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. If dronedarone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like dronedarone can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If dronedarone is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Ibutilide: (Contraindicated) Concurrent use of ibutilide and dronedarone is contraindicated. Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated.
    Idelalisib: (Contraindicated) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with dronedarone, a CYP3A substrate, as dronedarone toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with dronedarone is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Dronedarone is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Iloperidone: (Contraindicated) The concomitant use of dronedarone and iloperidone is contraindicated. Dronedarone is an inhibitor of CYP2D6 and CYP3A. Iloperidone is a substrate for CYP2D6 and CYP3A4. Coadministration of dronedarone and iloperidone may result in increased plasma concentrations of iloperidone. In addition, iloperidone has been established to have a possible association with QT prolongation and Torsade de Pointes (TdP). Dronedarone is associated with dose-related increases 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.
    Imipramine: (Contraindicated) Coadministration of dronedarone and tricyclic antidepressants is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Tricyclic antidepressants (TCAs) have pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). 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.
    Indinavir: (Contraindicated) The concomitant use of dronedarone and indinavir is contraindicated. Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Indinavir is a strong inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Repeated doses of ketoconazole, also a strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. No data exist regarding the safe administration of dronedarone with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. Also, the effects of dronedarone on the pharmacokinetics of indinavir have not been described, although an increase in indinavir serum concentrations is possible.
    Infigratinib: (Major) Avoid concomitant use of infigratinib and dronedarone. Coadministration may increase infigratinib exposure, increasing the risk of adverse effects. Infigratinib is a CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor.
    Inotuzumab Ozogamicin: (Contraindicated) Coadministration of inotuzumab with dronedarone is contraindicated due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). Inotuzumab has been associated with QT interval prolongation. 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.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with dronedarone may result in increased serum concentrations of both drugs. Dronedarone is a substrate and inhibitor of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of dronedarone with rifampin due to the potential for decreased dronedarone exposure and efficacy. Dronedarone is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin significantly decreased dronedarone exposure.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of dronedarone with rifampin due to the potential for decreased dronedarone exposure and efficacy. Dronedarone is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin significantly decreased dronedarone exposure.
    Isradipine: (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with dronedarone is necessary. Isradipine is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor.
    Itraconazole: (Contraindicated) Use of dronedarone during and for 2 weeks after discontinuation of itraconazole treatment is contraindicated due to the potential for elevated dronedarone concentrations and QT prolongation. Serious cardiovascular events such as EKG changes (i.e., QT prolongation) and cardiac arrhythmias, including ventricular arrhythmias and torsade de pointes, may occur. Dronedarone is a CYP3A4 substrate that is associated with a dose-related increase in the QTc interval. Itraconazole is a strong CYP3A4 substrate that is also associated with QT prolongation. Repeated doses of another strong CYP3A4 inhibitor increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold.
    Ivabradine: (Major) Avoid coadministration of ivabradine and dronedarone as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; dronedarone inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ivacaftor: (Major) If dronedarone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Ivosidenib: (Contraindicated) Coadministration of dronedarone and ivosidenib is contraindicated. Dronedarone administration is associated with a dose-related increase in the QTc interval. Ivosidenib has been associated with QTc prolongation and ventricular arrhythmias. 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.
    Ixabepilone: (Major) Dronedarone is metabolized by and is an inhibitor of CYP3A. Ixabepilone is a substrate for CYP3A4. In addition, ixabepilone is a P-glycoprotein (Pgp) substrate and dronedarone is a Pgp inhibitor. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. If concurrent treatment with a strong CYP3A4 inhibitor is necessary, strongly consider an ixabepilone dose reduction. Closely monitor patients for ixabepilone-related toxicities. If a strong CYP3A4 inhibitor is discontinued, allow 7 days to elapse before increasing the ixabepilone dose.
    Ketoconazole: (Contraindicated) Concomitant use of dronedarone and ketoconazole is contraindicated. Dronedarone is metabolized by CYP3A and is a moderate inhibitor of CYP3A. Repeated doses of ketoconazole, a strong CYP3A4 inhibitor and also a CYP3A substrate, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. The effects of dronedarone on the pharmacokinetics of ketoconazole have not been described, although an increase in ketoconazole serum concentrations is possible.
    Labetalol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Lacosamide: (Moderate) Lacosamide causes PR interval prolongation in some patients. Caution is advised during coadministration of lacosamide with other drugs that cause PR prolongation, such as dronedarone, since further PR prolongation is possible. If concurrent use is necessary, an ECG is recommended prior to initiation of lacosamide and after the drug is titrated to the maintenence dose. Patients receiving intravenous lacosamide should be closely monitored due to the potential for profound bradycardia and AV block during coadministration.
    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 dronedarone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Lansoprazole: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Lansoprazole is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Lansoprazole; Amoxicillin; Clarithromycin: (Contraindicated) Concomitant use of dronedarone with clarithromycin is contraindicated. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Lansoprazole is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Lansoprazole; Naproxen: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Lansoprazole is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Lapatinib: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of lapatinib with dronedarone is contraindicated. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib. Dronedarone administration is also associated with a dose-related increase in the QTc interval. 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.
    Lefamulin: (Contraindicated) Coadministration of dronedarone with lefamulin is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. 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 1,600 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.
    Lemborexant: (Major) Avoid coadministration of lemborexant and dronedarone as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. Coadministration of lemborexant with another moderate CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
    Lenvatinib: (Contraindicated) Because of the potential for torsades de pointes (TdP), use of dronedarone with lenvatinib is contraindicated. 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. Prolongation of the QT interval has also been reported with lenvatinib therapy.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of dronedarone; monitor for potential reduction in efficacy. Dronedarone is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of dronedarone; monitor for potential reduction in efficacy. Dronedarone is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of dronedarone is expected if given with letermovir. Coadministration is contraindicated in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified.
    Leuprolide: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of leuprolide with dronedarone is contraindicated. 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 1,600 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. Androgen deprivation therapy (e.g., leuprolide) may also prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of leuprolide with dronedarone is contraindicated. 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 1,600 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. Androgen deprivation therapy (e.g., leuprolide) may also prolong the QT/QTc interval.
    Levamlodipine: (Moderate) Monitor for evidence of hypotension and edema if amlodipine is coadministered with dronedarone; an amlodipine dose adjustment may be necessary due to increased amlodipine exposure. Dronedarone is a moderate CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate.
    Levobetaxolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Levobunolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Levofloxacin: (Contraindicated) Concurrent use of levofloxacin and dronedarone is contraindicated. Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Rare cases of torsade de pointes (TdP) have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce TdP and is contraindicated.
    Levoketoconazole: (Contraindicated) Concomitant use of dronedarone and ketoconazole is contraindicated. Dronedarone is metabolized by CYP3A and is a moderate inhibitor of CYP3A. Repeated doses of ketoconazole, a strong CYP3A4 inhibitor and also a CYP3A substrate, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. The effects of dronedarone on the pharmacokinetics of ketoconazole have not been described, although an increase in ketoconazole serum concentrations is possible.
    Levonorgestrel; Ethinyl Estradiol: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and dronedarone may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; dronedarone inhibits CYP3A4.
    Lidocaine; Epinephrine: (Moderate) Concomitant use of systemic lidocaine and dronedarone may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; dronedarone inhibits CYP3A4. (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and dronedarone may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; dronedarone inhibits CYP3A4.
    Lithium: (Contraindicated) Lithium has been associated with QT prolongation. 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. Because of the potential for TdP, use of lithium with dronedarone is contraindicated.
    Lofexidine: (Contraindicated) Concomitant use of lofexidine and dronedarone is contraindicated due to the potential for additive QT prolongation. Lofexidine is a CYP2D6 substrate that prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes (TdP). Dronedarone is a CYP2D6 inhibitor and 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.
    Lonafarnib: (Contraindicated) Coadministration of lonafarnib and dronedarone is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; dronedarone is a sensitive CYP3A4 substrate and moderate CYP3A4 inhibitor.
    Loperamide: (Contraindicated) 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. Because high doses of loperamide have been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest, coadministration is contraindicated.
    Loperamide; Simethicone: (Contraindicated) 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. Because high doses of loperamide have been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest, coadministration is contraindicated.
    Lopinavir; Ritonavir: (Contraindicated) Coadministration of lopinavir; ritonavir with dronedarone is contraindicated due to the potential for additive QT prolongation. Dronedarone is highly dependent on CYP3A for clearance. 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 1,600 mg twice daily. Lopinavir; ritonavir is a potent CYP3A inhibitor and is also associated with QT prolongation. (Contraindicated) The concomitant use of dronedarone and ritonavir is contraindicated. Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ritonavir is a strong inhibitor of CYP3A4, is an inducer of CYP3A, and is a substrate of CYP3A and P-gp. Repeated doses of ketoconazole, also a strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. Furthermore, coadministration of dronedarone and ritonavir may, theoretically, result in decreased concentrations of dronedarone due to CYP3A induction by ritonavir; the net effect on dronedarone plasma concentrations is not known. However, no data exist regarding the safe administration of dronedarone with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. Also, the effects of dronedarone on the pharmacokinetics of ritonavir have not been described, although an increase in ritonavir serum concentrations is possible.
    Losartan: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Losartan is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Losartan is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Lovastatin: (Major) Although FDA-approved labeling for lovastatin recommends limiting the dose of lovastatin to 20 mg/day if combined with dronedarone, guidelines recommend limiting the lovastatin dose to 10 mg/day during concurrent use. Lovastatin exposure may increase resulting in increased risk of myopathy/rhabdomyolysis. Lovastatin is a CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor.
    Lovastatin; Niacin: (Major) Although FDA-approved labeling for lovastatin recommends limiting the dose of lovastatin to 20 mg/day if combined with dronedarone, guidelines recommend limiting the lovastatin dose to 10 mg/day during concurrent use. Lovastatin exposure may increase resulting in increased risk of myopathy/rhabdomyolysis. Lovastatin is a CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor.
    Lumacaftor; Ivacaftor: (Major) If dronedarone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may reduce the efficacy of dronedarone by decreasing its systemic exposure; avoid concomitant use. Dronedarone is a substrate and moderate inhibitor of CYP3A. Ivacaftor is a sensitive CYP3A substrate and lumacaftor is a strong CYP3A inducer. Induction of dronedarone through the CYP3A pathway may lead to decreased drug efficacy. Although ivacaftor exposure may increase when given with a CYP3A inhibitor, ivacaftor; lumacaftor dosage adjustments are not recommended with concomitant use of a moderate CYP3A inducer such as dronedarone.
    Lumateperone: (Major) Avoid coadministration of lumateperone and dronedarone as concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased lumateperone exposure by approximately 2-fold.
    Lurasidone: (Major) Dronedarone is a moderate inhibitor of CYP3A4 and has the potential for interactions with substrates of CYP3A4 such as lurasidone. Concurrent use of these medications may lead to an increased risk of lurasidone-related adverse reactions. If a moderate inhibitor of CYP3A4 is being prescribed and lurasidone is added in an adult patient, the recommended starting dose of lurasidone is 20 mg/day and the maximum recommended daily dose of lurasidone is 80 mg/day. If a moderate CYP3A4 inhibitor is added to an existing lurasidone regimen, reduce the lurasidone dose to one-half of the original dose. Patients should be monitored for efficacy and toxicity.
    Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and dronedarone due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. If concomitant use is unavoidable, consider reducing the dose of lurbinectedin if clinically indicated. Lurbinectedin is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor.
    Macimorelin: (Contraindicated) Because of the potential for TdP, use of macimorelin with dronedarone is contraindicated. Before administering macimorelin, discontinue use of dronedarone and allow a sufficient washout period to pass. 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.
    Maprotiline: (Contraindicated) Concomitant use of dronedarone and maprotiline is contraindicated. Dronedarone is an inhibitor of CYP2D6. Maprotiline is a substrate for CYP2D6. Coadministration of dronedarone and maprotiline may result in elevated plasma concentrations of maprotiline. In addition, maprotiline has been established to have a possible risk of 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.
    Maraviroc: (Moderate) Use caution if coadministration of maraviroc with dronedarone is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A and P-glycoprotein (P-gp) substrate and dronedarone is a CYP3A4/P-gp inhibitor. Monitor for an increase in adverse effects with concomitant use.
    Mefloquine: (Contraindicated) There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data and the potential for torsade de pointes (TdP), concurrent use of mefloquine and dronedarone is contraindicated. 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.
    Meloxicam: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Meloxicam is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Meperidine; Promethazine: (Contraindicated) Dronedarone administration is associated with a dose-related increase in the QTc interval. Promethazine carries a possible risk of QT prolongation. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated.
    Mestranol; Norethindrone: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Mestranol is converted to ethinyl estradiol. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives.
    Metformin; Repaglinide: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Repaglinide is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Metformin; Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and dronedarone are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as dronedarone.
    Methadone: (Contraindicated) The concomitant use of dronedarone and methadone is contraindicated. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Methamphetamine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Methamphetamine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Methylprednisolone: (Moderate) Coadministration of methylprednisolone with dronedarone may cause elevated methylprednisolone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Monitor closely. Methylprednisolone is a CYP3A4 substrate and dronedarone is an inhibitor of CYP3A4.
    Metoprolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Metronidazole: (Contraindicated) Avoid concomitant use of metronidazole and dronedarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Midazolam: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Midazolam is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Midostaurin: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of midostaurin with dronedarone is contraindicated. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds (msec) at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 msec at doses of 1,600 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.
    Mifepristone: (Contraindicated) Because of the potential for torsades de pointes, concurrent use of dronedarone and mifepristone is contraindicated. 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. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated.
    Mirtazapine: (Contraindicated) Because of the potential for torsade de pointes (TdP), concurrent use of dronedarone and mirtazapine is contraindicated. Dronedarone is associated with a dose-related increase in the QTc interval. The increase in QTc is about 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. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Mitapivat: (Moderate) Do not exceed mitapivat 20 mg PO twice daily during coadministration with dronedarone and monitor hemoglobin and for adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased mitapivat overall exposure by 2.6-fold.
    Mitotane: (Major) Avoid the concomitant use of mitotane with dronedarone; if coadministration cannot be avoided, monitor for decreased efficacy of dronedarone. Mitotane is a strong CYP3A4 inducer and dronedarone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of dronedarone. The AUC and Cmax of dronedarone were significantly reduced when given with rifampin, another strong CYP3A4 inducer.
    Mobocertinib: (Contraindicated) Avoid concomitant use of mobocertinib and dronedarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase mobocertinib exposure and the risk for mobocertinib-related adverse reactions. If use cannot be avoided, reduce the dose of mobocertinib by approximately 50% and monitor the QT interval more frequently. Mobocertinib is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor. Use of a moderate CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 100% to 200%.
    Moxifloxacin: (Contraindicated) Concurrent use of dronedarone and moxifloxacin is contraindicated. Prolongation of the QT interval has been reported with administration of moxifloxacin. Post-marketing surveillance has identified very rare cases of ventricular arrhythmias including torsade de pointes (TdP), usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce TdP and is contraindicated.
    Nadolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Nafcillin: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Nafcillin induces CYP3A4. Coadministration of CYP3A4 inducers, such as nafcillin, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
    Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with dronedarone. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; dronedarone is a weak P-gp inhibitor and a moderate CYP3A4 inhibitor.
    Naloxegol: (Major) Avoid concomitant administration of naloxegol and dronedarone due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with dronedarone is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid coadministration of sirolimus with dronedarone as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and dronedarone is a moderate CYP3A and P-gp inhibitor. Concomitant use of another moderate CYP3A and P-gp inhibitor increased sirolimus overall exposure by 4.2-fold.
    Naproxen; Esomeprazole: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Esomeprazole is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Nebivolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Nebivolol; Valsartan: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Nefazodone: (Contraindicated) The concomitant use of dronedarone and nefazodone is contraindicated due to the potential for increased exposure to dronedarone; nefazodone concentrations may also increase. Dronedarone is metabolized by CYP3A and is a moderate inhibitor of CYP3A. Nefazodone is a strong inhibitor of CYP3A4 and is a CYP3A substrate. Repeated doses of another strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. No data exist regarding the safe administration of dronedarone with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. The effects of dronedarone on the pharmacokinetics of nefazodone have not been described, although an increase in nefazodone serum concentrations is possible.
    Nelfinavir: (Moderate) Dronedarone and nelfinavir should be coadministered with caution. Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Nelfinavir is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with imatinib may result in increased plasma concentrations of either drug.
    Neratinib: (Major) Avoid concomitant use of dronedarone with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and dronedarone is a dual moderate CYP3A4/P-glycoprotein (P-gp) inhibitor. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another dual moderate CYP3A4/P-gp inhibitor may increase neratinib exposure by 299%.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Coadminister dronedarone and palonosetron together with caution. Dronedarone is an inhibitor of CYP2D6 and CYP3A4. Palonsetron is a substrate for CYP2D6 and CYP3A4. Coadministration of dronedarone and palonosetron may result in elevated plasma concentrations of palonsetron. (Moderate) Concomitant use of dronedarone and netupitant; palonosetron should be approached with caution due to a possible risk of QT prolongation and torsade de pointes (TdP) from dronedarone. Dronedarone is an inhibitor of CYP2D6 and CYP3A4, and a primary substrate for CYP3A4. Palonosetron is metabolized by CYP3A4. Netupitant is a substrate and moderate inhibitor of CYP3A4. Coadministration of dronedarone and netupitant; palonosetron may result in elevated plasma concentrations of palonsetron, netupitant, or dronedarone. Dronedarone is associated with dose-related increases in the QTc interval. Co-administration of single dose netupitant 600 mg and palonosetron 1.5 mg had no significant effects on the QTc interval.
    Nevirapine: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Nevirapine induces CYP3A4. Coadministration of CYP3A4 inducers, such as nevirapine, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
    Niacin; Simvastatin: (Major) Do not exceed a simvastatin dose of 10 mg/day in patients taking dronedarone due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on dronedarone, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of dronedarone and simvastatin against the potential risks. Dronedarone increases the simvastatin exposure by approximately 4-fold.
    Nifedipine: (Moderate) Monitor for an increase in nifedipine-related adverse reactions, including hypotension, if coadministration with dronedarone is necessary. Nifedipine is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor.
    Nilotinib: (Contraindicated) Concomitant use of dronedarone and nilotinib is contraindicated. Nilotinib prolongs the QT interval. 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.
    Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with dronedarone is necessary. Nimodipine is a CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor.
    Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as dronedarone, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Dronedarone is a moderate inhibitor of P-gp and a mild inhibitor of CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Nirmatrelvir; Ritonavir: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and dronedarone is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase dronedarone exposure resulting in increased toxicity. Dronedarone is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Contraindicated) The concomitant use of dronedarone and ritonavir is contraindicated. Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ritonavir is a strong inhibitor of CYP3A4, is an inducer of CYP3A, and is a substrate of CYP3A and P-gp. Repeated doses of ketoconazole, also a strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. Furthermore, coadministration of dronedarone and ritonavir may, theoretically, result in decreased concentrations of dronedarone due to CYP3A induction by ritonavir; the net effect on dronedarone plasma concentrations is not known. However, no data exist regarding the safe administration of dronedarone with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. Also, the effects of dronedarone on the pharmacokinetics of ritonavir have not been described, although an increase in ritonavir serum concentrations is possible.
    Nisoldipine: (Major) In general, coadministration of nisoldipine with dronedarone should be avoided due to increased nisoldipine exposure. Dronedarone is a moderate CYP3A inhibitor and nisoldipine is a sensitive CYP3A substrate.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE.
    Norethindrone; Ethinyl Estradiol: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE.
    Norfloxacin: (Contraindicated) Concurrent use of norfloxacin and dronedarone is contraindicated. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, torsade de pointes has been reported during post-marketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory. ronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce TdP and is contraindicated.
    Norgestimate; Ethinyl Estradiol: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE.
    Nortriptyline: (Contraindicated) Coadministration of dronedarone and tricyclic antidepressants is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Tricyclic antidepressants (TCAs) have pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). 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.
    Octreotide: (Contraindicated) Concomitant use of dronedarone and octreotide is contraindicated. Dronedarone is metabolized by CYP3A. Octreotide is an inhibitor CYP3A4. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy warranting more cautious monitoring during octreotide administration in higher risk patients with cardiac disease. 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. 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.
    Ofloxacin: (Contraindicated) Coadministration of dronedarone and ofloxacin is contraindicated. Some quinolones, including ofloxacin, have been associated with QT prolongation and infrequent cases of arrhythmia. Post-marketing surveillance for ofloxacin has identified very rare cases of torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce TdP and is contraindicated.
    Olanzapine: (Contraindicated) Concomitant use of dronedarone and olanzapine is contraindicated. Dronedarone is an inhibitor of CYP2D6. Olanzapine is a substrate for CYP2D6. Coadministration of dronedarone and olanzapine may result in elevated plasma concentrations of olanzapine. In addition, olanzapine has been established to have a possible risk of 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.
    Olanzapine; Fluoxetine: (Contraindicated) Concomitant use of dronedarone and olanzapine is contraindicated. Dronedarone is an inhibitor of CYP2D6. Olanzapine is a substrate for CYP2D6. Coadministration of dronedarone and olanzapine may result in elevated plasma concentrations of olanzapine. In addition, olanzapine has been established to have a possible risk of 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. (Contraindicated) QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Dronedarone administration is associated with a dose-related increase in the QTc interval. The concomitant use of dronedarone with fluoxetine may induce TdP and is contraindicated.
    Olanzapine; Samidorphan: (Contraindicated) Concomitant use of dronedarone and olanzapine is contraindicated. Dronedarone is an inhibitor of CYP2D6. Olanzapine is a substrate for CYP2D6. Coadministration of dronedarone and olanzapine may result in elevated plasma concentrations of olanzapine. In addition, olanzapine has been established to have a possible risk of 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.
    Olaparib: (Major) Avoid coadministration of olaparib with dronedarone due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 150 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after dronedarone is discontinued. Olaparib is a CYP3A substrate and dronedarone is a moderate CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with a moderate CYP3A inhibitor is predicted to increase the olaparib Cmax by 14% and the AUC by 121%.
    Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and dronedarone is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and dronedarone may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects; these effects may be more pronounced with dronedarone as it can inhibit multiple CYP enzymes. If dronedarone is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 and CYP2D6 substrate and dronedarone is a moderate CYP3A4 and CYP2D6 inhibitor.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for evidence of hypotension and edema if amlodipine is coadministered with dronedarone; an amlodipine dose adjustment may be necessary due to increased amlodipine exposure. Dronedarone is a moderate CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate.
    Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) The concomitant use of dronedarone and dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Dronedarone use is contraindicated with other drugs that prolong the QTc and may induce Torsade de Pointes (TdP), such as ritonavir. Furthermore, no data exist for the safe administration of dronedarone (CYP3A substrate/moderate inhibitor) with strong CYP3A4 inhibitors, such as ritonavir, and concomitant use is contraindicated. Elevated concentrations of each drug can be expected, followed by further risk of serious adverse reactions. Dronedarone is also a P-glycoprotein (P-gp) inhibitor. Ritonavir, paritaprevir, and dasabuvir are CYP3A and P-gp substrates; ombitasvir is also a P-gp substrate. (Contraindicated) The concomitant use of dronedarone and ritonavir is contraindicated. Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ritonavir is a strong inhibitor of CYP3A4, is an inducer of CYP3A, and is a substrate of CYP3A and P-gp. Repeated doses of ketoconazole, also a strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. Furthermore, coadministration of dronedarone and ritonavir may, theoretically, result in decreased concentrations of dronedarone due to CYP3A induction by ritonavir; the net effect on dronedarone plasma concentrations is not known. However, no data exist regarding the safe administration of dronedarone with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. Also, the effects of dronedarone on the pharmacokinetics of ritonavir have not been described, although an increase in ritonavir serum concentrations is possible.
    Omeprazole: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Omeprazole is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Omeprazole; Amoxicillin; Rifabutin: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Omeprazole is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Omeprazole; Sodium Bicarbonate: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Omeprazole is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Ondansetron: (Contraindicated) Concomitant use of dronedarone and ondansetron is contraindicated. Dronedarone is an inhibitor of CYP2D6, CYP3A, and P-gp. Ondansetron is a substrate for CYP2D6, CYP3A4, and P-gp. Coadministration of dronedarone and ondansetron may result in elevated plasma concentrations of ondansetron. In addition, ondansetron has been established to have a possible risk of 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.
    Oritavancin: (Major) Dronedarone is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of dronedarone may be reduced if these drugs are administered concurrently.
    Osilodrostat: (Contraindicated) Coadministration of dronedarone with osilodrostat is contraindicated due to the risk of additive QT prolongation. 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. Osilodrostat is associated with dose-dependent QT prolongation.
    Osimertinib: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of osimertinib with dronedarone is contraindicated. Dronedarone is associated with a risk for QT prolongation and TdP. Osimertinib causes concentration dependent prolongation of the QT interval at recommended dosing. Additive QT prolongation is possible.
    Oxaliplatin: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of oxaliplatin with dronedarone is contraindicated. 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. QT prolongation and ventricular arrhythmias including fatal TdP have also been reported with oxaliplatin use in post-marketing experience. Additive QT prolongation is possible.
    Oxcarbazepine: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Oxcarbazepine induces CYP3A4. Coadministration of CYP3A4 inducers, such as oxcarbazepine, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
    Oxybutynin: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Oxybutynin is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. If dronedarone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like dronedarone can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If dronedarone is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Ozanimod: (Contraindicated) Coadministration of dronedarone with ozanimod is contraindicated due to the risk for additive 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 1,600 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. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia.
    Paclitaxel: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A; dronedarone also inhibits P-gp. Paclitaxel is a substrate for CYP3A4 and P-gp. The concomitant administration of dronedarone with CYP3A4 and P-gp substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Pacritinib: (Contraindicated) Avoid concomitant use of dronedarone and pacritinib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase pacritinib exposure and the risk for other pacritinib-related adverse effects; pacritinib is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor.
    Paliperidone: (Contraindicated) Concurrent use of dronedarone and paliperidone is contraindicated. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. 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 1,600 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.
    Palonosetron: (Moderate) Coadminister dronedarone and palonosetron together with caution. Dronedarone is an inhibitor of CYP2D6 and CYP3A4. Palonsetron is a substrate for CYP2D6 and CYP3A4. Coadministration of dronedarone and palonosetron may result in elevated plasma concentrations of palonsetron.
    Panobinostat: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of panobinostat with dronedarone is contraindicated. QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. 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.
    Paricalcitol: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Paricalcitol is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Pasireotide: (Contraindicated) Because of the potential for torsades de pointes (TdP), use of pasireotide and dronedarone is contraindicated. Coadministration of pasireotide and drugs that prolong the QT interval may have additive effects on the prolongation of the QT interval. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce TdP and is contraindicated.
    Pazopanib: (Contraindicated) Concurrent use of pazopanib and dronedarone is contraindicated. Pazopanib has been reported to prolong the QT interval. 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.
    Pemigatinib: (Major) Avoid coadministration of pemigatinib and dronedarone due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If dronedarone is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of dronedarone. Pemigatinib is a CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase pemigatinib exposure by approximately 50% to 80%.
    Penbutolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Pentamidine: (Contraindicated) Concomitant use of dronedarone and pentamidine is contraindicated. Pentamidine has been associated with QT prolongation. 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.
    Perindopril; Amlodipine: (Moderate) Monitor for evidence of hypotension and edema if amlodipine is coadministered with dronedarone; an amlodipine dose adjustment may be necessary due to increased amlodipine exposure. Dronedarone is a moderate CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate.
    Perphenazine: (Contraindicated) Concurrent use of dronedarone and perphenazine is contraindicated. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation and/or 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.
    Perphenazine; Amitriptyline: (Contraindicated) Coadministration of dronedarone and tricyclic antidepressants is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Tricyclic antidepressants (TCAs) have pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). 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. (Contraindicated) Concurrent use of dronedarone and perphenazine is contraindicated. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation and/or 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.
    Pexidartinib: (Major) Avoid coadministration of pexidartinib with dronedarone as concurrent use may increase pexidartinib exposure and the risk of adverse events. If concurrent use cannot be avoided, reduce the dose of pexidartinib as follows: 800 mg/day or 600 mg/day of pexidartinib, reduce to 200 mg twice daily; 400 mg/day of pexidartinib, reduce to 200 mg once daily. If dronedarone is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of dronedarone. Pexidartinib is a CYP3A substrate; dronedarone is a moderate CYP3A inhibitor. Based on modeling and simulation data, coadministration with another moderate CYP3A inhibitor was predicted to increase the pexidartinib exposure by 67%.
    Phentermine; Topiramate: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Topiramate induces CYP3A4. Coadministration of CYP3A4 inducers, such as topiramate, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
    Phenytoin: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Phenytoin induces CYP3A4. Coadministration of CYP3A4 inducers, such as phenytoin, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
    Pimavanserin: (Contraindicated) 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. Because pimavanserin causes QT prolonging effects that may be additive to those of dronedarone, coadministration is contraindicated.
    Pimozide: (Contraindicated) Concomitant use of dronedarone and pimozide is contraindicated. Dronedarone is an inhibitor of CYP3A4. Pimozide is a substrate for CYP3A4. Coadministration of dronedarone and pimozide may result in elevated plasma concentrations of pimozide. In addition, pimozide has been established to have a causal association with QT prolongation and Torsade de Pointes (TdP). Dronedarone is associated with dose-related increases in the QTc interval. 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; concomitant use is contraindicated.
    Pindolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Pitolisant: (Contraindicated) Coadministration of dronedarone with pitolisant is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Pitolisant prolongs the QT interval. 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 1,600 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.
    Ponesimod: (Contraindicated) Coadministration of dronedarone with ponesimod is contraindicated due to the risk for additive 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 1,600 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. ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia.
    Posaconazole: (Contraindicated) The concurrent use of posaconazole and dronedarone is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Both posaconazole and dronedarone are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of dronedarone. Further, dronedarone 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 dronedarone and an increased risk for serious adverse events. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes. 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.
    Prednisolone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Prednisolone is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Prednisone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A; dronedarone also inhibits P-gp. Prednisone is a substrate for CYP3A4 and P-gp. The concomitant administration of dronedarone with CYP3A4 and P-gp substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Prilocaine; Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
    Primaquine: (Contraindicated) Primaquine has the potential to prolong the QT interval. 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. Because of the potential for TdP, use of primaquine with dronedarone is contraindicated.
    Probenecid; Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and dronedarone in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Dronedarone can inhibit colchicine's metabolism via P-glycoprotein (P-gp) and CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken a moderate CYP3A4 inhibitor like dronedarone in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg twice daily or 0.6 mg once daily or if the original dose is 0.6 mg once daily, decrease the dose to 0.3 mg once daily; for treatment of gout flares, give 1.2 mg as a single dose and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed 1.2 mg/day.
    Procainamide: (Contraindicated) Concurrent use of procainamide and dronedarone is contraindicated. Procainamide is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Prochlorperazine: (Contraindicated) Concurrent use of dronedarone and prochlorperazine is contraindicated. Prochlorperazine is associated with a possible risk for QT prolongation and/or 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.
    Promethazine: (Contraindicated) Dronedarone administration is associated with a dose-related increase in the QTc interval. Promethazine carries a possible risk of QT prolongation. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated.
    Promethazine; Dextromethorphan: (Contraindicated) Dronedarone administration is associated with a dose-related increase in the QTc interval. Promethazine carries a possible risk of QT prolongation. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated. (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Promethazine; Phenylephrine: (Contraindicated) Dronedarone administration is associated with a dose-related increase in the QTc interval. Promethazine carries a possible risk of QT prolongation. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated.
    Propafenone: (Contraindicated) 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.
    Propranolol: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Propranolol; Hydrochlorothiazide, HCTZ: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Protriptyline: (Contraindicated) Coadministration of dronedarone and tricyclic antidepressants is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Tricyclic antidepressants (TCAs) have pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). 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.
    Quazepam: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Quazepam is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Quetiapine: (Contraindicated) Concomitant use of dronedarone and quetiapine is contraindicated. Dronedarone is an inhibitor of CYP3A. Quetiapine is a substrate for CYP3A4. Coadministration of dronedarone and quetiapine may result in elevated plasma concentrations of quetiapine. In addition, quetiapine has been established to have a possible risk for 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.
    Quinidine: (Contraindicated) Concurrent use of dronedarone and quinidine is contraindicated. Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Quinine: (Contraindicated) Concomitant use of dronedarone with other drugs that prolong the QTc, such as quinine, may induce torsade de pointes (TdP) and is contraindicated. 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.
    Rabeprazole: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Rabeprazole is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Ramelteon: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Ramelteon is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Ranolazine: (Contraindicated) Concomitant use of dronedarone and ranolazine is contraindicated due to the risk of QT prolongation. Both dronedarone and ranolazine prolong the QT-interval in a dose-related manner. In addition, coadministration of dronedarone and ranolazine may result in elevated plasma concentrations of both drugs, further increasing the risk of QT prolongation and torsade de pointes (TdP). Dronedarone and ranolazine are both substrates and inhibitors of CYP3A. In addition, ranolazine is a substrate of P-glycoprotein (P-gp), and dronedarone is a P-gp inhibitor.
    Relugolix: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of relugolix with dronedarone is contraindicated. 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 1,600 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. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. Concomitant use may also increase relugolix exposure and the risk of relugolix-related adverse effects. Relugolix is a P-gp substrate and dronedarone is a P-gp inhibitor.
    Relugolix; Estradiol; Norethindrone acetate: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of relugolix with dronedarone is contraindicated. 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 1,600 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. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. Concomitant use may also increase relugolix exposure and the risk of relugolix-related adverse effects. Relugolix is a P-gp substrate and dronedarone is a P-gp inhibitor.
    Repaglinide: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Repaglinide is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Ribociclib: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of ribociclib with dronedarone is contraindicated. Additionally, the systemic exposure of ribociclib may be increased resulting in an increase in treatment-related adverse reactions (e.g., neutropenia, QT prolongation). Both drugs have been shown to prolong the QT interval in a concentration-dependent manner. 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. Ribociclib is also extensively metabolized by CYP3A4 and dronedarone is a moderate CYP3A4 inhibitor. Additionally, ribociclib is a strong CYP3A4 inhibitor and dronedarone is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of ribociclib with dronedarone is contraindicated. Additionally, the systemic exposure of ribociclib may be increased resulting in an increase in treatment-related adverse reactions (e.g., neutropenia, QT prolongation). Both drugs have been shown to prolong the QT interval in a concentration-dependent manner. 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. Ribociclib is also extensively metabolized by CYP3A4 and dronedarone is a moderate CYP3A4 inhibitor. Additionally, ribociclib is a strong CYP3A4 inhibitor and dronedarone is a CYP3A4 substrate.
    Rifampin: (Major) Avoid coadministration of dronedarone with rifampin due to the potential for decreased dronedarone exposure and efficacy. Dronedarone is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin significantly decreased dronedarone exposure.
    Rifapentine: (Major) Avoid coadministration of dronedarone with rifapentine due to the potential for decreased dronedarone exposure and efficacy. Dronedarone is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased dronedarone exposure.
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and dronedarone, 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: (Contraindicated) Concurrent use of dronedarone and rilpivirine is contraindicated. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. 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.
    Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with dronedarone; concurrent use may increase rimegepant exposure. Rimegepant is a CYP3A4 and P-gp substrate; dronedarone is a moderate CYP3A4 inhibitor and a P-gp inhibitor.
    Risperidone: (Contraindicated) Concomitant use of dronedarone with risperidone is contraindicated due to the potential risk of 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 1,600 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. Risperidone has been associated with a possible risk of QT prolongation and/or TdP, primarily in the overdose setting. In addition, dronedarone is an inhibitor of CYP2D6. Risperidone is a substrate for CYP2D6. Concomitant use of dronedarone with risperidone may increase risperidone concentration and further increase the risk for adverse cardiac effects.
    Ritonavir: (Contraindicated) The concomitant use of dronedarone and ritonavir is contraindicated. Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ritonavir is a strong inhibitor of CYP3A4, is an inducer of CYP3A, and is a substrate of CYP3A and P-gp. Repeated doses of ketoconazole, also a strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. Furthermore, coadministration of dronedarone and ritonavir may, theoretically, result in decreased concentrations of dronedarone due to CYP3A induction by ritonavir; the net effect on dronedarone plasma concentrations is not known. However, no data exist regarding the safe administration of dronedarone with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. Also, the effects of dronedarone on the pharmacokinetics of ritonavir have not been described, although an increase in ritonavir serum concentrations is possible.
    Rivaroxaban: (Moderate) Avoid concomitant administration of rivaroxaban and dronedarone in patients with CrCl 15 to 80 ml/min unless the potential benefit justifies the potential risk. Dronedarone is a moderate CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Pharmacokinetic data from a trial with erythromycin indicate that concurrent use of rivaroxaban and drugs that are combined P-gp inhibitors and moderate CYP3A4 inhibitors in patients with renal impairment results in increased exposure to rivaroxaban compared to patients with normal renal function and no inhibitor use. Significant increases in rivaroxaban exposure may increase bleeding risk. However, while an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 ml/min [HR (95% CI): 1.05 (0.77, 1.42)].
    Romidepsin: (Contraindicated) Concurrent use of romidepsin and dronedarone is contraindicated. Romidepsin has been reported to prolong the QT interval. 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.
    Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as dronedarone, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Saquinavir: (Contraindicated) The concurrent use of dronedarone and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation. 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. Both saquinavir boosted with ritonavir and dronedarone are inhibitors and substrates of the hepatic isoenzyme CYP3A4. Further, dronedarone is an inhibitor of the drug efflux pump, P-glycoprotein, for which saquinavir is a substrate. Repeated doses of ketoconazole, also a strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. No data exist regarding the safe administration of dronedarone with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. Also, the effects of dronedarone on the pharmacokinetics of saquinavir have not been described, although an increase in saquinavir serum concentrations is possible.
    Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and dronedarone are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as dronedarone.
    Segesterone Acetate; Ethinyl Estradiol: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE. (Minor) Coadministration of segesterone, a CYP3A4 substrate and a moderate CYP3A4 inhibitor, such as dronedarone, may increase the serum concentration of segesterone.
    Selpercatinib: (Contraindicated) Coadministration of of selpercatinib and dronedarone is contraindicated due to the risk of additive QT prolongation. 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 1,600 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. Concentration-dependent QT prolongation has been observed with selpercatinib therapy.
    Selumetinib: (Major) Avoid coadministration of selumetinib and dronedarone due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If dronedarone is discontinued, resume the original selumetinib dose after 3 elimination half-lives of dronedarone. Selumetinib is a CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
    Sertraline: (Contraindicated) Coadministration of dronedarone with sertraline is contraindicated due to the potential for 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. QTc prolongation and TdP have been reported during postmarketing use of sertraline; most cases had confounding risk factors. The risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with dronedarone is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor.
    Silodosin: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A; dronedarone also inhibits P-gp. Silodosin is a substrate for CYP3A4 and P-gp. The concomitant administration of dronedarone with CYP3A4 and P-gp substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and dronedarone. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by dronedarone may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionaly, simeprivir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dronedarone, a CYP3A4 substrate.
    Simvastatin: (Major) Do not exceed a simvastatin dose of 10 mg/day in patients taking dronedarone due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on dronedarone, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of dronedarone and simvastatin against the potential risks. Dronedarone increases the simvastatin exposure by approximately 4-fold.
    Simvastatin; Sitagliptin: (Major) Do not exceed a simvastatin dose of 10 mg/day in patients taking dronedarone due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on dronedarone, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of dronedarone and simvastatin against the potential risks. Dronedarone increases the simvastatin exposure by approximately 4-fold.
    Siponimod: (Contraindicated) Coadministration of dronedarone with siponimod is contraindicated due to the risk of QT prolongation; increased exposure to siponimod is also possible. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. 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. Siponimod is a CYP2C9 and CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
    Sirolimus: (Major) Avoid coadministration of sirolimus with dronedarone as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and dronedarone is a moderate CYP3A and P-gp inhibitor. Concomitant use of another moderate CYP3A and P-gp inhibitor increased sirolimus overall exposure by 4.2-fold.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with dronedarone. 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); dronedarone is an inhibitor of P-gp. Dronedarone is also an inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with dronedarone. 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); dronedarone is an inhibitor of P-gp. Dronedarone is also an inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Solifenacin: (Contraindicated) Coadministration of dronedarone and solifenacin is contraindicated, because of the potential for torsade de Pointes (TdP). Solifenacin has been associated dose-dependent prolongation of the QT interval. TdP has been reported with post-marketing use, although causality was not determined. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce TdP and is contraindicated.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and dronedarone; sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
    Sorafenib: (Contraindicated) Concurrent use of dronedarone and sorafenib is contraindicated. Sorafenib has been associated with QT prolongation. 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.
    Sotalol: (Contraindicated) Concurrent use of dronedarone and sotalol is contraindicated. Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce TdP and is contraindicated.
    St. John's Wort, Hypericum perforatum: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. St. John's Wort, Hypericum perforatum induces CYP3A4. Coadministration of CYP3A4 inducers, such as St. John's Wort, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if dronedarone must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. If dronedarone is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a moderate CYP3A4 inhibitor like dronedarone can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If dronedarone is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
    Sunitinib: (Contraindicated) Because of the potential for TdP, use of sunitinib with dronedarone is contraindicated. 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. Sunitinib can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points (TdP). 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.
    Suvorexant: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors and a maximum recommended dose of 10 mg/day. Dronedarone is a moderate CYP3A4 inhibitor, and increased plasma concentrations of suvorexant are possible during concurrent use of these drugs.
    Tacrolimus: (Contraindicated) Concomitant use of dronedarone and tacrolimus is contraindicated. Tacrolimus prolongs the QTc interval. 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.
    Tadalafil: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Tadalafil is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with dronedarone is necessary. Talazoparib is a P-glycoprotein (P-gp) substrate and dronedarone is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%.
    Tamoxifen: (Contraindicated) Concomitant use of tamoxifen with dronedarone is contraindicated due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. 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.
    Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of dronedarone. Tamsulosin is extensively metabolized by CYP2D6 and CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Therefore, concomitant use with drugs that inhibit both CYP2D6 and CYP3A4, such as dronedarone, should be avoided.
    Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and dronedarone. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as dronedarone, may increase exposure to tasimelteon with the potential for adverse reactions.
    Tazemetostat: (Major) Avoid coadministration of tazemetostat with dronedarone as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. If concomitant use is unavoidable, decrease current tazemetostat daily dosage by 50% (e.g., decrease 800 mg PO twice daily to 400 mg PO twice daily; 600 mg PO twice daily to 400 mg PO for first dose and 200 mg PO for second dose; 400 mg PO twice daily to 200 mg PO twice daily). If dronedarone is discontinued, wait at least 3 half-lives of dronedarone before increasing the dose of tazemetostat to the previous tolerated dose. Tazemetostat is a CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering dronedarone with telaprevir due to an increased potential for dronedarone-related adverse events. If dronedarone 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 pathways of dronedarone and telaprevir. Both dronedarone and telaprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4. Additionally, dronedarone is an inhibitor of the drug efflux transporter P-glycoprotein (PGP); telaprevir is partially metabolized by this efflux protein. When used in combination, the plasma concentrations of both medications may be elevated.
    Telavancin: (Contraindicated) Concurrent use of dronedarone and telavancin is contraindicated. Telavancin has been associated with QT prolongation. 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.
    Telithromycin: (Contraindicated) Concomitant use of dronedarone with telithromycin is contraindicated. Dronedarone is metabolized by CYP3A, and telithromycin is a strong inhibitor of CYP3A4. Repeated doses of ketoconazole, also a strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. In addition, telithromycin has been established to have a possible risk of 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.
    Telmisartan; Amlodipine: (Moderate) Monitor for evidence of hypotension and edema if amlodipine is coadministered with dronedarone; an amlodipine dose adjustment may be necessary due to increased amlodipine exposure. Dronedarone is a moderate CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate.
    Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with dronedarone is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and dronedarone is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Teniposide: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A; dronedarone also inhibits P-gp. Teniposide is a substrate for CYP3A4 and P-gp. Coadministration of dronedarone with CYP3A4 and P-gp substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Tenofovir, PMPA: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as dronedarone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering dronedarone. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4; dronedarone is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
    Tetrabenazine: (Contraindicated) Concomitant use of dronedarone and tetrabenazine is contraindicated. Tetrabenazine causes a small increase in the corrected QT interval (QTc). 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.
    Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with dronedarone; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); dronedarone is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If dronedarone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Theophylline, Aminophylline: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Aminophylline is a substrate for CYP3A4, CYP1A2, and CYP2E1. Although the concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate, data from clinical studies indicate dronedarone does not increase the steady state aminophylline exposure. (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Theophylline is a substrate for CYP3A4, CYP1A2, and CYP2E1. Although the concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate, data from clinical studies indicate dronedarone does not increase the steady state theophylline exposure.
    Thioridazine: (Contraindicated) Concomitant use of dronedarone and thioridazine is contraindicated. Dronedarone is an inhibitor of CYP2D6. Thioridazine is a substrate for CYP2D6. Coadministration of dronedarone and thioridazine may result in increased plasma concentrations of thioridazine. In addition, thioridazine 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.
    Tiagabine: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Tiagabine is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Ticagrelor: (Minor) Coadministration of ticagrelor and dronedarone may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and dronedarone is a P-gp inhibitor (potency unknown). 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) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Tinidazole: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Tinidazole is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Tipranavir: (Contraindicated) The concomitant use of dronedarone and tipranavir is contraindicated. Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Tipranavir is a strong inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Repeated doses of ketoconazole, also a strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. No data exist regarding the safe administration of dronedarone with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. Also, the effects of dronedarone on the pharmacokinetics of tipranavir have not been described, although an increase in tipranavir serum concentrations is possible.
    Tolterodine: (Contraindicated) Because of the potential for torsades de pointes (TdP), concurrent use of tolterodine and dronedarone is contraindicated. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce TdP and is contraindicated.
    Tolvaptan: (Major) Avoid coadministration of dronedarone when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with dronedarone. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Topiramate: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Topiramate induces CYP3A4. Coadministration of CYP3A4 inducers, such as topiramate, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
    Topotecan: (Major) Avoid coadministration of dronedarone with oral topotecan due to increased topotecan exposure; dronedarone may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and dronedarone 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: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of toremifene with dronedarone is contraindicated. Both drugs are 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.
    Tramadol: (Moderate) Dronedarone is metabolized by CYP3A and is an inhibitor of CYP2D6 and CYP3A. Tramadol is a substrate for CYP2D6 and CYP3A4. The concomitant administration of dronedarone with CYP2D6 and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Tramadol; Acetaminophen: (Moderate) Dronedarone is metabolized by CYP3A and is an inhibitor of CYP2D6 and CYP3A. Tramadol is a substrate for CYP2D6 and CYP3A4. The concomitant administration of dronedarone with CYP2D6 and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Trandolapril; Verapamil: (Major) If coadministered with dronedarone, initiate verapamil at a low dose and increase only after ECG verification of good tolerability. Both verapamil and dronedarone are substrates and moderate CYP3A4 inhibitors; increased exposure to both drugs may occur. Additionally, the conduction effects of dronedarone may be potentiated by concurrent use of calcium channel blockers with depressant effects on the sinus and AV nodes.
    Trazodone: (Contraindicated) Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc, such as trazodone, may induce Torsade de Pointes (TdP) and is contraindicated. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP.
    Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with dronedarone and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and dronedarone is a moderate CYP3A inhibitor.
    Triclabendazole: (Contraindicated) Coadministration of dronedarone with triclabendazole is contraindicated due to the risk of additive QT prolongation. 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. Transient prolongation of the mean QTc interval was noted on the ECG recordings in dogs administered triclabendazole.
    Tricyclic antidepressants: (Contraindicated) Coadministration of dronedarone and tricyclic antidepressants is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Tricyclic antidepressants (TCAs) have pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). 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.
    Trifluoperazine: (Contraindicated) Concurrent use of trifluoperazine and dronedarone is contraindicated. Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation and/or 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.
    Trimipramine: (Contraindicated) Coadministration of dronedarone and tricyclic antidepressants is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Tricyclic antidepressants (TCAs) have pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). 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.
    Triptorelin: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of triptorelin with dronedarone is contraindicated. 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 1,600 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. Androgen deprivation therapy (e.g., triptorelin) may also prolong the QT/QTc interval.
    Tucatinib: (Contraindicated) Coadministration of dronedarone with tucatinib is contraindicated due to the potential for increased dronedarone exposure and QT prolongation. Dronedarone is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
    Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with dronedarone. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 and P-gp substrate; dronedarone is a moderate CYP3A4 inhibitor and a P-gp inhibitor. Coadministration with another moderate CYP3A4 inhibitor resulted in a 3.5-fold increase in the exposure of ubrogepant.
    Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and dronedarone is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
    Valdecoxib: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Valdecoxib is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Vandetanib: (Contraindicated) Concurrent use of dronedarone and vandetanib is contraindicated. Vandetanib can prolong the QT interval in a concentration-dependent manner. Torsade de pointes (TdP) and sudden death have been reported in patients receiving vandetanib. Dronedarone administration is also 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.
    Vardenafil: (Contraindicated) Use of dronedarone with vardenafil is contraindicated due to an increased risk for QT prolongation and torsade de pointes. Increased vardenafil exposure may occur due to dronedarone inhibition of CYP3A4. An increase in vardenafil-related adverse effects, such as prolonged erection, hypotension, or QT prolongation, is possible. Dronedarone is associated with a dose-related increase in the QTc interval. Coadministration of other drugs that also prolong the QT interval may result in additive QT prolongation. Vardenafil is associated with QT prolongation. Therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval. Dronedarone is a moderate inhibitor of CYP3A4, the primary isoenzyme responsible for the metabolism of vardenafil. Increased systemic vardenafil exposure may occur.
    Vemurafenib: (Contraindicated) Concurrent use of vemurafenib and dronedarone is contraindicated. Vemurafenib has been associated with QT prolongation. 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.
    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 dronedarone due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of dronedarone. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; dronedarone is a CYP3A4 (moderate) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Venlafaxine: (Contraindicated) Concurrent use of dronedarone and venlafaxine is contraindicated. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use. 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.
    Verapamil: (Major) If coadministered with dronedarone, initiate verapamil at a low dose and increase only after ECG verification of good tolerability. Both verapamil and dronedarone are substrates and moderate CYP3A4 inhibitors; increased exposure to both drugs may occur. Additionally, the conduction effects of dronedarone may be potentiated by concurrent use of calcium channel blockers with depressant effects on the sinus and AV nodes.
    Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with dronedarone is necessary. Vinblastine is a CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor. Enhanced vinblastine toxicity was reported with coadministration of another moderate CYP3A4 inhibitor.
    Vincristine Liposomal: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A; dronedarone also inhibits P-gp. Vincristine is a substrate for CYP3A4 and P-gp. The concomitant administration of dronedarone with CYP3A4 and P-gp substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Vincristine: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A; dronedarone also inhibits P-gp. Vincristine is a substrate for CYP3A4 and P-gp. The concomitant administration of dronedarone with CYP3A4 and P-gp substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with dronedarone is necessary. Vinorelbine is a CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor.
    Voclosporin: (Contraindicated) Concomitant use of voclosporin and dronedarone is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Voclosporin exposure and the risk for voclosporin-related adverse effects may also be increased. If concomitant use is necessary, reduce the voclosporin dosage to 15.8 mg PO in the morning and 7.9 mg PO in the evening. Voclosporin is a sensitive CYP3A4 substrate that is associated with QT prolongation at supratherapeutic doses. Dronedarone is a moderate CYP3A4 inhibitor that is associated with a dose-related increase in the QTc interval. The dronedarone-induced increase in QTc is approximately 10 msec at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 msec at doses of 1,600 mg twice daily. Coadministration with moderate CYP3A4 inhibitors is predicted to increase voclosporin exposure by 3-fold.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and dronedarone. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with dronedarone, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Voriconazole: (Contraindicated) Concomitant use of dronedarone and voriconazole is contraindicated. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including 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.
    Vorinostat: (Contraindicated) Concurrent use of dronedarone and vorinostat is contraindicated. Vorinostat therapy is associated with a risk of QT prolongation. 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.
    Voxelotor: (Moderate) Monitor for increased toxicity of dronedarone during coadministration of voxelotor as concurrent use may increase the exposure of dronedarone. Dronedarone is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with dronedarone is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Dronedarone is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
    Yohimbine: (Moderate) Dronedarone is an inhibitor of CYP2D6. Yohimbine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Zafirlukast: (Moderate) Dronedarone and zafirlukast should be coadministered with caution. Dronedarone is metabolized by CYP3A. Zafirlukast is an inhibitor of CYP3A4. Concomitant use of dronedarone with zafirlukast may increase dronedarone concentrations.
    Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO twice daily if coadministered with dronedarone. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Further decrease the zanubrutinib dose as recommended if adverse reactions occur. After discontinuation of dronedarone, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. The AUC of zanubrutinib is predicted to increase by 157% to 317% when coadministered with other moderate CYP3A4 inhibitors.
    Zileuton: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Zileuton is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Ziprasidone: (Contraindicated) Coadministration of ziprasidone and dronedarone is contraindicated since there is an increased risk for QT prolongation and torsade de pointes (TdP). Dronedarone is contraindicated for concomitant use with drugs that prolong the QT interval and might increase the risk of TdP. Ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs, including dronedarone. Dronedarone induces a moderate (average of about 10 milliseconds but much greater effects have been observed) prolongation of the QTc (Bazett). Ziprasidone has been associated with a possible risk for QT prolongation and/or TdP.
    Zolpidem: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of dronedarone, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    Zonisamide: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Zonisamide is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.

    PREGNANCY AND LACTATION

    Pregnancy

    Dronedarone is classified as FDA pregnancy risk category X and is contraindicated in women who are or may become pregnant. Dronedarone may cause fetal harm when administered to pregnant women. It was found to be teratogenic to rats at the maximum recommended human dose and to rabbits at half the maximum recommended human dose. Teratogenic effects found in rats include cranioschisis, cleft palate, incomplete evagination of pineal body, brachygnathia, partially fused carotid arteries, truncus arteriosus, abnormal lobation of the liver, partially duplicated inferior vena cava, brachydactyly, ectrodactylia, syndactylia, and anterior and/or posterior club feet. Teratogenic effects seen in rabbits included anomalous ribcage and vertebrae and pelvic asymmetry. Premenopausal females who have not undergone a hysterectomy or oophorectomy must use effective contraception and be counseled regarding appropriate contraceptive choices while using dronedarone. If the patient becomes pregnant while taking dronedarone, the physician and patient need to discuss the risk to the pregnancy and the potential hazard to the fetus.

    According to the manufacturer, it is unknown whether dronedarone is excreted into human breast milk. It is excreted into the milk of lactating rats. Because of the potential for serious adverse reactions in breast-feeding infants from dronedarone, a decision should be made to discontinue nursing or discontinue dronedarone, taking into account the importance of the drug to the mother. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Dronedarone is a benzofuran derivative of amiodarone. The exact mechanism of action of dronedarone is unknown. Similar to amiodarone, dronedarone has a complex electrophysical profile and possesses antiarrhythmic properties belonging to all four Vaughan-Williams classes. Like Class III antiarrhythmics, dronedarone lengthens cardiac action potential and refractory periods by inhibiting the potassium currents IKr, IKl, IKACh, and Isus. Dronedarone also inhibits sodium channels, thereby decreasing the slope of the depolarization phase of the action potential, a Class Ib property, and also inhibits the slow L-type calcium channels, a class IV property. Furthermore, dronedarone also possesses antiadrenergic properties, which is a Class II property. In healthy subjects, dronedarone was found to significantly prolong the RR and QT interval in a dose-dependent manner.
     
    Structural modifications made to the dronedarone molecule include the removal of the iodine moiety and the addition of a methane-sulfonamyl group. These modifications result in a molecule with decreased lipophilicity, resulting in a shorter half-life, and lower tissue accumulation. Specifically, removal of the iodine moiety allows for a reduced risk of thyroid function abnormalities known to occur with amiodarone therapy. Animal studies indicate dronedarone does not affect circulating plasma thyroid hormones.

    PHARMACOKINETICS

    Dronedarone is administered orally.  Dronedarone and its metabolite are highly bound to plasma proteins (> 98%), mainly albumin. This protein binding is not saturable. Dronedarone is extensively metabolized, mainly involving the CYP3A isoenzyme. The main active metabolite is 1/10—1/3 as potent as dronedarone. Approximately 30 other uncharacterized metabolites also exist. About 6% of radiolabeled dronedarone is excreted in urine and 84% is excreted in feces, mainly as metabolites. The elimination half-life is 13—19 hours.
     
    Dronedarone possesses electrophysiological properties of all four Vaughan-Williams classes. It was evaluated in healthy volunteers receiving repeated oral doses of up to 1600 mg once daily or 800 mg twice daily for 14 days and 1600 mg twice daily for 10 days. A dose-dependent increase in the PR interval of 5 milliseconds occurred in the 400 mg twice daily group and an increase of up to 50 milliseconds occurred in the 1600 mg twice daily group. A similar dose-related effect occurred in the QT interval with an increase of 10 milliseconds in the 400 mg twice daily group and an increase of up to 25 milliseconds in the 1600 mg twice daily group.
     
    Affected cytochrome P450 isoenzymes and drug transporter: CYP3A, CYP2D6, P-gp
    Dronedarone is a moderate inhibitor of CYP3A and CYP2D6 and an inhibitor of P-glycoprotein (P-gp) transport. It is also a substrate of CYP3A.
     

    Oral Route

    Due to first pass metabolism, the bioavailability of dronedarone is approximately 4%. When administered with a high fat meal, the bioavailability increases to 15%. The peak plasma concentration of dronedarone and its main active metabolite, N-debutyl metabolite, are reached within 3—6 hours. The steady state concentration is reached within 4—8 days of repeated oral administration of 400 mg twice daily. A 2-fold increase in dose results in an approximate 2.5- to 3-fold increase in Cmax and AUC. Similar pharmacokinetic properties are seen with the main active metabolite.