Rythmol

Anti-arrhythmics, Class I-C

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

Oral Administration

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

Severe

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

Moderate

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

Mild

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

Apheresis, celiac disease, females, fever, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, mortality, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke

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

Rythmol, Rythmol SR

Rx

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

For the treatment of life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia.
NOTE: Initiate treatment in the hospital setting.
Oral dosage (immediate-release) Adults

150 mg PO every 8 hours, initially. May increase the dose to 225 mg PO every 8 hours after at least 3 to 4 days and then to 300 mg PO every 8 hours if needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of atrial fibrillation or atrial flutter. For the treatment of episodic atrial fibrillation or atrial flutter associated with disabling symptoms in persons without structural heart disease. Oral dosage (immediate-release) Adults

150 mg PO every 8 hours, initially. May increase the dose to 225 mg PO every 8 hours, and if necessary, to 300 mg PO every 8 hours after intervals of 3 to 4 days. The safety and efficacy of doses more than 900 mg/day have not been established. Guidelines recommend propafenone to maintain sinus rhythm in persons with atrial fibrillation without structural heart disease. Avoid use in persons with heart failure and/or left ventricular dysfunction.

Oral dosage (extended-release) Adults

225 mg PO every 12 hours, initially. May increase the dose to 325 mg PO every 12 hours, and if necessary, to 425 mg PO every 12 hours at intervals of 5 days or more. Guidelines recommend propafenone to maintain sinus rhythm in persons with atrial fibrillation without structural heart disease. Avoid use in persons with heart failure and/or left ventricular dysfunction.

For the treatment of recent-onset atrial fibrillation or atrial flutter as pharmacological cardioversion†. Oral dosage (immediate-release) Adults

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

For the treatment of premature ventricular contractions (PVCs)†. Oral dosage (immediate-release) Adults

150 to 300 mg PO every 8 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Guidelines suggest propafenone in the treatment of PVCs in the absence of structural heart disease; treatment with class I sodium channel-blocking medications is associated with an increased risk of death in the post-myocardial infarction population.

Oral dosage (extended-release) Adults

225 to 425 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Guidelines suggest propafenone in the treatment of PVCs in the absence of structural heart disease; treatment with class I sodium channel-blocking medications is associated with an increased risk of death in the post-myocardial infarction population.

For paroxysmal supraventricular tachycardia (PSVT) prophylaxis in persons without structural heart disease, including Wolff-Parkinson-White (WPW) syndrome†. Oral dosage (immediate-release) Adults

150 mg PO every 8 hours, initially. May increase the dose to 225 mg PO every 8 hours, and if necessary, to 300 mg PO every 8 hours after intervals of 3 to 4 days.

Children† and Adolescents†

8 to 10 mg/kg/day PO in 3 divided doses, initially. Increase the dose by 2 to 3 mg/kg/day every 2 to 3 days as needed up to 15 mg/kg/day in 3 divided doses. Alternatively, 100 to 200 mg/m2/day PO in 3 divided doses. Increase the dose by 100 mg/m2/day every 3 days as needed up to 600 mg/m2/day in 3 divided doses. Usual dose: 13 to 16 mg/kg/day or 300 to 380 mg/m2/day.

Infants†

100 to 200 mg/m2/day PO in 3 divided doses. Increase the dose by 100 mg/m2/day every 3 days as needed up to 600 mg/m2/day in 3 divided doses. Usual dose: 300 to 500 mg/m2/day.

†Indicates off-label use

Hepatic Impairment

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

Renal Impairment

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

Abarelix: (Contraindicated) Since abarelix can cause QT prolongation, abarelix should be used cautiously, if at all, with other drugs that are associated with QT prolongation including propafenone.
Acebutolol: (Major) Pharmacologically, beta-blockers, like acebutolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with propafenone may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of propafenone could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Propafenone is a moderate inhibitor of CYP2D6.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
Acetaminophen; Dextromethorphan: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Dextromethorphan; Doxylamine: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
Acyclovir: (Moderate) Monitor for increased propafenone toxicity if concomitant use of acyclovir is necessary. Concomitant use may increase propafenone exposure; propafenone is a CYP1A2 substrate and acyclovir is a weak CYP1A2 inhibitor.
Adagrasib: (Major) Avoid concurrent use of propafenone and adagrasib; concurrent use may increase plasma concentrations of propafenone and result in additive risk for QT/QTc prolongation and torsade de pointes (TdP). Propafenone is a CYP2D6 and CYP3A substrate, adagrasib is a moderate CYP2D6 inhibitor and a strong 3A inhibitor, and both medications have been associated with QT interval prolongation.
Afatinib: (Moderate) If the concomitant use of propafenone and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of propafenone. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
Alfuzosin: (Major) Concomitant use of propafenone and alfuzosin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Amiodarone: (Major) The use of propafenone with other antiarrhythmics has not been well-studied. Class III antiarrhythmics are associated with QT prolongation and ventricular arrhythmias, including torsades de pointes (TdP). The concurrent use of amiodarone with propafenone is not recommended by the manufacturer, In addition to potential for additive effects on cardiac conduction and repolarization, amiodarone is a CYP2D6 inhibitor and may inhibit the metabolism of propafenone (CYP2D6 substrate). In general, combination therapy with Class III and Class IC antiarrhythmics has been reported to increase the risk of proarrhythmias. In one pediatric trial, combined therapy with amiodarone and propafenone resulted in electrocardiographic abnormalities. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Amisulpride: (Major) Concomitant use of propafenone and amisulpride increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Amitriptyline: (Minor) Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with propafenone is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; propafenone is a P-gp inhibitor.
Amlodipine; Celecoxib: (Moderate) Monitor for increased propafenone toxicity if coadministered with celecoxib; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and celecoxib with a CYP3A4 inhibitor. Propafenone is a CYP3A4 and CYP2D6 substrate and celecoxib is a weak CYP2D6 inhibitor.
Amoxapine: (Major) Because most cyclic antidepressants are partially metabolized by CYP2D6, caution is advisable during co-administration of amoxapine and potent CYP2D6 inhibitors such as quinidine. Elevated plasma concentrations of amoxapine may result in more pronounced anticholinergic effects and the risk of seizures may be increased. Anti-arrhythmics that are less potent inhibitors of CYP2D6, such as propafenone, may similarly interact with amoxapine. CYP2D6 substrates including flecainide may compete with amoxapine for the same metabolic pathway.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Concomitant use of propafenone and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Anagrelide: (Major) Concomitant use of propafenone and anagrelide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Apomorphine: (Major) Concomitant use of propafenone and apomorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Aprepitant, Fosaprepitant: (Major) Use caution if propafenone and aprepitant, fosaprepitant are used concurrently and monitor for an increase in propafenone-related adverse effects for several days after administration of a multi-day aprepitant regimen. Propafenone is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of propafenone. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Major) Concomitant use of aripiprazole and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase aripiprazole exposure and other aripiprazole-related adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. If concomitant use is necessary, monitor for aripiprazole-related adverse reactions and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Patients receiving both a CYP3A inhibitor plus propafenone may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form and CYP3A inhibitor strength. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects; use may also increase the risk for QT/QTc prolongation and TdP. Aripiprazole is a CYP2D6 and CYP3A substrate, propafenone is a weak CYP2D6 inhibitor, and both medications have been associated with QT/QTc prolongation.
Arsenic Trioxide: (Major) Concomitant use of propafenone and arsenic trioxide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor and propafenone is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased propafenone concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as propafenone, should be avoided. Consider ECG monitoring if propafenone must be used with or after artemether; lumefantrine treatment.
Asciminib: (Moderate) Monitor for increased propafenone toxicity if coadministered with asciminib; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and asciminib with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate; asciminib is a weak CYP3A inhibitor.
Asenapine: (Major) Concomitant use of propafenone and asenapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
Atazanavir: (Major) Avoid coadministration of atazanavir and propafenone when possible. Caution should be used in patients receiving atazanavir concurrently with drugs metabolized via CYP3A4 and known to cause QT prolongation. Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of propafenone and an increased potential for QT prolongation or other adverse effects. Serious and/or life-threatening drug interactions could potentially occur between atazanavir and propafenone.
Atazanavir; Cobicistat: (Major) Avoid coadministration of atazanavir and propafenone when possible. Caution should be used in patients receiving atazanavir concurrently with drugs metabolized via CYP3A4 and known to cause QT prolongation. Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of propafenone and an increased potential for QT prolongation or other adverse effects. Serious and/or life-threatening drug interactions could potentially occur between atazanavir and propafenone. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of propafenone with cobicistat. Propafenone is a substrate for CYP3A4 and a substrate and inhibitor of CYP2D6; cobicistat is a substrate and inhibitor of both these enzymes. Concurrent use may result in elevated propafenone plasma concentration.
Atenolol: (Moderate) Pharmacologically, beta-blockers, like atenolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
Atenolol; Chlorthalidone: (Moderate) Pharmacologically, beta-blockers, like atenolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
Atomoxetine: (Major) Concomitant use of propafenone and atomoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with propafenone is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; propafenone is a P-gp inhibitor.
Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with propafenone is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; propafenone is a P-gp inhibitor.
Avacopan: (Moderate) Monitor for increased propafenone toxicity if coadministered with avacopan; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and avacopan with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate; avacopan is a weak CYP3A inhibitor.
Azithromycin: (Major) Concomitant use of azithromycin and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bedaquiline: (Major) Concomitant use of propafenone and bedaquiline increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Belumosudil: (Moderate) Monitor for increased propafenone toxicity if coadministered with belumosudil; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and belumosudil with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate; belumosudil is a weak CYP3A inhibitor.
Berotralstat: (Major) Avoid concurrent use of propafenone and berotralstat; concurrent use may increase plasma concentrations of propafenone, which may lead to cardiac arrhythmias and exaggerated beta-blocking activity. The exposure of berotralstat may also be increased. If use together is unavoidable, decrease the berotralstat dose to 110 mg once daily. Monitor patients closely for drug toxicity. Propafenone is a CYP3A4 and CYP2D6 substrate and P-gp inhibitor; berotralstat is a P-gp substrate and moderate CYP3A4 and CYP2D6 inhibitor.
Betaxolol: (Major) Pharmacologically, beta-blockers, like betaxolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving propafenone. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving propafenone. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; propafenone inhibits P-gp.
Bicalutamide: (Moderate) Monitor for increased propafenone toxicity if coadministered with bicalutamide; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and bicalutamide with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A4 and CYP2D6 substrate; bicalutamide is a weak CYP3A4 inhibitor.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bisoprolol: (Moderate) Pharmacologically, beta-blockers, like bisoprolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Pharmacologically, beta-blockers, like bisoprolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
Bretylium: (Major) Avoid the use of propafenone with bretylium. Withhold bretylium for at least 5 half-lives before dosing with propafenone.
Brimonidine; Timolol: (Major) Pharmacologically, beta-blockers, like timolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
Brompheniramine; Dextromethorphan; Phenylephrine: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Bupivacaine; Lidocaine: (Major) There is limited experience with the use of propafenone with Class IB antiarrhythmics. No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients. However, the concomitant use of propafenone and lidocaine has been reported to increase the risks of central nervous system side effects of lidocaine. When propafenone is coadministered, the dose of lidocaine should be titrated to the desired therapeutic effects.
Buprenorphine: (Major) Concomitant use of propafenone and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Buprenorphine; Naloxone: (Major) Concomitant use of propafenone and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bupropion: (Moderate) Monitor for increased propafenone toxicity if coadministered with bupropion; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and bupropion with a CYP3A4 inhibitor. Propafenone is a CYP3A4 and CYP2D6 substrate; bupropion is a strong CYP2D6 inhibitor.
Bupropion; Naltrexone: (Moderate) Monitor for increased propafenone toxicity if coadministered with bupropion; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and bupropion with a CYP3A4 inhibitor. Propafenone is a CYP3A4 and CYP2D6 substrate; bupropion is a strong CYP2D6 inhibitor.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
Cabotegravir; Rilpivirine: (Major) Concomitant use of rilpivirine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Cannabidiol: (Moderate) Coadministration of cannabidiol may increase propafenone concentrations, which may lead to cardiac arrhythmias. Consider a dose reduction of propafenone as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Propafenone is a CYP1A2 substrate and cannabidiol is a weak CYP1A2 inhibitor.
Capmatinib: (Moderate) Monitor for increased propafenone toxicity if concomitant use of capmatinib is necessary. Concomitant use may increase propafenone exposure; propafenone is a CYP1A2 substrate and capmatinib is a moderate CYP1A2 inhibitor.
Carvedilol: (Moderate) Pharmacologically, beta-blockers, like carvedilol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
Celecoxib: (Moderate) Monitor for increased propafenone toxicity if coadministered with celecoxib; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and celecoxib with a CYP3A4 inhibitor. Propafenone is a CYP3A4 and CYP2D6 substrate and celecoxib is a weak CYP2D6 inhibitor.
Celecoxib; Tramadol: (Moderate) Monitor for increased propafenone toxicity if coadministered with celecoxib; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and celecoxib with a CYP3A4 inhibitor. Propafenone is a CYP3A4 and CYP2D6 substrate and celecoxib is a weak CYP2D6 inhibitor. (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with propafenone is necessary. If propafenone is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and propafenone is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Ceritinib: (Major) Avoid coadministration of ceritinib with propafenone if possible due to the risk of QT prolongation; plasma concentrations of propafenone may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Avoid coadministration altogether if the patient either has CYP2D6 deficiency or is taking a concomitant CYP2D6 inhibitor, as the risk of proarrhythmia and other adverse events is increased. Propafenone is a CYP2D6 and CYP3A4 substrate as well as a Class IC antiarrhythmic which increases the QT interval, largely due to prolongation of the QRS interval. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation.
Chlordiazepoxide; Amitriptyline: (Minor) Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
Chloroquine: (Major) Concomitant use of propafenone and chloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
Chlorpheniramine; Dextromethorphan: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with propafenone may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of propafenone could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Propafenone is a moderate inhibitor of CYP2D6.
Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
Chlorpromazine: (Major) Concomitant use of propafenone and chlorpromazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Cimetidine: (Major) Avoid concurrent use of propafenone and cimetidine; concurrent use may increase plasma concentrations of propafenone, which may lead to cardiac arrhythmias and exaggerated beta-blocking activity. Concomitant administration of propafenone immediate-release tablets and cimetidine in healthy subjects (n = 12) resulted in a 20% increase in steady-state plasma concentrations of propafenone. Propafenone is a CYP1A2, CYP2D6, and CYP3A substrate; propafenone is a weak CYP1A2 inhibitor, weak CYP2D6 inhibitor, and weak CYP3A inhibitor.
Cinacalcet: (Moderate) Monitor for increased propafenone toxicity if coadministered with cinacalcet; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and cinacalcet with a CYP3A inhibitor. Propafenone is a CYP3A and CYP2D6 substrate; cinacalcet is a moderate CYP2D6 inhibitor.
Ciprofloxacin: (Major) Concomitant use of ciprofloxacin and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Cisapride: (Contraindicated) Avoid concomitant use of propafenone and cisapride due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Citalopram: (Major) Concomitant use of propafenone and citalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). In addition, concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Avoid simultaneous use of propafenone and citalopram with a CYP3A4 inhibitor. Propafenone is a CYP3A4 and a CYP2D6 substrate and citalopram is a weak CYP2D6 inhibitor.
Clarithromycin: (Major) Concomitant use of propafenone and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clobazam: (Moderate) A dosage reduction of CYP2D6 substrates, such as propafenone, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. If these agents are used in combination, it is advisable to monitor the patient for propafenone-related adverse reactions.
Clofazimine: (Major) Concomitant use of clofazimine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clomipramine: (Minor) Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
Clozapine: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation such as propafenone. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. In addition, propafenone is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary.
Cobicistat: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of propafenone with cobicistat. Propafenone is a substrate for CYP3A4 and a substrate and inhibitor of CYP2D6; cobicistat is a substrate and inhibitor of both these enzymes. Concurrent use may result in elevated propafenone plasma concentration.
Cobimetinib: (Minor) If concurrent use of cobimetinib and propafenone is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and propafenone is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Codeine: (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of promethazine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
Codeine; Promethazine: (Major) Concomitant use of promethazine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Concomitant use of codeine with propafenone may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of propafenone could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If propafenone is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Propafenone is a moderate inhibitor of CYP2D6.
Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and propafenone 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. Propafenone can inhibit colchicine's metabolism via P-glycoprotein (P-gp), 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 P-gp inhibitor like propafenone 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 once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
Colesevelam: (Moderate) Colesevelam may decrease the bioavailability of propafenone if coadministered. To minimize potential for interactions, consider administering oral antiarrhythmics such as propafenone at least 1 hour before or at least 4 hours after colesevelam.
Conivaptan: (Moderate) Monitor for increased propafenone toxicity if coadministered with conivaptan; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and conivaptan with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate; conivaptan is a moderate CYP3A inhibitor.
Crizotinib: (Major) Concomitant use of propafenone and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with propafenone, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like propafenone in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with propafenone, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
Dacomitinib: (Moderate) Monitor for increased toxicity of propafenone if coadministered with dacomitinib. Coadministration may increase serum concentrations of propafenone. Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity. Propafenone is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor. Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous. Therefore, avoid simultaneous use of propafenone with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.
Dalfopristin; Quinupristin: (Moderate) Coadministration of propafenone with dalfopristi

n; quinupristin may result in elevated propafenone plasma concentrations. If these drugs are used together, closely monitor for signs of propafenone-related adverse events. Propafenone is a substrate of CYP3A; dalfopristin; quinupristin is a weak CYP3A inhibitor.
Darifenacin: (Moderate) Monitor for increased toxicity of propafenone if coadministered with darifenacin. Coadministration may increase serum concentrations of propafenone. Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity. Propafenone is a CYP2D6 substrate; darifenacin is a moderate CYP2D6 inhibitor. Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous. Therefore, avoid simultaneous use of propafenone with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.
Darunavir: (Major) Coadministration of darunavir with propafenone should be done with extreme caution. Therapeutic monitoring of antiarrhythmic concentrations is recommended. Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme should be expected with concurrent use.
Darunavir; Cobicistat: (Major) Coadministration of darunavir with propafenone should be done with extreme caution. Therapeutic monitoring of antiarrhythmic concentrations is recommended. Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme should be expected with concurrent use. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of propafenone with cobicistat. Propafenone is a substrate for CYP3A4 and a substrate and inhibitor of CYP2D6; cobicistat is a substrate and inhibitor of both these enzymes. Concurrent use may result in elevated propafenone plasma concentration.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of darunavir with propafenone should be done with extreme caution. Therapeutic monitoring of antiarrhythmic concentrations is recommended. Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme should be expected with concurrent use. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of propafenone with cobicistat. Propafenone is a substrate for CYP3A4 and a substrate and inhibitor of CYP2D6; cobicistat is a substrate and inhibitor of both these enzymes. Concurrent use may result in elevated propafenone plasma concentration.
Dasatinib: (Major) Concomitant use of propafenone and dasatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Degarelix: (Major) Concomitant use of propafenone and degarelix increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Delavirdine: (Major) Caution is recommended when administering propafenone with delavirdine. Delavirdine is a CYP2D6 inhibitor and propafenone is significantly metabolized by this enzyme. Concurrent use may result in elevated propafenone plasma concentrations. Propafenone exhibits a narrow therapeutic range and large increases in serum concentrations may be associated with severe cardiovascular adverse reactions.
Desipramine: (Minor) Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
Deutetrabenazine: (Major) The risk of QT prolongation may be increased with coadministration of deutetrabenazine and propafenone. 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. Propafenone is a Class IC antiarrhythmic that increases the QT interval, but largely due to prolongation of the QRS interval.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextromethorphan: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Dextromethorphan; Bupropion: (Moderate) Monitor for increased propafenone toxicity if coadministered with bupropion; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and bupropion with a CYP3A4 inhibitor. Propafenone is a CYP3A4 and CYP2D6 substrate; bupropion is a strong CYP2D6 inhibitor. (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Dextromethorphan; Guaifenesin: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Dextromethorphan; Quinidine: (Contraindicated) Class IA antiarrhythmics are associated with QT prolongation and ventricular arrhythmias including torsades de pointes (TdP), and concurrent use with propafenone is not recommended by the manufacturer. Before switching from another antiarrhythmic drug to propafenone therapy, Class IA antiarrhythmics and Class III antiarrhythmics generally should be withheld for at least five half-lives prior to initiating propafenone. Quinidine is a CYP2D6 inhibitor with potential to inhibit propafenone metabolism, and coadministration is contraindicated. Small doses of quinidine completely inhibit the CYP2D6 hydroxylation metabolic pathway, with the result that extensive metabolizers become poor metabolizers. Coadministration with quinidine markedly decreases propafenone clearance in extensive metabolizers, and increases plasma propafenone concentrations by 2 to 3-fold at steady-state. Steady-state plasma concentrations increased more than 2-fold for propafenone, and decreased 50% for 5-OH-propafenone. (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Digoxin: (Major) Propafenone reduces the clearance of digoxin and may lead to digoxin toxicity. Increases in digoxin serum concentrations may occur in over 80% of patients when propafenone is added to the regimen. Concomitant use of propafenone and digoxin has been reported to increase the steady-state AUC of orally administered digoxin by 60 to 270%, and decrease digoxin clearance by 31 to 67%. When propafenone is coadministered with intravenous (IV) digoxin, the serum concentration of digoxin is increased by 28%. Although the exact mechanism for this interaction has not been established, several mechanisms have been proposed including reduced distribution volume and nonrenal clearance of digoxin, as well as potential inhibition of P-glycoprotein renal tubular transport of digoxin. Measure serum digoxin concentrations before initiating propafenone. Reduce digoxin concentrations by decreasing the oral digoxin dose by approximately 30 to 50%, decreasing the IV digoxin dose by 15 to 30%, or by modifying the dosing frequency and continue monitoring.
Diltiazem: (Major) Coadministration of propafenone with diltiazem has the potential to cause additive decreases in AV conduction and/or negative inotropic effects. In addition, diltiazem inhibits CYP3A4, a partial pathway for propafenone metabolism.
Disopyramide: (Major) Concomitant use of propafenone and disopyramide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dofetilide: (Major) Concomitant use of propafenone and dofetilide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dolasetron: (Major) Concomitant use of propafenone and dolasetron increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dolutegravir; Rilpivirine: (Major) Concomitant use of rilpivirine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Propafenone has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, propafenone inhibits CYP2D6, one of the isoenzymes involved in the metabolism of donepezil. In theory, co-administration of propafenone and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Propafenone has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, propafenone inhibits CYP2D6, one of the isoenzymes involved in the metabolism of donepezil. In theory, co-administration of propafenone and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with propafenone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and propafenone is a P-gp inhibitor.
Dorzolamide; Timolol: (Major) Pharmacologically, beta-blockers, like timolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
Doxepin: (Minor) Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, such as propafenone, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy.
Doxorubicin Liposomal: (Major) Avoid coadministration of propafenone with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Propafenone is a CYP2D6 and P-gp inhibitor and doxorubicin is a CYP2D6 and P-gp substrate. Concurrent use of CYP2D6 and/or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of propafenone with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Propafenone is a CYP2D6 and P-gp inhibitor and doxorubicin is a CYP2D6 and P-gp substrate. Concurrent use of CYP2D6 and/or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronedarone: (Contraindicated) Avoid concomitant use of propafenone and dronedarone due to an increased risk for torsade de pointes (TdP) and QT prolongation.
Droperidol: (Major) Concomitant use of propafenone and droperidol increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dutasteride; Tamsulosin: (Moderate) Use caution if coadministration of propafenone with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP2D6 substrate and propafenone is a moderate CYP2D6 inhibitor.
Duvelisib: (Moderate) Monitor for increased toxicity of propafenone if coadministered with duvelisib. Coadministration may increase the exposure of propafenone. Propafenone is a CYP3A4 substrate; duvelisib is a moderate CYP3A4 inhibitor.
Edoxaban: (Moderate) Coadministration of edoxaban and propafenone may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of propafenone; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
Efavirenz: (Major) Although data are limited, coadministration of efavirenz and propafenone may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. In addition, efavirenz is an inducer of CYP3A4; propafenone concentrations may be decreased with coadministration.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Although data are limited, coadministration of efavirenz and propafenone may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. In addition, efavirenz is an inducer of CYP3A4; propafenone concentrations may be decreased with coadministration. (Moderate) Coadministration of tenofovir disoproxil fumarate with propafenone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and propafenone is a P-gp inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Although data are limited, coadministration of efavirenz and propafenone may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. In addition, efavirenz is an inducer of CYP3A4; propafenone concentrations may be decreased with coadministration. (Moderate) Coadministration of tenofovir disoproxil fumarate with propafenone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and propafenone is a P-gp inhibitor.
Elbasvir; Grazoprevir: (Moderate) Administering propafenone with elbasvir; grazoprevir may result in elevated propafenone plasma concentrations. Propafenone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Eliglustat: (Major) Coadministration of propafenone and eliglustat may result in a complex drug interaction that increases the risk of QT prolongation and cardiac arrhythmias; coadministration must be approached with extreme caution and careful patient selection. Coadministration of eliglustat with both propafenone and a CYP3A inhibitor is contraindicated. In extensive or intermediate CYP2D6 metabolizers (EMs or IMs), coadministration requires dosage reduction of eliglustat to 84 mg PO once daily. In addition, consider reducing the dosage of propafenone and titrate to clinical effect with careful monitoring. Coadministration can increase plasma concentrations of either or both drugs. Propafenone is a CYP2D6 substrate and moderate CYP2D6 inhibitor that can increase the QT interval. Eliglustat is a CYP2D6 inhibitor and a substrate of CYP2D6 and CYP3A that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of propafenone with cobicistat. Propafenone is a substrate for CYP3A4 and a substrate and inhibitor of CYP2D6; cobicistat is a substrate and inhibitor of both these enzymes. Concurrent use may result in elevated propafenone plasma concentration.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of propafenone with cobicistat. Propafenone is a substrate for CYP3A4 and a substrate and inhibitor of CYP2D6; cobicistat is a substrate and inhibitor of both these enzymes. Concurrent use may result in elevated propafenone plasma concentration. (Moderate) Coadministration of tenofovir disoproxil fumarate with propafenone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and propafenone is a P-gp inhibitor.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Concomitant use of rilpivirine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Concomitant use of rilpivirine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. (Moderate) Coadministration of tenofovir disoproxil fumarate with propafenone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and propafenone is a P-gp inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with propafenone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and propafenone is a P-gp inhibitor.
Encorafenib: (Major) Concomitant use of propafenone and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Entrectinib: (Major) Concomitant use of propafenone and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Eribulin: (Major) Concomitant use of propafenone and eribulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Erythromycin: (Major) Concomitant use of propafenone and erythromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). In addition, concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Avoid simultaneous use of propafenone and erythromycin with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A4 substrate and erythromycin is a moderate CYP3A4 inhibitor.
Escitalopram: (Major) Concomitant use of escitalopram and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Avoid simultaneous use of propafenone and escitalopram with a CYP3A4 inhibitor. Propafenone is a CYP3A4 and a CYP2D6 substrate and escitalopram is a moderate CYP2D6 inhibitor.
Esmolol: (Major) Pharmacologically, beta-blockers, like esmolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
Etravirine: (Moderate) Use caution with coadministration of propafenone and etravirine; concurrent use may decrease propafenone exposure and efficacy. Propafenone concentration monitoring is recommended, if available.
Everolimus: (Major) Avoid concurrent use of propafenone and everolimus; concurrent use may increase plasma concentrations of propafenone, which may lead to cardiac arrhythmias and exaggerated beta-blocking activity; everolimus exposure may also increase. Propafenone is a CYP3A4 and CYP2D6 substrate and a P-glycoprotein (P-gp) substrate; everolimus is a P-gp substrate, a competitive CYP2D6 inhibitor, and a weak CYP3A4 inhibitor.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with propafenone is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; propafenone is a P-gp inhibitor.
Fedratinib: (Major) Avoid coadministration of fedratinib and propafenone as propafenone exposure and adverse effects may be increased. Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity. Propafenone is a CYP3A4 and CYP2D6 substrate; fedratinib is a moderate inhibitor of both CYP3A4 and CYP2D6. The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous.
Fingolimod: (Major) Concomitant use of propafenone and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Flecainide: (Major) Concomitant use of flecainide and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase the exposure of flecainide, further increasing the risk of adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Flecainide is a CYP2D6 substrate and propafenone is a moderate CYP2D6 inhibitor.
Fluconazole: (Contraindicated) Due to the risk of life-threatening arrhythmias such as torsade de pointes (TdP), coadministration of fluconazole with drugs that both prolong the QT interval and are CYP3A4 substrates, like propafenone, is contraindicated. Fluconazole has been associated with QT prolongation and rare cases of TdP. Additonally, fluconazole is an inhibitor of CYP3A4. Coadministration may result in elevated plasma concentrations of propafenone, causing an increased risk for adverse events such as QT prolongation.
Fluoxetine: (Major) Concomitant use of fluoxetine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase the exposure of propafenone, further increasing the risk of proarrhythmias. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Propafenone is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant administration of propafenone and fluoxetine in extensive metabolizers increases the S-propafenone Cmax and AUC by 39% and 50%, and the R-propafenone Cmax and AUC by 71% and 50%.
Fluphenazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering fluphenazine with propafenone. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
Fluvoxamine: (Major) Concomitant use of propafenone and fluvoxamine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fosamprenavir: (Moderate) Monitor for increased propafenone toxicity if coadministered with fosamprenavir; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid use of propafenone and fosamprenavir if boosted with ritonavir or with another CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate; fosamprenavir is a moderate CYP3A inhibitor.
Foscarnet: (Major) Concomitant use of propafenone and foscarnet increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fostemsavir: (Major) Concomitant use of propafenone and fostemsavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with fostemsavir is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with propafenone is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and propafenone is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Gemifloxacin: (Major) Concomitant use of propafenone and gemifloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Gemtuzumab Ozogamicin: (Major) Concomitant use of propafenone and gemtuzumab ozogamicin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Gilteritinib: (Major) Concomitant use of propafenone and gilteritinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ginger, Zingiber officinale: (Minor) In vitro studies have demonstrated the positive inotropic effects of certain gingerol constituents of ginger; but it is unclear if whole ginger root exhibits these effects clinically in humans. It is theoretically possible that excessive doses of ginger could affect the action of antiarrhythmics; however, no clinical data are available.
Glasdegib: (Major) Concomitant use of propafenone and glasdegib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and propafenone as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp); propafenone is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and propafenone as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); propafenone is a P-gp inhibitor.
Goserelin: (Major) Concomitant use of propafenone and goserelin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Granisetron: (Major) Concomitant use of propafenone and granisetron increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Grapefruit juice: (Major) Drugs that inhibit CYP1A2 and CYP3A4 can be expected to increase the serum concentrations of propafenone. When propafenone is co-administered with inhibitors of CYP1A2 or CYP3A4, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals. Grapefruit juice is a CYP 3A4 inhibitor.
Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
Halogenated Anesthetics: (Major) Concomitant use of propafenone and halogenated anesthetics increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Haloperidol: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with haloperidol. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. QT prolongation and TdP have also been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. In addition, haloperidol is a substrate for CYP2D6 and propafenone is a CYP2D6 substrate/inhibitor. Mild to moderate increases in haloperidol plasma concentrations may occur during concurrent use.
Histrelin: (Major) Concomitant use of propafenone and histrelin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
Hydrocodone: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with propafenone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of propafenone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If propafenone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Propafenone is a moderate inhibitor of CYP2D6.
Hydroxychloroquine: (Major) Concomitant use of hydroxychloroquine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Concomitant use of hydroxyzine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ibutilide: (Major) Concomitant use of propafenone and ibutilide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Idelalisib: (Contraindicated) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with propafenone, a CYP3A substrate, as propafenone toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Iloperidone: (Major) Concomitant use of propafenone and iloperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Imatinib: (Major) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering imatinib with CYP2D6 substrates that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions including propafenone.
Imipramine: (Minor) Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
Indinavir: (Major) Propafenone should be used with caution with drugs that inhibit CYP3A4, such as antiretroviral protease inhibitors, which could decrease the hepatic metabolism of propafenone.
Inotuzumab Ozogamicin: (Major) Concomitant use of propafenone and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with propafenone may result in increased serum concentrations of propafenone. Propafenone is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Rifampin may reduce the bioavailability of oral propafenone via induction of propafenone metabolism. Rifampin induces Phase I and Phase II metabolism of propafenone, increasing drug clearance via N-dealkylation and glucuronidation pathways by over 4-fold, but does not appear to induce hydroxylation of propafenone. The extent of reduction in propafenone mean bioavailability is greater in extensive metabolizers of propafenone (reduced from 30% to 10%), although bioavailability is also significantly reduced in poor metabolizers (81% to 48%). The manufacturer reports that concomitant administration of rifampin and propafenone in extensive metabolizers decreases the plasma concentrations of propafenone by 67%, with a corresponding decrease of 5OH-propafenone by 65%. The concentrations of norpropafenone is increased by 30%. In poor metabolizers, there is 50% decrease in propafenone plasma concentrations, and increased the AUC and Cmax of norpropafenone by 74 and 20%, respectively. Urinary excretion of propafenone and its metabolites decreased significantly. Similar results were noted in elderly patients; both the AUC and Cmax propafenone decreased by 84%, with a corresponding decrease in AUC and Cmax of 5OH-propafenone by 69 and 57%. When propafenone is coadministered with rifamycins which induce hepatic metabolism (e.g., rifampin, rifabutin, rifapentine), monitor therapeutic response and adjust dosage as needed to attain antiarrhythmic efficacy endpoints.
Isoniazid, INH; Rifampin: (Major) Rifampin may reduce the bioavailability of oral propafenone via induction of propafenone metabolism. Rifampin induces Phase I and Phase II metabolism of propafenone, increasing drug clearance via N-dealkylation and glucuronidation pathways by over 4-fold, but does not appear to induce hydroxylation of propafenone. The extent of reduction in propafenone mean bioavailability is greater in extensive metabolizers of propafenone (reduced from 30% to 10%), although bioavailability is also significantly reduced in poor metabolizers (81% to 48%). The manufacturer reports that concomitant administration of rifampin and propafenone in extensive metabolizers decreases the plasma concentrations of propafenone by 67%, with a corresponding decrease of 5OH-propafenone by 65%. The concentrations of norpropafenone is increased by 30%. In poor metabolizers, there is 50% decrease in propafenone plasma concentrations, and increased the AUC and Cmax of norpropafenone by 74 and 20%, respectively. Urinary excretion of propafenone and its metabolites decreased significantly. Similar results were noted in elderly patients; both the AUC and Cmax propafenone decreased by 84%, with a corresponding decrease in AUC and Cmax of 5OH-propafenone by 69 and 57%. When propafenone is coadministered with rifamycins which induce hepatic metabolism (e.g., rifampin, rifabutin, rifapentine), monitor therapeutic response and adjust dosage as needed to attain antiarrhythmic efficacy endpoints.
Istradefylline: (Moderate) Monitor for propafenone-related adverse reactions if coadministration of istradefylline 40 mg daily is necessary. Propafenone is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Itraconazole: (Major) Use caution during coadministration of itraconazole and propafenone due to the potential for additive effects on the QT interval and increased exposure to propafenone. Both propafenone and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with propafenone (a CYP3A4 substrate) may result in elevated propafenone plasma concentrations and an increased risk for adverse events, including QT prolongation. It may be prudent to avoid use of propafenone for up to 2 weeks after discontinuing itraconazole, unless benefits of treatment outweigh the potential risk for side effects. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Ivosidenib: (Major) Concomitant use of propafenone and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and propafenone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Drugs that inhibit CYP3A4 (such as ketoconazole) can be expected to cause increased plasma levels of propafenone. The combination may increase the risk of adverse reactions, including proarrhythmia. Propafenone is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
Labetalol: (Major) Pharmacologically, beta-blockers, like labetalol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction, such as Class IC antiarrhythmics, because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with propafenone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and propafenone is a P-gp inhibitor.
Lamotrigine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IC antiarrhythmics. Concomitant use of class IC antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Concomitant use of propafenone and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Lapatinib: (Major) Monitor for an increase in treatment-related adverse reactions if coadministration with propafenone is necessary; also monitor ECGs for QT prolongation and monitor electrolytes. Correct any electrolyte abnormalities prior to treatment. Because of its metabolism, coadministration of lapatinib with propafenone, and either CYP2D6 deficiency or CYP2D6 inhibition is potentially hazardous. Therefore, avoid simultaneous use of propafenone with both a CYP2D6 inhibitor and lapatinib. Lapatinib is a P-glycoprotein (P-gp) substrate and a weak CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Propafenone is a P-gp inhibitor, CYP3A4 substrate, and Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors. Drugs that inhibit CYP3A4 can be expected to cause increased plasma levels of propafenone, which may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity.
Lefamulin: (Major) Avoid coadministration of lefamulin with propafenone as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 and P-gp substrate that 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. Propafenone is a P-gp inhibitor that increases the QT interval, but largely due to prolongation of the QRS interval.
Lenacapavir: (Moderate) Monitor for increased propafenone toxicity if coadministered with lenacapavir; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and lenacapavir with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate; lenacapavir is a moderate CYP3A inhibitor.
Leniolisib: (Moderate) Monitor for increased propafenone toxicity if concomitant use of leniolisib is necessary. Concomitant use may increase propafenone exp osure; propafenone is a CYP1A2 substrate and leniolisib is a weak CYP1A2 inhibitor.
Lenvatinib: (Major) Concomitant use of propafenone and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of propafenone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Propafenone is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Leuprolide: (Major) Concomitant use of propafenone and leuprolide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Leuprolide; Norethindrone: (Major) Concomitant use of propafenone and leuprolide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levofloxacin: (Major) Concomitant use of levofloxacin and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and propafenone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Drugs that inhibit CYP3A4 (such as ketoconazole) can be expected to cause increased plasma levels of propafenone. The combination may increase the risk of adverse reactions, including proarrhythmia. Propafenone is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
Lidocaine: (Major) There is limited experience with the use of propafenone with Class IB antiarrhythmics. No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients. However, the concomitant use of propafenone and lidocaine has been reported to increase the risks of central nervous system side effects of lidocaine. When propafenone is coadministered, the dose of lidocaine should be titrated to the desired therapeutic effects.
Lidocaine; Epinephrine: (Major) There is limited experience with the use of propafenone with Class IB antiarrhythmics. No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients. However, the concomitant use of propafenone and lidocaine has been reported to increase the risks of central nervous system side effects of lidocaine. When propafenone is coadministered, the dose of lidocaine should be titrated to the desired therapeutic effects.
Lidocaine; Prilocaine: (Major) There is limited experience with the use of propafenone with Class IB antiarrhythmics. No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients. However, the concomitant use of propafenone and lidocaine has been reported to increase the risks of central nervous system side effects of lidocaine. When propafenone is coadministered, the dose of lidocaine should be titrated to the desired therapeutic effects.
Lithium: (Major) Concomitant use of propafenone and lithium increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Lofexidine: (Major) Monitor ECG for QT prolongation and monitor for bradycardia during concurrent use of lofexidine and propafenone. Lofexidine may prolong the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
Lonafarnib: (Moderate) Monitor for increased propafenone toxicity if coadministered with lonafarnib; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and lonafarnib with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A4 and CYP2D6 substrate; lonafarnib is a strong CYP3A4 inhibitor.
Loperamide: (Major) Concomitant use of loperamide and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a P-gp substrate and propafenone is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Major) Concomitant use of loperamide and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a P-gp substrate and propafenone is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Major) Avoid use of propafenone and ritonavir; concurrent use may increase propafenone exposure and therefore increase the risk for arrhythmias. This combination is listed as a contraindication in the ritonavir FDA-approved labeling. Propafenone is a CYP3A and CYP2D6 substrate; ritonavir is CYP2D6 and strong CYP3A inhibitor. (Major) Concomitant use of propafenone and lopinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Luliconazole: (Moderate) The manufacturer of propafenone warns that it should be used with caution with drugs that inhibit CYP1A2 and CYP3A4, which could theoretically reduce metabolism of propafenone to N-depropylpropafenone. N-depropylpropafenone is formed via dual metabolic pathways (CYP1A2 and/or CYP3A4). Drugs that inhibit CYP1A2 and CYP3A4 can be expected to increase the serum concentrations of propafenone. When propafenone is coadministered with inhibitors of CYP1A2 or CYP3A4, the patients should be closely monitored and the dosage of propafenone adjusted as needed to meet therapeutic goals. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP3A4 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
Macimorelin: (Major) Concomitant use of propafenone and macimorelin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Maprotiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with maprotiline. The need to coadminister these drugs should be done with a careful assessment of risk versus benefit; consider alternative therapy. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Additionally, propafenone may inhibit the CYP2D6 metabolism of maprotiline.
Maraviroc: (Moderate) Use caution and careful monitoring with the coadministration of maraviroc and propafenone as increased maraviroc concentrations may occur. Maraviroc is a substrate of P-glycoprotein (P-gp); propafenone is an inhibitor of P-gp. The effects of P-gp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
Maribavir: (Moderate) Monitor for increased propafenone toxicity if coadministered with maribavir; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and maribavir with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate; maribavir is a weak CYP3A inhibitor.
Mavacamten: (Moderate) Expect additive negative inotropic effects during concomitant use of mavacamten and propafenone. If concomitant therapy with propafenone is initiated, or if the dose is increased, monitor left ventricular ejection fraction closely until stable doses and clinical response have been achieved.
Mefloquine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with mefloquine. There is evidence that the use of halofantrine after mefloquine causes significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation; however due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval, such as propafenone. In addition, mefloquine is metabolized by P-glycoprotein (P-gp) and propafenone is a P-gp inhibitor. Coadministration may increase mefloquine systemic exposure and further increasing the risk for QT prolongation.
Methadone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with methadone. The need to coadminister these drugs should be done with a careful assessment of treatment risks versus benefits. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Methadone is also considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). In addition, methadone is a substrate for CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Propafenone inhibits CYP2D6 and P-gp. Concurrent use may result in increased serum concentrations of methadone.
Methamphetamine: (Minor) Propafenone inhibits CYP2D6. Propafenone may theoretically increase concentrations of other drugs metabolized by the CYP2D6 isoenzyme. Caution is recommended when administering propafenone with other CYP2D6 substrates, such as methamphetamine, that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions.
Metoprolol: (Major) Pharmacologically, beta-blockers, like metoprolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Propafenone a CYP2D6 inhibitor, has been shown to increase the plasma concentrations and prolong the elimination half-life of metoprolol, with potential for adverse effects. Dosages of metoprolol may need to be reduced when used concomitantly with propafenone.
Metoprolol; Hydrochlorothiazide, HCTZ: (Major) Pharmacologically, beta-blockers, like metoprolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Propafenone a CYP2D6 inhibitor, has been shown to increase the plasma concentrations and prolong the elimination half-life of metoprolol, with potential for adverse effects. Dosages of metoprolol may need to be reduced when used concomitantly with propafenone.
Metronidazole: (Major) Concomitant use of metronidazole and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mexiletine: (Moderate) The concomitant use of mexiletine with other antiarrhythmics can lead to additive pharmacodynamic, electrophysiologic, and/or toxic effects of the drug combination compared with either agent alone.
Midostaurin: (Major) Concomitant use of propafenone and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mifepristone: (Major) Concomitant use of mifepristone and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as propafenone may be increased when administered with mirabegron. This is especially true for patients who are also CYP2D6 poor metabolizers (PMs). Therefore, appropriate monitoring and dose adjustment may be necessary.
Mirtazapine: (Major) Concomitant use of propafenone and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mobocertinib: (Major) Concomitant use of mobocertinib and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Moxifloxacin: (Major) Concomitant use of propafenone and moxifloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Nadolol: (Major) Pharmacologically, beta-blockers, like nadolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and propafenone. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and propafenone is a P-gp inhibitor.
Nefazodone: (Moderate) Nefazodone is a CYP3A4 inhibitors which theoretically may decrease the hepatic metabolism of propafenone.
Nelfinavir: (Major) Propafenone should be used with caution with drugs that inhibit CYP3A4, such as antiretroviral protease inhibitors, which could decrease the hepatic metabolism of propafenone.
Niacin; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with propafenone is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; propafenone is a P-gp inhibitor.
Nicardipine: (Moderate) Certain calcium-channel blockers, such as nicardipine, inhibit CYP3A4, a partial pathway for propafenone metabolism.
Nifedipine: (Major) Because both propafenone and nifedipine have negative inotropic properties, additive effects are possible especially in patients with abnormal ventricular function. It may be prudent to monitor patients closely if nifedipine is used with other drugs that are negative inotropes such as propafenone.
Nilotinib: (Major) Concomitant use of propafenone and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Nirmatrelvir; Ritonavir: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and propafenone is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase propafenone exposure resulting in increased toxicity. Propafenone is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Major) Avoid use of propafenone and ritonavir; concurrent use may increase propafenone exposure and therefore increase the risk for arrhythmias. This combination is listed as a contraindication in the ritonavir FDA-approved labeling. Propafenone is a CYP3A and CYP2D6 substrate; ritonavir is CYP2D6 and strong CYP3A inhibitor.
Nortriptyline: (Minor) Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
Obeticholic Acid: (Moderate) Monitor for increased propafenone toxicity if concomitant use of obeticholic acid is necessary. Concomitant use may increase propafenone exposure; propafenone is a CYP1A2 substrate and obeticholic acid is a weak CYP1A2 inhibitor.
Ofloxacin: (Major) Concomitant use of ofloxacin and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) Concomitant use of propafenone and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine; Fluoxetine: (Major) Concomitant use of fluoxetine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase the exposure of propafenone, further increasing the risk of proarrhythmias. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Propafenone is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant administration of propafenone and fluoxetine in extensive metabolizers increases the S-propafenone Cmax and AUC by 39% and 50%, and the R-propafenone Cmax and AUC by 71% and 50%. (Major) Concomitant use of propafenone and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine; Samidorphan: (Major) Concomitant use of propafenone and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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 propafenone is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and propafenone may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If propafenone is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP2D6 substrate and propafenone is a moderate CYP2D6 inhibitor.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Rifabutin is an inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of propafenone.
Ondansetron: (Major) Concomitant use of ondansetron and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Oritavancin: (Moderate) Propafenone is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Plasma concentrations and efficacy of propafenone may be reduced if these drugs are administered concurrently.
Orlistat: (Major) Orlistat may limit the fraction of propafenone available for absorption. In post-marketing reports, abrupt cessation of orlistat in patients stabilized on propafenone therapy has resulted in severe adverse events including convulsions, AV block and acute circulatory failure.
Osilodrostat: (Major) Avoid coadministration of propafenone and osilodrostat. Concurrent use may increase plasma concentrations of propafenone, which may lead to cardiac arrhythmias and exaggerated beta-blocking activity; additive QT prolongation may also occur. Propafenone is a CYP3A4 and CYP2D6 substrate which increases the QT interval, but largely due to prolongation of the QRS interval. Osilodrostat is a weak CYP3A4 and CYP2D6 inhibitor that is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Concomitant use of propafenone and osimertinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Oxaliplatin: (Major) Concomitant use of propafenone and oxaliplatin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking propafenone due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
Pacritinib: (Major) Concomitant use of propafenone and pacritinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase propafenone exposure and the risk for other propafenone-related adverse effects. Avoid simultaneous use of propafenone and pacritinib with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Propafenone is a substrate of CYP3A4, CYP2D6, and CYP1A2; pacritinib is a weak CYP3A4 and CYP1A2 inhibitor.
Paliperidone: (Major) Concomitant use of propafenone and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Panobinostat: (Major) The co-administration of panobinostat with propafenone is not recommended; QT prolongation has been reported with both of these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of propafenone toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and propafenone is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Paroxetine: (Moderate) Monitor for increased propafenone toxicity if coadministered with paroxetine; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and paroxetine with a CYP3A4 inhibitor. Propafenone is a CYP3A4 and CYP2D6 substrate; paroxetine is a strong CYP2D6 inhibitor.
Pasireotide: (Major) Concomitant use of propafenone and pasireotide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib and propafenone have been reported to prolong the QT interval. If pazopanib and propafenone must be continued, closely monitor the patient for QT interval prolongation. In addition, pazopanib is a weak inhibitor of CYP3A4 and a substrate for P-glycoprotein (P-gp). Propafenone is a substrate for CYP3A4 and an inhibitor of P-gp. Concurrent administration of propafenone and pazopanib may result in increased pazopanib concentrations and/or increased propafenone concentrations. Use caution when concurrent administration of propafenone and pazopanib is necessary.
Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to propafenone if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while propafenone is a CYP2D6 substrate.
Pentamidine: (Major) Concomitant use of propafenone and pentamidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Perphenazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering perphenazine with propafenone. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
Perphenazine; Amitriptyline: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering perphenazine with propafenone. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval. (Minor) Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
Pimavanserin: (Major) Concomitant use of propafenone and pimavanserin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Pimozide: (Contraindicated) Avoid concomitant use of propafenone and pimozide due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Pindolol: (Major) Pharmacologically, beta-blockers, like pindolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
Pirtobrutinib: (Moderate) Monitor for increased propafenone toxicity if coadministered with pirtobrutinib; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and pirtobrutinib with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate; pirtobrutinib is a weak CYP3A inhibitor.
Pitolisant: (Major) Concomitant use of propafenone and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking propafenone due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. 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. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
Posaconazole: (Contraindicated) Concurrent use of posaconazole and propafenone is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of propafenone. Further, propafenone is an inhibitor of the drug efflux protein, P-glycoprotein, for which posaconazole is a substrate and an inhibitor. This complex interaction may ultimately result in altered plasma concentrations of both posaconazole and propafenone. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as propafenone.
Pralsetinib: (Major) Avoid concomitant use of propafenone with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a P-gp substrate and propafenone is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased the overall exposure of pralsetinib by 81%.
Primaquine: (Major) Concomitant use of propafenone and primaquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Probenecid; Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and propafenone 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. Propafenone can inhibit colchicine's metabolism via P-glycoprotein (P-gp), 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 P-gp inhibitor like propafenone 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 once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
Procainamide: (Major) Concomitant use of propafenone and procainamide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Prochlorperazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with prochlorperazine. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Phenothiazines, such as prochlorperazine, have been reported to prolong the QT interval. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
Promethazine: (Major) Concomitant use of promethazine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Dextromethorphan: (Major) Concomitant use of promethazine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Promethazine; Phenylephrine: (Major) Concomitant use of promethazine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propranolol: (Major) Pharmacologically, beta-blockers, like propranolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Additionally, propafenone, a CYP2D6 inhibitor, appears to inhibit the metabolism of propranolol. Coadministration of propafenone with propranolol increases the plasma concentrations and prolongs the elimination half-life of propranolol; these affects were associated with a 15% decrease in diastolic blood pressure. Patients should be monitored closely and a reduction in the dosage of propranolol may be indicated.
Propranolol; Hydrochlorothiazide, HCTZ: (Major) Pharmacologically, beta-blockers, like propranolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Additionally, propafenone, a CYP2D6 inhibitor, appears to inhibit the metabolism of propranolol. Coadministration of propafenone with propranolol increases the plasma concentrations and prolongs the elimination half-life of propranolol; these affects were associated with a 15% decrease in diastolic blood pressure. Patients should be monitored closely and a reduction in the dosage of propranolol may be indicated.
Protriptyline: (Minor) Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
Quetiapine: (Major) Concomitant use of propafenone and quetiapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Quinidine: (Contraindicated) Class IA antiarrhythmics are associated with QT prolongation and ventricular arrhythmias including torsades de pointes (TdP), and concurrent use with propafenone is not recommended by the manufacturer. Before switching from another antiarrhythmic drug to propafenone therapy, Class IA antiarrhythmics and Class III antiarrhythmics generally should be withheld for at least five half-lives prior to initiating propafenone. Quinidine is a CYP2D6 inhibitor with potential to inhibit propafenone metabolism, and coadministration is contraindicated. Small doses of quinidine completely inhibit the CYP2D6 hydroxylation metabolic pathway, with the result that extensive metabolizers become poor metabolizers. Coadministration with quinidine markedly decreases propafenone clearance in extensive metabolizers, and increases plasma propafenone concentrations by 2 to 3-fold at steady-state. Steady-state plasma concentrations increased more than 2-fold for propafenone, and decreased 50% for 5-OH-propafenone.
Quinine: (Major) Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP). In addition, quinine is an inhibitor of both CYP3A4 and CYP2D6. Avoid concurrent use of quinine with other drugs that prolong the QT and are CYP3A4/CYP2D6 substrates. such as propafenone, which also may prolong the QT interval. Coadministration may result in an elevated plasma concentrations, as quinine inhibits CYP2D6 and may increase concentrations of drugs metabolized by this enzyme, such as propafenone. Also, quinine is a substrate of P-glycoprotein (P-gp) and propafenone is a P-gp inhibitor; therefore, quinine concentrations could be increased with coadministration. Caution is recommended. Monitor patients for increased side effects, such as fast, irregular heartbeat, if these drugs must be used together. Consider alternative therapy to quinine if possible.
Quizartinib: (Major) Concomitant use of quizartinib and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ranolazine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with ranolazine. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. In addition, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Coadministration of ranolazine with inhibitors of CYP2D6, such as propafenone, may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects.
Relugolix: (Major) Avoid concomitant use of relugolix and oral propafenone. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects; QT prolongation may also occur. If concomitant use is unavoidable, administer propafenone at least six hours after relugolix and monitor for adverse reactions. Relugolix is a P-gp substrate that may prolong the QT/QTc interval. Propafenone is a P-gp inhibitor and a Class IC antiarrhythmic which also increases the QT interval, largely due to prolongation of the QRS interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral propafenone. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects; QT prolongation may also occur. If concomitant use is unavoidable, administer propafenone at least six hours after relugolix and monitor for adverse reactions. Relugolix is a P-gp substrate that may prolong the QT/QTc interval. Propafenone is a P-gp inhibitor and a Class IC antiarrhythmic which also increases the QT interval, largely due to prolongation of the QRS interval.
Ribociclib: (Major) Avoid coadministration of ribociclib with propafenone due to an increased risk for QT prolongation. Systemic exposure of propafenone may also be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Propafenone is a CYP3A4 substrate and Class IC antiarrhythmic that increases the QT interval, but largely due to prolongation of the QRS interval. Concomitant use may increase the risk for QT prolongation.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with propafenone due to an increased risk for QT prolongation. Systemic exposure of propafenone may also be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Propafenone is a CYP3A4 substrate and Class IC antiarrhythmic that increases the QT interval, but largely due to prolongation of the QRS interval. Concomitant use may increase the risk for QT prolongation.
Rifabutin: (Moderate) Rifabutin is an inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of propafenone.
Rifampin: (Major) Rifampin may reduce the bioavailability of oral propafenone via induction of propafenone metabolism. Rifampin induces Phase I and Phase II metabolism of propafenone, increasing drug clearance via N-dealkylation and glucuronidation pathways by over 4-fold, but does not appear to induce hydroxylation of propafenone. The extent of reduction in propafenone mean bioavailability is greater in extensive metabolizers of propafenone (reduced from 30% to 10%), although bioavailability is also significantly reduced in poor metabolizers (81% to 48%). The manufacturer reports that concomitant administration of rifampin and propafenone in extensive metabolizers decreases the plasma concentrations of propafenone by 67%, with a corresponding decrease of 5OH-propafenone by 65%. The concentrations of norpropafenone is increased by 30%. In poor metabolizers, there is 50% decrease in propafenone plasma concentrations, and increased the AUC and Cmax of norpropafenone by 74 and 20%, respectively. Urinary excretion of propafenone and its metabolites decreased significantly. Similar results were noted in elderly patients; both the AUC and Cmax propafenone decreased by 84%, with a corresponding decrease in AUC and Cmax of 5OH-propafenone by 69 and 57%. When propafenone is coadministered with rifamycins which induce hepatic metabolism (e.g., rifampin, rifabutin, rifapentine), monitor therapeutic response and adjust dosage as needed to attain antiarrhythmic efficacy endpoints.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with propafenone is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and propafenone is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rilpivirine: (Major) Concomitant use of rilpivirine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with propafenone; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and propafenone is a P-gp inhibitor.
Risperidone: (Major) Concomitant use of risperidone and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ritlecitinib: (Moderate) Monitor for increased propafenone toxicity if coadministered with ritlecitinib; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and ritlecitinib with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A, CYP2D6, and CYP1A2 substrate; ritlecitinib is a moderate CYP3A and CYP1A2 inhibitor.
Ritonavir: (Major) Avoid use of propafenone and ritonavir; concurrent use may increase propafenone exposure and therefore increase the risk for arrhythmias. This combination is listed as a contraindication in the ritonavir FDA-approved labeling. Propafenone is a CYP3A and CYP2D6 substrate; ritonavir is CYP2D6 and strong CYP3A inhibitor.
Rolapitant: (Major) Monitor for propafenone-related adverse effects, including QT prolongation, if coadministered with rolapitant. Increased exposure to propafenone may occur . Propafenone is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
Romidepsin: (Major) Romidepsin is a substrate for P-glycoprotein (P-gp). Propafenone is an inhibitor of P-gp. Concurrent administration of romidepsin with an inhibitor of P-gp may cause an increase in systemic romidepsin concentrations. In addition, romidepsin has been reported to prolong the QT interval. Propafenone may also prolong the QT interval. If romidepsin and propafenone must be continued, closely monitor the patient for QT interval prolongation.
Rucaparib: (Major) Avoid concurrent use of propafenone and rucaparib; concurrent use may increase plasma concentrations of propafenone, which may lead to cardiac arrhythmias and exaggerated beta-blocking activity. Propafenone is a CYP3A4, CYP2D6, and CYP1A2 substrate; rucaparib is a weak CYP3A4 inhibitor, a weak CYP2D6 inhibitor, and a moderate CYP1A2 inhibitor.
Saquinavir: (Contraindicated) Concurrent use of propafenone and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Saquinavir boosted with ritonavir is an inhibitor of CYP3A4 and CYP2D6, two enzymes responsible for the metabolism of propafenone. These drugs used together may result in large increases in propafenone serum concentrations, which could cause fatal cardiac arrhythmias. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as propafenone.
Selpercatinib: (Major) Concomitant use of selpercatinib and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sertraline: (Major) Use caution and monitor patients for QT prolongation when administering Class IC Antiarrhythmics with sertraline. Class IC antiarrhythmics increase the QT interval, but largely due to prolongation of the QRS interval. QTc prolongation and torsade de pointes (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). In addition, sertraline is a mild to moderate inhibitor of CYP2D6, and inhibition of CYP2D6 can result in increased concentrations of antiarrhythmic drugs metabolized via the same pathway, including flecainide and propafenone.
Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with propafenone is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; propafenone is a P-gp inhibitor.
Siponimod: (Major) Concomitant use of siponimod and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of propafenone. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and propafenone is a P-gp inhibitor.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with propafenone. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); propafenone is an inhibitor of P-gp.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with propafenone. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); propafenone is an inhibitor of P-gp.
Solifenacin: (Major) Concomitant use of solifenacin and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sorafenib: (Major) Concomitant use of sorafenib and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sotalol: (Major) Concomitant use of propafenone and sotalol increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider t aking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Class III antiarrhythmics generally should be withheld for at least five half-lives prior to initiating propafenone.
Spironolactone: (Moderate) Monitor for increased propafenone toxicity if coadministered with spironolactone; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and spironolactone with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A4 and CYP2D6 substrate; spironolactone is a weak CYP3A4 inhibitor.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased propafenone toxicity if coadministered with spironolactone; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and spironolactone with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A4 and CYP2D6 substrate; spironolactone is a weak CYP3A4 inhibitor.
Streptogramins: (Moderate) Coadministration of propafenone with dalfopristin; quinupristin may result in elevated propafenone plasma concentrations. If these drugs are used together, closely monitor for signs of propafenone-related adverse events. Propafenone is a substrate of CYP3A; dalfopristin; quinupristin is a weak CYP3A inhibitor.
Sunitinib: (Major) Concomitant use of sunitinib and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tacrolimus: (Major) Concurrent use of tacrolimus and propafenone should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Tacrolimus prolongs the QT interval. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval. In addition, both drugs are metabolized by CYP3A4. Although the manufacturer recommends dose adjustment and close monitoring when tacrolimus is coadminsitered with other drugs that prolong the QT interval and are substrates or inhibitors of CYP3A4, it may be prudent to avoid coadministration as the risk of TdP may be increased.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with propafenone is necessary. Talazoparib is a P-gp substrate and propafenone is a P-gp inhibitor.
Tamoxifen: (Major) Concomitant use of tamoxifen and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tamsulosin: (Moderate) Use caution if coadministration of propafenone with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP2D6 substrate and propafenone is a moderate CYP2D6 inhibitor.
Telavancin: (Major) Concomitant use of telavancin and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with propafenone is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with propafenone may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and propafenone is a P-gp inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with propafenone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and propafenone is a P-gp inhibitor.
Terbinafine: (Major) Class IC antiarrhythmics are metabolized by CYP2D6 isoenzymes. Caution is recommended when administering them with CYP2D6 inhibitors, such as terbinafine; Class IC antiarrhythmics exhibit a narrow therapeutic range and large increases in serum concentrations may be associated with severe adverse reactions.
Teriflunomide: (Moderate) As teriflunomide is a weak inducer of CYP1A2, exposure to propafenone, a CYP1A2 substrate, may be reduced. Caution should be exercised with concurrent use. Patients should be monitored for loss of antiarrhythmic effect if teriflunomide therapy is initiated. Conversely, propafenone doses may need adjustment if teriflunomide treatment is discontinued.
Tetrabenazine: (Major) Concomitant use of tetrabenazine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Theophylline, Aminophylline: (Moderate) Although limited data are available, it appears that propafenone may affect theophylline clearance. In several patients, theophylline concentrations increased after the addition of propafenone and in at least one patient, symptoms of theophylline toxicity were suspected. Until more data are available, lower doses of theophylline should be considered in patients receiving propafenone.
Thioridazine: (Contraindicated) Avoid concomitant use of thioridazine and propafenone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Thiothixene: (Major) Propafenone prolongs the QT interval. Combined use with thiothixene could lead to additive orthostatic hypotension and/or prolonged QT syndrome and torsade de pointes. If concomitant use unavoidable, use together with caution and close monitoring.
Ticagrelor: (Moderate) Coadministration of ticagrelor and propafenone may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
Timolol: (Major) Pharmacologically, beta-blockers, like timolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
Tipranavir: (Contraindicated) Coadminsitration of tipranavir with propafenone is contraindicated due to the potential for serious and/or life-threatening cardiac arrhythmias. Tipranavir inhibits the CYP3A4 metabolism of propafenone resulting in elevated propafenone plasma concentrations.
Tizanidine: (Major) Avoid concomitant use of tizanidine and propafenone as increased tizanidine exposure may occur. If use together is necessary, initiate tizanidine at 2 mg and increase by 2 to 4 mg/day based on clinical response. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occurs. Tizanidine is a CYP1A2 substrate and propafenone is a weak CYP1A2 inhibitor.
Tolterodine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with propafenone. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
Topotecan: (Major) Avoid coadministration of propafenone with oral topotecan due to increased topotecan exposure; propafenone may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and propafenone is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Toremifene: (Major) Concomitant use of toremifene and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tramadol: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with propafenone is necessary. If propafenone is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and propafenone is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with propafenone is necessary. If propafenone is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and propafenone is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Trandolapril; Verapamil: (Moderate) Coadministration of propafenone with verapamil has the potential to cause additive decreases in AV conduction and/or negative inotropic effects. In addition, concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and verapamil with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A4 and CYP2D6 substrate and verapamil is a moderate CYP3A4 inhibitor.
Trazodone: (Major) Concomitant use of propafenone and trazodone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Triclabendazole: (Major) Concomitant use of triclabendazole and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tricyclic antidepressants: (Minor) Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
Trifluoperazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with trifluoperazine. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Trifluoperazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
Trimipramine: (Minor) Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with TCA use, but rarely occur when TCAs are used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
Triptorelin: (Major) Concomitant use of triptorelin and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Trofinetide: (Moderate) Monitor for increased propafenone toxicity if coadministered with trofinetide; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and trofinetide with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate; trofinetide is a weak CYP3A inhibitor.
Tucatinib: (Moderate) Monitor for increased propafenone toxicity if coadministered with tucatinib; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and tucatinib with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A4 and CYP2D6 substrate; tucatinib is a strong CYP3A4 inhibitor.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with propafenone. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the P-gp drug transporter; propafenone is a P-gp inhibitor.
Vandetanib: (Major) Concomitant use of vandetanib and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Vardenafil: (Major) Concomitant use of vardenafil and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as propafenone, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, propafenone is a substrate of CYP 1A2, 2D6, and 3A4 and is an inhibitor of P-glycoprotein (P-gp). Vemurafenib is an inhibitor of CYP1A2, a weak inhibitor of CYP2D6, a substrate/inducer of CYP3A4, and a substrate/inhibitor of P-glycoprotein (P-gp) . Concentrations of both propafenone and vemurafenib may be altered with concomitant use.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with propafenone due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of propafenone. Venetoclax is a P-glycoprotein (P-gp) substrate; propafenone is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Venlafaxine: (Major) Concomitant use of propafenone and venlafaxine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Verapamil: (Moderate) Coadministration of propafenone with verapamil has the potential to cause additive decreases in AV conduction and/or negative inotropic effects. In addition, concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and verapamil with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A4 and CYP2D6 substrate and verapamil is a moderate CYP3A4 inhibitor.
Viloxazine: (Moderate) Monitor for increased propafenone toxicity if coadministered with viloxazine; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Propafenone is a CYP3A and CYP2D6 substrate; viloxazine is a weak CYP3A4 and a weak CYP2D6 inhibitor.
Vincristine Liposomal: (Major) Propafenone inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
Vincristine: (Major) Propafenone inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
Voclosporin: (Major) Concomitant use of voclosporin and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with voclosporin is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Vonoprazan; Amoxicillin: (Moderate) Monitor for increased propafenone toxicity if coadministered with vonoprazan; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and vonoprazan with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate and vonoprazan is a weak CYP3A inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Concomitant use of propafenone and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Monitor for increased propafenone toxicity if coadministered with vonoprazan; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and vonoprazan with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate and vonoprazan is a weak CYP3A inhibitor.
Voriconazole: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as propafenone. Both drugs are associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a strong CYP3A4 inhibitor) with propafenone (a CYP3A4 substrate) may result in elevated propafenone plasma concentrations and an increased risk for adverse events, including QT prolongation. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Vorinostat: (Major) Concomitant use of vorinostat and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Voxelotor: (Moderate) Monitor for increased propafenone toxicity if coadministered with voxelotor; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and voxelotor with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate; voxelotor is a moderate CYP3A inhibitor.
Warfarin: (Major) Concomitant use of propafenone and warfarin results in a significant increase in warfarin plasma levels by 39%, with an increase in prothrombin time of about 25%. Warfarin dosages should be adjusted as needed to attain appropriate INR goals for the individual patient.
Zafirlukast: (Moderate) In vitro data indicate that zafirlukast inhibits CYP3A4 at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, especially those drugs, like propafenone, with narrow therapeutic ranges.
Ziprasidone: (Major) Concomitant use of ziprasidone and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.

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

Adults

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

Elderly

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

Adolescents

Safety and efficacy have not been established.

Children

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

Infants

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

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

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

Oral Route

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

Pregnancy

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