Propafenone

Oral
Supraventricular arrhythmias, Ventricular arrhythmias

Oral
Atrial fibrillation

Pharmacogenomics:

Propafenone is primarily metabolised by CYP2D6 isoenzyme into 5-hydroxypropafenone and to a lesser extent by CYP3A4 and CYP1A2 isoenzymes into norpropafenone. CYP2D6 polymorphism may influence the plasma concentrations of propafenone.

Individuals with reduced CYP2D6 activity, known as CYP2D6 poor metabolisers, have slower propafenone metabolism as compared to those with normal CYP2D6 activity. Approximately 6% of Caucasians in the U.S. population are naturally deficient in CYP2D6 activity and other demographic groups are deficient to a somewhat lesser extent.

CYP2D6 genetic testing is currently available and may serve as a guide to help clinicians in prescribing propafenone.

CYP2D6 ultrarapid metabolisers (carriers of >2 normal function alleles e.g. CYP2D6*xN of *1, *2, *33, *35)
Decreased propafenone and 5-hydroxypropafenone plasma concentrations resulting in increased risk of reduced or loss of efficacy.
Monitor plasma concentrations, perform an ECG, or select an alternative antiarrhythmic agent that is not metabolised by CYP2D6 (e.g. sotalol, disopyramide, quinidine, amiodarone).

CYP2D6 intermediate metabolisers (carriers of 2 decreased function alleles, or 1 normal function allele and 1 no function allele, or 1 decreased function allele and 1 no function allele e.g. normal function alleles *1, *2, *33, *35; decreased function alleles *9, *10, *17, *29, *36, *41; no function alleles *3-*8, *11-*16, *19-*21, *38, *40, *42)
Increased propafenone and 5-hydroxypropafenone plasma concentrations resulting in increased risk of adverse effects.
Consider therapeutic drug monitoring to guide propafenone dosing, perform an ECG, or select an alternative antiarrhythmic agent that is not metabolised by CYP2D6 (e.g. sotalol, disopyramide, quinidine, amiodarone).

CYP2D6 poor metabolisers (carriers of 2 no function alleles e.g. CYP2D6*3, *4, *5, *6)
Increased propafenone and 5-hydroxypropafenone plasma concentrations resulting in increased risk of adverse effects.
Consider dose reduction, perform an ECG, and monitor plasma concentrations.

Dose reduction may be necessary.

Should be taken with food. Swallow whole, do not chew/crush.

Significant structural heart disease, MI within the last 3 months, uncontrolled CHF with LVEF below 35%, cardiogenic shock (unless arrhythmia-induced), severe symptomatic bradycardia, severe hypotension, known Brugada syndrome, marked electrolyte imbalance (e.g. K metabolism disorders, hypomagnesaemia), myasthenia gravis, bronchospastic disorders or severe obstructive pulmonary disease; sinus node dysfunction, atrial conduction defects, 2nd degree or greater atrioventricular (AV) block, bundle branch block or distal block in the absence of a pacemaker. Concomitant use with ritonavir.

Patients with pacemakers, mild to moderate obstructive airways disease (e.g. asthma). May potentially convert paroxysmal atrial fibrillation to atrial flutter with 2:1 or 1:1 conduction block. Renal and hepatic impairment. Elderly. Pregnancy and lactation. CYP2D6 ultrarapid, intermediate, and poor metabolisers.

Significant: Cardiac conduction disorder (e.g. slows AV conduction), CNS effects (e.g. dizziness, blurred vision, fatigue), agranulocytosis, elevated antinuclear antibody (ANA) titre, hepatic abnormalities, fulminant hepatitis.
Blood and lymphatic system disorders: Thrombocytopenia, leucopenia, granulocytopenia.
Cardiac disorders: Palpitations, bradycardia, tachycardia.
Gastrointestinal disorders: Nausea, vomiting, dry mouth, dysgeusia, constipation, diarrhoea, abdominal pain, flatulence.
General disorders and administration site conditions: Asthenia, chest pain, pyrexia.
Hepatobiliary disorders: Abnormal hepatic function, jaundice.
Metabolism and nutrition disorders: Decreased appetite.
Musculoskeletal and connective tissue disorders: Lupus-like syndrome.
Nervous system disorders: Headache, paraesthesia, syncope, convulsion.
Psychiatric disorders: Anxiety, sleep disorders, nightmare.
Reproductive system and breast disorders: Erectile dysfunction.
Respiratory, thoracic and mediastinal disorders: Dyspnoea.
Skin and subcutaneous tissue disorders: Rash, pruritus, erythema, urticaria.
Vascular disorders: Hypotension, orthostatic hypotension.
Potentially Fatal: Proarrhythmic effects (e.g. ventricular fibrillation, ventricular tachycardia, asystole, torsade de pointes).

PO: C

This drug may cause dizziness, blurred vision, fatigue, or postural hypotension, if affected, do not drive or operate machinery.

Closely monitor ECG, blood pressure, and pulse at treatment initiation. Monitor vital signs, pacemaker function, and ANA titre.

Symptoms: Myocardial effects: PQ prolongation, QRS widening, suppression of sinus node automaticity, AV block, ventricular tachycardia, flutter or fibrillation, and hypotension which can lead to CV shock. Non-cardiac effects: Headache, dizziness, blurred vision, tremor, dry mouth, nausea, constipation. In severe cases, clonic-tonic convulsions, paraesthesia, somnolence, coma, respiratory arrest may occur. Management: Symptomatic and supportive treatment. Defibrillation, as well as administration of dopamine or isoproterenol infusion to control rhythm and blood pressure. Administer IV diazepam to alleviate convulsions. May consider mechanical respiratory assistance and external cardiac massage.

Increased plasma levels with CYP2D6, CYP3A4 and CYP1A2 inhibitors (e.g. fluoxetine, paroxetine, sertraline, quinidine; ketoconazole, cimetidine, erythromycin, saquinavir, amiodarone, nicotine). Increased risk of adverse effects of lidocaine. Increased risk of conduction and repolarisation abnormalities with amiodarone. May reduce plasma levels with CYP3A4 inducers (e.g. phenobarbital, rifampicin). Increased risk of arrhythmia when used with antiarrhythmics/arrhythmogenic drugs. Increased plasma concentrations of oral anticoagulants (e.g. warfarin, phenprocoumon), propranolol, metoprolol, desipramine, ciclosporin, theophylline, digoxin, venlafaxine. Absorption may be reduced by orlistat.
Potentially Fatal: Increased plasma concentrations with ritonavir.

Increased plasma levels with grapefruit or grapefruit juice. May increase plasma levels and bioavailability with food (single dose).

Description:
Mechanism of Action: Propafenone is a class 1C antiarrhythmic drug with local anaesthetic effects and direct stabilising activity on myocardial membranes. It inhibits the fast inward Na current and slows the rate of increase of the action potential. Propafenone prolongs the conduction and refractoriness in all areas of the myocardium (with slightly more pronounced activity on intraventricular conduction). It prolongs the effective refractory period, reduces spontaneous automaticity, and exhibits some β-blockade action.
Pharmacokinetics:
Absorption: Readily and almost completely absorbed from the gastrointestinal tract. Bioavailability: Dose and dosage form dependent. Time to peak plasma concentration: 3.5 hours (immediate release); 3-8 hours (extended release).
Distribution: Crosses placenta and enters breast milk. Volume of distribution: 252 L. Plasma protein binding: >95%, mainly to α₁-acid glycoprotein.
Metabolism: Extensively metabolised in the liver mainly by CYP2D6 isoenzyme into 5-hydroxypropafenone, and to a lesser extent by CYP1A2 and CYP3A4 isoenzymes into N-depropylpropafenone (norpropafenone), then to glucuronide or sulfate conjugates.
Excretion: Via urine (<1% as unchanged drug, remainder as glucuronide or sulfate conjugates); faeces. Elimination half-life: 2-10 hours (extensive metabolisers); 10-32 hours (poor metabolisers).

Source: National Center for Biotechnology Information. PubChem Database. Propafenone, CID=4932, https://pubchem.ncbi.nlm.nih.gov/compound/Propafenone (accessed on Jan. 23, 2020)

Store at 25°C.

Thuốc tim

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