Propafenone


Thông tin thuốc gốc
Chỉ định và Liều dùng
Oral
Supraventricular arrhythmias, Ventricular arrhythmias
Adult: For prophylaxis and treatment of ventricular arrhythmias, paroxysmal supraventricular tachyarrhythmias including paroxysmal atrial flutter or fibrillation and paroxysmal re-entrant tachycardias involving AV node or accessory pathway, where standard treatment is ineffective or contraindicated: As immediate-release tab: Initially, 150 mg tid, may be increased to 300 mg bid at intervals of at least 3-4 days if necessary. Max: 300 mg tid. For patients <70 kg: Reduction of total daily dose is recommended. Individualise dosing according to ECG monitoring and blood pressure control. If the QRS interval is prolonged by >20%, consider a dose reduction or discontinuation until the ECG returns to normal limits.
Elderly: Dose reduction is recommended.

Oral
Atrial fibrillation
Adult: For preventing the recurrence in patients with episodic (paroxysmal or persistent) cases who do not have structural heart disease: As extended-release/sustained-release cap: Initially, 225 mg 12 hourly, may be increased up to 325-425 mg 12 hourly at intervals of at least 5 days according to individual response and tolerance.
Special Patient Group
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.
Hepatic Impairment
Dose reduction may be necessary.
Cách dùng
Should be taken with food. Swallow whole, do not chew/crush.
Chống chỉ định
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.
Thận trọng
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.
Phản ứng phụ
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).
Thông tin tư vấn bệnh nhân
This drug may cause dizziness, blurred vision, fatigue, or postural hypotension, if affected, do not drive or operate machinery.
MonitoringParameters
Closely monitor ECG, blood pressure, and pulse at treatment initiation. Monitor vital signs, pacemaker function, and ANA titre.
Quá liều
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.
Tương tác
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.
Food Interaction
Increased plasma levels with grapefruit or grapefruit juice. May increase plasma levels and bioavailability with food (single dose).
Tác dụng
Description: 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).
Đặc tính

Chemical Structure Image
Propafenone

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

Bảo quản
Store at 25°C.
Phân loại MIMS
References
Dean L. Propafenone Therapy and CYP2D6 Genotype. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US). 2017 Apr. Accessed 09/10/2019. PMID: 28520383

Annotation of DPWG Guideline for Propafenone and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 09/10/2019.

Annotation of FDA Label for Propafenone and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 09/10/2019.

Annotation of HCSC Label for Propafenone and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 09/10/2019.

Anon. Propafenone. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 09/10/2019.

Buckingham R (ed). Propafenone Hydrochloride. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/10/2019.

Joint Formulary Committee. Propafenone Hydrochloride. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/10/2019.

Rythmol SR - Capsule, Extended Release (GlaxoSmithKline LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 09/10/2019.

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  • Rythmol
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