Propafenone - Rythmol/Rythmol SR

Question 1

Antiarrhythmic class

Answer 1

• Class IC

Question 2

Mechanism of action

Answer 2

• Membrane stabilizer • Prolongs conduction, primarily in His-Purkinje fibers and AV Node • ↑ diastolic excitability threshold and refractory period

Question 3

Indications

Answer 3

Rythmol • To prolong time to recurrence of paroxysmal AF or paroxysmal SVT in patients without structural heart disease and associated with disabling symptoms • To treat life-threatening, documented VA Rythmol SR • In patients with episodic (most likely paroxysmal or persistent) AF who do not have structural heart disease, prolongs time to recurrence of symptomatic AF

Question 4

Oral Dosing Strengths

Answer 4

Rythmol • 150 mg, 225 mg Rythmol SR • 225 mg, 325 mg, 425 mg

Question 5

Dosing

Answer 5

Rythmol • Individually titrated • Initially 150 mg TID • ↑ at 3 to 4-day intervals to 225 mg TID (max 300 mg TID) Rythmol SR • Initially 225 mg BID • ↑ at 5-day intervals to 325 mg BID (425 mg BID if needed) In patients with hepatic impairment or those with significant widening of the QRS complex or second- or third-degree AV block, consider reducing the dose.

Question 6

Treatment setting

Answer 6

Rythmol • Start in hospital facility Rythmol SR • Not addressed

Question 7

Monitoring requirements at initiation

Answer 7

• Evaluate ECG prior to and during therapy

Question 8

Pharmacokinetics

Answer 8

• Nonlinear • Large intersubject variability in blood levels necessitates careful dose titration for all patients

Question 9

Bioavailability/ absorption

Answer 9

• Presystemic biotransformation; dose-dependent bioavailability of 3.4% (150 mg) to 10.6% (300 mg) for immediate-release tablet • ↓ liver function ↑ bioavailability to 60%-70% (immediate release) • Bioavailability of 325 mg BID SR tablet approximates 150 mg TID immediate-release tablet • Steady state after 4-5 days

Question 10

Half-life

Answer 10

• 2–10 hours • 10–32 hours in slow metabolizers

Question 11

Protein binding

Answer 11

Rythmol • Not addressed Rythmol SR • >95% • ↓ to 88% with severe hepatic dysfunction

Question 12

Metabolism

Answer 12

• Extensive metabolism; first-pass hepatic metabolism CYP3A4, CYP1A2, CYP2D6 • Some patients (<10%) are slow metabolizers and 5-hydroxypropafenone is not formed

Question 13

Major active metabolite

Answer 13

• 2 active metabolites — N-depropylpropafenone (norpropafenone): similar Na and Ca activity as propafenone — 5-hydroxypropafenone: 10x less b-blocking activity as propafenone

Question 14

Route of elimination

Answer 14

• ~50% metabolites are renally excreted (immediate-release tablets); not known for SR

Question 15

Overdosage

Answer 15

• Symptoms: hypotension, somnolence, bradycardia, intraatrial, and intraventricular conduction disturbances, convulsions, VA • Treatment: IV diazepam, mechanical respiration, defibrillation, infusion of dopamine and isoproterenol, external cardiac massage

Question 16

Contraindications

Answer 16

• Heart failure • Cardiogenic shock • Sinoatrial, atrioventricular, and intraventricular disorders of impulse generation or conduction (e.g., sick sinus node syndrome, AV block) in the absence of an artificial pacemaker • Known Brugada Syndrome • Bradycardia • Marked hypotension • Bronchospastic disorders or severe obstructive pulmonary disease • Marked electrolyte imbalance

Question 17

Boxed Warning

Answer 17

• Mortality: As shown by results of CAST trial with flecainide, all Class IC AADs have significant mortality risk in patients with structural heart disease

Question 18

Warnings(except boxed warning—see above)

Answer 18

Warnings and Precautions • May cause new or worsened arrhythmias • May unmask Brugada or Brugada-like Syndrome • Avoid use with other drugs that prolong the QT interval • Avoid simultaneous use of propafenone with both a CYP450 2D6 inhibitor and a 3A4 inhibitor • May provoke overt heart failure • May cause dose-related first-degree AV block or other conduction disturbances • May affect artificial pacemakers • Agranulocytosis: Patients should report signs of infection • May exacerbate myasthenia gravis

Question 19

Precautions

Answer 19

See Warnings

Question 20

Drug interactions

Answer 20

• Drugs that inhibit CYP2D6 (desipramine, paroxetine, ritonavir, sertraline), CYP1A2 (amiodarone), and CYP3A4 (ketoconazole, ritonavir, saquinavir, erythromycin, and grapefruit juice) may affect propafenone exposure • Other drugs that may affect propafenone exposure: — Quinidine — Cimetidine — Rifampin — Fluoxetine • Other drugs that may be affected by propafenone: — Digoxin — b-blockers (propranolol, metoprolol) — Warfarin • Pharmacodynamic interactions: — Local anesthetics (lidocaine) — Orlistat — Amiodarone

Question 21

Adverse Reactions

Answer 21

Rythmol • Most common AEs in 474 SVT patients included unusual taste (14%), nausea/vomiting (11%), dizziness (9%), constipation (8%), headache (6%), fatigue (6%), blurred vision (3%), weakness (3%) • Some patients with atrial flutter have developed 1:1 conduction, producing an increase in ventricular rate Rythmol SR • Safety evaluated in patients given Rythmol SR BID 225 mg (n=126), 325 mg (n=135), 425 mg (n=136), placebo (n=126) for up to 39 weeks • Most common AEs (>5% and greater than placebo) were dizziness, palpitations, chest pain, dyspnea, taste disturbance, nausea, fatigue, anxiety, constipation, upper respiratory tract infection, edema, and influenza