Prpms-PROPAFENONE (propafenone hydrochloride) Film-coated 150 mg and 300 mg tablets
Antiarrhythmic Agent
propafenone is an antiarrhythmic agent which possesses class 1C properties in the modified electrophysiological classification of Vaughan-Williams. Propafenone has a direct stabilizing action on myocardial cell membranes. The electrophysiological effect of propafenone manifests itself as a reduction of the upstroke velocity (Phase 0) of the monophasic action potential, while phase 4 spontaneous automaticity is depressed. Diastolic excitability threshold is increased and effective refractory period prolonged. In Purkinje fibers, and to a lesser extent myocardial fibers, propafenone reduces the fast inward sodium current. In addition to a local anesthetic effect, approximately equal to procaine, propafenone has weak beta-blocking activity. Clinical trials employing isoproterenol challenge and exercise testing suggest that the affinity of propafenone for beta-adrenergic receptors, as calculated from dose ratios and drug concentrations, is about 1/40 that of propranolol. Propafenone also inhibits the slow calcium influx at high concentrations, however, this action is weak (approximately 1/100 of verapamil) and does not contribute to its antiarrhythmic effect.
Electrophysiology studies have shown that propafenone prolongs atrioventricular conduction and in some instances significantly lengthens sinus nodal recovery times with a non-significant effect on sinus cycle length. Both atrioventricular (AV) nodal conduction time (AH interval) and His- Purkinje conduction time (HV interval) are prolonged. Propafenone increases atrial, AV nodal and ventricular effective refractory periods. Propafenone causes a dose-dependent increase in the PR interval and QRS complex duration. Non-significant increases in the QTc interval and occasional slowing of the heart rate have also been observed.
Propafenone can exert a negative inotropic effect on the myocardium. Increases in pulmonary capillary wedge pressure and systemic and pulmonary vascular resistance, with a concurrent mild depression of cardiac output and cardiac index, have occurred following propafenone hydrochloride administration. Decreases in left ventricular function have been recorded in patients with depressed baseline function.
Due to a genetically determined presence or deficiency of one metabolizing pathway (CYP2D6), patients may be categorized into fast (over 90% of all patients) or slow metabolizers of propafenone, resulting in low or high plasma concentrations respectively. Following oral administration in fast metabolizers, propafenone hydrochloride is nearly completely absorbed and undergoes extensive first-pass hepatic metabolism resulting in a dose-dependent absolute bioavailability ranging from 3 to 40%. Peak plasma concentrations occur within 3 hours. For fast metabolizers of propafenone, the elimination t1/2 is 5.5 +- 2.1 hours; for slow metabolizers, the elimination t1/2 is 17.2 +- 8.0 hours. In fast metabolizers, there is a non-linear increase in drug plasma concentration and bioavailability with increase in dosage, presumably due to saturation of first pass hepatic metabolism. This departure from dose linearity occurs when single doses above 150 mg are given. A 300 mg dose gives plasma levels six times that of a 150 mg dose. Similarly, for a 3-fold increase in daily dose from 300 to 900 mg/day there is a 10-fold increase in steady-state plasma concentration. In slow metabolizers, as opposed to fast metabolizers, a linear relationship between propafenone hydrochloride dose and plasma concentration was observed. In fast metabolizers, propafenone undergoes extensive hepatic metabolism with <1% excreted as unchanged drug. The major active metabolites are: 5-hydroxypropafenone (5-OHP) which is formed by CYP2D6 and N-depropylpropafenone (NDPP) which is formed by CYP3A4 and CYP1A2; both metabolites occurring in concentrations less than 20% of the parent compound. In vitro preparations and animal studies have shown that the 5-OHP metabolite possesses antiarrhythmic and beta-adrenoreceptor blocking activity comparable to propafenone. Slow metabolizers had higher propafenone plasma concentrations which they required for suppression of arrhythmia since they did not produce the active metabolite 5-OHP. These higher propafenone plasma concentrations may lead to clinically evident beta-blockade. Despite these differences in pharmacokinetics, steady-state conditions are achieved after 3 to 4 days in all patients. Therapeutic plasma levels of propafenone appear to be in the range of 0.5 to 2.0 ug/mL. Propafenone is 97% bound to plasma proteins. Bioavailability is enhanced by administration of the drug with food.
No antiarrhythmic drug has been shown to reduce the incidence of sudden death in patients with asymptomatic ventricular arrhythmias. Most antiarrhythmic drugs have the potential to cause dangerous arrhythmias; some have been shown to be associated with an increased incidence of sudden death. In light of the above, physicians should carefully consider the risks and benefits of antiarrhythmic therapy for all patients with ventricular arrhythmias. pms-PROPAFENONE (propafenone hydrochloride) is indicated for the treatment of documented life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia. Propafenone hydrochloride may also be used for the treatment of patients with documented symptomatic ventricular arrhythmias when the symptoms are of sufficient severity to require treatment. Because of the proarrhythmic effects of propafenone hydrochloride, its use should be reserved for patients in whom, in the opinion of the physician, the benefit of treatment clearly outweighs the risks. For patients with sustained ventricular tachycardia, propafenone hydrochloride therapy should be initiated in the hospital. Initiation in hospital may also be required for certain other patients depending on their cardiac status and underlying cardiac disease. The effects of propafenone hydrochloride in patients with recent myocardial infarction have not been adequately studied and, therefore, its use in this condition cannot be recommended. There is no evidence from controlled clinical trials that the use of propafenone hydrochloride favourably affects survival or the incidence of sudden death.
Propafenone is contraindicated in the presence of the following:
severe or uncontrolled congestive heart failure (see WARNINGS)
cardiogenic shock
sinoatrial, atrioventricular and intraventricular disorders of impulse conduction and sinus node dysfunction (e.g. sick sinus syndrome) in the absence of an artificial pacemaker
severe bradycardia (less than 50 beats/min)
marked hypotension
bronchospastic disorders
severe disorders of electrolyte balance
severe hepatic failure (see PRECAUTIONS)
known hypersensitivity to the drug
The results of the Cardiac Arrhythmia Suppression Trials (CAST) in post-myocardial infarction patients with asymptomatic ventricular arrhythmias showed a significant increase in mortality and in the non-fatal cardiac arrest rate in patients treated with flecainide or encainide compared with a matched placebo-treated group. CAST was continued using a revised protocol with the moricizine and placebo arms only. The trial was prematurely terminated because of a trend towards an increase in mortality in the moricizine treated group. The applicability of these results to other populations or other antiarrhythmic agents is uncertain, but at present it is prudent to consider these results when using any antiarrhythmic agent in patients with structural heart disease.
Propafenone may cause new or worsen existing arrhythmias. Such proarrhythmic effects range from an increase in frequency of PVCs to the development of more severe ventricular tachycardia, ventricular fibrillation or torsade de pointes. It is therefore essential that each patient administered propafenone hydrochloride be evaluated clinically and electrocardiographically prior to, and during therapy to determine whether the response to propafenone supports continued treatment. Overall in clinical trials with propafenone hydrochloride, 4.7% of all patients had new or worsened ventricular arrhythmia possibly representing a proarrhythmic event (0.7% was an increase in PVCs, 4.0% a worsening, or new appearance, of VT or VF). Of the patients who had worsening of VT (4%), 92% had a history of VT and/or VT/VF, 71% had coronary artery disease, and 68% had a prior myocardial infarction. The incidence of proarrhythmia in patients with less serious or benign arrhythmias which include patients with an increase in frequency of PVCs, was 1.6%. Although most proarrhythmic events occurred during the first week of therapy, late events also were seen and the CAST study (see above) suggests that a risk is present throughout treatment.
During treatment with oral propafenone hydrochloride in patients with depressed baseline function (mean EF=33.5%), no significant decreases in ejection fraction were seen. In clinical trial experience, new or worsened congestive heart failure (CHF) has been reported in 3.7% of patients; of those 0.9% were considered probably or definitely related to propafenone hydrochloride. Of the patients with CHF probably related to propafenone hydrochloride, 80% had preexisting heart failure and 85% had coronary artery disease. CHF attributable to propafenone hydrochloride developed rarely (<0.2%) in patients who had no previous history of CHF. Propafenone exerts both beta blockade and a dose related direct negative inotropic effect on myocardium. Therefore, propafenone hydrochloride should not be prescribed in patients with uncontrolled congestive heart failure where left ventricular output is less than 35%. Caution should be exercised when using propafenone hydrochloride in patients with minimal cardiac reserve or in those who are receiving other drugs with negative inotropic potential.
Propafenone slows cardiac conduction which may result in a dose-related prolongation of PR interval and QRS complex, development of first or higher degree AV block, bundle branch block and intraventricular conduction delay (see ADVERSE REACTIONS). Therefore, development of signs of increasing depression of cardiac conductivity during propafenone hydrochloride therapy requires a reduction in dosage or a discontinuation of propafenone hydrochloride unless the ventricular rate is adequately controlled by a pacemaker.
Agranulocytosis has been reported infrequently in patients taking propafenone hydrochloride. The onset is generally within 4 to 6 weeks and presenting symptoms have included fever, fatigue, and malaise. Agranulocytosis occurs in less than 0.1% of patients taking propafenone hydrochloride. Patients should be instructed to immediately report fever, fatigue, malaise or any signs of infection, especially in the first three months of therapy. Prompt discontinuation of propafenone hydrochloride therapy is recommended when a decreased white blood cell count or other signs and symptoms warrant consideration of agranulocytosis/granulocytopenia. Cessation of propafenone hydrochloride therapy is usually followed by recovery of blood counts within two weeks.
(e.g. chronic bronchitis, emphysema)
Patients with bronchospastic disease should, in general, not receive propafenone hydrochloride or other agents with beta-adrenergic blocking activity (see CONTRAINDICATIONS).
Patients with permanent pacemakers should have their existing thresholds re-evaluated after initiation of or change in Propafenone therapy because of a possible increase in endocardial stimulation threshold.
Since propafenone is highly metabolized by the liver it should be administered cautiously to patients with impaired hepatic function (see
). Administration of propafenone hydrochloride to these patients results in an increase in bioavailability to approximately 70% compared to 3 to 40% for patients with normal liver function, prolongation of the half life, a decrease in the systemic clearance, and a reduction in the serum protein binding of the drug. As a result, the dose of propafenone hydrochloride given to patients with impaired hepatic function should be reduced (see
). It is important to monitor electrocardiographic intervals for signs of excessive pharmacological effects (see
) and/or adverse reactions, until an individualized dosage regimen has been determined.
To date there is no experience with use of oral propafenone hydrochloride in patients with impaired renal function. Since a considerable percentage of propafenone metabolites are excreted in the urine (18.5 to 38% of the dose/48 hrs), propafenone hydrochloride should be used cautiously in patients with renal impairment and only after consideration of the benefit/risk ratio. These patients should be carefully monitored for signs of toxicity (see
). The dose in these patients has not been determined.
Exacerbation of myasthenia gravis has been reported during propafenone hydrochloride therapy.
In long term studies positive antinuclear antibody (ANA) titres have been reported in 21% of patients receiving propafenone hydrochloride. However, it is impossible to determine what exact percentage of patients had a new positive ANA titre as a result of propafenone hydrochloride therapy. This laboratory finding has not been associated with clinical symptoms. One case of Lupus-like syndrome has been reported which resolved upon discontinuation of therapy. Laboratory evaluation for antinuclear antibodies should be performed initially and at regular intervals. It is recommended that patients in whom an abnormal ANA test has occurred be evaluated regularly. If worsening elevation of ANA titres or clinical symptoms are detected, propafenone hydrochloride should be discontinued.
Clinical evaluation of spermatogenesis was undertaken in 11 normal subjects, given oral propafenone hydrochloride 300 mg b.i.d. for 4 days which was then increased to 300 mg t.i.d. for an additional 4 days. Patients were followed for 128 days post-treatment and demonstrated a 28% reduction in semen sample volume following the last dose (day 8) and a 27% reduction in sperm count, on day 72. FSH and testosterone levels were also slightly decreased. Neither the decrease in sperm count nor the decrease in sample volume were sustained beyond the single visit in which they occurred, and both values remained within the laboratories normal reference range. Reduced spermatogenesis was also observed in animal experiments. The significance of these findings is uncertain.
A slight increase in the incidence of dizziness was observed in elderly patients. Because of the possible increased risk of impaired hepatic or renal function in this age group, propafenone hydrochloride should be used with caution. The effective dose may be lower in these patients.
The use of propafenone hydrochloride in children is not recommended, since safety and efficacy have not been established.
Propafenone has been shown to be embryotoxic in the rat when given in doses of 600 mg/kg (about 6 times the maximum recommended human dose on a mg/m2 basis) and in the rabbit when given in doses of 150 mg/kg (about 3 times the maximum recommended human dose on a mg/m2 basis). In a perinatal and postnatal study in rats, propafenone produced dose-dependent increases in maternal and neonatal mortality, decreased maternal and pup body weight gain and reduced neonatal physiological development. There are no adequate and well controlled studies in pregnant women. Propafenone hydrochloride should be used during pregnancy only when the potential benefit outweighs the risk to the fetus. Propafenone is known to pass the placental barrier in humans. The concentration of propafenone in the umbilical cord has been reported to be about 30% of that in the maternal blood.
It is not known whether the use of propafenone hydrochloride during labour or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labour or increases the need for forceps delivery or other obstetrical intervention.
Propafenone and 5-hydroxypropafenone are excreted in human milk. Because of possible serious adverse reactions in nursing infants, an alternative method of infant feeding should be considered when the use of propafenone hydrochloride is considered essential.
Drugs that inhibit CYP2D6 (for example, quinidine), CYP1A2 (for example, cimetidine) and CYP3A4 (for example, ketoconazole, cimetidine, erythromycin and grapefruit juice) might lead to increased plasma levels of propafenone. When propafenone hydrochloride is administered with inhibitors of these enzymes, the patients should be closely monitored and the dose adjusted accordingly. Coadministration of propafenone hydrochloride with drugs metabolized by CYP2D6 (such as venlafaxine) might lead to increased levels of these drugs and/or of propafenone.
Digitalis
: Propafenone has been shown to produce dose-related increases in serum digoxin levels ranging from approximately 35% at 450 mg/day to 85% at 900 mg/day of propafenone without affecting digoxin renal clearance. Elevations of digoxin levels were maintained for up to 16 months during concomitant administration. Plasma digoxin levels of patients on concomitant therapy should be measured, and digoxin dosage should ordinarily be reduced when propafenone hydrochloride is started, especially if a relatively large digoxin dose is used or if plasma concentrations are relatively high.
$-Antagonists
: In a study involving healthy subjects, concomitant administration of propafenone hydrochloride and propranolol resulted in substantial increases in propranolol plasma concentration and elimination t1/2 with no change in propafenone plasma levels from control values. Similar observations have been reported with metoprolol. Propafenone appears to inhibit the hydroxylation pathway for the two beta-antagonists (just as quinidine inhibits propafenone metabolism). Increased plasma concentrations of metoprolol could overcome its relative cardioselectivity. In propafenone hydrochloride clinical trials, patients who were receiving beta-
blockers concurrently did not experience an increased incidence of side effects. While the therapeutic range for beta-blockers is wide, a reduction in dosage may be necessary during concomitant administration with propafenone hydrochloride.
Anticoagulants
: In a study of eight healthy subjects receiving propafenone hydrochloride and concomitant warfarin, mean steady-state warfarin plasma concentrations increased 39% with a corresponding prolongation in prothrombin times of approximately 25%. It is therefore recommended that in patients treated with propafenone hydrochloride and anticoagulants (e.g. warfarin, acenocoumarol) concomitantly, prothrombin time should be carefully monitored and the dose of anticoagulant adjusted as necessary.
Cimetidine
: Concomitant administration of propafenone hydrochloride tablets and cimetidine resulted in a 20% increase in steady-state plasma concentrations of propafenone with no detectable changes in electrocardiographic parameters beyond that measured on propafenone hydrochloride alone. Therefore, patients should be carefully monitored and the dose of propafenone hydrochloride adjusted when appropriate.
Lidocaine:
No clinically significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in healthy volunteers. However, the concomitant use of propafenone hydrochloride and intravenous lidocaine has been reported to increase the frequency and severity of central nervous system side effects of lidocaine. Therefore, the combination of propafenone hydrochloride and lidocaine should be used with caution.
Desipramine
: Concomitant administration of propafenone hydrochloride and desipramine may result in elevated serum desipramine levels. Both desipramine, a tricyclic antidepressant, and propafenone are cleared by oxidative pathways of demethylation and hydroxylation carried out by the hepatic P-450 cytochrome.
Cyclosporin:
Propafenone hydrochloride therapy may increase levels of cyclosporin.
Theophylline
: Propafenone hydrochloride may increase theophylline concentration during concomitant therapy with the development of theophylline toxicity.
Rifampin
: Rifampin may accelerate the metabolism and decrease the plasma levels and antiarrhythmic efficacy of propafenone.
Ritonavir,
Lopinavir/ritonavir
: Due to the potential for increased plasma concentrations, co-administration of 800-1200 mg/day doses of ritonavir and propafenone hydrochloride is contraindicated.
Furthermore, based on results of a desipramine interaction study, lopinavir/ritonavir does not inhibit CYP2D6-mediated metabolism at clinically relevant concentrations. However, caution should be used when co- administering propafenone with any ritonavir-boosted protease inhibitors.
Amiodarone
: Combination therapy of amiodarone and propafenone hydrochloride can affect conduction and repolarization and lead to abnormalities that have the potential to
be proarrhythmic. Dose adjustments of both compounds based on therapeutic response may be required.
Phenobarbital
: Phenobarbital is a known inducer of CYP3A4. Response to propafenone hydrochloride therapy should be monitored during concomitant chronic phenobarbital use.
Fluoxetine, Paroxetine and Fluvoxamine: Concomitant administration of propafenone hydrochloride and fluoxetine in extensive metabolizers increased the S propafenone Cmax and AUC by 39 and 50% and the R propafenone Cmax and AUC by 71 and 50%. Elevated levels of plasma propafenone may occur when propafenone hydrochloride is used concomitantly with paroxetine. Lower doses of propafenone may be sufficient to achieve the desired therapeutic response. In poor metabolizers, concomitant administration of propafenone hydrochloride and fluvoxamine may require a dose reduction of propafenone.
In 2127 patients treated with Propafenone (propafenone hydrochloride) in North American controlled and open clinical trials, the most common adverse reactions reported were dizziness (12.5%), nausea and/or vomiting (10.7%), unusual taste (8.8%) and constipation (7.2%). The adverse effects judged to be most severe were aggravation or induction of arrhythmia (4.7%), congestive heart failure (3.7%) and ventricular tachycardia (3.4%). The incidences for these three adverse reactions in patients with a previous history of myocardial infarction (MI) were 6.9%, 5.3% and 5.5%, while in patients without a history of MI the incidences were 3.0%, 2.4% and 1.8%, respectively. Approximately 20% of patients had propafenone hydrochloride discontinued due to adverse reactions. Adverse reactions were dose related and occurred most frequently during the first month of therapy. The adverse events listed in Table 1 were observed in greater than one percent of patients.
| Table 1 Adverse Events Observed in Greater than 1% of Patients Treated with Propafenone Tablets | |||||
| Incidence by Total Daily Dose | Overall Incidence at Any Dose (N=2127) | % of Patients who Discontinued | |||
| 450 mg | 600 mg | 900 mg | |||
| CARDIOVASCULAR SYSTEM | |||||
| Dyspnea | 2.2% | 2.3% | 3.6% | 5.3% | 1.6% |
| Proarrhythmia | 2.0 | 2.1 | 2.9 | 4.7 | 4.7 |
| Angina | 1.7 | 2.1 | 3.2 | 4.6 | 0.5 |
| Congestive Heart Failure | 0.8 | 2.2 | 2.6 | 3.7 | 1.4 |
| Ventricular Tachycardia | 1.4 | 1.6 | 2.9 | 3.4 | 1.2 |
| Palpitations | 0.6 | 1.6 | 2.6 | 3.4 | 0.5 |
| First Degree AV Block | 0.8 | 1.2 | 2.1 | 2.5 | 0.3 |
| Syncope | 0.8 | 1.3 | 1.4 | 2.2 | 0.7 |
| QRS Duration, Increased | 0.5 | 0.9 | 1.7 | 1.9 | 0.5 |
| Bradycardia | 0.5 | 0.8 | 1.1 | 1.5 | 0.5 |
| PVC's | 0.6 | 0.6 | 1.1 | 1.5 | 0.1 |
| Edema | 0.6 | 0.4 | 1.0 | 1.4 | 0.2 |
| Bundle Branch Block | 0.3 | 0.7 | 1.0 | 1.2 | 0.5 |
| Atrial Fibrillation | 0.7 | 0.7 | 0.5 | 1.2 | 0.4 |
| Intraventricular Conduction Delay | 0.2 | 0.7 | 0.9 | 1.1 | 0.1 |
| Hypotension | 0.1 | 0.5 | 1.0 | 1.1 | 0.4 |
| CENTRAL NERVOUS SYSTEM | |||||
| Dizziness | 3.6% | 6.6% | 11.0% | 12.5% | 2.4% |
| Headaches | 1.5 | 2.5 | 2.8 | 4.5 | 1.0 |
| Blurred Vision | 0.6 | 2.4 | 3.1 | 3.8 | 0.8 |
| Ataxia | 0.3 | 0.6 | 1.5 | 1.6 | 0.2 |
| Insomnia | 0.3 | 1.3 | 0.7 | 1.5 | 0.3 |
| Tremor(s) | 0.3 | 0.8 | 1.1 | 1.4 | 0.3 |
| Drowsiness | 0.6 | 0.5 | 0.7 | 1.2 | 0.2 |
| Incidence by Total Daily Dose | Overall Incidence at Any Dose (N=2127) | % of Patients who Discontinued | |||
| 450 mg | 600 mg | 900 mg | |||
| GASTROINTESTINAL SYSTEM | |||||
| Nausea and/or Vomiting | 2.4% | 6.1% | 8.9% | 10.7% | 3.4% |
| Unusual Taste | 2.5 | 4.9 | 6.3 | 8.8 | 0.7 |
| Constipation | 2.0 | 4.1 | 5.3 | 7.2 | 0.5 |
| Dyspepsia | 1.3 | 1.7 | 2.5 | 3.4 | 0.9 |
| Diarrhea | 0.5 | 1.6 | 1.7 | 2.5 | 0.6 |
| Dry Mouth | 0.9 | 1.0 | 1.4 | 2.4 | 0.2 |
| Anorexia | 0.5 | 0.7 | 1.6 | 1.7 | 0.4 |
| Abdominal Pain/Cramping | 0.8 | 0.9 | 1.1 | 1.7 | 0.4 |
| Flatulence | 0.3 | 0.7 | 0.9 | 1.2 | 0.1 |
| OTHER | |||||
| Fatigue | 1.8% | 2.8% | 4.1% | 6.0% | 1.0% |
| Rash | 0.6 | 1.4 | 1.9 | 2.6 | 0.8 |
| Weakness | 0.6 | 1.6 | 1.7 | 2.4 | 0.7 |
| Atypical Chest Pain | 0.5 | 0.7 | 1.4 | 1.8 | 0.2 |
| Anxiety | 0.7 | 0.5 | 0.9 | 1.5 | 0.6 |
| Diaphoresis | 0.6 | 0.4 | 1.1 | 1.4 | 0.3 |
| Pain, Joints | 0.2 | 0.4 | 0.9 | 1.0 | 0.1 |
In addition, the following adverse reactions were reported less frequently than 1% either in clinical trials or in marketing experience (adverse events from marketing experience are given in italics). Causality and relationship to propafenone hydrochloride therapy cannot necessarily be judged from these events.
Cardiovascular
System: Atrial flutter, AV dissociation, cardiac arrest, flushing, hot flashes, sick sinus syndrome, sinus pause or arrest, supraventricular tachycardia, Torsades de Pointes, ventricular fibrillation.
Gastrointestinal
System
: A number of patients with liver abnormalities associated with propafenone hydrochloride therapy have been reported in foreign post-marketing experience. Some appeared due to hepatocellular injury, some were cholestatic and some showed a mixed picture. Some of these reports were simply discovered through clinical chemistries, others because of clinical symptoms. One case was rechallenged with a positive outcome.
Cholestasis (0.1%), elevated liver enzymes (alkaline phosphatase, serum transaminases) (0.2%), gastroenteritis, hepatitis (0.03%), jaundice. General Disorders: Chest pain. Hematologic: Agranulocytosis (see WARNINGS), anemia, bruising, granulocytopenia, increased bleeding time, leukopenia, purpura, thrombocytopenia. Immune System: Allergic reactions. Nervous System: Abnormal dreams, abnormal speech, abnormal vision, apnea, coma, confusion, depression, memory loss, numbness, paresthesias, psychosis/mania, seizures (0.3%), tinnitus, unusual smell sensation, vertigo.
Skin and Subcutaneous Tissue: Urticaria. Other: Alopecia, eye irritation, hyponatremia/inappropriate ADH secretion, impotence, increased glucose, kidney failure, positive ANA (0.7%), Lupus erythematosis, muscle cramps, muscle weakness, nephrotic syndrome, pain, pruritus.
Post-Market Adverse Drug Reactions
There have been post-marketing reports of patients experiencing conversion of paroxysmal atrial fibrillation to atrial flutter with accompanying 2:1 or 1:1 conduction block. However, the clinical significance has not been established.
The symptoms of overdose may include hypotension, somnolence, convulsions, bradycardia, conduction disturbances, ventricular tachycardia and/or ventricular fibrillation. Death may occur. If ingestion is recent perform gastric lavage or induce emesis. Supportive measures such as mechanical respiratory assistance and cardiac massage may be necessary. Defibrillation and the use of a temporary pacemaker, as well as infusion of isoproterenol and dopamine have been effective in controlling cardiac rhythm and blood pressure. Convulsions have been alleviated with intravenous diazepam. Detoxification measures such as forced diuresis, hemoperfusion and hemodialysis have not proven useful.
The dose of pms-PROPAFENONE (propafenone hydrochloride) must be individually determined on the basis of patient's response and tolerance. The usefulness of monitoring plasma levels for optimization of therapy has not been established. The recommended dose titration regimen can be used for both fast and slow metabolizers (see CLINICAL PHARMACOLOGY). The initial dose of propafenone hydrochloride is 150 mg given every 8 hours (450 mg/day). Dosage may be increased at 3 to 4 day intervals to 300 mg every 12 hours (600 mg/day). Should a further increase in dosage be necessary a maximum dose of 300 mg every 8 hours (900 mg/day) may be given. In those patients in whom widening of the QRS complex (>0.12 sec) or prolongation of PR interval (>0.24 sec) occurs, the dosage of propafenone hydrochloride should be reduced. Administration of propafenone hydrochloride with food is recommended. In patients with mild to moderate hepatic insufficiency (see PRECAUTIONS) propafenone hydrochloride therapy should be initiated with 150 mg given once (150 mg/day) daily. The dosage may be increased at a minimum of 4 day intervals to 150 mg twice (300 mg/day) daily then to 150 mg every 8 hours (450 mg/day) and, if necessary, to 300 mg every 12 hours (600 mg/day). There is no information on dosing with propafenone hydrochloride in patients with renal impairment. Propafenone hydrochloride should be used cautiously in these patients and only after consideration of the benefit/risk ratio. These patients should be carefully monitored for signs of toxicity. Lower doses may be required (see PRECAUTIONS). In elderly patients the effective dose of propafenone hydrochloride may be lower (see PRECAUTIONS). There is no information on the appropriate regimen for the transfer from lidocaine to propafenone hydrochloride.
pms-PROPAFENONE
Propafenone hydrochloride
2'-(2-hydroxy-3-propylaminopropoxy)-3-phenylpropriophenone
hydrochloride
:
Molecular weight: 377.92 Molecular formula: - C21H27N03!HCl
:
Propafenone hydrochloride occurs as colourless crystals or white crystalline powder with a very bitter taste. It has a pKa of 8.8 +- 0.3 and is slightly soluble in water (20degC), sparingly soluble in hot water, hot chloroform and methanol and is practically insoluble in ethanol and acetone. Propafenone hydrochloride has a pH of 5.2 to 6.2 (0.5% m/v in water) and has a melting point of 172.0 to 174.0degC.
:
Each pms-PROPAFENONE (propafenone hydrochloride) tablet contains 150 mg or 300 mg propafenone hydrochloride; croscarmellose sodium Ph. Eur. ; hydroxypropyl methylcellulose, Ph. Eur. ; magnesium stearate Ph. Eur. ; maize starch Ph. Eur. ; microcrystalline cellulose, Ph. Eur. ; polyethylene glycol 400 and 6000, Ph. Eur. ; titanium dioxide Ph. Eur.
Store propafenone hydrochloride at controlled room temperature, between 15 to 25degC.
pms-PROPAFENONE(propafenone hydrochloride) is available in bottles of 100 tablets. Each white, biconvex, film-coated propafenone hydrochloride 150 mg tablet embossed with <150' over a triangle of arched sides on one side contains 150 mg propafenone hydrochloride. Each white, biconvex, film-coated propafenone hydrochloride 300 mg tablet embossed with a score on both sides with a triangle of arched sides above and <300' below the score on one side contains 300 mg propafenone hydrochloride. Do not use beyond the expiry date indicated on the label.
The antiarrhythmic effect of propafenone has been demonstrated in a number of different animal models. Electrically-induced ventricular fibrillation was controlled by propafenone (2 mg/kg i.v.) in the guinea pig and rabbit. Chloroform- and adrenaline-induced arrhythmias were reduced or abolished by propafenone in the cat (1 mg/kg i.v., 2 to 10 mg/kg i.v.) and dog (1 mg/kg i.v., 10 mg/kg oral) as were arrhythmias induced by calcium chloride, glycoside and coronary ligature in the dog (1 to 4 mg/kg i.v. ). Aconitine-induced arrhythmias were also controlled by propafenone in the rabbit (3 mg/kg i.v. ). Propafenone can be classified as an antiarrhythmic drug with a membrane stabilizing effect.
In the dog, the force of ventricular contraction and blood pressure were not affected by doses of 3 mg/kg i.v.. However, after higher doses of 12 mg/kg i.v. or in hearts predamaged by coronary ligature, or when administering beta-blockers concomitantly, a fall in blood pressure, a reduction in the heart rate and contractility, and an increase in ECG-intervals (PR and QRS) have been seen.
Structural similarities between propafenone and propranolol prompted several animal investigations into the possible beta-blocking effects of propafenone. A beta1-sympatholytic action on isolated heart preparations (guinea pigs) and a beta2-sympatholytic action on the coronary arteries and tracheal muscles (bovine) have been demonstrated in vitro. In vivo studies in rats showed that the antiarrhythmic effect occurred with i.v. doses seven times lower than necessary for the beta- blocking effect (ED50 at 0.437 mg/kg and 3.25 mg/kg respectively). However, the in vitro beta- blocking effect of propafenone occurred in the same dose range as the antiarrhythmic effect. In in vitro studies of bovine coronary arteries, propafenone (56.0 mg/L) yielded a relaxing effect weaker than that of etafenone, papaverine, hexobendine, fendiline and oxifedrine but stronger than that of theophylline, aminophylline and carbocromen. In bovine tracheal muscle, and guinea pig colon, the potency of propafenone was the same as that of papaverine. In vivo, canine duodenum tone decreased slightly after i.v. propafenone, 0.5 to 4.0 mg/kg, with a marked decrease of the amplitude of peristalsis following propafenone, 1.0 to 4.0 mg/kg. The local anesthetic activity of propafenone was demonstrated in the cornea of conscious guinea pigs with a 0.5% solution of propafenone.
| Table 2 LD 5 0 Values Observed in the Acute Toxicity Studies | ||||
| Species | Route | Sex | LD 50 | (95% Confidence Interval) |
| Mouse | oral | male | 650 | (445-888) mg/kg |
| female | 605 | (434-840) mg/kg | ||
| i.v. | male | 29.3 | (26.6-32.7) mg/kg | |
| female | 31.1 | (28.3-35.7) mg/kg | ||
| Rat (Adult) | oral | male | 1,316 | (978-1,729) mg/kg |
| female | 1,250 | (263-5,934) mg/kg * | ||
| i.v. | male | 18.6 | (16.8-22.0) mg/kg | |
| female | 16.8 | (14.4-19.4) mg/kg | ||
| Rat (Juvenile) | oral | male | 3,556 | (2,731-4,885) mg/kg |
| female | 2,902 | (2,090-4,484)mg/kg | ||
| i.v. | male | 23.0 | (16.0-32.0) mg/kg | |
| female | 23.1 | (16.1-31.8) mg/kg | ||
| * 90% confidence interval | ||||
In an acute oral dose tolerance study in dogs with 2 animals per dose level, no dogs died at 350 mg/kg, 1 dog died at 500 mg/kg and both dogs died at 650 mg/kg. In a similar study in cats, no animals died at 60 mg/kg and both cats died at the 100 mg/kg dose level. Primary symptoms of toxicity were ataxia, attenuated reflexes and tonic-clonic convulsions.
The studies are summarized in Table 3. For all studies, animals in each group were equally divided by sex.
| Table 3 Summary of Subacute and Chronic Toxicity Studies | ||||||
| Species | Route of Dosing | Duration of Dosing | Daily Dose (mg/kg) | No. of Animals Per Dose Group | No. of Deaths Per Dose Group | Toxic Effects |
| Rabbit | i.v. | 3 weeks | 0 | 4 | 0 | Dose related reduction in body weight increases and elevated SPGT values were |
| 0.3 | 4 | 0 | observed in the high dose group. High dose group had significantly increased heart | |||
| 0.5 | 4 | 0 | weights, with focal muscle cell degeneration. Reduced spermatogenesis was found on | |||
| 1.0 | 4 | 0 | histological examination in all groups. | |||
| Rat | i.v. | 4 weeks | 0 | 30 | 0 | Changes were observed in the 3.5 mg/kg group. Sedation, tremor and reduced alertness |
| (Wistar) | 0.35 | 30 | 0 | were noted as well as reduction in body weight gain and food and water consumption. | ||
| 1.75 | 30 | 0 | Clinical laboratory tests revealed decreases in erythrocyte count and serum urea, sodium | |||
| 3.5 | 30 | 0 | and phosphorus values. Increases in serum chloride were also noted. | |||
| Rat | oral | 4 weeks | 0 | 20 | 0 | A decrease in serum sodium values was observed in rats receiving 300 mg/kg. |
| (Wistar) | (gavage) | 30 | 20 | 0 | ||
| 150 | 20 | 0 | ||||
| 300 | 20 | 0 | ||||
| Rat | oral | 6 months | 0 | 30 | 0 | Due to high mortality, the intermediate and high doses were reduced after eight weeks. |
| (Wistar) | (gastric | 90 | 30 | 0 | Death was preceded by weight loss or reduced weight gain. Intermediate doses produced | |
| tube) | 270(180) | 30 | 3 | sedation and reduced reflexes. Sedation, apathy, ataxia, impaired coordination, shaggy | ||
| 600(360) | 30 | 11 | skin, loose stool and intermittent tonic-clonic convulsions occurred in the high dose group. | |||
| Histopathology revealed a dose related increase in fatty liver cells and kidney protein | ||||||
| cylinders in the tubuli. Nephritis was observed in the high dose group. Focal to complete | ||||||
| degeneration of the tubular epithelial cells in the testes was observed equally in all dose | ||||||
| groups. | ||||||
| Rat | oral | 26 weeks | 0 | 52 | 0 | Due to high mortality, the high dose was decreased after 6 weeks. Primarily in the high |
| (Sprague- | (gavage) | 90 | 52 | 0 | dose group, observations included unkempt coat, sedation, ataxia and apathy. Inhibition | |
| Dawley) | 180 | 52 | 14 | of body weight gain occurred in all groups. Inflammatory renal lesions (nephritis and | ||
| 500 (360) | 52 | 27 | nephrohydrosis) caused by precipitations of propafenone in the upper tubules was noted | |||
| in several high dose and one intermediate dose animal. | ||||||
| Table 3 Summary of Subacute and Chronic Toxicity Studies | ||||||
| Species | Route of Dosing | Duration of Dosing | Daily Dose (mg/kg) | No. of Animals Per Dose Group | No. of Deaths Per Dose Group | Toxic Effects |
| Dog | i.v. | 4 weeks | 0 | 6 | 0 | The 5 mg/kg animals showed a reduction in bodyweight and food consumption, and increased |
| (Beagle) | 0.3 | 6 | 0 | restlessness, timidity, anxiety and shaggy coats. Tremor, reduced responses and spontaneous | ||
| 1.0 | 6 | 0 | defecation were observed immediately post injection. ECG tracings taken at the end of the stay revealed | |||
| 5.0 | 6 | 0 | significant heart rate reduction. Laboratory evaluations revealed significantly lowered LDH, BUN, Na, CI, | |||
| and inorganic phosphorus. Complete cessation of spermatogenesis was observed on histopathology. | ||||||
| Dog | i.v. | 4 weeks | 0 | 6 | 0 | The 5 mg/kg group showed a decrease in serum potassium. |
| (Beagle) | 1.0 | 6 | 0 | |||
| 2.2 | 6 | 0 | ||||
| 5.0 | 6 | 0 | ||||
| Dog | oral | 4 weeks | 0 | 2 | 0 | Reduction in bodyweight and increased heart and liver weights were observed in the high dose group. |
| (Mongrel) | 20 | 2 | 0 | |||
| 50 | 2 | 0 | ||||
| 100 | 2 | 0 | ||||
| Dog | oral | 6 months | 0 | 6 | 0 | The following effects were observed in the 120 mg/kg group: sedation, intermittent tremor, reduced body |
| (Beagle) | 30 | 6 | 0 | weight gain and food consumption. Prothrombin time was also shortened. Due to one death and the | ||
| 120 | 6 | 0 | marked deterioration of remaining animals in the 240 mg/kg group, the dose was reduced to 180 mg/kg | |||
| 240 (180) | 6 | 1 | at 9 weeks and gradually increased to 240 mg/kg at the thirtieth week. At this dose, animals exhibited | |||
| (210) | apathy, sedation, ataxia, convulsions, vomiting, salivation, diarrhea, reduced body weight gain and food | |||||
| (240) | intake, reduced prothrombin time, decreased LDH values and increased uric acid. | |||||
| Dog | oral | 52 weeks | 0 | 10 | 0 | Vomiting was observed in the 60 mg/kg dosed dogs. The 120 mg/kg dogs exhibited vomiting, ataxia and |
| (Beagle) | 30 | 10 | 0 | tremor with tonic-clonic spasm. Biochemical analysis showed decreased total protein and globulins. One | ||
| 60 | 10 | 1 | animal at 60 mg/kg and 3 animals at 120 mg/kg died. Probable cause of death: circulatory collapse. | |||
| 120 | 10 | 3 | ||||
| Monkey | i.v. | 4 weeks | 0 | 4 | 0 | A dose related decrease in body weight gain was reported. All animals treated showed a decrease in the |
| (Rhesus) | 2.0 | 4 | 0 | ejaculation volume and sperm count. Death of all spermatozoa was observed in the high dose group. | ||
| 5.0 | 4 | 0 | The following was observed on histopathology: inhibition of spermatogenesis in the 2.0 mg/kg group and | |||
| more severe disorders of spermatogenesis (including absence of spermatozoa maturation, severe | ||||||
| degree of atypical nuclei with hyperchromasia and an increased number of nucleus pycnosis) in the 5.0 | ||||||
| mg/kg dose group. Sperm counts returned to normal within 8 weeks post study. | ||||||
Fertility and General Reproductive Performance
: SPF albino rats (24/sex/dose) received 0, 30, 90, 270 mg/kg/day of propafenone hydrochloride p.o. (gavage). Males were treated for 70 days prior to mating and females began treatment 14 days prior to mating. Both continued treatment for a maximum of 14 days during the mating period. Propafenone hydrochloride did not produce any adverse effects on fertility but increased the time required for mating.
Male Wistar rats (20/group) and male albino rabbits (10/group) received oral propafenone hydrochloride at doses of 0 or 150 mg/kg (rats) and 0 or 120 mg/kg (rabbits) over 10 weeks (6 days/week). On the last day of treatment in the rat and after termination of treatment in the rabbit, each male was paired with 2 non-treated females. There was no effect in either species on fertility, mating behaviour, or litter size.
Teratology Studies
: Female Wistar rats (20/group) received oral propafenone hydrochloride (gavage) at doses of 0, 90, 270 or 600 mg/kg from the 5th to the 15th day of pregnancy. There was no evidence of teratogenicity at any dose. An embryotoxic effect (i.e. increased resorption rates and decreased fetal weights), was detected at the highest dose level. This dose was already toxic to dams as evidenced by reduced weight gain.
White pregnant female New Zealand rabbits received oral (gavage) propafenone hydrochloride at doses of 0, 15, 30 or 150 mg/kg/day from the 6th to the 18th day of pregnancy. Fetuses of the intermediate and high dose group showed variations (retarded ossification of the skull, the coccygeal vertebra and end-phalanx). The number of resorption and dead fetuses was increased in the high dose group. This dose was toxic to the dam as evidenced by reduced weight gain and increased mortality.
Intravenous administration of propafenone hydrochloride in doses of 0.3, 0.5 and 1.0 mg/kg for 3 weeks to NZ-rabbits (2/dose) resulted in reduced spermatogenesis. The dose of 1.0 mg/kg produced degenerated spermatogenic epithelium in the testes of all animals. Additional studies of spermatogenesis were performed in the monkey, dog and rabbit. After i.v. administration of 2 and 5 mg/kg propafenone hydrochloride per day to monkeys for 4 weeks, decreased spermatogenesis occurred, but was reversible 8 weeks after discontinuation of propafenone hydrochloride. Minor alterations in the spermatogram (oligospermia) were observed in dogs administered 5 mg/kg i.v. for 4 weeks and rabbits administered 3.5 and 5 mg/kg i.v. for 6 days. The phenomenon was reversible 4 weeks after discontinuation of propafenone hydrochloride. No injury to the parenchyma of the testes occurred, nor did electron microscopy demonstrate any changes in the spermatogenic epithelium of rabbits.
The mutagenic potential of propafenone was investigated in bacteria in vitro (Salmonella/ microsome assay) as well as in Chinese hamsters, rats and mice in vivo. No indication of mutagenic activity was detected in any of these studies.
Propafenone hydrochloride was administered in doses of 60, 180 and 540 (360) mg/kg to NMR mice for 104 weeks. After 21 weeks, the maximum dose was reduced to 360 mg/kg for the remainder of the study. Sprague-Dawley rats were given doses of 30, 90 and 270 mg/kg in the food for 30 months. In these studies propafenone hydrochloride was not carcinogenic.
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