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Propafenone

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Overview

What is Propafenone?

Propafenone hydrochloride is an antiarrhythmic drug supplied in extended-release capsules of 225 mg, 325 mg and 425 mg for oral administration.

The structural formula of propafenone HCl is given below:

Propafenone HCl has some structural similarities to beta-blocking agents. Propafenone HCl occurs as colorless crystals or white crystalline powder with a very bitter taste. It is slightly soluble in water (20ºC), chloroform and ethanol. Propafenone extended release are capsules filled with granules containing the following inactive ingredients: ethylcellulose, lactose anhydrous, magnesium stearate and povidone. The capsules consist of D&C Red #28, FD&C Blue #1, FD&C Red #40, FD&C Yellow #5, FD&C Yellow #6, gelatin and titanium dioxide. In addition the ink consists of D&C Yellow #10 aluminum lake, iron oxide black, n-butyl alcohol, propylene glycol, FD&C Blue #2 aluminum lake, FD&C Red #40 aluminum lake, FD&C Blue #1 aluminum lake and shellac glaze~45% (20% esterfied) in ethanol.



What does Propafenone look like?



What are the available doses of Propafenone?

Sorry No records found.

What should I talk to my health care provider before I take Propafenone?

Sorry No records found

How should I use Propafenone?

Propafenone Extended Release Capsules are indicated to prolong the time to recurrence of symptomatic atrial fibrillation in patients without structural heart disease.

The use of propafenone ER capsules in patients with permanent atrial fibrillation or in patients exclusively with atrial flutter or PSVT has not been evaluated. Propafenone ER capsules should not be used to control ventricular rate during atrial fibrillation.

The effect of propafenone ER capsules on mortality has not been determined (see black box ).

The dose of propafenone ER capsules must be individually titrated on the basis of response and tolerance. Therapy should be initiated with propafenone ER capsules 225 mg given every twelve hours. Dosage may be increased at a minimum of five day interval to 325 mg given every twelve hours. If additional therapeutic effect is needed, the dose of propafenone ER capsules may be increased to 425 mg given every twelve hours.

In patients with hepatic impairment or having significant widening of the QRS complex or second or third degree AV block, dose reduction should be considered.

Propafenone ER capsules can be taken with or without food. Do not crush or further divide the contents of the capsule.


What interacts with Propafenone?

Propafenone ER capsules are contraindicated in the presence of congestive heart failure, cardiogenic shock, sinoatrial, atrioventricular and intraventricular disorders of impulse generation or conduction (e.g., sick sinus node syndrome, atrioventricular block) in the absence of an artificial pacemaker, bradycardia, marked hypotension, bronchospastic disorders, electrolyte imbalance, or hypersensitivity to the drug.



What are the warnings of Propafenone?

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of , and surgical evaluation should be instituted as clinically indicated.

Mortality:

In the National Heart, Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-center, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than six days but less than two years previously, an increased rate of death or reversed cardiac arrest rate (7.7%; 56/730) was seen in patients treated with encainide or flecainide (Class 1C antiarrhythmics) compared with that seen in patients assigned to placebo (3.0%; 22/725). The average duration of treatment with encainide or flecainide in this study was ten months.

The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) or other antiarrhythmic drugs is uncertain, but at present, it is prudent to consider any 1C antiarrhythmic to have a significant risk in patients with structural heart disease. Given the lack of any evidence that these drugs improve survival, antiarrhythmic agents should generally be avoided in patients with non-life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs.

Proarrhythmic Effects:

Propafenone has caused new or worsened arrhythmias. Such proarrhythmic effects include sudden death and life-threatening ventricular arrhythmias such as ventricular fibrillation, ventricular tachycardia, asystole and Torsade de Pointes. It may also worsen premature ventricular contractions or supraventricular arrhythmias, and it may prolong the QT interval. It is therefore essential that each patient given propafenone ER capsules be evaluated electrocardiographically prior to and during therapy, to determine whether the response to propafenone ER capsules sup­ports continued treatment. Because propafenone prolongs the QRS interval in the electrocardiogram, changes in the QT interval are difficult to interpret.

In a 474 patient U.S. uncontrolled, open label multicenter trial using the immediate release formulation in patients with symptomatic SVT, 1.9% (9/474) of these patients experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the study. However, in four of the nine patients, the ventricular tachycardia was of atrial origin. Six of the nine patients that developed ventricular arrhythmias did so within 14 days of onset of therapy. About 2.3% (11/474) of all patients had recurrence of SVT during the study which could have been a change in the patients’ arrhythmia behavior or could represent a proarrhythmic event. Case reports in patients treated with propafenone HCl for atrial fibrillation/flutter have included increased PVCs, VT, VF, Torsade de Pointes, asystole, and death.

In the RAFT study, there were five deaths, three in the pooled propafenone ER capsules group (0.8%) and two in the placebo group (1.6%). In the overall propafenone ER capsules and propafenone HCl immediate release database of eight studies, the mortality rate was 2.5% per year on propafenone HCl and 4% per year on placebo. Concurrent use of propafenone with other antiarrhythmic agents has not been well studied.

Use with Drugs that Prolong the QT Interval and Antiarrhythmic Agents:

The use of propafenone ER capsules (propafenone hydrochloride) in conjunction with other drugs that prolong the QT interval has not been extensively studied and is not recommended. Such drugs may include many antiarrhythmics, some phenothiazines, cisapride, bepridil, tricyclic antidepressants and oral macrolides. Class Ia and III antiarrhythmic agents should be withheld for at least five half-lives prior to dosing with propafenone ER capsules. The use of propafenone with Class Ia and III antiarrhythmic agents (including quinidine and amiodarone) is not recommended. There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics.

Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema)

Patients with bronchospastic disease should not, in general, receive propafenone or other agents with beta-adrenergic-blocking activity.

Congestive Heart Failure

Propafenone exerts a negative inotropic activity on the myocardium as well as beta-blockade effects and may provoke overt congestive heart failure. In the U.S. trial (RAFT) in patients with symptomatic atrial fibrillation, congestive heart failure was reported in four (1%) patients receiving propafenone ER capsules (all doses), compared to one (0.8%) patient receiving placebo. Proarrhythmic effects are more likely to occur when propafenone is administered to patients with congestive heart failure (NYHA III and IV) or severe myocardial ischemia (see ).

Conduction Disturbances:

Propafenone causes dose-related first degree AV block. Average PR interval prolongation and increases in QRS duration are also dose-related.

Propafenone should not be given to patients with atrioventricular and intraventricular conduction defects in the absence of a pacemaker (see ).

In a U.S. trial (RAFT) in 523 patients with a history of symptomatic atrial fibrillation treated with propafenone ER capsules, electrocardiograms obtained in response to symptoms were associated with no patients having sinus rhythm with Mobitz Type I (Wenckenbach) second degree AV block, sinus rhythm with Mobitz Type II second degree AV block, or third degree AV block. Sinus bradycardia (rate
Effects on Pacemaker Threshold:

Propafenone may alter both pacing and sensing thresholds of artificial pacemakers. Pacemakers should be monitored and programmed accordingly during therapy.

Hematologic Disturbances:

Agranulocytosis (fever, chills, weakness, and neutropenia) has been reported in patients receiving propafenone. Generally, the agranulocytosis occurred within the first two months of propafenone therapy and upon discontinuation of therapy, the white count usually normalized by 14 days. Unexplained fever and/or decrease in white cell count, particularly during the initial three months of therapy, warrant consideration of possible agranulocytosis or granulocytopenia. Patients should be instructed to report promptly the development of any signs of infection such as fever, sore throat, or chills.


What are the precautions of Propafenone?

Hepatic Dysfunction

Propafenone is highly metabolized by the liver and should, therefore, be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction increases the bioavailability of propafenone to approximately 70% compared to 3-40% in patients with normal liver function when given propafenone HCl immediate release tablets. In eight patients with moderate to severe liver disease administered propafenone HCl immediate release tablets, the mean half-life was approximately nine hours. No studies are currently available comparing bioavailability of propafenone from propafenone ER capsules in patients with normal and impaired hepatic function. Increased bioavailability of propafenone in these patients may result in excessive accumulation. Careful monitoring for excessive pharmacological effects (see ) should be performed for patients with impaired hepatic function.

Renal Dysfunction

Approximately 50% of propafenone metabolites are excreted in the urine following administration of propafenone HCl immediate release tablets. No studies have been performed to assess the percentage of metabolites eliminated in the urine following the administration of propafenone ER capsules.

Until further data are available, propafenone ER capsules should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for signs of overdosage (see ).

Information for Patients

Medications and Supplements:

Assessment of patients’ medication history should include all over-the-counter, prescription and herbal/natural preparations with emphasis on preparations that may affect the pharmacodynamics or kinetics of propafenone ER capsules (see ). Patients should be instructed to notify their health care providers of any change in over-the-counter, prescription and supplement use. If a patient is hospitalized or is prescribed new medication for any condition, the patient must inform the health care provider of ongoing propafenone ER capsules therapy. Patients should also check with their health care providers prior to taking a new over-the-counter medicine.

Electrolyte Imbalance:

If patients experience symptoms that may be associated with altered electrolyte balance, such as excessive or prolonged diarrhea, sweating, vomiting, or loss of appetite or thirst, these conditions should be immediately reported to their health care provider.

Dosing Schedule:

Patients should be instructed NOT to double the next dose if a dose is missed. The next dose should be taken at the usual time.

Elevated ANA Titers:

Positive ANA titers have been reported in patients receiving propafenone. They have been reversible upon cessations of treatment and may disappear even in the face of continued propafenone therapy. These laboratory findings were usually not associated with clinical symptoms, but there is one published case of drug-induced lupus erythematosus (positive rechallenge); it resolved completely upon discontinuation of therapy. Patients who develop an abnormal ANA test should be carefully evaluated and, if persistent or worsening elevation of ANA titers is detected, consideration should be given to discontinuing therapy.

The 225 mg capsules contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No.5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

Impaired Spermatogenesis:

Reversible disorders of spermatogenesis have been demonstrated in monkeys, dogs and rabbits after high dose intravenous administration of propafenone. Evaluation of the effects of short-term propafenone HCl administration on spermatogenesis in 11 normal subjects suggested that propafenone produced a reversible, short-term drop (within normal range) in sperm count. Subsequent evaluations in 11 patients receiving propafenone HCl chronically have found no effect of propafenone on sperm count.

Neuromuscular Dysfunction

Exacerbation of myasthenia gravis has been reported during propafenone HCl immediate release tablet therapy.

Drug Interactions

Propafenone is metabolized by CYP2D6 (major pathway) and CYP1A2 and CYP3A4. Drugs that inhibit CYP2D6 (such as desipramine, paroxetine, ritonavir, sertraline), CYP1A2 (such as amiodarone), and CYP3A4 (such as ketaconazole, ritonavir, saquinavir, erythromycin, and grapefruit juice) can be expected to cause increased plasma levels of propafenone. Appropriate monitoring is recommended when propafenone ER capsules are used together with such drugs. In addition, propafenone is an inhibitor of CYP2D6. Coadministration of propafenone with drugs metabolized by CYP2D6 (such as desipramine, imipramine, haloperidol, venlafaxine) might lead to increased plasma concentrations of these drugs. The effect of propafenone on the P-Glycoprotein transporter has not been studied.

CLINICAL PHARMACOLOGY

Digoxin:

Lidocaine:

Beta-Antagonists:

Warfarin:

Cimetidine:

Rifampin:

Fluoxetine:

Amiodarone:

Post Marketing Reports:

Orlistat may limit the fraction of propafenone available for absorption. In post marketing reports, abrupt cessation of orlistat in patients stabilized on propafenone has resulted in severe adverse events including convulsions, atrioventricular block and acute circulatory failure.

Renal and Hepatic Toxicity in Animals:

Renal changes have been observed in the rat following six months of oral administration of propafenone HCl at doses of 180 and 360 mg/kg/day (about two and four times, respectively, the maximum recommended human daily dose [MRHD] on a mg/m² basis). Both inflammatory and non-inflammatory changes in the renal tubules, with accompanying interstitial nephritis, were observed. These changes were reversible, as they were not found in rats allowed to recover for six weeks. Fatty degenerative changes of the liver were found in rats following longer durations of administration of propafenone HCl at a dose of 270 mg/kg/day (about three times the MRHD on a mg/m² basis). There were no renal or hepatic changes at 90 mg/kg/day (equivalent to the MRHD on a mg/m² basis).

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Lifetime maximally tolerated oral dose studies in mice (up to 360 mg/kg/day, about twice the maximum recommended human oral daily dose [MRHD] on a mg/m² basis) and rats (up to 270 mg/kg/day, about three times the MRHD on a mg/m² basis) provided no evidence of a carcinogenic potential for propafenone HCl.

Propafenone HCl tested negative for mutagenicity in the Ames (salmonella) test and in the mouse dominant lethal test. It tested negative for clastogenicity in the human lymphocyte chromosome aberration assay and in rat and Chinese hamster micronucleus tests, and other tests for chromosomal aberrations in rat bone marrow and Chinese hamster bone marrow and spermatogonia.

Propafenone HCl, administered intravenously to rabbits, dogs, and monkeys, has been shown to decrease spermatogenesis. These effects were reversible, were not found following oral dosing of propafenone HCl, were seen at lethal or near lethal dose levels and were not seen in rats treated either orally or intravenously (see ). Treatment of male rabbits for 10 weeks prior to mating at an oral dose of 120 mg/kg/day (about 2.4 times the MRHD on a mg/m² basis) or an intravenous dose of 3.5 mg/kg/day (a spermatogenesis-impairing dose) did not result in evidence of impaired fertility. Nor was there evidence of impaired fertility when propafenone HCl was administered orally to male and female rats at dose levels up to 270 mg/kg/day (about 3 times the MRHD on a mg/m² basis).

Pregnancy

Teratogenic Effects: Pregnancy Category C. Propafenone HCl has been shown to be embryotoxic (decreased survival) in rabbits and rats when given in oral maternally toxic doses of 150 mg/kg/day (about three times the maximum recommended human dose [MRHD] on a mg/m² basis) and 600 mg/kg/day (about six times the MRHD on a mg/m² basis), respectively. Although maternally tolerated doses (up to 270 mg/kg/day, about three times the MRHD on a mg/m² basis) produced no evidence of embryotoxicity in rats, post-implantation loss was ele­vated in all rabbit treatment groups (doses as low as 15 mg/kg/day, about 1/3 the MRHD on a mg/m² basis). There are no adequate and well-controlled studies in pregnant women. Propafenone ER capsules (propafenone hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Non-Teratogenic Effects: In a study in which female rats received daily oral doses of propafenone HCl from mid-gestation through weaning of their offspring, doses as low as 90 mg/kg/day (equivalent to the MRHD on a mg/m² basis) produced increases in maternal deaths. Doses of 360 or more mg/kg/day (four or more times the MRHD on a mg/m² basis) resulted in reductions in neonatal survival, body weight gain and physiological development.

Labor and Delivery

It is not known whether the use of propafenone during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetrical intervention.

Nursing Mothers

Propafenone is excreted in human milk. Caution should be exercised when propafenone ER capsules are administered to a nursing mother.

Pediatric Use

The safety and effectiveness of propafenone in pediatric patients have not been established.

Geriatric Use

Of the total number of subjects in Phase III clinical studies of propafenone ER capsules (propafenone hydrochloride) 45.7 percent were 65 and over, while 15.7 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals at higher doses cannot be ruled out. The effect of age on the pharmacokinetics and pharmacodynamics of propafenone has not been studied.


What are the side effects of Propafenone?

The data described below reflect exposure to propafenone ER capsules 225 mg BID in 126 patients, to propafenone ER capsules 325 mg BID in 135 patients, to propafenone ER capsules 425 mg BID in 136 patients, and to placebo in 126 patients for up to 39 weeks in a placebo-controlled trial (RAFT) conducted in the U.S. The most commonly reported adverse events in the trial included dizziness, chest pain, palpitations, taste disturbance, dyspnea, nausea, constipation, anxiety, fatigue, upper respiratory tract infection, influenza, first degree heart block and vomiting. The frequency of discontinuation due to adverse events was highest during the first 14 days of treatment. The majority of the patients with serious adverse events who withdrew or were discontinued recovered without sequelae.

Adverse events occurring in 2% or more of the patients in any of the RAFT propafenone ER capsules treatment groups and more common with propafenone than with placebo, excluding those that are common in the population and those not plausibly related to drug therapy, are listed in Table 2.

No clinically important differences in incidence of adverse reactions were noted by age, or gender. Too few non-White patients were enrolled to assess adverse events according to race. Adverse events occurring in 2% or more of the patients in any of the ERAFT propafenone ER treatment groups and not listed in Table 2 include the following: bundle branch block left, bundle branch block right, conduction disorders, sinus bradycardia and hypotension.

Other adverse events reported with propafenone clinical trials not already listed in Table 2 include the following adverse events by body and preferred term.

Blood and lymphatic system disorders:

Cardiac disorders:

Ear and labyrinth disorders:

Eye disorders:

Gastrointestinal disorders

General disorders and administration site conditions:

Hepato-biliary disorders:

Investigations:

Metabolism and nutrition disorders:

Musculoskeletal, connective tissue and bone disorders:

Nervous system disorders:

Psychiatric disorders:

Renal and urinary disorders:

Reproductive system and breast disorders:

Respiratory, thoracic and mediastinal disorders:

Skin and subcutaneous tissue disorders:

Vascular disorders:

Table 2: Most common adverse events (≥2% in any RAFT propafenone ER treatment group and more common on propafenone than on placebo)
MeDRA Body System/Preferred Term225 mg BID (N = 126) n (%)325 mg BID (N = 135) n (%)425 mg BID (N = 136) n (%)Placebo (N=126 n (%)
Mean exposure (days) 124 149 141 91
Cardiac disorders
Angina pectoris 0 (0) 0 (0) 3 (2) 0 (0)
Atrial flutter 3 (2) 2 (1) 0 (0) 1 (1)
AV block first degree 3 (2) 3 (2) 4 (3) 0 (0)
Bradycardia 4 (3) 4 (3) 6 (4) 1 (1)
Cardiac failure congestive 0 (0) 1 (1) 3 (2) 1 (1)
Cardiac murmur 2 (2) 3 (2) 6 (4) 0 (0)
Edema 6 (5) 18 (13) 10 (7) 8 (6)
Eye disorders
Vision blurred 1 (1) 1 (1) 5 (4) 0 (0)
Gastrointestinal disorders
Constipation 10 (8) 19 (14)16 (12)3 (2)
Diarrhea 2 (2) 3 (2)5 (4)3 (2)
Dry mouth 1 (1) 1 (1)5 (4)1 (1)
Flatulence 3 (2) 3 (2)1 (1)0 (0)
Nausea 11 (9) 15 (11)23 (17)11 (9)
Vomiting 1 (1) 0 (0)8 (6)3 (2)
General disorder and administration site
Fatigue 14 (11) 17 (13) 17 (13) 7 (6)
Weakness 4 (3) 6 (4) 6 (4) 3 (2)
Infections and Infestations
Upper respiratory tract infection   11 (9)  16 (12)  11 (8))  7 (6)
Investigations
Blood alkaline phosphatase increased0 (0)0 (0)4 (3)0 (0)
Cardioactive drug level above therapeutic1 (1) 1 (1) 3 (2) 1 (1)
Hematuria2 (2)2 (1)4 (3)3 (2)
Musculoskeletal, connective tissue and bone
Muscle weakness1 (1)5 (4)1 (1)0 (0)
Nervous system disorders
Dizziness (excluding vertigo)  29 (23)  28 (21)  29 (21)  18 (14)
Headache 8 (6) 12 (9) 14 (10) 11 (9)
Taste disturbance 7 (6) 18 (13) 30 (22) 1 (1)
Tremor 2 (2) 0 (0) 3 (2) 1 (1)
Somnolence 1 (1) 1 (1) 4 (3) 0 ( 0)
Psychiatric disorders
Anxiety12 (10)17 (13)16 (12)13 (10)
Depression1 (1)4 (3)0 (0)2 (2)
Respiratory, thoracic and mediastinal disorder
Dyspnea16 (13)23 (17)17 (13)9 (7)
Rales2 (2)1 (1)3 (2)0 (0)
Wheezing0 (0) 0 (0) 3 (2) 0 (0)
Skin & subcutaneous tissue disorders
Ecchymosis2 (2)3 (2)5 (4)0 (0)


Laboratory: Electrocardiograms

Propafenone prolongs the PR and QRS intervals in patients with atrial and ventricular arrhythmias. Prolongation of the QRS interval makes it difficult to interpret the effect of propafenone on the QT interval.

In RAFT, the distribution of the maximum changes in QTc compared to baseline over the study in each patient was similar in the propafenone ER capsules 225 mg BID, 325 mg BID, and 425 mg BID and placebo dose groups. Similar results were seen in the ERAFT study.

Table 3: Mean Change in 12-Lead Electrocardiogram Results (RAFT)
*Calculated using Bazett’s correction factor.
Propafenone ER Capsules BID dosing
225 mg 325 mg 425 mg Placebo
n=126 n=135 n=136 n=126
PR (ms) 9±22 12±23 21±24 1±16
QRS (ms) 4±14 6±15 6±15 -2±12
QTc* (ms) 2±30 5±36 6±37 5±35
Table 4: Number of patients according to the range of maximum QTc change compared to baseline over the study in each dose group (RAFT study)
Range of maximum Propafenone ER CapsulesPlacebo
225 mg BID 325 mg BID 425 mg BID
N=119 N=129 N=123 N=100
n (%) n (%) n (%) n (%)
>20% 1 (1%) 6 (5%) 3 (2%) 5 (4%)
10-20% 19 (16%) 28 (22%) 32 (26%) 24 (20%)
≤10% 99 (83%) 95 (74%) 88 (72%) 91 (76%)



What should I look out for while using Propafenone?

Propafenone ER capsules are contraindicated in the presence of congestive heart failure, cardiogenic shock, sinoatrial, atrioventricular and intraventricular disorders of impulse generation or conduction (e.g., sick sinus node syndrome, atrioventricular block) in the absence of an artificial pacemaker, bradycardia, marked hypotension, bronchospastic disorders, electrolyte imbalance, or hypersensitivity to the drug.

Mortality:

In the National Heart, Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-center, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than six days but less than two years previously, an increased rate of death or reversed cardiac arrest rate (7.7%; 56/730) was seen in patients treated with encainide or flecainide (Class 1C antiarrhythmics) compared with that seen in patients assigned to placebo (3.0%; 22/725). The average duration of treatment with encainide or flecainide in this study was ten months.

The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) or other antiarrhythmic drugs is uncertain, but at present, it is prudent to consider any 1C antiarrhythmic to have a significant risk in patients with structural heart disease. Given the lack of any evidence that these drugs improve survival, antiarrhythmic agents should generally be avoided in patients with non-life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs.


What might happen if I take too much Propafenone?

The symptoms of overdosage may include hypotension, somnolence, bradycardia, intra-atrial and intraventricular conduction disturbances, and rarely convulsions and high grade ventricular arrhythmias. Defibrillation as well as infusion of dopamine and isoproterenol have been effective in controlling abnormal ventricular rhythm and blood pressure. Convulsions have been alleviated with intravenous diazepam. General supportive measures such as mechanical respira­tory assistance and external cardiac massage may be necessary.

The hemodialysis of propafenone in patients with an overdose is expected to be of limited value in the removal of propafenone as a result of both its high protein binding (>95%) and large volume of distribution.


How should I store and handle Propafenone?

Store bottles at controlled room temperature, 59° to 86°F (15° to 30°C) and dispense in tight, light-resistant containers (USP).Propafenone Extended Release Capsules, 325 mg are available as hard gelatin capsules containing 325 mg of propafenone HCl. The capsule is an orange opaque cap printed “par/210” in black ink and white opaque body printed “par/210” in black ink.NDC 49884-210-02 Bottles of 60 capsulesNDC 49884-210-01 Bottles of 100 capsulesNDC 49884-210-05 Bottles of 500 capsulesNDC 49884-210-10 Bottles of 1000 capsulesStorage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.Manufactured by:Par Pharmaceutical Companies, Inc.Spring Valley, NY 10977I03/10Repackaged by:Rebel Distributors CorpThousand Oaks, CA 91320Propafenone Extended Release Capsules, 325 mg are available as hard gelatin capsules containing 325 mg of propafenone HCl. The capsule is an orange opaque cap printed “par/210” in black ink and white opaque body printed “par/210” in black ink.NDC 49884-210-02 Bottles of 60 capsulesNDC 49884-210-01 Bottles of 100 capsulesNDC 49884-210-05 Bottles of 500 capsulesNDC 49884-210-10 Bottles of 1000 capsulesStorage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.Manufactured by:Par Pharmaceutical Companies, Inc.Spring Valley, NY 10977I03/10Repackaged by:Rebel Distributors CorpThousand Oaks, CA 91320Propafenone Extended Release Capsules, 325 mg are available as hard gelatin capsules containing 325 mg of propafenone HCl. The capsule is an orange opaque cap printed “par/210” in black ink and white opaque body printed “par/210” in black ink.NDC 49884-210-02 Bottles of 60 capsulesNDC 49884-210-01 Bottles of 100 capsulesNDC 49884-210-05 Bottles of 500 capsulesNDC 49884-210-10 Bottles of 1000 capsulesStorage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.Manufactured by:Par Pharmaceutical Companies, Inc.Spring Valley, NY 10977I03/10Repackaged by:Rebel Distributors CorpThousand Oaks, CA 91320Propafenone Extended Release Capsules, 325 mg are available as hard gelatin capsules containing 325 mg of propafenone HCl. The capsule is an orange opaque cap printed “par/210” in black ink and white opaque body printed “par/210” in black ink.NDC 49884-210-02 Bottles of 60 capsulesNDC 49884-210-01 Bottles of 100 capsulesNDC 49884-210-05 Bottles of 500 capsulesNDC 49884-210-10 Bottles of 1000 capsulesStorage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.Manufactured by:Par Pharmaceutical Companies, Inc.Spring Valley, NY 10977I03/10Repackaged by:Rebel Distributors CorpThousand Oaks, CA 91320Propafenone Extended Release Capsules, 325 mg are available as hard gelatin capsules containing 325 mg of propafenone HCl. The capsule is an orange opaque cap printed “par/210” in black ink and white opaque body printed “par/210” in black ink.NDC 49884-210-02 Bottles of 60 capsulesNDC 49884-210-01 Bottles of 100 capsulesNDC 49884-210-05 Bottles of 500 capsulesNDC 49884-210-10 Bottles of 1000 capsulesStorage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.Manufactured by:Par Pharmaceutical Companies, Inc.Spring Valley, NY 10977I03/10Repackaged by:Rebel Distributors CorpThousand Oaks, CA 91320Propafenone Extended Release Capsules, 325 mg are available as hard gelatin capsules containing 325 mg of propafenone HCl. The capsule is an orange opaque cap printed “par/210” in black ink and white opaque body printed “par/210” in black ink.NDC 49884-210-02 Bottles of 60 capsulesNDC 49884-210-01 Bottles of 100 capsulesNDC 49884-210-05 Bottles of 500 capsulesNDC 49884-210-10 Bottles of 1000 capsulesStorage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.Manufactured by:Par Pharmaceutical Companies, Inc.Spring Valley, NY 10977I03/10Repackaged by:Rebel Distributors CorpThousand Oaks, CA 91320Propafenone Extended Release Capsules, 325 mg are available as hard gelatin capsules containing 325 mg of propafenone HCl. The capsule is an orange opaque cap printed “par/210” in black ink and white opaque body printed “par/210” in black ink.NDC 49884-210-02 Bottles of 60 capsulesNDC 49884-210-01 Bottles of 100 capsulesNDC 49884-210-05 Bottles of 500 capsulesNDC 49884-210-10 Bottles of 1000 capsulesStorage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.Manufactured by:Par Pharmaceutical Companies, Inc.Spring Valley, NY 10977I03/10Repackaged by:Rebel Distributors CorpThousand Oaks, CA 91320Propafenone Extended Release Capsules, 325 mg are available as hard gelatin capsules containing 325 mg of propafenone HCl. The capsule is an orange opaque cap printed “par/210” in black ink and white opaque body printed “par/210” in black ink.NDC 49884-210-02 Bottles of 60 capsulesNDC 49884-210-01 Bottles of 100 capsulesNDC 49884-210-05 Bottles of 500 capsulesNDC 49884-210-10 Bottles of 1000 capsulesStorage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.Manufactured by:Par Pharmaceutical Companies, Inc.Spring Valley, NY 10977I03/10Repackaged by:Rebel Distributors CorpThousand Oaks, CA 91320Propafenone Extended Release Capsules, 325 mg are available as hard gelatin capsules containing 325 mg of propafenone HCl. The capsule is an orange opaque cap printed “par/210” in black ink and white opaque body printed “par/210” in black ink.NDC 49884-210-02 Bottles of 60 capsulesNDC 49884-210-01 Bottles of 100 capsulesNDC 49884-210-05 Bottles of 500 capsulesNDC 49884-210-10 Bottles of 1000 capsulesStorage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.Manufactured by:Par Pharmaceutical Companies, Inc.Spring Valley, NY 10977I03/10Repackaged by:Rebel Distributors CorpThousand Oaks, CA 91320Propafenone Extended Release Capsules, 325 mg are available as hard gelatin capsules containing 325 mg of propafenone HCl. The capsule is an orange opaque cap printed “par/210” in black ink and white opaque body printed “par/210” in black ink.NDC 49884-210-02 Bottles of 60 capsulesNDC 49884-210-01 Bottles of 100 capsulesNDC 49884-210-05 Bottles of 500 capsulesNDC 49884-210-10 Bottles of 1000 capsulesStorage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.Manufactured by:Par Pharmaceutical Companies, Inc.Spring Valley, NY 10977I03/10Repackaged by:Rebel Distributors CorpThousand Oaks, CA 91320Propafenone Extended Release Capsules, 325 mg are available as hard gelatin capsules containing 325 mg of propafenone HCl. The capsule is an orange opaque cap printed “par/210” in black ink and white opaque body printed “par/210” in black ink.NDC 49884-210-02 Bottles of 60 capsulesNDC 49884-210-01 Bottles of 100 capsulesNDC 49884-210-05 Bottles of 500 capsulesNDC 49884-210-10 Bottles of 1000 capsulesStorage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.Manufactured by:Par Pharmaceutical Companies, Inc.Spring Valley, NY 10977I03/10Repackaged by:Rebel Distributors CorpThousand Oaks, CA 91320Propafenone Extended Release Capsules, 325 mg are available as hard gelatin capsules containing 325 mg of propafenone HCl. The capsule is an orange opaque cap printed “par/210” in black ink and white opaque body printed “par/210” in black ink.NDC 49884-210-02 Bottles of 60 capsulesNDC 49884-210-01 Bottles of 100 capsulesNDC 49884-210-05 Bottles of 500 capsulesNDC 49884-210-10 Bottles of 1000 capsulesStorage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.Manufactured by:Par Pharmaceutical Companies, Inc.Spring Valley, NY 10977I03/10Repackaged by:Rebel Distributors CorpThousand Oaks, CA 91320Propafenone Extended Release Capsules, 325 mg are available as hard gelatin capsules containing 325 mg of propafenone HCl. The capsule is an orange opaque cap printed “par/210” in black ink and white opaque body printed “par/210” in black ink.NDC 49884-210-02 Bottles of 60 capsulesNDC 49884-210-01 Bottles of 100 capsulesNDC 49884-210-05 Bottles of 500 capsulesNDC 49884-210-10 Bottles of 1000 capsulesStorage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.Manufactured by:Par Pharmaceutical Companies, Inc.Spring Valley, NY 10977I03/10Repackaged by:Rebel Distributors CorpThousand Oaks, CA 91320


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Clinical Information

Chemical Structure

No Image found
Clinical Pharmacology

Propafenone is a Class 1C antiarrhythmic drug with local anesthetic effects, and a direct stabilizing action on myocardial membranes. The electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and to a lesser extent myocardial fibers, propafenone reduces the fast inward current carried by sodium ions. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity.

Studies in anesthetized dogs and isolated organ preparations show that propafenone has beta-sympatholytic activity at about 1/50 the potency of propranolol. Clinical studies employing isoproterenol challenge and exercise testing after single doses of propafenone indicate a beta-adrenergic blocking potency (per mg) about 1/40 that of propranolol in man. In clinical trials with the immediate release formulation, resting heart rate decreases of about 8% were noted at the higher end of the therapeutic plasma concentration range. At very high concentrations in vitro, propafenone can inhibit the slow inward current carried by calcium, but this calcium antagonist effect probably does not contribute to antiarrhythmic efficacy. Moreover, propafenone inhibits a variety of cardiac potassium currents in in vitro studies (i.e. the transient outward, the delayed rectifier, and the inward rectifier current). Propafenone has local anesthetic activity approximately equal to procaine. Compared to propafenone, the main metabolite, 5-hydroxypropafenone, has similar sodium and calcium channel activity, but about 10 times less beta-blocking activity (N-depropylpropafenone has weaker sodium channel activity but equivalent affinity for beta-receptors).

Non-Clinical Toxicology
Propafenone ER capsules are contraindicated in the presence of congestive heart failure, cardiogenic shock, sinoatrial, atrioventricular and intraventricular disorders of impulse generation or conduction (e.g., sick sinus node syndrome, atrioventricular block) in the absence of an artificial pacemaker, bradycardia, marked hypotension, bronchospastic disorders, electrolyte imbalance, or hypersensitivity to the drug.

Mortality:

In the National Heart, Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-center, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than six days but less than two years previously, an increased rate of death or reversed cardiac arrest rate (7.7%; 56/730) was seen in patients treated with encainide or flecainide (Class 1C antiarrhythmics) compared with that seen in patients assigned to placebo (3.0%; 22/725). The average duration of treatment with encainide or flecainide in this study was ten months.

The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) or other antiarrhythmic drugs is uncertain, but at present, it is prudent to consider any 1C antiarrhythmic to have a significant risk in patients with structural heart disease. Given the lack of any evidence that these drugs improve survival, antiarrhythmic agents should generally be avoided in patients with non-life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs.

Propafenone is metabolized by CYP2D6 (major pathway) and CYP1A2 and CYP3A4. Drugs that inhibit CYP2D6 (such as desipramine, paroxetine, ritonavir, sertraline), CYP1A2 (such as amiodarone), and CYP3A4 (such as ketaconazole, ritonavir, saquinavir, erythromycin, and grapefruit juice) can be expected to cause increased plasma levels of propafenone. Appropriate monitoring is recommended when propafenone ER capsules are used together with such drugs. In addition, propafenone is an inhibitor of CYP2D6. Coadministration of propafenone with drugs metabolized by CYP2D6 (such as desipramine, imipramine, haloperidol, venlafaxine) might lead to increased plasma concentrations of these drugs. The effect of propafenone on the P-Glycoprotein transporter has not been studied.





































Propafenone is highly metabolized by the liver and should, therefore, be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction increases the bioavailability of propafenone to approximately 70% compared to 3-40% in patients with normal liver function when given propafenone HCl immediate release tablets. In eight patients with moderate to severe liver disease administered propafenone HCl immediate release tablets, the mean half-life was approximately nine hours. No studies are currently available comparing bioavailability of propafenone from propafenone ER capsules in patients with normal and impaired hepatic function. Increased bioavailability of propafenone in these patients may result in excessive accumulation. Careful monitoring for excessive pharmacological effects (see ) should be performed for patients with impaired hepatic function.

The data described below reflect exposure to propafenone ER capsules 225 mg BID in 126 patients, to propafenone ER capsules 325 mg BID in 135 patients, to propafenone ER capsules 425 mg BID in 136 patients, and to placebo in 126 patients for up to 39 weeks in a placebo-controlled trial (RAFT) conducted in the U.S. The most commonly reported adverse events in the trial included dizziness, chest pain, palpitations, taste disturbance, dyspnea, nausea, constipation, anxiety, fatigue, upper respiratory tract infection, influenza, first degree heart block and vomiting. The frequency of discontinuation due to adverse events was highest during the first 14 days of treatment. The majority of the patients with serious adverse events who withdrew or were discontinued recovered without sequelae.

Adverse events occurring in 2% or more of the patients in any of the RAFT propafenone ER capsules treatment groups and more common with propafenone than with placebo, excluding those that are common in the population and those not plausibly related to drug therapy, are listed in Table 2.

No clinically important differences in incidence of adverse reactions were noted by age, or gender. Too few non-White patients were enrolled to assess adverse events according to race. Adverse events occurring in 2% or more of the patients in any of the ERAFT propafenone ER treatment groups and not listed in Table 2 include the following: bundle branch block left, bundle branch block right, conduction disorders, sinus bradycardia and hypotension.

Other adverse events reported with propafenone clinical trials not already listed in Table 2 include the following adverse events by body and preferred term.

Blood and lymphatic system disorders:

Cardiac disorders:

Ear and labyrinth disorders:

Eye disorders:

Gastrointestinal disorders

General disorders and administration site conditions:

Hepato-biliary disorders:

Investigations:

Metabolism and nutrition disorders:

Musculoskeletal, connective tissue and bone disorders:

Nervous system disorders:

Psychiatric disorders:

Renal and urinary disorders:

Reproductive system and breast disorders:

Respiratory, thoracic and mediastinal disorders:

Skin and subcutaneous tissue disorders:

Vascular disorders:

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Professional

Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72
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Tips

Tips

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Interactions

Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).