Propafenone

341.44

341.44

258-955-6

DTXSID9045184

C01BC03|C - Cardiovascular system

58.6

3.2

Solid

0.88-0.92

115-154°F

approx 700°F

390°F

1.557

H2O: Slightly soluble

2-8°C

5.02X10-11 mm Hg at 25 deg C (est)

Combustible Solid

Henry's Law constant = 1.50X10-15 atm-cu m/mol at 25 °C (est)

pKa = 8.91 (est)

178.5 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

MW: 377.90. Fine white crystals; slightly bitter taste. Soluble in basic lower aliphatic alcohols, carbon tetrachloride, hot water; slightly soluble in cold water. Insoluble in ether /Propafenone hydrochloride/|Hydroxyl radical reaction rate constant = 1.32X10-10 cu cm/molec-sec at 25 °C (est)

1993

3

46-22

53-36/37/39-45

UH2833000

T

P261, P264, P271, P304+P340, P305+P351+P338, P312, P337+P313, P403+P233, P405, P501

H320

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including propafenone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Propafenone hydrochloride/

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 2 companies from 1 notifications to the ECHA C&L Inventory.

Use a NIOSH-approved respirator, if it is determined to be necessary by an industrial hygiene survey involving air monitoring. If a respirator is not required, an approved dust mask should be used.

This material is assumed to be combustible.

Water spray, dry chemical, carbon dioxide, or foam as appropriate for surrounding fire and materials. ... As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing.

Wear approved respiratory protection, chemically compatible gloves, and protective clothing. Wipe up spillage or collect spillage using a high- efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately labeled container for disposal. Wash spill site.

As a general rule, when handling USP Reference Standards, avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling.|As with all dry powders, it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.|Engineering controls such as exhaust ventilation are recommended.

Symptoms of propafenone overdose (usually most severe within the first 3 hours) may include convulsions (rarely), heartbeat irregularities, low blood pressure, and sleepiness.

In clinical trials, propafenone was associated with a low rate of serum aminotransferase and alkaline phosphatase elevations. Since its approval and more widescale use, propafenone has been linked to rare instances of clinically apparent liver injury, at least a dozen cases of which have been reported in the literature. Patients usually present with symptoms of jaundice and pruritus 2 to 8 weeks after starting propafenone, and the pattern of serum enzyme elevations are typically mixed (Case 1) or cholestatic (Case 2). Immunoallergic and autoimmune features are uncommon. While the jaundice can be prolonged, patients typically recover in 1 to 3 months and there have been no instances of acute liver failure, chronic hepatitis or vanishing bile duct syndrome attributed to its use.

Although specific pharmacokinetic drug interaction studies are not available, the manufacturer of propafenone states that the drug should not be used concomitantly with other drugs that prolong the QT interval, including certain phenothiazines, cisapride, bepridil (not currently commercially available in the US), tricyclic antidepressant agents, or macrolides.|Although specific pharmacokinetic drug interaction studies are not available, the manufacturer of ritonavir states that ritonavir should not be used concomitantly with certain cardiovascular agents, including propafenone, because of the potential for substantially increased plasma concentrations of these cardiovascular drugs and potentially serious and/or life-threatening adverse effects. This pharmacokinetic interaction may occur because ritonavir has high affinity for several cytochrome P-450 (CYP) isoenzymes (e.g., CYP3A, CYP2D6, CYP1A2) involved in propafenone metabolism.|Increased serum theophylline concentrations have been reported in patients receiving theophylline concomitantly with propafenone and some clinicians suggest that serum theophylline concentrations and ECGs be monitored closely in patients receiving such combined therapy.|The manufacturer states that concomitant use of propafenone and local anesthetic agents (i.e., during pacemaker implantation, surgery, or dental procedures) may increase the risk of adverse nervous system effects.|For more Interactions (Complete) data for Propafenone (24 total), please visit the HSDB record page.

LD50 Dogt iv 10 mg/kg /Propafenone hydrochloride/|LD50 Rat iv 18,800 ug/kg /Propafenone hydrochloride/|LD50 Rat oral 700 mg/kg /Propafenone hydrochloride/

Propafenone is extensively metabolized in the liver, and dosage should be reduced substantially in patients with impaired hepatic function. The drug also should be used with caution in patients with renal dysfunction since a considerable portion of the dose is excreted in urine as active metabolites.|Propafenone (immediate-release formulation) is contraindicated in patients with uncontrolled congestive heart failure; the extended-release formulation of the drug is contraindicated in patients with congestive heart failure. Propafenone is contraindicated in patients with cardiogenic shock, atrioventricular or intraventricular disorders of impulse generation and/or conduction (e.g., sick sinus node syndrome, atrioventricular block) unless an artificial pacemaker is present, bradycardia, severe hypotension, marked electrolyte imbalance.|Propafenone has been reported to exacerbate myasthenia gravis, and it has been suggested that use of the drug be avoided in patients with this condition.|Propafenone, like other agents with nonselective beta-adrenergic blocking activity, generally should not be used in patients with asthma/bronchospastic disease or nonallergic bronchospastic disease (e.g., chronic bronchitis, emphysema) since the drugs may inhibit bronchodilation produced by endogenous catecholamines.

97%

Used to prolong the time to recurrence of paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms in patients without structural heart disease. Also used for the treatment of life-threatening documented ventricular arrhythmias, such as sustained ventricular tachycardia.|FDA Label

Propafenone is an oral antiarrhythmic agent that has been in wide use for several decades. Long term propafenone therapy is associated with a low rate of serum aminotransferase elevations and therapy rarely can cause a self-limited, acute cholestatic liver injury.

Antiarrhythmic Agents

Anti-Arrhythmia Agents|When given as immediate-release tablets, propafenone hydrochloride is used to prolong the time to recurrence of symptomatic, disabling paroxysmal supraventricular tachycardia (PSVT) (e.g., atrioventricular (AV) nodal reentrant tachycardia or AV reentrant tachycardia ( Wolff-Parkinson-White syndrome)) and symptomatic, disabling paroxsymal atrial fibrillation/flutter (PAF) in patients without structural heart disease. While comparative studies are limited, propafenone appears to be comparable to other antiarrhythmic agents (e.g., quinidine, disopyramide, flecainide, procainamide, sotalol) in preventing recurrences of PAF and maintaining sinus rhythm following successful cardioversion of atrial fibrillation. /Included in US product label/|When given as extended-release capsules, propafenone is used to prolong the time to recurrence of symptomatic paroxysmal atrial fibrillation in patients without structural heart disease.289 The safety and efficacy of propafenone as extended-release capsules have not been established in patients with exclusively PSVT or atrial flutter. /Included in US product label/|Propafenone hydrochloride (immediate-release tablets) is used orally to suppress and prevent the recurrence of documented life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation). Based on the results of the Cardiac Arrhythmia Suppression Trial (CAST), the US Food and Drug Administration (FDA), the manufacturer, and many clinicians recommend that therapy with antiarrhythmic agents, including propafenone, be reserved for the suppression and prevention of documented ventricular tachyarrhythmias that, in the clinician's judgment, are considered life-threatening. /Included in US product label/|For more Therapeutic Uses (Complete) data for Propafenone (10 total), please visit the HSDB record page.

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.|The most common adverse effects of propafenone involve the GI, cardiovascular, and central nervous systems and generally are dose related. Discontinuance of propafenone therapy was required in about 20% of patients receiving the drug in clinical trials. Drug discontinuance in patients treated for ventricular arrhythmias was required most frequently (i.e., in greater than 1% of patients) for proarrhythmia (4.7%), nausea and/or vomiting (3.4%), dizziness (2.4%), dyspnea (1.6%), congestive heart failure (1.4%), and ventricular tachycardia (1.2%). In patients treated for supraventricular arrhythmias in clinical trials, discontinuance of therapy was required most frequently (i.e., in greater than 1% of patients) for nausea and/or vomiting (2.9%), wide-complex tachycardia (1.9%), dizziness (1.7%), fatigue (1.5%), unusual taste (1.3%), and weakness (1.3%).|Adverse nervous system effects reported in US clinical trials in patients receiving propafenone for the treatment of ventricular arrhythmias included dizziness and/or lightheadedness of patients, fatigue/lethargy in 6%, and headache in 5%.1 Weakness, ataxia, insomnia, or anxiety was reported in 2%, and tremor or drowsiness in 1% of patients receiving propafenone for ventricular arrhythmias. Pain or loss of balance also has been reported with propafenone therapy in patients with ventricular arrhythmias.|Transient global amnesia, which resolved within hours after drug discontinuance, has been reported in at least one patient receiving propafenone. Peripheral neuropathy, which was characterized by episodic jabbing and crushing pain in the hands and feet and hyperesthesia of the extremities and resolved following discontinuance of the drug, has been reported rarely with propafenone therapy.|For more Drug Warnings (Complete) data for Propafenone (31 total), please visit the HSDB record page.

Propafenone is a Class 1C antiarrhythmic drug with local anesthetic effects, and a direct stabilizing action on myocardial membranes. It is used in the treatment of atrial and ventricular arrhythmias. It acts by inhibiting sodium channels to restrict the entry of sodium into cardiac cells resulting in reduced excitation. Propafenone has local anesthetic activity approximately equal to procaine.

A class of drugs that inhibit the activation of VOLTAGE-GATED SODIUM CHANNELS. (See all compounds classified as Voltage-Gated Sodium Channel Blockers.)|Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade. (See all compounds classified as Anti-Arrhythmia Agents.)

Nearly completely absorbed following oral administration (90%). Systemic bioavailability ranges from 5 to 50%, due to significant first-pass metabolism. This wide range in systemic bioavailability is related to two factors: presence of food (food increases bioavailability) and dosage (bioavailability is 3.4% for a 150-mg tablet compared to 10.6% for a 300-mg tablet).|Approximately 50% of propafenone metabolites are excreted in the urine following administration of immediate release tablets.|252 L|In patients with ventricular arrhythmias and the extensive-metabolizer phenotype receiving 337.5, 450, 675, or 900 mg of propafenone hydrochloride daily (immediate-release tablets), the proportions of 5-hydroxypropafenone (5-OHP) to propafenone in plasma were 45, 40, 24, or 19%, respectively, while a subset of patients with the poor-metabolizer phenotype had higher relative plasma concentrations of the parent drug at each dosage and no detectable 5-OHP. Ratios of N-depropylpropafenone (NDPP) to propafenone are similar in extensive and poor metabolizers (approximately 10 and 6%, respectively). In poor metabolizers, NDPP is the principal metabolite and 5-OHP may not be detectable. Following oral administration of propafenone hydrochloride 300 mg (immediate-release tablets) every 8 hours for 14 days, plasma propafenone, 5-OHP, and NDPP concentrations averaged 1010, 174, and 179 ng/mL, respectively, in healthy individuals with the extensive-metabolizer phenotype. In an individual presumed to have the poor-metabolizer phenotype, plasma concentrations of propafenone, 5-OHP, and NDPP concentrations were 1048, undetectable, and 219 ng/mL, respectively, following oral administration of immediate-release tablets. Following administration of extended-release capsules of propafenone hydrochloride, plasma concentrations of 5-OHP and NDPP are generally less than 40 and 10% of plasma propafenone concentrations, respectively.|The pattern of plasma concentrations of propafenone and its metabolites observed in an individual patient with long-term oral propafenone therapy depends principally on the genetically determined metabolizer phenotype and, to a lesser extent, on hepatic blood flow and enzyme function. Following oral administration of propafenone (immediate-release tablets), steady-state plasma concentrations of the parent drug and its metabolites are attained within 4-5 days in individuals with normal hepatic and renal function. Plasma concentrations of 5-hydroxypropafenone (5-OHP) and N-depropylpropafenone (NDPP) generally average less than 20% those of propafenone. Poor metabolizers achieve plasma propafenone concentrations 1.5-2 times higher than those of extensive metabolizers at propafenone hydrochloride dosages of 675-900 mg (immediate-release tablets) daily; at lower dosages, poor metabolizers may attain plasma propafenone concentrations more than fivefold higher than those of extensive metabolizers.|The considerable degree of interindividual variability observed in the pharmacokinetics of propafenone in individuals with the extensive-metabolizer phenotype is principally attributable to first-pass hepatic metabolism and non-linear pharmacokinetics. The degree of interindividual variability in propafenone pharmacokinetic parameters is increased following single and multiple dose administration of propafenone hydrochloride extended-release capsules. The fact that interindividual variability in the pharmacokinetics of propafenone appears to be substantially less in individuals with the poor-metabolizer phenotype than in those with the extensive-metabolizer phenotype suggests that such variability may be due to CYP2D6 polymorphism rather than to the formulation.|In healthy individuals, administration of propafenone hydrochloride as a single oral (300 or 450 mg immediate-release tablet) or IV (35-50 mg) dose produced similar peak plasma concentrations of the parent drug (278 versus 295 ng/mL, respectively). However, neither 5-hydroxypropafenone (5-OHP) nor N-depropylpropafenone (NDPP) was detectable in plasma after IV administration in these individuals. Since 5-OHP and NDPP has clinically important antiarrhythmic activity, propafenone's effect may differ with oral versus IV administration. Considerable interindividual variation exists in plasma concentrations of propafenone and its metabolites with a given dosage. Peak plasma concentrations of 5-OHP and NDPP average 101-288 and 8-40 ng/mL, respectively, in healthy individuals after administration of a single oral dose (300-450 mg) of propafenone hydrochloride immediate-release tablets. Propafenone, 5-OHP, and NDPP exhibit nonlinear pharmacokinetics in patients with the extensive-metabolizer phenotype, although the pharmacokinetics of 5-OHP and NDPP deviate from linearity only to a small extent. The pharmacokinetic profiles of propafenone, 5-OHP, and NDPP apparently are not affected substantially by age or gender.|For more Absorption, Distribution and Excretion (Complete) data for Propafenone (15 total), please visit the HSDB record page.

Metabolized primarily in the liver where it is rapidly and extensively metabolized to two active metabolites, 5-hydroxypropafenone and N-depropylpropafenone. These metabolites have antiarrhythmic activity comparable to propafenone but are present in concentrations less than 25% of propafenone concentrations.|In individuals with the extensive-metabolizer phenotype, propafenone is metabolized in the liver to 2 active metabolites and at least 9 additional metabolites. The 2 active metabolites, 5-hydroxypropafenone (5-OHP) and N-depropylpropafenone (NDPP), are formed through hydroxylation and dealkylation of the parent drug. Propafenone hydroxylation via cytochrome CYP2D6, a cytochrome P-450 isoenzyme under genetic control, produces 5-OHP. Formation of NDPP is catalyzed by different isoenzymes, cytochrome CYP1A2 and CYP3A4. Differences in metabolism between R- and S-propafenone related to stereoselective interaction with the CYP2D6 isoenzyme have been observed in animals and humans receiving single enantiomers of the drug. Following a 250 mg oral dose of R- or S-propafenone hydrochloride administered to adults with the extensive-metabolizer phenotype, the mean values for elimination half-life, clearance, and volume of distribution for R-propafenone were smaller than those for S-propafenone, while AUC was larger; however, these stereospecific effects were not observed in an adult with the poor-metabolizer phenotype who received the separate drug enantiomers. In vitro and in vivo studies indicate that the R-enantiomer is cleared faster than the S-enantiomer via the 5-hydroxylation pathway (CYP2D6). This results in a higher ratio of the S-enantiomer to R-enantiomer at steady state. Although the enantiomers have equivalent sodium-channel blocking potency, the S-enantiomer is a more potent beta-adrenergic antagonist than the R-enantiomer. Following administration of propafenone hydrochloride (immediate-release tablets or extended-release capsules), the observed ratio of S-enantiomer to R-enantiomer (S/R ratio) for AUC was approximately 1.7. The S/R ratios after administration of 225, 325, or 425 mg extended-release capsules were independent of dose. In addition, similar S/R ratios were observed among metabolizer genotypes and following long-term administration|There are two principal patterns of propafenone metabolism. These patterns are genetically determined by an individual's ability to metabolize the drug via a hepatic oxidation pathway. The ability to oxidatively metabolize propafenone is dependent on an individual's ability to metabolize debrisoquin (debrisoquin phenotype). The debrisoquin phenotype or the observed pattern of propafenone metabolites may be used to determine an individual's metabolic phenotype for propafenone. Individuals who extensively metabolize propafenone via the oxidation pathway exhibit the extensive-metabolizer phenotype, while those who have an impaired ability to metabolize the drug by this pathway exhibit the poor-metabolizer phenotype. Approximately 90-95% of Caucasians exhibit the extensive-metabolizer phenotype, with the remainder being poor metabolizers. Propafenone metabolism in patients with the poor-metabolizer phenotype is characterized by a linear dose-concentration relationship and a relatively long terminal elimination half-life; these individuals have increased plasma propafenone concentrations relative to individuals with the extensive-metabolizer phenotype and are more likely to experience beta-adrenergic blocking and adverse effects of the drug.|Propafenone has known human metabolites that include 5-Hydroxypropafenone and N-Despropylpropafenone.

2-10 hours|Following single or multiple oral doses of immediate-release tablets in adults with the extensive-metabolizer phenotype and normal renal and hepatic function, the elimination half-life of propafenone averages about 1-3 hours (range: 2-10 hours). The half-life of propafenone averages approximately 8-13 hours (range: 6-36 hours) in adults with the poor-metabolizer phenotype. Following a single oral dose of 300 mg of propafenone hydrochloride as immediate-release tablets, a half-life of 3.5 hours was reported; after administration of 300 mg of propafenone hydrochloride daily for 1 and 3 months, the reported half-lives were 6.7 and 5.8 hours, respectively. Steady-state plasma elimination half-life of propafenone is prolonged in poor metabolizers, averaging 17.2 hours (range: 10-32 hours) compared with 5.5 hours (range: 2-10 hours) in extensive metabolizers.

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, which is responsible for the drugs antiarrhythmic actions. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity. 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.|The effects of the antiarrhythmic drug propafenone at Kv2.1 channels were studied with wild-type and mutated channels expressed in Xenopus laevis oocytes. Propafenone decreased the Kv2.1 currents in a time- and voltage-dependent manner (decrease of the time constants of current rise, increase of block with the duration of voltage steps starting from a block of less than 19%, increase of block with the amplitude of depolarization yielding a fractional electrical distance delta of 0.11 to 0.16). Block of Kv2.1 appeared with application to the intracellular, but not the extracellular, side of membrane patches. In mutagenesis experiments, all parts of the Kv2.1 channel were successively exchanged with those of the Kv1.2 channel, which is much more sensitive to propafenone. The intracellular amino and carboxyl terminus and the intracellular linker S4-S5 reduced the blocking effect of propafenone, whereas the linker S5-S6, as well as the segment S6 of the Kv1.2 channel, abolished it to the value of the Kv1.2 channel. In the linker S5-S6, this effect could be narrowed down to two groups of amino acids (groups 372 to 374 and 383 to 384), which also affected the sensitivity to tetraethylammonium. In segment S6, several amino acids in the intracellularly directed part of the helix significantly reduced propafenone sensitivity. The results suggest that propafenone blocks the Kv2.1 channel in the open state from the intracellular side by entering the inner vestibule of the channel. These results are consistent with a direct interaction of propafenone with the lower part of the pore helix and/or residues of segment S6.|Propafenone is considered a class I (membrane-stabilizing) antiarrhythmic agent, although the antiarrhythmic and electrophysiologic actions of the drug are complex in that it also has demonstrated some beta-adrenergic blocking and calcium-channel blocking activity. Like encainide and flecainide, the principal effect of propafenone on cardiac tissue appears to be a concentration-dependent inhibition of the transmembrane influx of extracellular sodium ions via fast sodium channels, as indicated by a decrease in the maximal rate of depolarization of phase 0 of the action potential and a shift of the membrane-responsiveness curve in the hyperpolarizing direction. Since this effect is greater at higher stimulation frequencies and less negative membrane potentials, the drug's sodium blockade is enhanced in ischemic cardiac tissue. Studies in cardiac tissue in animals indicate that propafenone binds to fast sodium channels in both their active and inactive states; the drug thereby inhibits recovery after repolarization in a time- and voltage-dependent manner, which is associated with subsequent dissociation of the drug from the sodium channels. Propafenone induces phasic (frequency-dependent) sodium channel blockade faster than encainide or flecainide, while recovery is similar to flecainide and faster than encainide. Propafenone also appears to have a slight inhibitory effect (approximately 1/75 the potency of verapamil) on the transmembrane influx of extracellular calcium ions via slow calcium channels (calcium-channel blocking effect), but this effect generally occurs only at high drug concentrations and probably does not contribute to antiarrhythmic efficacy. Propafenone has no vagomimetic or vagolytic effect on cardiac muscle.

Intoxication caused by propafenone is very rare, and there are no known detailed epidemiological studies. We present the clinical manifestation of severe propafenone intoxication successfully treated in a 17 year-old male. He was brought to the Intensive Care Unit after he had taken 3.0 g propafenone. The main clinical findings included: sudden cardiac arrest, coma, hypotension, left ventricular failure, bradycardia, sinoatrial block, atrioventricular junctional or/and ventricular tachycardia. During the treatment, transient heart pacing was performed and catecholamines were administered by means of continuous intravenous infusion of pressure doses as well as of infusion liquids. Cessation of toxic signs four hours after admission to hospital was observed. This relatively rare, fully symptomatic intoxication with propafenone deserved to be presented due to the drug's common usage in the treatment of dysrhythmia and life-threatening symptoms of overdosing. The course of the disease was dramatic and the patient survived only thanks to quick resuscitation, artificial ventilation, transient heart pacing, acidosis treatment and administration of pressure doses of catecholamines.|Propafenone is an anti-arrhythmic drug used in the management of supraventricular and ventricular arrhythmias. It is metabolised through cytochrome P450 2D6 pathways; the major metabolites possess anti-arrhythmic activity. The cytochrome P450 CYP2D6 is coded by more than 70 alleles resulting in great genetic polymorphism of CYP2D6 isoenzymes, and up to 7% of Caucasian population are poor metabolisers. This case report describes a patient with severe overdose of propafenone who presented with coma, seizures and cardiotoxicity. The patient was managed with intravenous glucagon, hypertonic sodium bicarbonate, hypertonic saline and inotropic support. The propafenone and its 5-hydroxypropafenone (5-OHP) metabolite were measured by high-performance liquid chromatography with ultraviolet detection (no assay was available at the time to measure N-despropyl propafenone concentrations). Toxicological screen showed propafenone concentrations at a maximum of 1.26 mg/L at 9-10 hr post-presentation, falling to 0.25 mg/L at 27-28 hr post-presentation. No propafenone metabolite 5-OHP was detected in any sample analyzed. No antidepressant or analgesic drugs were detected in toxicological screen. Propafenone overdose has been reported to be associated with features of severe cardiovascular and CNS toxicity. Aggressive treatment, meticulous monitoring and supportive care was associated with a good outcome in this case.|Emergency and supportive measures. Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Continuously monitor vital signs and ECG for a minimum of 6 hours after exposure, and admit the patient for 24 hours of intensive monitoring if there is evidence of toxicity. /Antiarrhythmic drugs/|Specific drugs and antidotes. In patients with intoxication by type 1a or type 1c drugs, QRS prolongation, bradyarrhythmias, and hypoentsion may respond to sodium bicarbonate ... . The sodium bicarbonate reverses cardiac-depressant effects caused by inhibition of the fast sodium channel. /Antiarrhythmic drugs/|For more Antidote and Emergency Treatment (Complete) data for Propafenone (8 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ In general, overdosage of propafenone may be expected to produce effects that are extensions of the drug's pharmacologic effects, particularly those involving cardiac conduction and function and the CNS. Overdosage of propafenone may result in nausea and/or vomiting, hypotension, somnolence, bradycardia, intra-atrial and intraventricular conduction disturbances, and in rare cases, seizures and high-grade ventricular arrhythmias; fatalities also have occurred. Cardiac manifestations may occur within 30-120 minutes after ingestion. Manifestations of overdosage generally are most severe during the 3 hours following the overdose. Nausea generally is the first manifestation of toxicity and may occur within 30 minutes of ingestion of the drug.|/CASE REPORTS/ A 71-year-old woman with atrial fibrillation developed elevations of greater than two times the upper limit of normal in alkaline phosphatase (ALK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyltransferase (GGT) after initiation of propafenone therapy. The patient developed elevations of greater than two times the upper limit of normal in ALK, ALT, and AST, one month after initiating propafenone therapy. The propafenone dose was decreased from 900 to 675 mg/day and, ten days later, the ALK, ALT, and AST were decreased slightly, but still above the upper limit of normal. One month later, serum transaminases had returned to baseline, but propafenone therapy was discontinued because of recurrent atrial fibrillation, persistent elevation in ALK, and elevation in GGT. Two months after discontinuing propafenone, serum aminotransaminase and ALK concentrations had normalized and GGT had decreased and remained only slightly elevated. The occurrence of liver injury secondary to propafenone therapy is rare. Reported cases appear to be secondary to hepatocellular injury, cholestasis, or a combination of the two. In this case, the pattern demonstrated by elevations in liver enzymes may be classified as acute cholestatic liver injury. Because the reported incidence is 0.1-0.2 percent and there are no known fatalities secondary to propafenone liver injury, routine monitoring of liver function tests in all patients receiving propafenone cannot be recommended at this time. Baseline liver function tests prior to initiating propafenone therapy with follow-up laboratory studies one month later are recommended in patients with known liver dysfunction. If elevations are noted, a reduction in dose may result in lower liver enzyme concentrations, although discontinuation of therapy may be required in some cases.|/CASE REPORTS/ ... A patient with episodic jabbing and crushing pain in his hands and feet, aching in his forearms, and hyperesthesias of his extremities /is described/. He had been taking propafenone for 1 year because of ventricular arrhythmias. Results of a nerve conduction velocity test were abnormal. Electron microscopic findings on a sural nerve biopsy specimen represented distal small fiber neuropathy. Findings on a thermoregulatory sweat test and on autonomic tests were abnormal, compatible with a distal small fiber neuropathy. ... . In this patient, propafenone seemed to be responsible for the development of peripheral neuropathy, which resolved after use of the drug had been discontinued.|/CASE REPORTS/ A case of acute liver injury associated with the use of the antiarrhythmic drug propafenone in a 62-year-old woman undergoing clinical observation for recurrent atrial fibrillation is reported. Propafenone hydrochloride, a class 1C antiarrhythmic drug widely used in the clinical practice for the treatment of supraventricular and ventricular arrhythmias, rarely (0.1-0.2% of incidence) causes liver injury characterized by a rise in hepatic cell enzymes or cholestatic enzymes or both. Within 2 months of the discontinuation of therapy the liver function tests return to normal, therefore there are no known fatalities secondary to propafenone liver injury including fulminant hepatitis and death. The close temporal relationship between the administration of the drug and the acute onset of signs of liver injury, the marked rise in liver function tests following the increase of the drug dosage and their gradual normalization after its withdrawal strongly suggest that propafenone is involved in the pathogenesis of this syndrome. Although rare, hepatotoxicity due to this widely used antiarrhythmic drug should be borne in mind in the differential diagnosis of sudden hepatocellular or cholestatic syndrome of obscure origin. It seems prudent to obtain baseline liver function before starting therapy with propafenone and then follow up laboratory tests some months later at least in patients with known liver disease.|For more Human Toxicity Excerpts (Complete) data for Propafenone (26 total), please visit the HSDB record page.

Apo-Propafenone

Table: Propafenone Hydrochloride Preparations [Table#7780]

Analyte: propafenone hydrochloride; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /Propafenone/|Analyte: propafenone hydrochloride; matrix: chemical identification; procedure: dissolution of propafenone hydrochloride in water; heat; add sodium hydroxide; a precipitate is formed; cool mixture and filter; add nitric acid and silver nitrate; a precipitate is formed which dissolves with the addition of ammonium hydroxide. /Propafenone/|Analyte: propafenone hydrochloride; matrix: chemical purity; procedure: dissolution in methanol; add mercuric acetate; titrate with perchloric acid and determine the endpoint potentiometrically. /Propafenone/

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Pharmaceuticals