quinidine gluconate 324 MG Extended Release Oral Tablet

INDICATIONS AND USAGE Conversion of Atrial Fibrillation/Flutter In patients with symptomatic atrial fibrillation/flutter whose symptoms are not adequately controlled by measures that reduce the rate of ventricular response, quinidine sulfate is indicated as a means of restoring normal sinus rhythm. If this use of quinidine sulfate does not restore sinus rhythm within a reasonable time (see DOSAGE AND ADMINISTRATION ), then quinidine sulfate should be discontinued. Reduction of Frequency of Relapse Into Atrial Fibrillation/Flutter Chronic therapy with quinidine sulfate is indicated for some patients at high risk of symptomatic atrial fibrillation/flutter, generally patients who have had previous episodes of atrial fibrillation/flutter that were so frequent and poorly tolerated as to outweigh, in the judgement of the physician and the patient, the risks of prophylactic therapy with quinidine sulfate. The increased risk of death should specifically be considered. Quinidine sulfate should be used only after alternative measures ( e.g., use of other drugs to control the ventricular rate) have been found to be inadequate. In patients with histories of frequent symptomatic episodes of atrial fibrillation/flutter, the goal of therapy should be an increase in the average time between episodes. In most patients, the tachyarrhythmia will recur during therapy, and a single recurrence should not be interpreted as therapeutic failure. Suppression of Ventricular Arrhythmias Quinidine sulfate is also indicated for the suppression of recurrent documented ventricular arrhythmias, such as sustained ventricular tachycardia, that in the judgement of the physician are lifethreatening. Because of the proarrhythmic effects of quinidine, its use with ventricular arrhythmias of lesser severity is generally not recommended, and treatment of patients with asymptomatic ventricular premature contractions should be avoided. Where possible, therapy should be guided by the results of programmed electrical stimulation and/or Holter monitoring with exercise. Antiarrhythmic drugs (including quinidine sulfate) have not been shown to enhance survival in patients with ventricular arrhythmias. Treatment of Malaria Quinidine sulfate is also indicated in the treatment of life-threatening Plasmodium falciparum malaria .

DOSAGE AND ADMINISTRATION The dose of quinidine delivered by quinidine gluconate extended-release tablets may be titrated by breaking a tablet in half. If tablets are crushed or chewed, their extended-release properties will be lost. The dosage of quinidine varies considerably depending upon the general condition and the cardiovascular state of the patient. Conversion of atrial fibrillation/flutter to sinus rhythm Especially in patients with known structural heart disease or other risk factors for toxicity, initiation or dose-adjustment of treatment with quinidine gluconate should generally be performed in a setting where facilities and personnel for monitoring and resuscitation are continuously available. Patients with symptomatic atrial fibrillation/flutter should be treated with quinidine gluconate only after ventricular rate control (e.g., with digitalis or β-blockers) has failed to provide satisfactory control of symptoms. Adequate trials have not identified an optimal regimen of quinidine gluconate for conversion of atrial fibrillation/flutter to sinus rhythm. In one reported regimen, the patient first receives two tablets (648 mg; 403 mg of quinidine base) of quinidine gluconate every eight hours. If this regimen has not resulted in conversion after 3 or 4 doses, then the dose is cautiously increased. If, at any point during administration, the QRS complex widens to 130% of its pre-treatment duration; the QT c interval widens to 130% of its pre-treatment duration and is then longer than 500 ms; P waves disappear; or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension, then quinidine gluconate is discontinued, and other means of conversion (e.g., direct-current cardioversion) are considered. In another regimen sometimes used, the patient receives one tablet (324 mg; 202 mg of quinidine base) every eight hours for two days; then two tablets every twelve hours for two days; and finally two tablets every eight hours for up to four days. The four-day stretch may come at one of the lower doses if, in the judgment of the physician, the lower dose is the highest one that will be tolerated. The criteria for discontinuation of treatment with quinidine gluconate are the same as in the other regimen. Reduction in the frequency of relapse into atrial fibrillation/flutter In a patient with a history of frequent symptomatic episodes of atrial fibrillation/flutter, the goal of therapy with quinidine gluconate should be an increase in the average time between episodes. In most patients, the tachyarrhythmia will recur during therapy with quinidine gluconate, and a single recurrence should not be interpreted as therapeutic failure. Especially in patients with known structural heart disease or other risk factors for toxicity, initiation or dose-adjustment of treatment with quinidine gluconate should generally be performed in a setting where facilities and personnel for monitoring and resuscitation are continuously available. Monitoring should be continued for two or three days after initiation of the regimen on which the patient will be discharged. Therapy with quinidine gluconate should be begun with one tablet (324 mg; 202 mg of quinidine base) every eight or twelve hours. If this regimen is well tolerated, if the serum quinidine level is still well within the laboratory's therapeutic range, and if the average time between arrhythmic episodes has not been satisfactorily increased, then the dose may be cautiously raised. The total daily dosage should be reduced if the QRS complex widens to 130% of its pre-treatment duration; the QT c interval widens to 130% of its pre-treatment duration and is then longer than 500 ms; P waves disappear; or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension. Suppression of life-threatening ventricular arrhythmias Dosing regimens for the use of quinidine gluconate in suppressing life-threatening ventricular arrhythmias have not been adequately studied. Described regimens have generally been similar to the regimen described just above for the prophylaxis of symptomatic atrial fibrillation/flutter. Where possible, therapy should be guided by the results of programmed electrical stimulation and/or Holter monitoring with exercise.

WARNINGS Mortality: In many trials of antiarrhythmic therapy for non-life-threatening arrhythmias, active antiarrhythmic therapy has resulted in increased mortality; the risk of active therapy is probably greatest in patients with structural heart disease. In the case of quinidine used to prevent or defer recurrence of atrial flutter/fibrillation, the best available data come from a meta-analysis described under CLINICAL PHARMACOLOGY/Clinical Effects above. In the patients studied in the trials there analyzed, the mortality associated with the use of quinidine was more than three times as great as the mortality associated with the use of placebo. Another meta-analysis, also described under CLINICAL PHARMACOLOGY/Clinical Effects , showed that in patients with various non-life-threatening ventricular arrhythmias, the mortality associated with the use of quinidine was consistently greater than that associated with the use of any of a variety of alternative antiarrhythmics. Proarrhythmic effects Like many other drugs (including all other Class Ia antiarrhythmics), quinidine prolongs the QT c interval, and this can lead to torsades de pointes , a life-threatening ventricular arrhythmia (see OVERDOSAGE ). The risk of torsades is increased by bradycardia, hypokalemia, hypomagnesemia or high serum levels of quinidine, but it may appear in the absence of any of these risk factors. The best predictor of this arrhythmia appears to be the length of QT c interval, and quinidine should be used with extreme care in patients who have preexisting long-QT syndromes, who have histories of torsades de pointes of any cause, or who have previously responded to quinidine (or other drugs that prolong ventricular repolarization) with marked lengthening of the QT c interval. Estimation of the incidence of torsades in patients with therapeutic levels of quinidine is not possible from the available data. Other ventricular arrhythmias that have been reported with quinidine include frequent extrasystoles, ventricular tachycardia, ventricular flutter, and ventricular fibrillation. Paradoxical increase in ventricular rate in atrial flutter/fibrillation When quinidine is administered to patients with atrial flutter/fibrillation, the desired pharmacologic reversion to sinus rhythm may (rarely) be preceded by a slowing of the atrial rate with a consequent increase in the rate of beats conducted to the ventricles. The resulting ventricular rate may be very high (greater than 200 beats per minute) and poorly tolerated. This hazard may be decreased if partial atrioventricular block is achieved prior to initiation of quinidine therapy, using conduction-reducing drugs such as digitalis, verapamil, diltiazem, or a β-receptor blocking agent. Exacerbated bradycardia in sick sinus syndrome In patients with the sick sinus syndrome, quinidine has been associated with marked sinus node depression and bradycardia. Pharmacokinetic considerations Renal or hepatic dysfunction causes the elimination of quinidine to be slowed, while congestive heart failure causes a reduction in quinidine's apparent volume of distribution. Any of these conditions can lead to quinidine toxicity if dosage is not appropriately reduced. In addition, interactions with coadministered drugs can alter the serum concentration and activity of quinidine, leading either to toxicity or to lack of efficacy if the dose of quinidine is not appropriately modified (see PRECAUTIONS/Drug Interactions ). Vagolysis Because quinidine opposes the atrial and A-V nodal effects of vagal stimulation, physical or pharmacological vagal maneuvers undertaken to terminate paroxysmal supraventricular tachycardia may be ineffective in patients receiving quinidine. Thrombocytopenia Quinidine-induced thrombocytopenia is an immune-mediated disorder characterized by a drug-dependent antibody that is itself nonreactive, but when soluble drug is present at pharmacologic concentrations, binds tightly to specific platelet membrane glycoproteins, causing platelet destruction. 1 Serologic testing for quinidine-specific antibody is commercially available and may be useful for identifying the specific cause of thrombocytopenia in individual cases. Testing is important because a patient with quinidine-dependent antibodies should not be re-exposed to quinidine. A case control study found a 125-fold increased risk of severe thrombocytopenia (platelets <30,000 µL, requiring hospitalization) with quinidine. 2 The incidence of quinidine-induced thrombocytopenia was 1.8 cases per 1,000 patient years of exposure. The incidence of less severe thrombocytopenia may be higher. Typically, a patient with immune thrombocytopenia will have taken drug for about 1 week or intermittently over a longer period of time (possibly years) before presenting with petechiae or bruising. Systemic symptoms, such as lightheadedness, chills, fever, nausea, and vomiting, often may precede bleeding events. Thrombocytopenia may be severe. Patients should have risk/benefit re-evaluated in order to continue treatment with quinidine. If the drug is stopped, symptoms usually resolve within 1 or 2 days and platelet count returns to normal in less than 1 week. If quinidine is not stopped, there is a risk of fatal hemorrhage. The onset of thrombocytopenia may be more rapid upon re-exposure.

CONTRAINDICATIONS Quinidine is contraindicated in patients who are known to be allergic to it, or who have a history of immune thrombocytopenia or have developed thrombocytopenic purpura during prior therapy with quinidine or quinine (see WARNINGS ). In the absence of a functioning artificial pacemaker, quinidine is also contraindicated in any patient whose cardiac rhythm is dependent upon a junctional or idioventricular pacemaker, including patients in complete atrioventricular block. Quinidine is also contraindicated in patients who, like those with myasthenia gravis, might be adversely affected by an anticholinergic agent.

CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism The absolute bioavailability of quinidine from quinidine sulfate tablets is about 70%, but this varies widely (45 to 100%) between patients. The less-than-complete bioavailability is the result of first-pass metabolism in the liver. Peak serum levels generally appear about 2 hours after dosing; the rate of absorption is somewhat slowed when the drug is taken with food, but the extent of absorption is not changed. The volume of distribution of quinidine is 2 to 3 L/kg in healthy young adults, but this may be reduced to as little as 0.5 L/kg in patients with congestive heart failure, or increased to 3 to 5 L/kg in patients with cirrhosis of the liver. At concentrations of 2 to 5 mg/L (6.5 to 16.2 μmol/L), the fraction of quinidine bound to plasma proteins (mainly to α 1 -acid glycoprotein and to albumin) is 80 to 88% in adults and older children, but it is lower in pregnant women, and in infants and neonates it may be as low as 50 to 70%. Because α 1 -acid glycoprotein levels are increased in response to stress, serum levels of total quinidine may be greatly increased in settings such as acute myocardial infarction, even though the serum content of unbound (active) drug may remain normal. Protein binding is also increased in chronic renal failure, but binding abruptly descends toward or below normal when heparin is administered for hemodialysis. Quinidine clearance typically proceeds at 3 to 5 mL/min/kg in adults, but clearance in children may be twice or three times as rapid. The elimination half-life is 6 to 8 hours in adults and 3 to 4 hours in children. Quinidine clearance is unaffected by hepatic cirrhosis, so the increased volume of distribution seen in cirrhosis leads to a proportionate increase in the elimination half-life. Most quinidine is eliminated hepatically via the action of cytochrome P450 IIIA4 ; there are several different hydroxylated metabolites, and some of these have antiarrhythmic activity. The most important of quinidine’s metabolites is 3-hydroxyquinidine (3HQ), serum levels of which can exceed those of quinidine in patients receiving conventional doses of quinidine sulfate. The volume of distribution of 3HQ appears to be larger than that of quinidine, and the elimination half-life of 3HQ is about 12 hours. As measured by antiarrhythmic effects in animals, by QT C prolongation in human volunteers, or by various in vitro techniques, 3HQ has at least half the antiarrhythmic activity of the parent compound, so it may be responsible for a substantial fraction of the effect of quinidine sulfate in chronic use. When the urine pH is less than 7, about 20% of administered quinidine appears unchanged in the urine, but this fraction drops to as little as 5% when the urine is more alkaline. Renal clearance involves both glomerular filtration and active tubular secretion, moderated by (pH-dependent) tubular reabsorption. The net renal clearance is about 1 mL/min/kg in healthy adults. When renal function is taken into account, quinidine clearance is apparently independent of patient age. Assays of serum quinidine levels are widely available, but the results of modern assays may not be consistent with results cited in the older medical literature. The serum levels of quinidine cited in this package insert are those derived from specific assays, using either benzene extraction or (preferably) reverse-phase high-pressure liquid chromatography. In matched samples, older assays might unpredictably have given results that were as much as two or three times higher. A typical “therapeutic” concentration range is 2 to 6 mg/L (6.2 to 18.5 μmol/L). Mechanisms of Action In patients with malaria, quinidine acts primarily as an intra-erythrocytic schizonticide, with little effect upon sporozites or upon pre-erythrocytic parasites. Quinidine is gametocidal to Plasmodium vivax and P. malariae , but not to P. falciparum . In cardiac muscle and in Purkinje fibers, quinidine depresses the rapid inward depolarizing sodium current, thereby slowing phase-0 depolarization and reducing the amplitude of the action potential without affecting the resting potential. In normal Purkinje fibers, it reduces the slope of phase-4 depolarization, shifting the threshold voltage upward toward zero. The result is slowed conduction and reduced automaticity in all parts of the heart, with increase of the effective refractory period relative to the duration of the action potential in the atria, ventricles, and Purkinje tissues. Quinidine also raises the fibrillation thresholds of the atria and ventricles, and it raises the ventricular defibrillation threshold as well. Quinidine’s actions fall into class 1A in the Vaughan-Williams classification. By slowing conduction and prolonging the effective refractory period, quinidine can interrupt or prevent reentrant arrhythmias and arrhythmias due to increased automaticity, including atrial flutter, atrial fibrillation, and paroxysmal supraventricular tachycardia. In patients with the sick sinus syndrome, quinidine can cause marked sinus node depression and bradycardia. In most patients, however, use of quinidine is associated with an increase in the sinus rate. Quinidine prolongs the QT interval in a dose-related fashion. This may lead to increased ventricular automaticity and polymorphic ventricular tachycardias, including torsades de pointes (see WARNINGS ). In addition, quinidine has anticholinergic activity, it has negative inotropic activity, and it acts peripherally as an α-adrenergic antagonist (that is, as a vasodilator). Clinical Effects Maintenance of Sinus Rhythm After Conversion From Atrial Fibrillation In six clinical trials (published between 1970 and 1984) with a total of 808 patients, quinidine (418 patients) was compared to nontreatment (258 patients) or placebo (132 patients) for the maintenance of sinus rhythm after cardioversion from chronic atrial fibrillation. Quinidine was consistently more efficacious in maintaining sinus rhythm, but a metaanalysis found that mortality in the quinidine-exposed patients (2.9%) was significantly greater than mortality in the patients who had not been treated with active drug (0.8%). Suppression of atrial fibrillation with quinidine has theoretical patient benefits ( e.g., improved exercise tolerance; reduction in hospitalization for cardioversion; lack of arrhythmiarelated palpitations, dyspnea, and chest pain; reduced incidence of systemic embolism and/or stroke), but these benefits have never been demonstrated in clinical trials. Some of these benefits ( e.g., reduction in stroke incidence) may be achievable by other means (anticoagulation). By slowing the rate of atrial flutter/fibrillation, quinidine can decrease the degree of atrioventricular block and cause an increase, sometimes marked, in the rate at which supraventricular impulses are successfully conducted by the atrioventricular node, with a resultant paradoxical increase in ventricular rate (see WARNINGS ). Non-Life-Threatening Ventricular Arrhythmias In studies of patients with a variety of ventricular arrhythmias (mainly frequent ventricular premature beats and non-sustained ventricular tachycardia), quinidine (total N=502) has been compared to flecainide (N=141), mexiletine (N=246), propafenone (N=53), and tocainide (N=67). In each of these studies, the mortality in the quinidine group was numerically greater than the mortality in the comparator group. When the studies were combined in a metaanalysis, quinidine was associated with a statistically significant threefold relative risk of death. At therapeutic doses, quinidine’s only consistent effect upon the surface electrocardiogram is an increase in the QT interval. This prolongation can be monitored as a guide to safety, and it may provide better guidance than serum drug levels (see WARNINGS ).