QUINIDINE GLUCONATE- quinidine gluconate tablet, extended release
Sun Pharmaceutical Industries, Inc.
Quinidine is an antimalarial schizonticide and an antiarrhythmic agent with Class Ia activity; it is the d-isomer of quinine, and its molecular weight is 324.43. Quinidine gluconate is the gluconate salt of quinidine; its chemical name is cinchonan-9-ol, 6′-methoxy-, (9S)-, mono-D-gluconate; its structural formula is:
Its empirical formula is C20 H24 N2 O2 • C6 H12 O7 , and its molecular weight is 520.58, of which 62.3% is quinidine base.
Each quinidine gluconate extended-release tablet contains 324 mg of quinidine gluconate (202 mg of quinidine base) in a matrix to provide extended-release; the inactive ingredients include corn starch, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, povidone, silicon dioxide, and sodium alginate.
This product complies with USP Drug Release Test 5.
Pharmacokinetics and Metabolism
The absolute bioavailability of quinidine from quinidine gluconate is 70 to 80%. Relative to a solution of quinidine sulfate, the bioavailability of quinidine from quinidine gluconate is reported to be 1.03. The less-than-complete bioavailability is thought to be due to first-pass elimination by the liver. Peak serum levels generally appear 3 to 5 hours after dosing; when the drug is taken with food, absorption is increased in both rate (27%) and extent (17%). The rate and extent of absorption of quinidine from quinidine gluconate are not significantly affected by the coadministration of an aluminum-hydroxide antacid. The rate of absorption of quinidine following the ingestion of grapefruit juice may be decreased.
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 α1 -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 α1 -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 P450IIIA4 ; there are several different hydroxylated metabolites, and some of these have antiarrhythmic activity.
The most important of quinidine’s metabolites is 3-hydroxy-quinidine (3HQ), serum levels of which can approach those of quinidine in patients receiving conventional doses of quinidine gluconate. 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 on animals, by QTc 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 gluconate 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).
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 de fibrillation threshold as well. Quinidine’s actions fall into Class Ia in the Vaughn-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 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.
Like other antiarrhythmic drugs with Class Ia activity, 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).
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 meta-analysis 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 arrhythmia-related 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 atrial rate in 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 with 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 meta-analysis, 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).
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 gluconate is indicated as a means of restoring normal sinus rhythm. If this use of quinidine gluconate does not restore sinus rhythm within a reasonable time (see DOSAGE AND ADMINISTRATION), then quinidine gluconate should be discontinued.
Reduction of frequency of relapse into atrial fibrillation/flutter
Chronic therapy with quinidine gluconate 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 judgment of the physician and the patient, the risks of prophylactic therapy with quinidine gluconate. The increased risk of death should specifically be considered. Quinidine gluconate 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 gluconate is also indicated for the suppression of recurrent documented ventricular arrhythmias, such as sustained ventricular tachycardia, that in the judgment of the physician are life-threatening. 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 gluconate) have not been shown to enhance survival in patients with ventricular arrhythmias.
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.
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.
Like many other drugs (including all other Class Ia antiarrhythmics), quinidine prolongs the QTc 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 QTc 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 QTc 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.
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).
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.
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.
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