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, hypocalcemia, 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 the 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.

e for conversion of atrial fibrillation/flutter to sinus rhythm. in one reported regimen, the patient first receives two tablets (400 mg; 332 mg of quinidine base) of quinidine sulfate every six hours. if this regimen has not resulted in conversion after 4 or 5 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 sulfate is discontinued, and other means of conversion ( e.g., direct-current cardioversion) are considered. reduction of 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 sulfate should be an increase in the average time between episodes. in most patients, the tachyarrhythmia will recur during therapy with quinidine sulfate, 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 sulfate 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 sulfate should be begun with 200 mg (equivalent to 166 mg of quinidine base) every six 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 pretreatment duration; the qt c interval widens to 130% of its pretreatment duration and is then longer than 500 ms; p waves disappear; or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension. suppression of ventricular arrhythmias dosing regimens for the use of quinidine sulfate 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.

ea can occur as isolated reactions to therapeutic levels of quinidine, but they may also be the first signs of cinchonism, a syndrome that may also include tinnitus, reversible high-frequency hearing loss, deafness, vertigo, blurred vision, diplopia, photophobia, headache, confusion, and delirium. cinchonism is most often a sign of chronic quinidine toxicity, but it may appear in sensitive patients after a single moderate dose. a few cases of hepatotoxicity , including granulomatous hepatitis, have been reported in patients receiving quinidine. all of these have appeared during the first few weeks of therapy, and most (not all) have remitted once quinidine was withdrawn. autoimmune and inflammatory syndromes associated with quinidine therapy have included fever, urticaria, flushing, exfoliative rash, bronchospasm, psoriaform rash, pruritus and lymphadenopathy, hemolytic anemia, vasculitis, pneumonitis, thrombocytopenic purpura, uveitis, angioedema, agranulocytosis, the sicca syndrome, arthralgia, myalgia, elevation in serum levels of skeletal-muscle enzymes, and a disorder resembling systemic lupus erythematosus. convulsions, apprehension, and ataxia have been reported, but it is not clear that these were not simply the results of hypotension and consequent cerebral hypoperfusion. there are many reports of syncope. acute psychotic reactions have been reported to follow the first dose of quinidine, but these reactions appear to be extremely rare. other adverse reactions occasionally reported include depression, mydriasis, disturbed color perception, night blindness, scotomata, optic neuritis, visual field loss, photosensitivity, and abnormalities of pigmentation. to report suspected adverse reactions, contact sandoz inc. at 1-800-525-8747 or fda at 1-800-fda-1088 or www.fda.gov/medwatch

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 ).