QUINIDINE GLUCONATE
INJECTION, USP
This product is to be used by the physician
or under his/her direction.

Quinidine is an antimalarial schizonticide and an antiarrhythmic agent with class 1a 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 C₂₀H₂₄N₂O₂•C₆H₁₂O₇, and its molecular weight is 520.58, of which 62.3% is quinidine base.

Each vial of Quinidine Gluconate Injection contains 800 mg (1.5 mmol) of quinidine gluconate (500 mg of quinidine) in 10 mL of Sterile Water for Injection, 0.005% of edetate disodium, 0.25% phenol, and (as needed) D–gluconic acid δ–lactone to adjust the pH.

After intramuscular injection of quinidine gluconate, peak serum levels of quinidine are achieved in a little less than two hours. This time to peak levels is identical to the time measured when quinidine salts are administered orally.

The volume of distribution of quinidine is typically 2–3 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 3–5 L/kg in patients with cirrhosis of the liver. At concentrations of 2–5 mg/L (6.5–16.2 μmol/L), the fraction of quinidine bound to plasma proteins (mainly to α₁–acid glycoprotein and to albumin) is 80–88% in adults and older children, but it is lower in pregnant women, and in infants and neonates it may be as low as 50–70%. 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 span 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 3–5 mL/min/kg in adults, but clearance in pediatric patients may be twice or three times as rapid. The elimination half–life is about 6–8 hours in adults and 3–4 hours in pediatric patients. 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 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 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 2–6 mg/L (6.2 – 18.5 μmol/L).

In patients with malaria, quinidine acts primarily as an intraerythrocytic schizonticide, with little effect upon sporozoites 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 Ia 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 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).

Intravenous quinidine has been associated with clearing of parasliia and high rates of survival in patients with severe P. falciparum malaria and hyperparasliia. Placebo–controlled trials have not been performed, but clearing of these levels of parasliia is unprecedented in the absence of effective therapy. Use of quinidine in patients infected with chloroquine–sensitive malaria or in chloroquine–resistant non–falciparum malaria has not been reported.

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 (eg, 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 (eg, 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).

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 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).

Quinidine gluconate injection is indicated for the treatment of life–threatening Plasmodium falciparum malaria.

Quinidine gluconate injection is also indicated (when rapid therapeutic effect is required, or when oral therapy is not feasible) as a means of restoring normal sinus rhythm in patients with symptomatic atrial fibrillation/flutter whose symptoms are not adequately controlled by measures that reduce the rate of ventricular response. If this use of quinidine gluconate does not restore sinus rhythm within a reasonable time, then its use should be discontinued.

Quinidine gluconate injection is also indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that in the judgement 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) have not been shown to enhance survival in patients with ventricular arrhythmias.

In patients without implanted pacemakers who are at high risk of complete atrioventricular block (eg, those with digitalis intoxication, second–degree atrioventricular block, or severe intraventricular conduction defects), quinidine should be used only with caution.

Quinine is said to be oxytocic in humans, but there are no adequate data as to quinidine's effect (if any) on human labor and delivery.

Quinidine is present in human milk at levels slightly lower than those in maternal serum; a human infant ingesting such milk should (scaling directly by weight) be expected to develop serum quinidine levels at least an order of magnitude lower than those of the mother. On the other hand, the pharmacokinetics and pharmacodynamics of quinidine in human infants have not been adequately studied, and neonates' reduced protein binding of quinidine may increase their risk of toxicity at low total serum levels. Administration of quinidine should (if possible) be avoided in lactating women who continue to nurse.

In antimalarial trials, quinidine was as safe and effective in pediatric patients as in adults. Notwithstanding the known pharmacokinetic differences between pediatric patients and adults (see Pharmacokinetics and Metabolism), pediatric patients in these trials received the same doses (on a mg/kg basis) as adults.

Safety and effectiveness of antiarrhythmic use in pediatric patients have not been established.

Safety and efficacy of quinidine in elderly patients has not been systematically studied. Clinical studies of quinidine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. The reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

Text revised June 9, 1999
Literature issued May 20, 2002

Eli Lilly and Company, Indianapolis, IN 46285, USA