Quinidine Sulfate Tablet

Description

DESCRIPTION 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 sulfate is the sulfate salt of quinidine; its chemical name is cinchonan-9-ol, 6’- methoxy-, (9S)-, sulfate (2:1) dihydrate; its structural formula is: Its molecular formula is: C 40 H 48 N 4 O 4 ∙H 2 SO 4 ∙2H 2 O; and its molecular weight is 782.96, of which 82.9% is quinidine base. Quinidine sulfate occurs as fine needle-like, white crystals, frequently cohering in masses, or fine, white powder. It is odorless, has a very bitter taste, and darkens on exposure to light. It is slightly soluble in water, soluble in alcohol and in chloroform, and insoluble in ether. Each tablet, for oral administration, contains 200 mg of quinidine sulfate (equivalent to 166 mg of quinidine base) 300 mg of quinidine sulfate (equivalent to 249 mg of quinidine base). In addition, each tablet contains the following inactive ingredients: confectioner’s sugar, corn starch, microcrystalline cellulose, pregelatinized starch and zinc stearate. structure-formula.jpg

What Is Quinidine Sulfate Tablet Used For?

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

DOSAGE AND ADMINISTRATION Treatment of P. Falcipum Malaria Quinidine sulfate tablets are used in one of the approved regimens for the treatment of life-threatening P. falciparum malaria. The central component of the regimen is Quinidine Gluconate Injection, and the regimen is described in the package insert of Quinidine Gluconate Injection. 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 sulfate 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 sulfate 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 sulfate 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...

Side Effects (Adverse Reactions)

ADVERSE REACTIONS Quinidine preparations have been used for many years, but there are only sparse data from which to estimate the incidence of various adverse reactions. The adverse reactions most frequently reported have consistently been gastrointestinal, including diarrhea, nausea, vomiting, and heartburn/esophagitis. In one study of 245 adult outpatients who received quinidine to suppress premature ventricular contractions, the incidences of reported adverse experiences were as shown in the table below. The most serious quinidine-associated adverse reactions are described above under WARNINGS . Adverse Experiences in a 245-Patient PVC Trial Incidence (%) Incidence (%) diarrhea 85 (35) “upper gastrointestinal distress” 55 (22) lightheadedness 37 (15) headache 18 (7) fatigue 17 (7) palpitations 16 (7) angina-like pain 14 (6) weakness 13 (5) rash 11 (5) visual problems 8 (3) change in sleep habits 7 (3) tremor 6 (2) nervousness 5 (2) discoordination 3 (1) Vomiting and diarrhea 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 Epic Pharma, LLC at 1-888-374-2791 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Drug Interactions

Drug Interactions Altered Pharmacokinetics of Quinidine Drugs that alkalinize the urine ( carbonic-anhydrase inhibitors, sodium bicarbonate, thiazide diuretics ) reduce renal elimination of quinidine. By pharmacokinetic mechanisms that are not well understood, quinidine levels are increased by coadministration of amiodarone or cimetidine . Very rarely, and again by mechanisms not understood, quinidine levels are decreased by coadministration of nifedipine . Hepatic elimination of quinidine may be accelerated by coadministration of drugs ( phenobarbital, phenytoin, rifampin ) that induce production of cytochrome P450 IIIA4 . Perhaps because of competition for the P450 IIIA4 metabolic pathway, quinidine levels rise when ketaconazole is coadministered. Coadministration of propranolol usually does not affect quinidine pharmacokinetics, but in some studies the β-blocker appeared to cause increases in the peak serum levels of quinidine, decreases in quinidine’s volume of distribution, and decreases in total quinidine clearance. The effects (if any) of coadministration of other β-blockers on quinidine pharmacokinetics have not been adequately studied. Diltiazem significantly decreases the clearance and increases the t 1/2 of quinidine, but quinidine does not alter the kinetics of diltiazem. Hepatic clearance of quinidine is significantly reduced during coadministration of verapamil , with corresponding increases in serum levels and half-life. Altered Pharmacokinetics of Other Drugs Quinidine slows the elimination of digoxin and simultaneously reduces digoxin’s apparent volume of distribution. As a result, serum digoxin levels may be as much as doubled. When quinidine and digoxin are coadministered, digoxin doses usually need to be reduced. Serum levels of digoxin are also raised when quinidine is coadministered, although the effect appears to be smaller. By a mechanism that is not understood, quinidine potentiates the anticoagulatory action of warfarin , and the anticoagulant dosage may need to be reduced. Cytochrome P450 IID6 is an enzyme critical to the metabolism of many drugs, notably including mexiletine, some phenothiazines , and most polycyclic antidepressants . Constitutional deficiency of cytochrome P450 IID6 is found in less than 1% of Orientals, in about 2% of American blacks, and in about 8% of American whites. Testing with debrisoquine is sometimes used to distinguish the P450 IID6 -deficient “poor metabolizers” from the majority-pheno-type “extensive metabolizers”. When drugs whose metabolism is P450 IID6 -dependent are given to poor metabolizers, the serum levels achieved are higher, sometimes much higher, than the serum levels achieved when identical doses are given to extensive metabolizers. To obtain similar clinical benefit without toxicity, doses given to poor metabolizers may need to be greatly reduced. In the cases of prodrugs whose actions are actually mediated by P450 IID6 -produced metabolites (for example, codeine and...

Contraindications

CONTRAINDICATIONS Quinidine is contraindicated in patients who are known to be allergic to it, or who have developed thrombocytopenic purpura during prior therapy with quinidine or quinine. 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.

Pregnancy and Breastfeeding

Pregnancy Pregnancy Category C Animal reproductive studies have not been conducted with quinidine. There are no adequate and well-controlled studies in pregnant women. Quinidine should be given to a pregnant woman only if clearly needed. Human placental transport of quinidine has not been systematically studied. In one neonate whose mother had received quinidine throughout her pregnancy, the serum level of quinidine was equal to that of the mother, with no apparent ill effect. The level of quinidine in amniotic fluid was about three times higher than that found in serum. In another case, the levels of quinidine and 3-hydroxyquinidine in cord blood were about 30% of simultaneous maternal levels.

Nursing Mothers 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.

Overdosage

OVERDOSAGE Overdoses with various oral formulations of quinidine have been well described. Death has been described after a 5-gram ingestion by a toddler, while an adolescent was reported to survive after ingesting 8 grams of quinidine. The most important ill effects of acute quinidine overdoses are ventricular arrhythmias and hypotension. Other signs and symptoms of overdose may include vomiting, diarrhea, tinnitus, high-frequency hearing loss, vertigo, blurred vision, diplopia, photophobia, headache, confusion, and delirium. Arrhythmias Serum quinidine levels can be conveniently assayed and monitored, but the electrocardiographic QT C interval is a better predictor of quinidine-induced ventricular arrhythmias. The necessary treatment of hemodynamically unstable polymorphic ventricular tachycardia (including torsades de pointes ) is withdrawal of treatment with quinidine and either immediate cardioversion or, if a cardiac pacemaker is in place or immediately available, immediate overdrive pacing. After pacing or cardioversion, further management must be guided by the length of the QT C interval. Quinidine-associated ventricular tachyarrhythmias with normal underlying QT C intervals have not been adequately studied. Because of the theoretical possibility of QT-prolonging effects that might be additive to those of quinidine, other antiarrhythmics with Class I (disopyramide, procainamide) or Class III activities should (if possible) be avoided. Similarly, although the use of bretylium in quinidine overdose has not been reported, it is reasonable to expect that the α–blocking properties of bretylium might be additive to those of quinidine, resulting in problematic hypotension. If the post-cardioversion QT C interval is prolonged, then the precardioversion polymorphic ventricular tachyarrhythmia was (by definition) torsades de pointes . In this case, lidocaine and bretylium are unlikely to be of value, and other Class I antiarrhythmics (disopyramide, procainamide) are...

How Supplied

HOW SUPPLIED Quinidine Sulfate Tablets are supplied as follows: 200 mg - White tablet scored imprinted E511 NDC 42806-513-30 bottles of 30 NDC 42806-513-01 bottles of 100 300 mg - White tablet scored imprinted E512 NDC 42806-512-30 bottles of 30 NDC 42806-512-01 bottles of 100 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container. KEEP OUT OF THE REACH OF CHILDREN. Distributed by: Epic Pharma, LLC Laurelton, NY 11413 Rev.06-2023-00 MF512REV06/23 OS0005