Quinidine Extended Release Tablets

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.

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.

Vomiting and diarrhea can occur as isolated reactions to therapeutic levels of quinidine, but they also may be the first signs of cinchonism, a syndrome that also may 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 All of these have appeared during the first few weeks of therapy, and most (not all) have remitted once quinidine was withdrawn.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 syndromesassociated with quinidine therapy have included pneumonitis, fever, urticaria, flushing, exfoliative rash, bronchospasm, psoriasiform rash, pruritus and lymphadenopathy, hemolytic anemia, vasculitis, 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.

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.

A case of tablet ingestion by a 16-month-old infant has been reported in which a concretion or bezoar was formed in the stomach, resulting in nondeclining toxic levels of quinidine. The mass was only dimly visible on plain radiographs, but a gastric aspirate revealed quinidine levels approximately 50 times higher than those in plasma. In cases of massive overdose with prolonged high plasma levels, diagnostic/therapeutic endoscopy may be appropriate.

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.

Arrythmias

Serum quinidine levels can be conveniently assayed and monitored, but the electrocardiographic QTc 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 QTc interval.

Quinidine-associated ventricular tachyarrhythmias with normal underlying QTc 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 "-blocking properties of bretylium might be additive to those of quinidine, resulting in problematic hypotension.

If the post-cardioversion QTc interval is prolonged, then the pre-cardioversion 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 likely to exacerbate the situation. Factors contributing to QTc prolongation (especially hypokalemia and hypomagnesemia) should be sought out and (if possible) aggressively corrected. Prevention of recurrent torsades may require sustained overdrive pacing or the cautious administration of isoproterenol (30 to 150 ng/kg/min).

Hypotension

Quinidine-induced hypotension that is not due to an arrhythmia is likely to be a consequence of quinidine-related α-blockade and vasorelaxation. Simple repletion of central volume (Trendelenburg positioning, saline infusion) may be sufficient therapy; other interventions reported to have been beneficial in this setting are those that increase peripheral vascular resistance, including α-agonist catecholamines (norepinephrine, metaraminol) and the Military Anti-Shock Trousers.

Treatment

Adequate studies of orally-administered activated charcoal in human overdoses of quinidine have not been reported, but there are animal data showing significant enhancement of systemic elimination following this intervention, and there is at least one human case report in which the elimination half-life of quinidine in the serum was apparently shortened by repeated gastric lavage. Activated charcoal should be avoided if an ileus is present; the conventional dose is 1 gram/kg, administered every 2 to 6 hours as a slurry with 8 mL/kg of tap water.

Although renal elimination of quinidine might theoretically be accelerated by maneuvers to acidify the urine, such maneuvers are potentially hazardous and of no demonstrated benefit.

Quinidine is not usefully removed from the circulation by dialysis. Following quinidine overdose, drugs that delay elimination of quinidine (cimetidine, carbonic-anhydrase inhibitors, thiazide diuretics) should be withdrawn unless absolutely required.

In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your 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 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. Therapy with quinidine sulfate should begin with one tablet (300 mg; 249 mg of quinidine base) every 8 to 12 hours. If this regimen is well tolerated, if the serum quinidine level is still well within the laboratory’s therapeutic range, and if this regimen has not resulted in conversion, then the dose may be cautiously raised. If, at any point during administration, the QRS complex widens to 130% of its pre-treatment duration; the QTc 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 begin with one tablet (300 mg; 249 mg of quinidine base) every eight to 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 QTc 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 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.

Quinidine Sulfate Extended-release Tablets, USP are 300 mg, white film-coated, round, unscored tablets debossed “93” “175” on one side and plain on the other side.

The tablets are available in bottles of 100 and 250.

Store at controlled room temperature, between 20° and 25°C (68° and 77°F) (see USP).

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Manufactured By:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. C 6/2003