Quinidine Sulfate 300 mg Tablet, 100-count — NDC 42806-512-01 (Billing 42806-0512-01)

WARNINGS Mortality 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 metaanalysis 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 metaanalysis, 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. Proarrhythmic Effects Like many 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.

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 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 hydrocodone , whose analgesic and antitussive effects appear to be mediated by morphine and hydromorphone, respectively), it may not be possible to achieve the desired clinical benefits in poor metabolizers. Quinidine is not metabolized by cytochrome P450 IID6 , but therapeutic serum levels of quinidine inhibit the action of cytochrome P450 IID6 , effectively converting extensive metabolizers into poor metabolizers.

Caution must be exercised whenever quinidine is prescribed together with drugs metabolized by cytochrome P450 IID6 . Perhaps by competing for pathways of renal clearance, coadministration of quinidine causes an increase in serum levels of procainamide . Serum levels of haloperidol are increased when quinidine is coadministered.

Presumably because both drugs are metabolized by cytochrome P450 IID6 , coadministration of quinidine causes variable slowing of the metabolism of nifedipine . Interactions with other dihydropyridine calcium-channel blockers have not been reported, but these… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS Heart Block In patients without implanted pacemakers who are at high risk of complete atrioventricular block ( e.g., those with digitalis intoxication, second-degree atrioventricular block, or severe intraventricular conduction defects), quinidine should be used only with caution. 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 hydrocodone , whose analgesic and antitussive effects appear to be mediated by morphine and hydromorphone, respectively), it may not be possible to achieve the desired clinical benefits in poor metabolizers.

Quinidine is not metabolized by cytochrome P450 IID6 , but therapeutic serum levels of quinidine inhibit the action of cytochrome P450 IID6 , effectively converting extensive metabolizers into poor metabolizers. Caution must be exercised whenever quinidine is prescribed together with drugs metabolized by cytochrome P450 IID6 . Perhaps by competing for pathways of renal clearance, coadministration of quinidine causes an increase in serum levels of procainamide .

Serum levels of haloperidol are increased… [Excerpted — this section continues on DailyMed.]