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 meta-analysis described under 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 meta-analysis, 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 QTc 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, 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 QTc 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 QTc 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 Heart 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 and Diet 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.
PRECAUTIONS
General
All the precautions applying to regular quinidine therapy apply to this product. Hypersensitivity or anaphylactoid reactions to quinidine, although rare, should be considered, especially during the first weeks of therapy. Hospitalization for close clinical observation, electrocardiographic monitoring, and determination of serum quinidine levels are indicated when large doses of quinidine are used or with patients who present an increased risk.
Laboratory Tests
Periodic blood counts and liver and kidney function tests should be performed during long-term therapy; the drug should be discontinued if blood dyscrasias or evidence of hepatic or renal dysfunction occurs.
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 and Diet 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 P450IIIA4 (P450 3A4).
Perhaps because of competition for the P450 3A4metabolic pathway, quinidine levels rise when ketoconazole 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 t1/2 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.
Grapefruit juice inhibits P450 3A4-mediated metabolism of quinidine to 3-hydroxyquinidine. Although the clinical significance of this interaction is unknown, grapefruit juice should be avoided.
The rate and extent of quinidine absorption may be affected by changes in dietary salt intake; a decrease in dietary salt intake may lead to an increase in plasma quinidine concentrations.
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 digitoxin 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 (P450 2D6) is an enzyme critical to the metabolism of many drugs, notably including mexiletine, some phenothiazines, and most polycyclic antidepressants. Constitutional deficiency of P450 2D6 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 2D6-deficient “poor metabolizers” from the majority-phenotype “extensive metabolizers.”
When drugs whose metabolism is P450 2D6-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 2D6-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 P450 2D6, but therapeutic serum levels of quinidine inhibit the action of P450 2D6, effectively converting extensive metabolizers into poor metabolizers. Caution must be exercised whenever quinidine is prescribed together with drugs metabolized by P450 2D6.
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 P450 3A4, coadministration of quinidine causes variable slowing of the metabolism of nifedipine. Interactions with other dihydropyridine calcium-channel blockers have not been reported, but these agents (including felodipine, nicardipine, and nimodipine) are all dependent upon P450 3A4 for metabolism, so similar interactions with quinidine should be anticipated.
Altered pharmacodynamics of other drugs
Quinidine’s anticholinergic, vasodilating, and negative inotropic actions may be additive to those of other drugs with these effects, and antagonistic to those of drugs with cholinergic, vasoconstricting, and positive inotropic effects. For example, when quinidine and verapamil are coadministered in doses that are each well tolerated as monotherapy, hypotension attributable to additive peripheral α-blockade is sometimes reported.
Quinidine potentiates the actions of depolarizing (succinylcholine, decamethonium) and nondepolarizing (d-tubocurarine, pancuronium) neuromuscular blocking agents. These phenomena are not well understood, but they are observed in animal models as well as in humans. In addition, in vitro addition of quinidine to the serum of pregnant women reduces the activity of pseudocholinesterase, an enzyme that is essential to the metabolism of succinylcholine.
Non-interactions of quinidine with other drugs
Quinidine has no clinically significant effect on the pharmacokinetics of diltiazem, flecainide, mephenytoin, metoprolol, propafenone, propranolol, quinine, timolol, or tocainide.
Conversely, the pharmacokinetics of quinidine are not significantly affected by caffeine, ciprofloxacin, digoxin, felodipine, omeprazole, or quinine. Quinidine’s pharmacokinetics are also unaffected by cigarette smoking.
Information for Patients
Before prescribing Quinidine Sulfate Extended-release Tablets as prophylaxis against recurrence of atrial fibrillation, the physician should inform the patient of the risks and benefits to be expected (see CLINICAL PHARMACOLOGY). Discussion should include the facts
- that the goal of therapy will be a reduction (probably not to zero) in the frequency of episodes of atrial fibrillation; and
- that reduced frequency of fibrillatory episodes may be expected, if achieved, to bring symptomatic benefit; but
- that no data are available to show that reduced frequency of fibrillatory episodes will reduce the risks of irreversible harm through stroke or death; and in fact
- that such data as are available suggest that treatment with quinidine sulfate is likely to increase the patient’s risk of death.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal studies to evaluate quinidine’s carcinogenic or mutagenic potential have not been performed. Similarly, there are no animal data as to quinidine’s potential to impair fertility.
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.
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.
Labor and Delivery
Quinine is said to be oxytocic in humans, but there are no adequate data as to quinidine’s effects (if any) on human labor and delivery.
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.
Pediatric Use
In antimalarial trials, quinidine was as safe and effective in pediatric patients as in adults. Notwithstanding the known pharmacokinetic differences between the pediatric population and adults (see CLINICAL PHARMACOLOGY, Pharmacokinetics), pediatric patients in these trials received the same doses (on a mg/kg basis) as adults.
Safety and effectiveness of the antiarrhythmic use of quinidine in pediatric patients have not been established in well-controlled clinical trials.
Geriatric Use
Clinical studies of quinidine generally were not adequate to determine if significant safety or efficacy differences exist between elderly patients (65 years or older) and younger patients.
Quinidine clearance is apparently independent of age (see CLINICAL PHARMACOLOGY, Pharmacokinetics). However, renal or hepatic dysfunction causes the elimination of quinidine to be slowed (see WARNINGS, Pharmacokinetic Considerations), and since these conditions are more common in the elderly, appropriate dosing reductions should be considered in these individuals.
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