QUINIDINE PHENYLETHYL BARBITURATE
DESCRIPTION:
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.
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 polygalacturonate is a polymer of quinidine and galacturonic
acid.
Its empirical formula is
(C20H24N2O2--C6H10O7--H2O)n. The molecular weight of the monomer is 536.58, of
which 60.46% is quinidine base.
Quinidine polygalacturonate is a creamy white, amorphous powder, sparingly
soluble in water but freely soluble in hot 40% ethanol. Each CARDIOQUIN tablet
contains 275 mg of quinidine polygalacturonate (166 mg of quinidine base); the
inactive ingredients include corn starch, lactose, magnesium stearate, povidone,
and talc.
ACTIONS/CLINICAL PHARMACOLOGY:
PHARMACOKINETICS AND METABOLISM The absolute bioavailability of orally-
administered CARDIOQUIN is about 70%, but this varies widely (45-100%) between
patients. The less-than-complete bioavailability is the result of first-pass
metabolism in the liver. Peak serum levels generally appear about 2 hours after
dosing; absorption is delayed, but not changed in extent, when the drug is taken
with food.
The VOLUME OF DISTRIBUTION of quinidine is 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 mumol/L), the fraction of quinidine bound
to plasma proteins (mainly to alpha1-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 alpha1-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 content 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 children may be twice or three times as rapid. The elimination half-life is
about 6-8 hours in adults and 3-4 hours in children. 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 CARDIOQUIN. 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 QTc 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 CARDIOQUIN 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
mumol/L).
MECHANISMS OF ACTION In patients with malaria, quinidine acts primarily as an
intra-erythrocytic 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-O 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 1a in the Vaughn-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, 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 alpha-adrenergic antagonist (that is,
as a vasodilator).
CLINICAL EFFECTS
MAINTENANCE OF SINUS RHYTHM AFTER CONVERSION FROM ATRIAL FIBRILLATION: In six
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 (e.g., 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 (e.g., 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).
NON-LIFE-THREATENING VENTRICULAR ARRHYTHMIAS: 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).
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, CARDIOQUIN is indicated as a means
of restoring normal sinus rhythm. If this use of CARDIOQUIN does not restore
sinus rhythm within a reasonable time (see DOSAGE AND ADMINISTRATION), then
CARDIOQUIN should be discontinued.
REDUCTION OF FREQUENCY OF RELAPSE INTO ATRIAL FIBRILLATION/FLUTTER: Chronic
therapy with CARDIOQUIN 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 judgment of the physician and the
patient, the risks of prophylactic therapy with CARDIOQUIN. The increased risk
of death should specifically be considered. CARDIOQUIN 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: CARDIOQUIN is also indicated for the
suppression of recurrent documented ventricular arrhythmias, such as sustained
ventricular tachycardia, that in the judgment 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 CARDIOQUIN) have not been shown to enhance
survival in patients with ventricular arrhythmias.
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.
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 1a
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 any of: bradycardia, hypokalemia,
hypomagnesemia, and 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 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 beta-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.
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
P450IIIA4.
Perhaps because of competition for the P450IIIA4 metabolic pathway, quinidine
levels rise when KETOCONAZOLE is coadministered.
Coadministration of propranolol usually does not affect quinidine
pharmacokinetics, but in some studies the beta-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 BETA-BLOCKERS on quinidine pharmacokinetics
have not been adequately studied.
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 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 P450IID6 is an enzyme critical to the metabolism of many drugs,
notably including MEXILETINE, some PHENOTHIAZINES, and most POLYCYCLIC
ANTIDEPRESSANTS. Constitutional deficiency of cytochrome P450IID6 is found in
less than 1% of Orientals, in about 2% of American blacks, and in some 8% of
American whites.
Testing with debrisoquine is sometimes used to distinguish the P450IID6-
deficient "poor metabolizers" from the majority-phenotype "extensive
metabolizers."
When drugs whose metabolism is P450IID6-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 P450IID6-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 P450IID6, but therapeutic serum
levels of quinidine inhibit the action of cytochrome P450IID6, effectively
converting extensive metabolizers into poor metabolizers. Caution must be
exercised whenever quinidine is prescribed together with drugs metabolized by
cytochrome P450IID6.
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 P450IIIA4,
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 P450IIIA4 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 alpha- blockade is
sometimes reported.
Quinidine potentiates the actions of depolarizing (succinylcholine,
decamethonium) and nondepolarizing (delta-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
pseudo- cholinesterase, an enzyme that is essential to the metabolism of
succinylcholine.
NON-INTERACTION 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, DILTIAZEM, FELODIPINE, OMEPRAZOLE, or QUININE.
Quinidine's pharmacokinetics are also unaffected by cigarette smoking.
INFORMATION FOR PATIENTS: Before prescribing CARDIOQUIN 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 benefits; 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 CARDIOQUIN 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 known 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.
GERIATRIC USE
Safety and efficacy of quinidine in elderly patients has not been systematically
studied.
PEDIATRIC USE
In antimalarial trials, quinidine was as safe and effective in pediatric
patients as in adults. Notwithstanding the known pharmacokinetic differences
between children and adults (see PHARMACOKINETICS AND METABOLISM), children in
these trials received the same doses (on a mg/kg basis) as adults.
Safety and effectiveness of antiarrhythmic use in children have not been
established.
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
P450IIIA4.
Perhaps because of competition for the P450IIIA4 metabolic pathway, quinidine
levels rise when KETOCONAZOLE is coadministered.
Coadministration of propranolol usually does not affect quinidine
pharmacokinetics, but in some studies the beta-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 BETA-BLOCKERS on quinidine pharmacokinetics
have not been adequately studied.
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 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 P450IID6 is an enzyme critical to the metabolism of many drugs,
notably including MEXILETINE, some PHENOTHIAZINES, and most POLYCYCLIC
ANTIDEPRESSANTS. Constitutional deficiency of cytochrome P450IID6 is found in
less than 1% of Orientals, in about 2% of American blacks, and in some 8% of
American whites.
Testing with debrisoquine is sometimes used to distinguish the P450IID6-
deficient "poor metabolizers" from the majority-phenotype "extensive
metabolizers."
When drugs whose metabolism is P450IID6-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 P450IID6-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 P450IID6, but therapeutic serum
levels of quinidine inhibit the action of cytochrome P450IID6, effectively
converting extensive metabolizers into poor metabolizers. Caution must be
exercised whenever quinidine is prescribed together with drugs metabolized by
cytochrome P450IID6.
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 P450IIIA4,
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 P450IIIA4 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 alpha- blockade is
sometimes reported.
Quinidine potentiates the actions of depolarizing (succinylcholine,
decamethonium) and nondepolarizing (delta-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
pseudo- cholinesterase, an enzyme that is essential to the metabolism of
succinylcholine.
NON-INTERACTION 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, DILTIAZEM, FELODIPINE, OMEPRAZOLE, or QUININE.
Quinidine's pharmacokinetics are also unaffected by cigarette smoking.
INFORMATION FOR PATIENTS: Before prescribing CARDIOQUIN 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 benefits; 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 CARDIOQUIN is
likely to increase the patient's risk of death.
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 (%)
diarrhea 85 (35)
"upper gastrointestinal 55 (22)
distress"
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, psoriasi-
form 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, a disorder resembling systemic lupus erythematosus, and pneumonitis.
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.
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 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 treatment 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 alpha-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 (30-150 ng/kg/min).
HYPOTENSION: Quinidine-induced hypotension that is not due to an arrhythmia is
likely to be a consequence of quinidine-related alpha-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 alpha-agonist catecholamines (norepinephrine, metaraminol)
and the Military Anti-Shock Trousers.
TREATMENT: To obtain up-to-date information about the treatment of overdose, a
good resource is your certified Regional Poison Control Center. Telephone
numbers of certified poison control centers are listed in the Physicians' Desk
Reference (PDR). In managing overdose, consider the possibilities of multiple-
drug overdoses, drug-drug interactions, and unusual drug kinetics in your
patient.
ACCELERATED REMOVAL: 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 2-6 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.
DOSAGE AND ADMINISTRATION:
The dosage of quinidine varies considerably depending upon the general condition
and the cardiovascular state of the 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 CARDIOQUIN 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 CARDIOQUIN only after ventricular
rate control (e.g., with digitalis or beta-blockers) has failed to provide
satisfactory control of symptoms.
Adequate trials have not identified an optimal regimen of CARDIOQUIN for
conversion of atrial fibrillation/flutter to sinus rhythm. In one reported
regimen, the patient first receives two tablets (550 mg; 333 mg of quinidine
base) of CARDIOQUIN 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 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 CARDIOQUIN 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 CARDIOQUIN should be an increase
in the average time between episodes. In most patients, the tachyarrhythmia Will
Recur during therapy with CARDIOQUIN, 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 CARDIOQUIN 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 CARDIOQUIN should begin with one tablet (275 mg; 166 mg of
quinidine base) every six to eight 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 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 polygalacturonate 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.
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