BIQUIN DURULES®
Astra
Controlled Release Quinidine Bisulfate
Antiarrhythmic Agent
Action And Clinical Pharmacology: Quinidine is a class IA antiarrhythmic agent according to the modified Vaughan-Williams classification. Quinidine is considered a myocardial depressant. Direct actions on the heart include: decreased myocardial excitability; prolongation of the atrial, ventricular and Purkinje refractory periods; decreased atrial, Purkinje and ventricular conduction velocities; substantially decreased firing rate of cardiac Purkinje fibres by direct action; decreased myocardial contractility.
The primary indirect action of quinidine on the heart is through its vagal blocking effect. This effect tends to antagonize some of the depressant actions of quinidine on the heart by increasing the conductivity through the atrioventricular node. Quinidine has a peripheral vasodilating effect and may reduce arterial blood pressure, particularly when given parenterally.
Quinidine is rapidly absorbed from the small intestine. The maximum plasma concentration occurs within 4 hours after administration of a single dose. At therapeutic plasma concentrations, the plasma protein binding of quinidine varies between 70 and 95%. Approximately 10 to 20% is excreted unchanged in the urine within 24 hours. Decreased liver function does not seem to have a significant effect on the plasma clearance of quinidine.
The slow release mechanism of Durules results in a more gradual climb to the peak plasma concentration which then remains unchanged for a significantly longer time than after the administration of regular tablets. The plasma concentration can thus be kept constant for a longer period of time. Administration of Durules also results in higher morning plasma concentrations than conventional quinidine tablets.
Electrocardiographic Effects: The most common effect of quinidine on the ECG is an increased QT interval. Large doses may cause QRS prolongation. Such changes may precede the development of ventricular arrhythmias. In patients with normal conduction time, a 50% increase in QRS duration is dangerous and therefore the QRS should not exceed 25% of the control value.
Hemodynamics: In normal subjects, oral quinidine causes a fall in systemic arterial blood pressure due to vasodilatation of the systemic arterioles. Right ventricular pressure and cardiac output remain unchanged. However, in patients with cardiovascular disease, quinidine may lower blood pressure significantly. The decrease in peripheral vascular resistance appears to be due to depression of sympathetic receptors and direct vasodilatory action. Peripheral dilatation may contribute to the syncope encountered in some patients taking the drug.
Indications And Clinical Uses:
No antiarrhythmic drug has been shown to reduce the incidence of sudden death in patients with asymptomatic ventricular arrhythmias. Most antiarrhythmic drugs have the potential to cause dangerous arrhythmias; some have been shown to be associated with an increased incidence of sudden death. In light of the above, physicians should carefully consider the risks and benefits of antiarrhythmic therapy for all patients with ventricular arrhythmias.
Ventricular Arrhythmias: For the treatment of documented life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia. Quinidine may also be used for the treatment of patients with documented symptomatic ventricular arrhythmias when the symptoms are of sufficient severity to require treatment. Because of the proarrhythmic effects of quinidine its use should be reserved for patients in whom, in the opinion of the physician, the benefit of treatment clearly outweighs the risks.
For patients with sustained ventricular tachycardia, quinidine therapy should be initiated in the hospital. Hospitalization may also be required for certain other patients depending on their cardiac status and underlying cardiac disease.
The effects of quinidine in patients with recent myocardial infarction have not been adequately studied and, therefore, its use in this condition cannot be recommended.
Supraventricular Arrhythmias: For the treatment of premature atrial or AV junctional contractions, paroxysmal atrial or AV junctional tachycardia, atrial flutter, atrial fibrillation when this therapy is appropriate and maintenance therapy after electrical conversion of atrial fibrillation and/or flutter to sinus rhythm.
Contra-Indications: Second-degree or complete atrioventricular block in the absence of a pacemaker, junctional or idioventricular conduction disturbance that might be aggravated by quinidine, uncompensated heart failure, digitalis intoxication, prolonged QT interval (see also Warnings), patients manifesting either clinical signs or having a past history of idiosyncrasy or hypersensitivity to quinidine (e.g. febrile reactions, skin eruptions, thrombocytopenic purpura, SLE syndrome, etc.), myasthenia gravis.
Manufacturers’ Warnings In Clinical States: Mortality: The results of the Cardiac Arrhythmia Suppression Trial (CAST) in postmyocardial infarction patients with asymptomatic ventricular arrhythmias showed a significant increase in mortality and in nonfatal cardiac arrest rate in patients treated with encainide or flecainide compared with a matched placebo-treated group. CAST was continued using a revised protocol with the moricizine and placebo arms only. The trial was prematurely terminated because of a trend towards an increase in mortality in the moricizine treated group.
The applicability of these results to other populations or other antiarrhythmic agents is uncertain, but at present it is prudent to consider these results when using any antiarrhythmic agent.
Control of Ventricular Rate: Particular attention should be given to the following conditions: In the treatment of atrial fibrillation with rapid ventricular response, ventricular rate should be controlled with digitalis glycosides, b-blockers or verapamil prior to administration of quinidine.
In the treatment of atrial flutter with quinidine, reversion to sinus rhythm may be preceded by progressive reduction in the degree of AV block to 1:1 ratio resulting in an extremely high ventricular rate. This potential hazard may be reduced by digitalization prior to administration of quinidine.
Digitalis Intoxication: Recent reports have described increased, potentially toxic, digoxin plasma levels when quinidine is administered concurrently. When concurrent use is necessary, digoxin dosage should be reduced by approximately 50% and plasma concentration should be monitored and patients observed closely for digitalis intoxication.
Cardiotoxicity: Quinidine cardiotoxicity may be manifested by increased PR and QT intervals, 50% widening of QRS and/or ventricular ectopic beats or tachycardia. Appearance of these toxic signs during quinidine administration mandates immediate discontinuation of the drug, and/or close clinical and electrocardiographic monitoring. Note: Quinidine effect is enhanced by potassium and reduced in the presence of hypokalemia.
Syncopal Episodes: Quinidine Syncope may occur as a complication of long-term therapy. It is manifested by sudden loss of consciousness and ventricular arrhythmias with bizarre QRS complexes of the torsades de pointes type. This syndrome does not appear to be related to dose or plasma levels, but occurs more often with prolonged QT intervals.
Vagal Stimulation: Because quinidine antagonizes the effect of vagal excitation upon the atrium and the AV node, the administration of parasympathomimetic drugs (choline esters) or the use of any other procedure to enhance vagal activity may fail to terminate paroxysmal supraventricular tachycardia in patients receiving quinidine.
Hepatotoxicity: A few cases of hepatotoxicity, including granulomatous hepatitis, due to quinidine hypersensitivity have been reported in patients taking quinidine. Unexplained fever and/or elevation of hepatic enzymes, particularly in the early stages of therapy, warrant consideration of possible hepatotoxicity. Monitoring liver function during the first 4 to 8 weeks should be considered. Cessation of quinidine in these cases usually results in the disappearance of toxicity.
Quinidine should be used with extreme caution in: the presence of incomplete AV block, since a complete block and asystole may result. Quinidine may cause unpredictable abnormalities of rhythm in digitalized hearts; partial bundle branch block; severe congestive heart failure, cardiogenic shock, severe bradycardia and hypotensive states. Quinidine may have a depressant effect on myocardial contractility and arterial pressure; poor renal function, especially renal tubular acidosis, because of the potential accumulation of quinidine in plasma leading to toxic concentrations.
Precautions: Test for Hypersensitivity: A test dose of 0.2 g quinidine sulfate should be given by mouth initially in order to ascertain any possible hypersensitivity to quinidine.
Large Quinidine Doses: Hospitalization for close clinical observation, ECG monitoring, and possibly plasma quinidine levels, is indicated when large doses are used or with patients at increased risk when starting therapy, such as those with a history of syncope or presyncope due to ventricular arrhythmias.
Matrix: Due to the matrix structure of Durules, there is the potential for the matrix to pass through the digestive system apparently unchanged.
Drug Interactions: Drugs Affecting Quinidine: The effects of quinidine are enhanced by potassium and reduced by hypokalemia.
Quinidine, a weak base, may have its half-life prolonged in patients who are concurrently taking drugs that can alkalize the urine, such as thiazide diuretics, sodium bicarbonate, and carbonic anhydrase inhibitors. Quinidine and drugs which alkalize the urine should be used together cautiously.
Cimetidine: It has been reported that the histamine H2-antagonist cimetidine reduces renal clearance of quinidine resulting in higher plasma concentrations.
Rifampin: Rifampin induces the metabolism of quinidine, thereby reducing the plasma concentration to sub-therapeutic levels if the normal dosage is maintained.
Phenobarbital and Phenytoin: Bioavailability studies in healthy volunteers have indicated that phenobarbital and phenytoin reduce the half-life of quinidine by approximately 50% and increase the rate of plasma clearance, probably through an increase in the rate of metabolism. Quinidine dosage may require adjustment in patients in whom the concomitant administration of phenobarbital or phenytoin is initiated or discontinued.
Verapamil, Amiodarone, Nifedipine: Concomitant administration of verapamil or amiodarone can produce clinically important increases in serum quinidine concentrations. Simultaneous administration of nifedipine has resulted in reports about reduced as well as increased plasma quinidine levels. The clinical relevance is not clear. Appropriate quinidine dose changes and ECG monitoring should be carried out when these drugs are added or discontinued during quinidine therapy. A 30 to 50% change in quinidine dosage may be required in order to avoid systemic toxicity or lack of efficacy.
Desipramine and Imipramine: Quinidine inhibits the metabolism of desipramine and imipramine in the so-called rapid hydroxylators resulting in increased plasma concentrations. In addition they have additive antiarrhythmic properties. The combination should be avoided.
Procainamide: One case report indicates that the plasma concentration of procainamide and its main metabolite, N-acetyl-procainamide, may increase significantly if quinidine is given simultaneously.
Metoprolol: In the so-called rapid hydroxylators, quinidine may inhibit the metabolism of metoprolol resulting in increased plasma concentrations of metoprolol.
Propranolol: By reducing cardiac output, propranolol can reduce hepatic blood flow and decrease the clearance of quinidine, causing a tendency to higher plasma concentrations than predicted.
Drugs Affected by Quinidine: Quinidine potentiates the neuromuscular blocking effect of certain skeletal muscle relaxants, specifically the curariform and depolarizing types, and the neuromuscular blocking effect of antibiotics such as neomycin, kanamycin and streptomycin. Respiratory depression may cause apnea. Curare-like effects may occur when quinidine is administered at a later time.
Quinidine, by depressing prothrombin formation or inhibiting synthesis of vitamin K sensitive clotting factors in the liver, tends to potentiate the anticoagulant effect of coumarin derivatives, thus increasing any hemorrhagic tendencies.
In patients with myasthenia gravis who are well controlled by neostigmine, quinidine causes symptoms to return. Quinidine antagonizes neostigmine, physostigmine and related drugs.
Digoxin: In digitalized patients quinidine may increase the concentration of digoxin in plasma by up to 100%. Therefore, when starting quinidine therapy in patients who are taking digoxin, the clinical course, ECG and, if possible, serum digoxin levels should be followed closely. It may be necessary to reduce the dose of digoxin in these patients (see Warnings).
Digitoxin: The interaction between digitoxin and quinidine is a controversial issue. Several studies indicate, however, that quinidine increases the plasma concentration of digitoxin.
Quinidine exhibits a distinct anticholinergic activity in the myocardial tissues. An additive vagolytic effect may be seen when quinidine and drugs having anticholinergic blocking activity are used together. Drugs having cholinergic activity may be antagonized by quinidine.
Caution is indicated in combined therapy with other class I antiarrhythmic drugs and b-blockers due to possible additive cardiac depressant effects. Myocarditis or severe myocardial damage also requires caution.
Pregnancy: The use of quinidine in pregnancy should be reserved only for those cases in which the benefits outweigh the possible hazards to the patient and fetus. There have been no teratogenic effects reported since the introduction of quinidine in the early 1930’s. No clinical or epidemiological studies have however been made. In a single case report, similar maternal and fetal serum concentrations were observed at delivery.
Monitoring of quinidine concentrations in the mother is warranted to avoid adverse effects. Theoretically, changes in protein binding during pregnancy may result in lower total drug concentration that will underestimate the free (unbound) quinidine concentration. Judicious adjustment of dosage may be done if clinically indicated.
Lactation: Quinidine is secreted in milk with concentrations in milk similar to those in maternal serum. The amount of drug consumed by the infant however, is small when therapeutic doses are used and effects on the child are therefore unlikely. The benefit/risk ratio for continued nursing should be considered for each infant.
Adverse Reactions: The most frequent adverse reactions occurring in approximately 30% of patients are gastrointestinal disorders (diarrhea, nausea and vomiting). The central and peripheral nervous system is rarely affected. The most common cardiovascular adverse reaction is ventricular tachycardia, mostly of the torsades de pointes type or ventricular fibrillation. Rarely are there signs of hypotension and bradycardia, which may lead to cardiac arrest. There have been isolated cases of hepatitis, thrombocytopenia, pancytopenia, agranulocytosis, photosensitization, lupus erythematosis-like syndrome, myalgia, and arthralgia.
Reported adverse effects according to organ system are: Gastrointestinal: diarrhea, nausea, vomiting, anorexia, or combinations of the above.
Central and Peripheral Nervous System: Cinchonism: tinnitus, vertigo, blurred vision, headache, dizziness.
Cardiac: Arrhythmias or Alterations in Conduction: sino-atrial node depression, sinus arrest (with Xylocaine), sino-atrial block, acceleration of the SA node, AV block, acceleration of ventricular response to atrial tachyarrhythmias, junctional rhythm, increase in His Purkinje conduction time, ventricular premature beats, ventricular tachycardia, including torsades de pointes, ventricular fibrillation, sudden death, potentiation of digitalis intoxication.
Decreased Contractility.
Reduction in Blood Pressure.
ECG Abnormality (marked increase in PR, QRS and QT intervals).
Hypersensitivity Reactions: Fever: with hepatic granulomas, with transient leukopenia.
Hematologic: potentiation of coumarin anticoagulants, hemolytic anemia, immunohemolytic anemia and thrombocytopenia, hemolysis in Caucasian with G6PD deficiency, pancytopenia, thrombocytopenia, thrombocytopenia with leukopenia, reversible hypoplastic anemia with agranulocytosis, leukopenia with fever.
Dermatologic: urticaria, scarlatinoform or morbilliform eruptions, localized or generalized pruritus, flushing, fixed lichenoid lesions, eczema progressing to generalized scarlatinoform eruption, erythrodermic exacerbation of psoriasis, exfoliative dermatitis, contact dermatitis, photosensitivity reaction, SLE-like syndrome, angioneurotic edema.
Hepatic: hepatitis.
Miscellaneous: fatigue.
Symptoms And Treatment Of Overdose: Symptoms: Large doses may cause cinchonism, paradoxical tachycardia, ventricular tachycardia, cardiac standstill, ventricular fibrillation, embolism. Serious hypersensitivity reactions are manifested by respiratory embarrassment or vascular collapse.
Antidote: Cinchonism – same as for quinidine or quinine.
Treatment: Inasmuch as quinidine is rapidly destroyed in the body, the longer the patient survives the better the prognosis becomes. Absorption may be slow if fairly insoluble salts have been ingested. Therefore, the stomach should be copiously lavaged with water through the gastric tube, and alkaloid precipitants employed if they are readily available. Hypertonic sodium sulfate solution should be introduced in the stomach to hasten the passage of the unabsorbed quinidine through the bowel. The blood pressure should be supported and symptomatic measures employed to maintain renal function and overcome central depression. Caffeine, ephedrine, oxygen, and even artificial respiration may be needed to combat respiratory failure. Body temperature should be maintained. Hemoglobinuria may necessitate blood transfusion, and the use of alkali to prevent renal blockade may prove helpful. Angioneurotic or asthmatic phenomena may require the use of epinephrine and antiasthmatics. Residual visual impairment occasionally yields to vasodilators such as nitrates and methacholine; in the acute phase of toxic amaurosis caused by quinidine, sodium nitrate administered i.v. may have a salutary effect.
Dosage And Administration: Note: 0.25 g Biquin Durules is equivalent to 0.2 g quinidine sulfate.
Initiation of treatment, as with other antiarrhythmic agents used to treat life-threatening ventricular arrhythmias, should be carried out in hospital.
A test dose of 0.2 g quinidine sulfate should be administered in the morning to ascertain whether or not any hypersensitivity to quinidine exists. If no signs of a reaction occur, administer 2 Durules in the evening. Beginning the following day, 2 to 3 Durules can be given every 12 hours.
The usual maintenance dose is 2 to 5 Durules (0.5 to 1.25 g) morning and evening. The determination of dosage for maintenance of sinus rhythm should include assay of the serum concentration, beginning after about 1 week of treatment. The therapeutic serum concentration range of quinidine varies with the assay technique used; for the Abbott TDx assay the range is 2 to 5 mg/L (6 to 15 µmol/L). Due to interindividual variation of serum concentration versus response to quinidine, serum concentrations must be interpreted in the context of clinical parameters of efficacy and toxicity. The lowest effective maintenance dose which gives a morning level within the therapeutic range is the usual objective. The QT-time should be checked before and during treatment.
Concomitant food intake may decrease the likelihood of gastrointestinal side effects.
The tablets should not be broken or chewed but swallowed whole with liquid.
Patients with atrial fibrillation or flutter who are scheduled for elective cardioversion may be given the regimen described above for 2 days before the anticipated cardioversion. Appropriate doses of digoxin or verapamil may be needed to control ventricular response. About 33% of patients with atrial fibrillation and a similar proportion of patients with atrial flutter may convert to sinus rhythm on this dose of quinidine without DC shock. Others will require DC shock, but the required energy level may be reduced because of premedication with quinidine. Maintenance doses of quinidine according to the schedule given above may help to prevent recurrence of atrial fibrillation following cardioversion. The starting dose for maintenance treatment after conversion of atrial fibrillation is 3 Durules morning and evening.
Availability And Storage: Each white, oval, sustained release Biquin Durules tablet contains: quinidine bisulfate 0.25 g, equivalent to quinidine sulfate 0.2 g. Nonmedicinal ingredients: hydroxypropyl methylcellulose 6 cps, magnesium stearate, paraffin powder, polyethylene glycol 6000, polyvinyl acetate, polyvinyl chloride and titanium dioxide. Gluten- and tartrazine-free. Bottles of 100 and 500. Store at room temperature (15 to 30°C). Protect from light.
BIQUIN DURULES® Astra Controlled Release Quinidine Bisulfate Antiarrhythmic Agent
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