Quinidine Sulfate

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Overview

What is Quinidine Sulfate?

Quinidine is an antimalarial schizonticide and an antiarrhythmic agent with class 1A activity; it is the isomer of quinine, and its molecular weight is 324.43. Quinidine sulfate is the sulfate salt of quinidine; its chemical name is cinchonan-9-ol,6’- methoxy-,(9)-, sulfate(2:1) dihydrate; its structural formula is:

Its molecular formula is: CHNO•HSO•2HO; and its molecular weight is 782.96, of which 82.9% is quinidine base.

Quinidine sulfate occurs as fine needle-like, white crystals, frequently cohering in masses, or fine, white powder. It is odorless, has a very bitter taste, and darkens on exposure to light. It is slightly soluble in water, soluble in alcohol and in chloroform, and insoluble in ether.

Each tablet, for oral administration, contains 200 mg of quinidine sulfate (equivalent to 166 mg of quinidine base) 300 mg of quinidine sulfate (equivalent to 249 mg of quinidine base). In addition, each tablet contains the following inactive ingredients: confectioner’s sugar, corn starch, microcrystalline cellulose, pregelatinized starch and zinc stearate.

What does Quinidine Sulfate look like?

What are the available doses of Quinidine Sulfate?

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What should I talk to my health care provider before I take Quinidine Sulfate?

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How should I use Quinidine Sulfate?

Treatment of P. malaria

Quinidine sulfate tablets are used in one of the approved regimens for the treatment of life-threatening malaria. The central component of the regimen is Quinidine Gluconate Injection, and the regimen is described in the package insert of Quinidine Gluconate Injection.

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 (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. In one reported regimen, the patient first receives two tablets (400 mg; 332 mg of quinidine base) of quinidine sulfate 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 QT 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 (direct-current cardioversion) are considered.

Reduction of frequency orelease 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 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 be begun with 200 mg (equivalent to 166 mg of quinidine base) every six 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 pretreatment duration; the QTC interval widens to 130% of its pretreatment 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.

What interacts with Quinidine Sulfate?

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.

What are the warnings of Quinidine Sulfate?

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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.

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Proarrhythmic effects

Like many other drugs (including all other class IA antiarrhythmics), quinidine prolongs the QTC interval, and this can lead to a life-threatening ventricular arrhythmia (see ). The risk of 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 interval, and quinidine should be used with extreme care in patients who have preexisting long- QT syndromes, who have histories of of any cause, or who have previously responded to quinidine (or other drugs that prolong ventricular repolarization) with marked lengthening of the QT interval. Estimation of the incidence of 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 )

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.

What are the precautions of Quinidine Sulfate?

Heart Block

In patients without implanted pacemakers who are at high risk of complete atrioventricular block(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

carbonic-anhydrase inhibitors, sodium bicarbonate,thiazide diuretics

By pharmacokinetic mechanisms that are not well understood, quinidine levels are increased by coadministration of or Very rarely, and again by mechanisms not understood, quinidine levels are decreased by coadministration of

Hepatic elimination of quinidine may be accelerated by coadministration of drugs () that induce production of cytochrome P450.

Perhaps because of competition for the P450 metabolic pathway, quinidine levels rise when is coadministered.

Coadministration of 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 βon quinidine pharmacokinetics have not been adequately studied.

Diltiazem significantly decreases the clearance and increases the tof quinidine, but quinidine does not alter the kinetics of diltiazem. Hepatic clearance of quinidine is significantly reduced during coadministration of , with corresponding increases in serum levels and half-life.

Altered pharmacokinetics of other drugs

digoxin

digoxin

By a mechanism that is not understood, quinidine potentiates the anticoagulatory action of , and the anticoagulant dosage may need to be reduced. Cytochrome P450 is an enzyme critical to the metabolism of many drugs, notably including , some , and most . Constitutional deficiency of cytochrome P450IID6 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-deficient “poor metabolizers” from the majority-pheno-type “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 P450-produced metabolites (for example, and , 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, but therapeutic serum levels of quinidine inhibit the action of cytochrome P450, effectively converting extensive metabolizers into poor metabolizers. Caution must be exercised whenever quinidine is prescribed together with drugs metabolized by cytochrome P450.

Perhaps by competing for pathways of renal clearance, coadministration of quinidine causes an increase in serum levels of .

Serum levels of are increased when quinidine is coadministered.

Presumably because both drugs are metabolized by cytochrome P450, coadministration of quinidine causes variable slowing of the metabolism of . Interactions with other dihydropyridine calcium-channel blockers have not been reported, but these agents (including , , and ) are all dependent upon P450 for metabolism, so similar interactions with quinidine should be anticipated.

Altered pharmacodynamics of other drugs

verapamil

Quinidine potentiates the actions of depolarizing (succinylcholine, decamethonium) and nondepolarizing (-tubocurarine, pancuronium) . These phenomena are not well understood, but they are observed in animal models as well as in humans. In addition, 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

diltiazem,flecainide, mephenytoin,metoprolol, propafenone, propranolol,quinine, timolol,

tocainide

Conversely, the pharmacokinetics of quinidine are not significantly affected by or Quinidine’s pharmacokinetics are also unaffected by cigarette smoking.

Information for patients

Before prescribing quinidine sulfate as prophylaxis against recurrence of atrial fibrillation, the physician should inform the patient of the risks and benefits to be expected (see ). 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

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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.

Human placental transport of quinidine has not been systematically studied. 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. In another case, the levels of quinidine and 3-hydroxyquinidine in cord blood were about 30% of simultaneous maternal levels.

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.

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 ), children in these trials received the same doses (on a mg/kg basis) as adults.

Safety and effectiveness of antiarrhythmic use in pediatric patients have not been established.

What are the side effects of Quinidine Sulfate?

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

Vomiting and diarrhea can occur as isolated reactions to therapeutic levels of quinidine, but they may also be the first signs of 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 , 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

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.

	Incidence (%)
diarrhea	85 (35)
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)

What should I look out for while using Quinidine Sulfate?

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.

Mortality

What might happen if I take too much Quinidine Sulfate?

Sorry No Records found

How should I store and handle Quinidine Sulfate?

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Freezing does not adversely affect the product, but exposure to elevated temperatures should be avoided. Protect from light. Store vials in carton until used.Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Freezing does not adversely affect the product, but exposure to elevated temperatures should be avoided. Protect from light. Store vials in carton until used.Quinidine Sulfate Tablets are supplied as follows:200 mg - White tablet scored imprinted 300 mg - White tablet scored imprinted Both are supplied in bottles of 100 and 1000Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container.To report SUSPECTEDADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747or FDA at 1-800-FDA-108 8or www.fda.gov/medwatchManufactured for Sandoz Inc.Princeton, NJ 08540Manufactured byEpic Pharma, LLCLaurelton, NY 11413Rev. 11/08MF1047REV11/08OS7281MG #16904Quinidine Sulfate Tablets are supplied as follows:200 mg - White tablet scored imprinted 300 mg - White tablet scored imprinted Both are supplied in bottles of 100 and 1000Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container.To report SUSPECTEDADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747or FDA at 1-800-FDA-108 8or www.fda.gov/medwatchManufactured for Sandoz Inc.Princeton, NJ 08540Manufactured byEpic Pharma, LLCLaurelton, NY 11413Rev. 11/08MF1047REV11/08OS7281MG #16904Quinidine Sulfate Tablets are supplied as follows:200 mg - White tablet scored imprinted 300 mg - White tablet scored imprinted Both are supplied in bottles of 100 and 1000Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container.To report SUSPECTEDADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747or FDA at 1-800-FDA-108 8or www.fda.gov/medwatchManufactured for Sandoz Inc.Princeton, NJ 08540Manufactured byEpic Pharma, LLCLaurelton, NY 11413Rev. 11/08MF1047REV11/08OS7281MG #16904Quinidine Sulfate Tablets are supplied as follows:200 mg - White tablet scored imprinted 300 mg - White tablet scored imprinted Both are supplied in bottles of 100 and 1000Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container.To report SUSPECTEDADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747or FDA at 1-800-FDA-108 8or www.fda.gov/medwatchManufactured for Sandoz Inc.Princeton, NJ 08540Manufactured byEpic Pharma, LLCLaurelton, NY 11413Rev. 11/08MF1047REV11/08OS7281MG #16904Quinidine Sulfate Tablets are supplied as follows:200 mg - White tablet scored imprinted 300 mg - White tablet scored imprinted Both are supplied in bottles of 100 and 1000Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container.To report SUSPECTEDADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747or FDA at 1-800-FDA-108 8or www.fda.gov/medwatchManufactured for Sandoz Inc.Princeton, NJ 08540Manufactured byEpic Pharma, LLCLaurelton, NY 11413Rev. 11/08MF1047REV11/08OS7281MG #16904Quinidine Sulfate Tablets are supplied as follows:200 mg - White tablet scored imprinted 300 mg - White tablet scored imprinted Both are supplied in bottles of 100 and 1000Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container.To report SUSPECTEDADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747or FDA at 1-800-FDA-108 8or www.fda.gov/medwatchManufactured for Sandoz Inc.Princeton, NJ 08540Manufactured byEpic Pharma, LLCLaurelton, NY 11413Rev. 11/08MF1047REV11/08OS7281MG #16904Quinidine Sulfate Tablets are supplied as follows:200 mg - White tablet scored imprinted 300 mg - White tablet scored imprinted Both are supplied in bottles of 100 and 1000Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container.To report SUSPECTEDADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747or FDA at 1-800-FDA-108 8or www.fda.gov/medwatchManufactured for Sandoz Inc.Princeton, NJ 08540Manufactured byEpic Pharma, LLCLaurelton, NY 11413Rev. 11/08MF1047REV11/08OS7281MG #16904Quinidine Sulfate Tablets are supplied as follows:200 mg - White tablet scored imprinted 300 mg - White tablet scored imprinted Both are supplied in bottles of 100 and 1000Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container.To report SUSPECTEDADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747or FDA at 1-800-FDA-108 8or www.fda.gov/medwatchManufactured for Sandoz Inc.Princeton, NJ 08540Manufactured byEpic Pharma, LLCLaurelton, NY 11413Rev. 11/08MF1047REV11/08OS7281MG #16904Quinidine Sulfate Tablets are supplied as follows:200 mg - White tablet scored imprinted 300 mg - White tablet scored imprinted Both are supplied in bottles of 100 and 1000Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container.To report SUSPECTEDADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747or FDA at 1-800-FDA-108 8or www.fda.gov/medwatchManufactured for Sandoz Inc.Princeton, NJ 08540Manufactured byEpic Pharma, LLCLaurelton, NY 11413Rev. 11/08MF1047REV11/08OS7281MG #16904Quinidine Sulfate Tablets are supplied as follows:200 mg - White tablet scored imprinted 300 mg - White tablet scored imprinted Both are supplied in bottles of 100 and 1000Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container.To report SUSPECTEDADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747or FDA at 1-800-FDA-108 8or www.fda.gov/medwatchManufactured for Sandoz Inc.Princeton, NJ 08540Manufactured byEpic Pharma, LLCLaurelton, NY 11413Rev. 11/08MF1047REV11/08OS7281MG #16904Quinidine Sulfate Tablets are supplied as follows:200 mg - White tablet scored imprinted 300 mg - White tablet scored imprinted Both are supplied in bottles of 100 and 1000Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container.To report SUSPECTEDADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747or FDA at 1-800-FDA-108 8or www.fda.gov/medwatchManufactured for Sandoz Inc.Princeton, NJ 08540Manufactured byEpic Pharma, LLCLaurelton, NY 11413Rev. 11/08MF1047REV11/08OS7281MG #16904Quinidine Sulfate Tablets are supplied as follows:200 mg - White tablet scored imprinted 300 mg - White tablet scored imprinted Both are supplied in bottles of 100 and 1000Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container.To report SUSPECTEDADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747or FDA at 1-800-FDA-108 8or www.fda.gov/medwatchManufactured for Sandoz Inc.Princeton, NJ 08540Manufactured byEpic Pharma, LLCLaurelton, NY 11413Rev. 11/08MF1047REV11/08OS7281MG #16904Quinidine Sulfate Tablets are supplied as follows:200 mg - White tablet scored imprinted 300 mg - White tablet scored imprinted Both are supplied in bottles of 100 and 1000Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container.To report SUSPECTEDADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747or FDA at 1-800-FDA-108 8or www.fda.gov/medwatchManufactured for Sandoz Inc.Princeton, NJ 08540Manufactured byEpic Pharma, LLCLaurelton, NY 11413Rev. 11/08MF1047REV11/08OS7281MG #16904Quinidine Sulfate Tablets are supplied as follows:200 mg - White tablet scored imprinted 300 mg - White tablet scored imprinted Both are supplied in bottles of 100 and 1000Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container.To report SUSPECTEDADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747or FDA at 1-800-FDA-108 8or www.fda.gov/medwatchManufactured for Sandoz Inc.Princeton, NJ 08540Manufactured byEpic Pharma, LLCLaurelton, NY 11413Rev. 11/08MF1047REV11/08OS7281MG #16904Quinidine Sulfate Tablets are supplied as follows:200 mg - White tablet scored imprinted 300 mg - White tablet scored imprinted Both are supplied in bottles of 100 and 1000Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container.To report SUSPECTEDADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747or FDA at 1-800-FDA-108 8or www.fda.gov/medwatchManufactured for Sandoz Inc.Princeton, NJ 08540Manufactured byEpic Pharma, LLCLaurelton, NY 11413Rev. 11/08MF1047REV11/08OS7281MG #16904Quinidine Sulfate Tablets are supplied as follows:200 mg - White tablet scored imprinted 300 mg - White tablet scored imprinted Both are supplied in bottles of 100 and 1000Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container.To report SUSPECTEDADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747or FDA at 1-800-FDA-108 8or www.fda.gov/medwatchManufactured for Sandoz Inc.Princeton, NJ 08540Manufactured byEpic Pharma, LLCLaurelton, NY 11413Rev. 11/08MF1047REV11/08OS7281MG #16904

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Pharmacokinetics and Metabolism

The absolute bioavailability of quinidine from quinidine sulfate tablets is about 70%, but this varies widely (45 to 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; the rate of absorption is somewhat slowed when the drug is taken with food, but the extent of absorption is not changed.

The of quinidine is 2 to 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 to 5 L/kg in patients with cirrhosis of the liver. At concentrations of 2 to 5 mg/L (6.5 to 16.2 μmol/L), the fraction of quinidine bound to plasma proteins (mainly to α-acid glycoprotein and to albumin) is 80 to 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 to 70%. Because α-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 typically proceeds at 3 to 5 mL/min/kg in adults, but clearance in children may be twice or three times as rapid. The elimination half-life is 6 to 8 hours in adults and 3 to 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 P450; there are several different hydroxylated metabolites, and some of these have antiarrhythmic activity.

The most important of quinidine’s metabolites is 3-hydroxyquinidine (3HQ), serum levels of which can exceed those of quinidine in patients receiving conventional doses of quinidine sulfate. 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 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 quinidine sulfate 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

Mechanisms of Action

In patients with malaria, quinidine acts primarily as an intra-erythrocytic schizonticide, with little effect upon sporozites or upon pre-erythrocytic parasites. Quinidine is gametocidal to and but not to .

In cardiac muscle and in Purkinje fibers, quinidine depresses the rapid inward depolarizing sodium current, thereby slowing phase-0 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 fibrillation threshold as well. Quinidine’s actions fall into class 1A in the Vaughan-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, use of quinidine is associated with an increase in the sinus rate.

Quinidine prolongs the QT interval in a dose-related fashion. This may lead to increased ventricular automaticity and polymorphic ventricular tachycardias, including (see ).

In addition, quinidine has anticholinergic activity, it has negative inotropic activity, and it acts peripherally as an α-adrenergic antagonist (that is, as a vasodilator).

Non-Clinical Toxicology

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.

Mortality

Heart Block

In patients without implanted pacemakers who are at high risk of complete atrioventricular block(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

carbonic-anhydrase inhibitors, sodium bicarbonate,thiazide diuretics

By pharmacokinetic mechanisms that are not well understood, quinidine levels are increased by coadministration of or Very rarely, and again by mechanisms not understood, quinidine levels are decreased by coadministration of

Hepatic elimination of quinidine may be accelerated by coadministration of drugs () that induce production of cytochrome P450.

Perhaps because of competition for the P450 metabolic pathway, quinidine levels rise when is coadministered.

Coadministration of 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 βon quinidine pharmacokinetics have not been adequately studied.

Diltiazem significantly decreases the clearance and increases the tof quinidine, but quinidine does not alter the kinetics of diltiazem. Hepatic clearance of quinidine is significantly reduced during coadministration of , with corresponding increases in serum levels and half-life.

Altered pharmacokinetics of other drugs

digoxin

digoxin

By a mechanism that is not understood, quinidine potentiates the anticoagulatory action of , and the anticoagulant dosage may need to be reduced. Cytochrome P450 is an enzyme critical to the metabolism of many drugs, notably including , some , and most . Constitutional deficiency of cytochrome P450IID6 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-deficient “poor metabolizers” from the majority-pheno-type “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 P450-produced metabolites (for example, and , 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, but therapeutic serum levels of quinidine inhibit the action of cytochrome P450, effectively converting extensive metabolizers into poor metabolizers. Caution must be exercised whenever quinidine is prescribed together with drugs metabolized by cytochrome P450.

Perhaps by competing for pathways of renal clearance, coadministration of quinidine causes an increase in serum levels of .

Serum levels of are increased when quinidine is coadministered.

Presumably because both drugs are metabolized by cytochrome P450, coadministration of quinidine causes variable slowing of the metabolism of . Interactions with other dihydropyridine calcium-channel blockers have not been reported, but these agents (including , , and ) are all dependent upon P450 for metabolism, so similar interactions with quinidine should be anticipated.

Altered pharmacodynamics of other drugs

verapamil

Quinidine potentiates the actions of depolarizing (succinylcholine, decamethonium) and nondepolarizing (-tubocurarine, pancuronium) . These phenomena are not well understood, but they are observed in animal models as well as in humans. In addition, 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

diltiazem,flecainide, mephenytoin,metoprolol, propafenone, propranolol,quinine, timolol,

tocainide

Conversely, the pharmacokinetics of quinidine are not significantly affected by or Quinidine’s pharmacokinetics are also unaffected by cigarette smoking.

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

Vomiting and diarrhea can occur as isolated reactions to therapeutic levels of quinidine, but they may also be the first signs of 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 , 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

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.

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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