Rhythmochin I

Procainamide Hydrochloride:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Rhythmochin I (Procainamide Hydrochloride) reviews

INDICATIONS AND USAGE

Rhythmochin I (Procainamide Hydrochloride) hydrochloride injection is indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that, in the judgement of the physician, are life-threatening. Because of the proarrhythmic effects of Rhythmochin I (Procainamide Hydrochloride), its use with lesser arrhythmias is generally not recommended. Treatment of patients with asymptomatic ventricular premature contractions should be avoided.

Initiation of Rhythmochin I (Procainamide Hydrochloride) treatment, as with other antiarrhythmic agents used to treat life-threatening arrhythmias, should be carried out in the hospital.

Antiarrhythmic drugs have not been shown to enhance survival in patients with ventricular arrhythmias.

Because Rhythmochin I (Procainamide Hydrochloride) has the potential to produce serious hematological disorders (0.5 percent) particularly leukopenia or agranulocytosis (sometimes fatal), its use should be reserved for patients in whom, in the opinion of the physician, the benefits of treatment clearly outweigh the risks. (see WARNINGS and Boxed Warning.)

CONTRAINDICATIONS

Complete Heart Block: Rhythmochin I (Procainamide Hydrochloride) should not be administered to patients with complete heart block because of its effects in suppressing nodal or ventricular pacemakers and the hazard of asystole. It may be difficult to recognize complete heart block in patients with ventricular tachycardia, but if significant slowing of ventricular rate occurs during PA treatment without evidence of A-V conduction appearing, PA should be stopped. In cases of second degree A-V block or various types of hemiblock, PA should be avoided or discontinued because of the possibility of increased severity of block, unless the ventricular rate is controlled by an electrical pacemaker.

Idiosyncratic Hypersensitivity: In patients sensitive to procaine or other ester-type local anesthetics, cross sensitivity to PA is unlikely. However, it should be borne in mind, and PA should not be used if it produces acute allergic dermatitis, asthma, or anaphylactic symptoms.

Lupus Erythematosus: An established diagnosis of systemic lupus erythematosus is a contraindication to PA therapy, since aggravation of symptoms is highly likely.

Torsades de Pointes: In the unusual ventricular arrhythmia called "les torsades de pointes" (twistings of the points), characterized by alternation of one or more ventricular premature beats in the directions of the QRS complexes on ECG in persons with prolonged Q-T and often enhanced U waves, Group 1A antiarrhythmic drugs are contraindicated. Administration of PA in such cases may aggravate this special type of ventricular extrasystole or tachycardia instead of suppressing it.

WARNINGS

Mortality:

In the National Heart, Lung and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicentered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate (7.7%) was seen in patients treated with encainide or flecainide compared with that seen in patients assigned to matched placebo-treated group (3.0%). The average duration of treatment with encainide or flecainide in this study was ten months.

The applicability of the CAST results to other populations (e.g., those without recent myocardial infarctions) is uncertain. Considering the known proarrhythmic properties of Rhythmochin I (Procainamide Hydrochloride) and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, the use of Rhythmochin I (Procainamide Hydrochloride) as well as other antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias.

Blood Dyscrasias: Agranulocytosis, bone marrow depression, neutropenia, hypoplastic anemia and thrombocytopenia in patients receiving Rhythmochin I (Procainamide Hydrochloride) hydrochloride have been reported at a rate of approximately 0.5%. Most of these patients received Rhythmochin I (Procainamide Hydrochloride) within the recommended dosage range. Fatalities have occurred (with approximately 20–25 percent mortality in reported cases of agranulocytosis). Since most of these events have been noted during the first 12 weeks of therapy, it is recommended that complete blood counts including white cell, differential and platelet counts be performed at weekly intervals for the first three months of therapy, and periodically thereafter. Complete blood counts should be performed promptly if the patient develops any signs of infection (such as fever, chills, sore throat or stomatitis), bruising or bleeding. If any of these hematologic disorders are identified, Rhythmochin I (Procainamide Hydrochloride) therapy should be discontinued. Blood counts usually return to normal within one month of discontinuation. Caution should be used in patients with pre-existing marrow failure or cytopenia of any type. (See ADVERSE REACTIONS ).

Digitalis Intoxication

Caution should be exercised in the use of Rhythmochin I (Procainamide Hydrochloride) in arrhythmias associated with digitalis intoxication. Rhythmochin I (Procainamide Hydrochloride) can suppress digitalis-induced arrhythmias; however, if there is concomitant marked disturbance of atrioventricular conduction, additional depression of conduction and ventricular asystole or fibrillation may result. Therefore, use of Rhythmochin I (Procainamide Hydrochloride) should be considered only if discontinuation of digitalis, and therapy with potassium, lidocaine, or phenytoin are ineffective.

First Degree Heart Block

Caution should be exercised also if the patient exhibits or develops first degree heart block while taking PA, and dosage reduction is advised in such cases. If the block persists despite dosage reduction, continuation of PA administration must be evaluated on the basis of current benefit versus risk of increased heart block.

Predigitalization for Atrial Flutter or Fibrillation

Patients with atrial flutter or fibrillation should be cardioverted or digitalized prior to PA administration to avoid enhancement of A-V conduction which may result in ventricular rate acceleration beyond tolerable limits. Adequate digitalization reduces but does not eliminate the possibility of sudden increase in ventricular rate as the atrial rate is slowed by PA in these arrhythmias.

Congestive Heart Failure

For patients in congestive heart failure, and those with acute ischemic heart disease or cardiomyopathy, caution should be used in PA therapy, since even slight depression of myocardial contractility may further reduce cardiac output of the damaged heart.

Concurrent Other Antiarrhythmic Agents

Concurrent use of PA with other Group 1A antiarrhythmic agents such as quinidine or disopyramide may produce enhanced prolongation of conduction or depression of contractility and hypotension, especially in patients with cardiac decompensation. Such use should be reserved for patients with serious arrhythmias unresponsive to a single drug and employed only if close observation is possible.

Renal Insufficiency

Renal insufficiency may lead to accumulation of high plasma levels from conventional doses of PA, with effects similar to those of overdosage (see OVERDOSAGE ), unless dosage is adjusted for the individual patient.

Myasthenia Gravis

Patients with myasthenia gravis may show worsening of symptoms from PA due to its procaine-like effect on diminishing acetylcholine release at skeletal muscle motor nerve endings, so that PA administration may be hazardous without optimal adjustment of anticholinesterase medications and other precautions.

Sulfite Sensitivity

Rhythmochin I (Procainamide Hydrochloride) Hydrochloride Injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

PRECAUTIONS

Blood-Pressure and ECG Monitoring

Blood pressure should be monitored with the patient supine during parenteral, especially intravenous, administration of PA. There is a possibility that relatively high although transient plasma levels of PA may be attained and cause hypotension before the PA can be distributed from the plasma volume to its full apparent volume of distribution which is approximately 50 times greater. Therefore, caution should be exercised to avoid overly rapid administration of PA. If the blood pressure falls 15 mm Hg or more, PA administration should be temporarily discontinued. Electrocardiographic (ECG) monitoring is advisable as well, both for observation of the progress and response of the arrhythmia under treatment, and for early detection of any tendency to excessive widening of the QRS complex, prolongation of the P-R interval, or any signs of heart block (see OVERDOSAGE ). Parenteral therapy with PA should be limited to use in hospitals in which monitoring and intensive supportive care are available, or to emergency situations in which equivalent observation and treatment can be provided.

General

Immediately after initiation of PA therapy, patients should be closely observed for possible hypersensitivity reactions. In conversion of atrial fibrillation to normal sinus rhythm by any means, dislodgement of mural thrombi may lead to embolization, which should be kept in mind.

After achieving and maintaining therapeutic plasma concentrations and satisfactory electrocardiographic and clinical responses, continued frequent periodic monitoring of vital signs and electrocardiograms is advised. If evidence of QRS widening of more than 25 percent or marked prolongation of the Q-T interval occurs, concern for overdosage is appropriate, and interruption of the PA infusion is advisable if a 50 percent increase occurs. Elevated serum creatinine or urea nitrogen, reduced creatinine clearance or history of renal insufficiency, as well as use in older patients (over age 50), provide grounds to anticipate that less than the usual dosage or infusion rate may suffice, since the urinary elimination of PA and NAPA may be reduced, leading to gradual accumulation beyond normally-predicted amounts. If facilities are available for measurement of plasma PA and NAPA, or acetylation capability, individual dose adjustment for optimal therapeutic levels may be easier, but close observation of clinical effectiveness is the most important criterion.

Information for Patients

The patient should be encouraged to disclose any past history of drug sensitivity, especially to procaine or other local anesthetic agents, or aspirin, and to report any history of kidney disease, congestive heart failure, myasthenia gravis, liver disease, or lupus erythematosus.

The patient should be counseled to report any symptoms of arthralgia, myalgia, fever, chills, skin rash, easy bruising, sore throat or sore mouth, infections, dark urine or icterus, wheezing, muscular weakness, chest or abdominal pain, palpitations, nausea, vomiting, anorexia, diarrhea, hallucinations, dizziness, or depression.

Laboratory Tests

Laboratory tests such as complete blood count, electrocardiogram and serum creatinine or urea nitrogen may be indicated depending on the clinical situation, and periodic rechecking of the CBC and ANA may be helpful in early detection of untoward reactions.

Drug Interactions

If other antiarrhythmic drugs are being used, additive effects on the heart may occur with PA administration, and dosage reduction may be necessary (see WARNINGS ).

Anticholinergic drugs administered concurrently with PA may produce additive antivagal effects on A-V nodal conduction, although this is not as well documented for PA as for quinidine.

Patients taking PA who require neuromuscular blocking agents such as succinylcholine may require less than usual doses of the latter, due to PA effects on reducing acetylcholine release.

Drug/Laboratory Test Interactions

Suprapharmacologic concentrations of lidocaine and meprobamate may inhibit fluorescence of PA and NAPA, and propranolol shows a native fluorescence close to the PA/NAPA peak wavelengths, so that tests which depend on fluorescence measurement may be affected.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed.

Teratogenic Effects: Pregnancy Category C

Animal reproduction studies have not been conducted with PA. It also is not known whether PA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PA should be given to a pregnant woman only if clearly needed.

Nursing Mothers

Both PA and NAPA are excreted in human milk, absorbed by the nursing infant. Because of the potential for serious adverse reactions in nursing infants, a decision to discontinue nursing or the drug should be made, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS

Cardiovascular System : Hypotension and serious disturbances of cardiorhythm such as ventricular asystole or fibrillation are more common with intravenous administration of PA than with intramuscular administration. Because PA is a peripheral vasodilator in concentrations higher than the usual therapeutic range, transient high plasma levels which may occur especially during intravenous administration may produce temporary but at times severe lowering of blood pressure (see OVERDOSAGE and PRECAUTIONS ).

Multisystem: A lupus erythematosus-like syndrome of arthralgia, pleural or abdominal pain, and sometimes arthritis, pleural effusion, pericarditis, fever, chills, myalgia, and possibly related hematologic or skin lesions is fairly common after prolonged PA administration, perhaps more often in patients who are slow acetylators (See Boxed Warning and PRECAUTIONS ). While some series have reported less than 1 in 500, others have reported the syndrome in up to 30 percent of patients on long term oral PA therapy. If discontinuation of PA does not reverse the lupoid symptoms, corticosteroid treatment may be effective.

Hematologic: Neutropenia, thrombocytopenia, or hemolytic anemia may rarely be encountered. Agranulocytosis has occurred after repeated use of PA, and deaths have been reported. (See Boxed Warning, WARNINGS section.)

Skin: Angioneurotic edema, urticaria, pruritus, flushing, and maculopapular rash have also occurred.

Gastrointestinal System: Anorexia, nausea, vomiting, abdominal pain, diarrhea or bitter taste may occur in 3 to 4 percent of patients taking oral Rhythmochin I (Procainamide Hydrochloride).

Nervous System: Dizziness or giddiness, weakness, mental depression and psychosis with hallucinations have been reported.

Elevated Liver Enzymes : Elevations of transaminase with and without elevations of alkaline phosphatase and bilirubin have been reported. Some patients have had clinical symptoms (e.g., malaise, right upper quadrant pain). Deaths from liver failure have been reported.

OVERDOSAGE

Progressive widening of the QRS complex, prolonged Q-T and P-R intervals, lowering of the R and T waves, as well as increasing A-V block, may be seen with doses which are excessive for a given patient. Increased ventricular extrasystoles, or even ventricular tachycardia or fibrillation may occur. After intravenous administration but seldom after oral therapy, transient high plasma levels of PA may induce hypotension, affecting systolic more than diastolic pressures, especially in hypertensive patients. Such high levels may also produce central nervous depression, tremor, and even respiratory depression.

Plasma levels above 10 mcg/mL are increasingly associated with toxic findings, which are seen occasionally in the 10 to 12 mcg/mL range, more often in the 12 to 15 mcg/mL range, and commonly in patients with plasma levels greater than 15 mcg/mL.

Treatment of overdosage or toxic manifestations includes general supportive measures, close observation, monitoring of vital signs and possibly intravenous pressor agents and mechanical cardiorespiratory support. If available, PA and NAPA plasma levels may be helpful in assessing the potential degree of toxicity and response to therapy. Both PA and NAPA are removed from the circulation by hemodialysis but not peritoneal dialysis. No specific antidote for PA is known.

DOSAGE AND ADMINISTRATION

Rhythmochin I (Procainamide Hydrochloride) Hydrochloride Injection is useful for arrhythmias which require immediate suppression and for maintenance of arrhythmia control. Intravenous therapy allows most rapid control of serious arrhythmias, including those following myocardial infarction; it should be carried out in circumstances where close observation and monitoring of the patient are possible, such as in hospital or emergency facilities. Intramuscular administration is less apt to produce temporary high plasma levels but therapeutic plasma levels are not obtained as rapidly as with intravenous administration. Oral Rhythmochin I (Procainamide Hydrochloride) dosage forms are preferable for less urgent arrhythmias as well as for long-term maintenance after initial parenteral PA therapy.

Intramuscular administration may be used as an alternative to the oral route for patients with less threatening arrhythmias but who are nauseated or vomiting, who are ordered to receive nothing by mouth preoperatively, or who may have malabsorptive problems. An initial daily dose of 50 mg per kg body weight may be estimated. This amount should be divided into fractional doses of one-eighth to one-quarter to be injected intramuscularly every three to six hours until oral therapy is possible. If more than three injections are given, the physician may wish to assess patient factors such as age and renal function, clinical response and, if available, blood levels of PA and NAPA in adjusting further doses for that individual. For treatment of arrhythmias associated with anesthesia or surgical operation, the suggested dose is 100 to 500 mg by intramuscular injection.

Intravenous administration of Rhythmochin I (Procainamide Hydrochloride) Hydrochloride Injection should be done cautiously to avoid a possible hypotensive response (see PRECAUTIONS and OVERDOSAGE ). Initial arrhythmia control, under ECG monitoring, may usually be accomplished safely within a half-hour by either of the two methods which follows:

a) Direct injection into a vein or into tubing of an established infusion line should be done slowly at a rate not to exceed 50 mg per minute. It is advisable to dilute either the 100 mg/mL or the 500 mg/mL concentrations of Rhythmochin I (Procainamide Hydrochloride) hydrochloride prior to intravenous injection to facilitate control of dosage rate. Doses of 100 mg may be administered every 5 minutes at this rate until the arrhythmia is suppressed or until 500 mg has been administered, after which it is advisable to wait 10 minutes or longer to allow for more distribution into tissues before resuming.

b) Alternatively, a loading infusion containing 20 mg of Rhythmochin I (Procainamide Hydrochloride) Hydrochloride per mL (1 g diluted to 50 mL with 5% Dextrose Injection, USP) may be administered at a constant rate of 1 mL per minute for 25 to 30 minutes to deliver 500 to 600 mg of PA. Some effects may be seen after infusion of the first 100 or 200 mg; it is unusual to require more than 600 mg to achieve satisfactory antiarrhythmic effects.

The maximum advisable dosage to be given either by repeated bolus injections or such loading infusion is 1 g.

To maintain therapeutic levels, a more dilute intravenous infusion at a concentration of 2 mg/mL is convenient (1000 mg Rhythmochin I (Procainamide Hydrochloride) HCl in 500 mL of 5% Dextrose Injection, USP), and may be administered at 1 to 3 mL/minute. If daily total fluid intake must be limited, a 4 mg/mL concentration (1 g of Rhythmochin I (Procainamide Hydrochloride) Hydrochloride Injection in 250 mL of 5% Dextrose Injection, USP) administered at 0.5 to 1.5 mL/minute will deliver an equivalent 2 to 6 mg per minute. The amount needed in a given patient to maintain the therapeutic level should be assessed principally from the clinical response, and will depend upon the patient's weight and age, renal elimination, hepatic acetylation rate, and cardiac status, but should be adjusted for each patient based upon close observation. A maintenance infusion rate of 50 mcg/min/kg body weight to a person with a normal renal PA elimination half-time of three hours may be expected to produce a plasma level of approximately 6.5 mcg/mL.

Since the principal route for elimination of PA and NAPA is renal excretion, reduced excretion will prolong the half-life of elimination and lower the dose rate needed to maintain therapeutic levels. Advancing age reduces the renal excretion of PA and NAPA independently of reductions in creatinine clearance; compared to normal young adults, there is approximately 25 percent reduction at age 50 and 50 percent at age 75.

Intravenous therapy should be terminated if persistent conduction disturbances or hypotension develop. As soon as the patient's basic cardiac rhythm appears to be stabilized, oral antiarrhythmic maintenance therapy is preferable, if indicated and possible. A period of about three to four hours (one half-time for renal elimination, ordinarily) should elapse after the last intravenous dose before administering the first dose of Rhythmochin I (Procainamide Hydrochloride) Hydrochloride tablets or capsules.

Parenteral drug products should be examined visually for particulate matter and discoloration (see HOW SUPPLIED ) prior to administration.

HOW SUPPLIED

Rhythmochin I (Procainamide Hydrochloride) Hydrochloride Injection, USP is available in multiple-dose 10 mL vials providing 100 mg Rhythmochin I (Procainamide Hydrochloride) hydrochloride per mL and 2 mL vials providing 500 mg Rhythmochin I (Procainamide Hydrochloride) hydrochloride per mL.

The solutions, which are clear and colorless initially, may develop a slightly yellow color in time. This does not indicate a change which should preclude its use, but a solution any darker than light amber or otherwise discolored should not be used.

Store at 20 to 25°C (68 to 77°F).

Revised: December, 2007

Printed in USA EN-1666

Hospira, Inc., Lake Forest, IL 60045 USA

10 mL Multiple-dose

Rhythmochin I (Procainamide Hydrochloride)

HCl Injection, USP

1 gram/10 mL TOTAL

(100 mg/mL)

Hospira, Inc., Lake Forest, IL 60045 USA

CA-3078

Carton NDC 0409-1902-01

2 mL Multiple-dose

Rx only

NDC 0409-1903-01

Rhythmochin I (Procainamide Hydrochloride)

HCl Injection, USP

1 gram/2 mL TOTAL

(500 mg/mL)

Hospira, Inc., Lake Forest, IL 60045 USA

RL-2398 (11/07)

CA-3079

Carton NDC 0409-1903-01

Quinidine:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Rhythmochin I (Quinidine) reviews

DESCRIPTION

Rhythmochin I (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.

Rhythmochin I (Quinidine) sulfate is the sulfate salt of Rhythmochin I (Quinidine); its chemical name is cinchonan-9-ol, 6’-methoxy-, (9S)-, sulfate(2:1) dihydrate; its structural formula is:

Its molecular formula is: C₄₀H₄₈N₄O₄-H₂SO₄-2H₂O; and its molecular weight is 782.96, of which 82.9% is Rhythmochin I (Quinidine) base.

Rhythmochin I (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 and 300 mg of Rhythmochin I (Quinidine) sulfate (equivalent to 166 mg or 249 mg of Rhythmochin I (Quinidine) base). In addition, each tablet contains the following inactive ingredients: calcium stearate, microcrystalline cellulose, sodium starch glycolate and starch (corn).

Rhythmochin I (Quinidine) Sulfate Structural Formula

CLINICAL PHARMACOLOGY

Pharmacokinetics and Metabolism

The absolute bioavailability of Rhythmochin I from Rhythmochin I (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 volume of distribution of Rhythmochin I (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 Rhythmochin I (Quinidine) bound to plasma proteins (mainly to α₁-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 α₁-acid glycoprotein levels are increased in response to stress, serum levels of total Rhythmochin I (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.

Rhythmochin I (Quinidine) clearance 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. Rhythmochin I (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 Rhythmochin I (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-hydroxyquinidine (3HQ), serum levels of which can exceed those of Rhythmochin I (Quinidine) in patients receiving conventional doses of Rhythmochin I (Quinidine) sulfate. The volume of distribution of 3HQ appears to be larger than that of Rhythmochin I (Quinidine), and the elimination half-life of 3HQ is about 12 hours.

As measured by antiarrhythmic effects in animals, by QT_C 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 Rhythmochin I (Quinidine) sulfate in chronic use.

When the urine pH is less than 7, about 20% of administered Rhythmochin I (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, Rhythmochin I (Quinidine) clearance is apparently independent of patient age.

Assays of serum Rhythmochin I (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 Rhythmochin I (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 to 6 mg/L (6.2 to 18.5 μmol/L).

Mechanisms of Action

In patients with malaria, Rhythmochin I (Quinidine) acts primarily as an intra-erythrocytic schizonticide, with little effect upon sporozites or upon pre-erythrocytic parasites. Rhythmochin I (Quinidine) is gametocidal to Plasmodium vivax and P. malariae, but not to P. falciparum.

In cardiac muscle and in Purkinje fibers, Rhythmochin I (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. Rhythmochin I (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 Vaughan-Williams classification.

By slowing conduction and prolonging the effective refractory period, Rhythmochin I (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, Rhythmochin I (Quinidine) can cause marked sinus node depression and bradycardia. In most patients, however, use of Rhythmochin I (Quinidine) is associated with an increase in the sinus rate.

Rhythmochin I (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, Rhythmochin I (Quinidine) has anticholinergic activity, it has negative inotropic activity, and it acts peripherally as an α-adrenergic antagonist (that is, as a vasodilator).

Clinical Effects

Maintenance of sinus rhythm after conversion from atrial fibrillation: In six clinical trials (published between 1970 and 1984) with a total of 808 patients, Rhythmochin I (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. Rhythmochin I (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 Rhythmochin I (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, Rhythmochin I (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), Rhythmochin I (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 Rhythmochin I (Quinidine) group was numerically greater than the mortality in the comparator group. When the studies were combined in a meta-analysis, Rhythmochin I (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, Rhythmochin I sulfate is indicated as a means of restoring normal sinus rhythm. If this use of Rhythmochin I (Quinidine) sulfate does not restore sinus rhythm within a reasonable time (see DOSAGE AND ADMINISTRATION ), then Rhythmochin I (Quinidine) sulfate should be discontinued.

Reduction of frequency of relapse into atrial fibrillation/flutter

Chronic therapy with Rhythmochin I (Quinidine) sulfate 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 Rhythmochin I (Quinidine) sulfate. The increased risk of death should specifically be considered. Rhythmochin I (Quinidine) sulfate 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

Rhythmochin I sulfate 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 Rhythmochin I (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 Rhythmochin I (Quinidine) sulfate) have not been shown to enhance survival in patients with ventricular arrhythmias.

Treatment of malaria

Rhythmochin I (Quinidine) sulfate is also indicated in the treatment of life-threatening Plasmodium falciparum malaria.

CONTRAINDICATIONS

Rhythmochin I (Quinidine) is contraindicated in patients who are known to be allergic to it, or who have developed thrombocytopenic purpura during prior therapy with Rhythmochin I (Quinidine) or quinine.

In the absence of a functioning artificial pacemaker, Rhythmochin I (Quinidine) is also contraindicated in any patient whose cardiac rhythm is dependent upon a junctional or idioventricular pacemaker, including patients in complete atrioventricular block.

Rhythmochin I (Quinidine) is also contraindicated in patients who, like those with myasthenia gravis, might be adversely affected by an anticholinergic agent.

WARNINGS

Mortality

Proarrhythmic effects

Like many other drugs (including all other class IA antiarrhythmics), Rhythmochin I (Quinidine) prolongs the QT_C interval, and this can lead to torsades de pointes, a life-threatening ventricular arrhythmia (see OVERDOSAGE ). The risk of torsades is increased by bradycardia, hypokalemia, hypomagnesemia, hypocalcemia, or high serum levels of Rhythmochin I (Quinidine), but it may appear in the absence of any of these risk factors. The best predictor of this arrhythmia appears to be the length of the QT_C interval, and Rhythmochin I (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 Rhythmochin I (Quinidine) (or other drugs that prolong ventricular repolarization) with marked lengthening of the QT_C interval. Estimation of the incidence of torsades in patients with therapeutic levels of Rhythmochin I (Quinidine) is not possible from the available data.

Other ventricular arrhythmias that have been reported with Rhythmochin I (Quinidine) include frequent extrasystoles, ventricular tachycardia, ventricular flutter, and ventricular fibrillation.

Paradoxical increase in ventricular rate in atrial flutter/fibrillation

When Rhythmochin I 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 Rhythmochin I (Quinidine) therapy, using conduction-reducing drugs such as digitalis, verapamil, diltiazem, or a ß-receptor blocking agent.

Exacerbated bradycardia in sick sinus syndrome

In patients with the sick sinus syndrome, Rhythmochin I (Quinidine) has been associated with marked sinus node depression and bradycardia.

Pharmacokinetic considerations

Renal or hepatic dysfunction causes the elimination of Rhythmochin I to be slowed, while congestive heart failure causes a reduction in quinidine’s apparent volume of distribution. Any of these conditions can lead to Rhythmochin I (Quinidine) toxicity if dosage is not appropriately reduced. In addition, interactions with coadministered drugs can alter the serum concentration and activity of Rhythmochin I (Quinidine), leading either to toxicity or to lack of efficacy if the dose of Rhythmochin I (Quinidine) is not appropriately modified. (See PRECAUTIONS/Drug Interactions .)

Vagolysis

Because Rhythmochin I (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 Rhythmochin I (Quinidine).

PRECAUTIONS

Heart Block

In patients without implanted pacemakers who are at high risk of complete atrioventricular block, Rhythmochin I (Quinidine) should be used only with caution.

Drug Interactions

Altered pharmacokinetics of Rhythmochin I (Quinidine): Drugs that alkalinize the urine (carbonic-anhydrase inhibitors, sodium bicarbonate, thiazide diuretics) reduce renal elimination of Rhythmochin I (Quinidine).

By pharmacokinetic mechanisms that are not well understood, Rhythmochin I (Quinidine) levels are increased by coadministration of amiodarone or cimetidine. Very rarely, and again by mechanisms not understood, Rhythmochin I (Quinidine) levels are decreased by coadministration of nifedipine.

Hepatic elimination of Rhythmochin I (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, Rhythmochin I (Quinidine) levels rise when ketaconazole is coadministered.

Coadministration of propranolol usually does not affect Rhythmochin I (Quinidine) pharmacokinetics, but in some studies the ß-blocker appeared to cause increases in the peak serum levels of Rhythmochin I (Quinidine), decreases in quinidine’s volume of distribution, and decreases in total Rhythmochin I (Quinidine) clearance. The effects (if any) of coadministration of other ß-blockers on Rhythmochin I (Quinidine) pharmacokinetics have not been adequately studied.

Hepatic clearance of Rhythmochin I (Quinidine) is significantly reduced during coadministration of verapamil, with corresponding increases in serum levels and half-life.

Altered pharmacokinetics of other drugs: Rhythmochin I (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 Rhythmochin I (Quinidine) and digoxin are coadministered, digoxin doses usually need to be reduced. Serum levels of digitoxin are also raised when Rhythmochin I (Quinidine) is coadministered, although the effect appears to be smaller.

By a mechanism that is not understood, Rhythmochin I (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 about 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.

Rhythmochin I (Quinidine) is not metabolized by cytochrome P450IID6, but therapeutic serum levels of Rhythmochin I (Quinidine) inhibit the action of cytochrome P450IID6, effectively converting extensive metabolizers into poor metabolizers. Caution must be exercised whenever Rhythmochin I (Quinidine) is prescribed together with drugs metabolized by cytochrome P450IID6.

Perhaps by competing for pathways of renal clearance, coadministration of Rhythmochin I (Quinidine) causes an increase in serum levels of procainamide.

Serum levels of haloperidol are increased when Rhythmochin I (Quinidine) is coadministered.

Presumably because both drugs are metabolized by cytochrome P450IIIA4, coadministration of Rhythmochin I (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 Rhythmochin I (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 Rhythmochin I (Quinidine) and verapamil are coadministered in doses that are each well tolerated as monotherapy, hypotension attributable to additive peripheral α-blockade is sometimes reported.

Rhythmochin I (Quinidine) potentiates the actions of depolarizing (succinylcholine, decamethonium) and nondepolarizing (d-tubocurarine, pancuronium) neuromuscular blocking agents. These phenomena are not well understood, but they are observed in animal models as well as in humans. In addition, in vitro addition of Rhythmochin I (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 Rhythmochin I (Quinidine) with other drugs: Rhythmochin I (Quinidine) has no clinically significant effect on the pharmacokinetics of diltiazem, flecainide, mephenytoin, metoprolol, propafenone, propranolol, quinine, timolol, or tocainide.

Conversely, the pharmacokinetics of Rhythmochin I (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 Rhythmochin I sulfate 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:

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  that the goal of therapy will be a reduction (probably not to zero) in the frequency of episodes of atrial fibrillation; and
  

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  that reduced frequency of fibrillatory episodes may be expected, if achieved, to bring symptomatic benefit; but
  

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  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
  

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  that such data as are available suggest that treatment with Rhythmochin I (Quinidine) sulfate is likely to increase the patient’s risk of death.
  

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies to evaluate quinidine’s carcinogenic or mutagenic potential have not been performed. Similarly, there are no animal data as to quinidine’s potential to impair fertility.

Pregnancy

Pregnancy Category C

Animal reproductive studies have not been conducted with Rhythmochin I. There are no adequate and well-controlled studies in pregnant women. Rhythmochin I (Quinidine) should be given to a pregnant woman only if clearly needed.

Human placental transport of Rhythmochin I (Quinidine) has not been systematically studied. In one neonate whose mother had received Rhythmochin I (Quinidine) throughout her pregnancy, the serum level of Rhythmochin I (Quinidine) was equal to that of the mother, with no apparent ill effect. The level of Rhythmochin I (Quinidine) in amniotic fluid was about three times higher than that found in serum. In another case, the levels of Rhythmochin I (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

Rhythmochin I 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 Rhythmochin I (Quinidine) levels at least an order of magnitude lower than those of the mother. On the other hand, the pharmacokinetics and pharmacodynamics of Rhythmochin I (Quinidine) in human infants have not been adequately studied, and neonates’ reduced protein binding of Rhythmochin I (Quinidine) may increase their risk of toxicity at low total serum levels. Administration of Rhythmochin I (Quinidine) should (if possible) be avoided in lactating women who continue to nurse.

Geriatric Use

Safety and efficacy of Rhythmochin I (Quinidine) in elderly patients has not been systematically studied.

Pediatric Use

In antimalarial trials, Rhythmochin I (Quinidine) was as safe and effective in pediatric patients as in adults. Notwithstanding the known pharmacokinetic differences between children and adults (see CLINICAL PHARMACOLOGY, 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 pediatric patients have not been established.

ADVERSE REACTIONS

Rhythmochin I (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 Rhythmochin I (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 .

Vomiting and diarrhea can occur as isolated reactions to therapeutic levels of Rhythmochin I (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 Rhythmochin I (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 Rhythmochin I (Quinidine). All of these have appeared during the first few weeks of therapy, and most (not all) have remitted once Rhythmochin I (Quinidine) was withdrawn.

Autoimmune and inflammatory syndromes associated with Rhythmochin I (Quinidine) therapy have included fever, urticaria, flushing, exfoliative rash, bronchospasm, psoriaform rash, pruritus and lymphadenopathy, hemolytic anemia, vasculitis, pneumonitis, thrombocytopenic purpura, uveitis, angioedema, agranulocytosis, the sicca syndrome, arthralgia, myalgia, elevation in serum levels of skeletal-muscle enzymes, and a disorder resembling systemic lupus erythematosus.

Convulsions, apprehension, and ataxia have been reported, but it is not clear that these were not simply the results of hypotension and consequent cerebral hypoperfusion. There are many reports of syncope. Acute psychotic reactions have been reported to follow the first dose of Rhythmochin I (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 Rhythmochin I 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 Rhythmochin I (Quinidine).

The most important ill effects of acute Rhythmochin I (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 Rhythmochin I (Quinidine) levels can be conveniently assayed and monitored, but the electrocardiographic QT_C 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 Rhythmochin I (Quinidine) and either immediate cardioversion or, if a cardiac pacemaker is in place or immediately available, immediate overdrive pacing. After pacing or cardioversion, further management must be guided by the length of the QT_C interval.

Quinidine-associated ventricular tachyarrhythmias with normal underlying QT_C intervals have not been adequately studied. Because of the theoretical possibility of QT-prolonging effects that might be additive to those of Rhythmochin I (Quinidine), other antiarrhythmics with Class I (disopyramide, procainamide) or Class III activities should (if possible) be avoided. Similarly, although the use of bretylium in Rhythmochin I (Quinidine) overdose has not been reported, it is reasonable to expect that the α-blocking properties of bretylium might be additive to those of Rhythmochin I (Quinidine), resulting in problematic hypotension.

If the post-cardioversion QT_C 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 QT_C prolongation (especially hypokalemia, hypomagnesemia, and hypocalcemia) 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 to 150 ng/kg/min).

Hypotension

Quinidine-induced hypotension that is not due to an arrhythmia is likely to be a consequence of quinidine-related α-blockade and vasorelaxation. Simple repletion of central volume may be sufficient therapy; other interventions reported to have been beneficial in this setting are those that increase peripheral vascular resistance, including α-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 Rhythmochin I (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 Rhythmochin I (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 to 6 hours as a slurry with 8 mL/kg of tap water. Although renal elimination of Rhythmochin I (Quinidine) might theoretically be accelerated by maneuvers to acidify the urine, such maneuvers are potentially hazardous and of no demonstrated benefit.

Rhythmochin I (Quinidine) is not usefully removed from the circulation by dialysis.

Following Rhythmochin I (Quinidine) overdose, drugs that delay elimination of Rhythmochin I (Quinidine) (cimetidine, carbonic-anhydrase inhibitors, thiazide diuretics) should be withdrawn unless absolutely required.

DOSAGE AND ADMINISTRATION

Treatment of P. falciparum malaria

Rhythmochin I sulfate tablets are used in one of the approved regimens for the treatment of life-threatening P. falciparum malaria. The central component of the regimen is Rhythmochin I (Quinidine) Gluconate Injection, and the regimen is described in the package insert of Rhythmochin I (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 Rhythmochin I (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 Rhythmochin I (Quinidine) sulfate only after ventricular rate control (e.g., with digitalis or ß-blockers) has failed to provide satisfactory control of symptoms.

Adequate trials have not identified an optimal regimen of Rhythmochin I (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 Rhythmochin I (Quinidine) base) of Rhythmochin I (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_C 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 Rhythmochin I (Quinidine) sulfate is discontinued, and other means of conversion (e.g., direct-current cardioversion) are considered.

Reduction of frequency of release into atrial fibrillation/flutter

In a patient with a history of frequent symptomatic episodes of atrial fibrillation/flutter, the goal of therapy with Rhythmochin I sulfate should be an increase in the average time between episodes. In most patients, the tachyarrhythmia will recur during therapy with Rhythmochin I (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 Rhythmochin I (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 Rhythmochin I (Quinidine) sulfate should be begun with 200 mg (equivalent to 166 mg of Rhythmochin I (Quinidine) base) every six hours. If this regimen is well tolerated, if the serum Rhythmochin I (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 QT_C 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.

Suppression of ventricular arrhythmias

Dosing regimens for the use of Rhythmochin I (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.

HOW SUPPLIED

Rhythmochin I (Quinidine) Sulfate Tablets USP 200 mg are 12/32”, scored, round, white tablets imprinted DAN DAN and 5438 supplied in bottles of 100 and 1000.

Rhythmochin I (Quinidine) Sulfate Tablets USP 300 mg are 14/32”, scored, round, white tablets imprinted DAN DAN and 5454 supplied in bottles of 100.

Dispense in well-closed, light-resistant container with child-resistant closure.

Store at 20° - 25°C (68° - 77°F).

Protect from light and moisture.

Manufactured By:

Watson Pharma Private Limited

Verna, Salcette Goa 403 722 INDIA

Distributed By:

Watson Pharma, Inc.

Corona, CA 92880 USA

Revised: June 2009 190782

0609B