Drug: Corvert

CORVERT Injection (ibutilide fumarate injection) is an antiarrhythmic drug with predominantly class III (cardiac action potential prolongation) properties according to the Vaughan Williams Classification. Each milliliter of CORVERT Injection contains 0.1 mg of ibutilide fumarate (equivalent to 0.087 mg ibutilide free base), 0.189 mg sodium acetate trihydrate, 8.90 mg sodium chloride, hydrochloric acid to adjust pH to approximately 4.6, and Water for Injection. CORVERT (ibutilide fumarate injection) Injection is an isotonic, clear, colorless, sterile aqueous solution. Ibutilide fumarate has one chiral center, and exists as a racemate of the (+) and (-) enantiomers. The chemical name for ibutilide fumarate is Methanesulfonamide, N-{4-{4-(ethylheptylamino)-1-hydroxybutyl}phenyl}, (+) (-), (E)-2-butenedioate (1:0.5) (hemifumarate salt). Its molecular formula is C22H38N2O5S, and its molecular weight is 442.62. Ibutilide fumarate is a white to off-white powder with an aqueous solubility of over 100 mg/mL at pH 7 or lower. The structural formula is represented below:

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CORVERT (ibutilide fumarate injection) Injection was generally well tolerated in clinical trials. Of the 586 patients with atrial fibrillation or atrial flutter who received CORVERT (ibutilide fumarate injection) in phase II/III studies, 149 (25%) reported medical events related to the cardiovascular system, including sustained polymorphic ventricular tachycardia (1.7%) and nonsustained polymorphic ventricular tachycardia (2.7%). Other clinically important adverse events with an uncertain relationship to CORVERT (ibutilide fumarate injection) include the following (0.2% represents one patient): sustained monomorphic ventricular tachycardia (0.2%), nonsustained monomorphic ventricular tachycardia (4.9%), AV block (1.5%), bundle branch block (1.9%), ventricular extrasystoles (5.1%), supraventricular extrasystoles (0.9%), hypotension/postural hypotension (2.0%), bradycardia/sinus bradycardia (1.2%), nodal arrhythmia (0.7%), congestive heart failure (0.5%), tachycardia/sinus tachycardia/supraventricular tachycardia (2.7%), idioventricular rhythm (0.2%), syncope (0.3%), and renal failure (0.3%). The incidence of these events, except for syncope, was greater in the group treated with CORVERT (ibutilide fumarate injection) than in the placebo group. Another adverse reaction that may be associated with the administration of CORVERT (ibutilide fumarate injection) was nausea, which occurred with a frequency greater than 1% more in ibutilide-treated patients than those treated with placebo. The medical events reported for more than 1% of the placebo- and ibutilide-treated patients are shown in the following Table. Treatment-Emergent Medical Events With Frequency of More Than 1% and Higher Than That of Placebo
Event Placebo
N=127 All Ibutilide
N=586 Patients Patients n % n % CARDIOVASCULAR   Ventricular extrasystoles 1 0.8 30 5.1   Nonsustained monomorphic VT 1 0.8 29 4.9   Nonsustained polymorphic VT - - 16 2.7   Hypotension 2 1.6 12 2.0   Bundle branch block - - 11 1.9   Sustained polymorphic VT - - 10 1.7   AV block 1 0.8 9 1.5   Hypertension - - 7 1.2   QT segment prolonged - - 7 1.2   Bradycardia 1 0.8 7 1.2   Palpitation 1 0.8 6 1.0   Tachycardia 1 0.8 16 2.7 GASTROINTESTINAL   Nausea 1 0.8 11 1.9 CENTRAL NERVOUS SYSTEM   Headache 4 3.1 21 3.6 In the post-cardiac surgery study (see Clinical Studies), similar types of medical events were reported. In the 1 mg ibutilide fumarate treatment group (N=70), 2 patients (2.9%) developed sustained polymorphic ventricular tachycardia and 2 other patients (2.9%) developed nonsustained polymorphic ventricular tachycardia. Polymorphic ventricular tachycardia was not reported in the 73 patients in the 0.5 mg dose group or in the 75 patients in the 0.25 mg dose group. Read the Corvert (ibutilide fumarate injection) Side Effects Center for a complete guide to possible side effectsLearn More »

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The recommended dose based on controlled trials (see Clinical Studies) is outlined in the Table below. Ibutilide infusion should be stopped as soon as the presenting arrhythmia is terminated or in the event of sustained or nonsustained ventricular tachycardia, or marked prolongation of QT or QTc. Recommended Dose of CORVERT (ibutilide fumarate injection) Injection
Patient Weight Initial Infusion (over 10 minutes) Second Infusion 60 kg (132 lb)or more One vial (1 mg ibutilide fumarate) If the arrhythmia does not terminate within 10 minutes after the end of the initial infusion, asecond 10-minute infusion ofequal strength may be administered 10 minutes after completion of the first infusion. Less than 60 kg (132 lb) 0.1 mL/kg (0.01 mg/kg ibutilide fumarate) In a trial comparing ibutilide and sotalol (see Clinical Studies), 2 mg ibutilide fumarate administered as a single infusion to patients weighing more than 60 kg was also effective in terminating atrial fibrillation or atrial flutter. In the post-cardiac surgery study (see Clinical Studies), one or two intravenous infusions of 0.5 mg (0.005 mg/kg per dose for patients weighing less than 60 kg) was effective in terminating atrial fibrillation or atrial flutter. Patients should be observed with continuous ECG monitoring for at least 4 hours following infusion or until QTc has returned to baseline. Longer monitoring is required if any arrhythmic activity is noted. Skilled personnel and proper equipment (see WARNINGS, Proarrhythmia), such as a cardioverter/defibrillator, and medication for treatment of sustained ventricular tachycardia, including polymorphic ventricular tachycardia, must be available during administration of CORVERT (ibutilide fumarate injection) and subsequent monitoring of the patient. Dilution: CORVERT (ibutilide fumarate injection) Injection may be administered undiluted or diluted in 50 mL of diluent. CORVERT (ibutilide fumarate injection) may be added to 0.9% Sodium Chloride Injection or 5% Dextrose Injection before infusion. The contents of one 10 mL vial (0.1 mg/mL) may be added to a 50 mL infusion bag to form an admixture of approximately 0.017 mg/mL ibutilide fumarate. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Compatibility and Stability: The following diluents are compatible with CORVERT (ibutilide fumarate injection) Injection (0.1 mg/mL): 5% Dextrose Injection
0.9% Sodium Chloride Injection The following intravenous solution containers are compatible with admixtures of CORVERT (ibutilide fumarate injection) Injection (0.1 mg/mL): polyvinyl chloride plastic bags
polyolefin bags Admixtures of the product, with approved diluents, are chemically and physically stable for 24 hours at room temperature (15° to 30° C or 59° to 86° F) and for 48 hours at refrigerated temperatures (2° to 8°C or 36° to 46°F). Strict adherence to the use of aseptic technique during the preparation of the admixture is recommended in order to maintain sterility.

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No specific pharmacokinetic or other formal drug interaction studies were conducted. Digoxin: Supraventricular arrhythmias may mask the cardiotoxicity associated with excessive digoxin levels. Therefore, it is advisable to be particularly cautious in patients whose plasma digoxin levels are above or suspected to be above the usual therapeutic range. Coadministration of digoxin did not have effects on either the safety or efficacy of ibutilide in the clinical trials. Calcium channel blocking agents: Coadministration of calcium channel blockers did not have any effect on either the safety or efficacy of ibutilide in the clinical trials. Beta-adrenergic blocking agents: Coadministration of beta-adrenergic blocking agents did not have any effect on either the safety or efficacy of ibutilide in the clinical trials. Read the Corvert Drug Interactions Center for a complete guide to possible interactions Learn More »

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CORVERT (ibutilide fumarate injection) Injection is indicated for the rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm. Patients with atrial arrhythmias of longer duration are less likely to respond to CORVERT (ibutilide fumarate injection) . The effectiveness of ibutilide has not been determined in patients with arrhythmias of more than 90 days in duration. LIFE-THREATENING ARRHYTHMIAS-APPROPRIATE TREATMENT ENVIRONMENT CORVERT (ibutilide fumarate injection) can cause potentially fatal arrhythmias, particularly sustained polymorphic ventricular tachycardia, usually in association with QT prolongation (torsades de pointes), but sometimes without documented QT prolongation. In registration studies, these arrhythmias, which require cardioversion, occurred in 1.7% of treated patients during, or within a number of hours of, use of CORVERT (ibutilide fumarate injection) . These arrhythmias can be reversed if treated promptly (see WARNINGS, Proarrhythmia). It is essential that CORVERT (ibutilide fumarate injection) be administered in a setting of continuous ECG monitoring and by personnel trained in identification and treatment of acute ventricular arrhythmias, particularly polymorphic ventricular tachycardia. Patients with atrial fibrillation of more than 2 to 3 days' duration must be adequately anticoagulated, generally for at least 2 weeks. CHOICE OF PATIENTS Patients with chronic atrial fibrillation have a strong tendency to revert after conversion to sinus rhythm (see Clinical Studies) and treatments to maintain sinus rhythm carry risks. Patients to be treated with CORVERT (ibutilide fumarate injection) , therefore, should be carefully selected such that the expected benefits of maintaining sinus rhythm outweigh the immediate risks of CORVERT (ibutilide fumarate injection) , and the risks of maintenance therapy, and are likely to offer an advantage compared with alternative management.

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CORVERT (ibutilide fumarate injection) Injection is contraindicated in patients who have previously demonstrated hypersensitivity to ibutilide fumarate or any of the other product components. Last reviewed on RxList: 6/25/2008
This monograph has been modified to include the generic and brand name in many instances.

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Acute Experience in Animals: Acute overdose in animals results in CNS toxicity; notably, CNS depression, rapid gasping breathing, and convulsions. The intravenous median lethal dose in the rat was more than 50 mg/kg which is, on a mg/m2 basis, at least 250 times the maximum recommended human dose. Human Experience: In the registration trials with CORVERT (ibutilide fumarate injection) Injection, four patients were unintentionally overdosed. The largest dose was 3.4 mg administered over 15 minutes. One patient (0.025 mg/kg) developed increased ventricular ectopy and monomorphic ventricular tachycardia, another patient (0.032 mg/kg) developed AV block-3rd degree and nonsustained polymorphic VT, and two patients (0.038 and 0.020 mg/kg) had no medical event reports. Based on known pharmacology, the clinical effects of an overdosage with ibutilide could exaggerate the expected prolongation of repolarization seen at usual clinical doses. Medical events (eg, proarrhythmia, AV block) that occur after the overdosage should be treated with measures appropriate for that condition.

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CORVERT Injection (ibutilide fumarate injection) is supplied as an acetate-buffered isotonic solution at a concentration of 0.1 mg/mL that has been adjusted to approximately pH 4.6 in 10 mL clear glass, single-dose, flip-top vials. Single-dose 10 mL vial, 1 mg /10 mL (0.1 mg/mL)...................NDC 0009-3794-01 Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Store vial in carton until used. Distributed By Pharmacia and Upjohn Company, A Division of Pfizer Inc., NY, NY 10017. Revised February 2006. FDA Rev date: 10/17/2002 Last reviewed on RxList: 6/25/2008
This monograph has been modified to include the generic and brand name in many instances.

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General Antiarrhythmics: Class Ia antiarrhythmic drugs (Vaughan Williams Classification), such as disopyramide, quinidine, and procainamide, and other class III drugs, such as amiodarone and sotalol, should not be given concomitantly with CORVERT (ibutilide fumarate injection) Injection or within 4 hours postinfusion because of their potential to prolong refractoriness. In the clinical trials, class I or other class III antiarrhythmic agents were withheld for at least 5 half-lives prior to ibutilide infusion and for 4 hours after dosing, but thereafter were allowed at the physician's discretion. Other drugs that prolong the QT interval: The potential for proarrhythmia may increase with the administration of CORVERT (ibutilide fumarate injection) Injection to patients who are being treated with drugs that prolong the QT interval, such as phenothiazines, tricyclic antidepressants, tetracyclic antidepressants, and certain antihistamine drugs (H1 receptor antagonists). Heart block: Of the nine (1.5%) ibutilide-treated patients with reports of reversible heart block, five had first degree, three had second degree, and one had complete heart block. Laboratory Test Interactions None known. Carcinogenesis, Mutagenesis, Impairment of Fertility No animal studies have been conducted to determine the carcinogenic potential of CORVERT (ibutilide fumarate injection) ; however, it was not genotoxic in a battery of assays, (Ames assay, mammalian cell forward gene mutation assay, unscheduled DNA synthesis assay, and mouse micronucleus assay). Similarly, no drug-related effects on fertility or mating were noted in a reproductive study in rats in which ibutilide was administered orally to both sexes up to doses of 20 mg/kg/day. On a mg/m2 basis, corrected for 3% bioavailability, the highest dose tested was approximately four times the maximum recommended human dose (MRHD). Pregnancy Pregnancy Category C. Ibutilide administered orally was teratogenic (abnormalities included adactyly, interventricular septal defects, and scoliosis) and embryocidal in reproduction studies in rats. On a mg/m2 basis, corrected for the 3% oral bioavailability, the "no adverse effect dose" (5 mg/kg/day given orally) was approximately the same as the maximum recommended human dose (MRHD); the teratogenic dose (20 mg/kg/day given orally) was about four times the MRHD on a mg/m2 basis, or 16 times the MRHD on a mg/kg basis. CORVERT (ibutilide fumarate injection) should not be administered to a pregnant woman unless clinical benefit outweighs potential risk to the fetus. Nursing Mothers The excretion of ibutilide into breast milk has not been studied; accordingly, breastfeeding should be discouraged during therapy with CORVERT (ibutilide fumarate injection) . Pediatric Use Clinical trials with CORVERT (ibutilide fumarate injection) in patients with atrial fibrillation and atrial flutter did not include anyone under the age of 18. Safety and effectiveness of ibutilide in pediatric patients has not been established. Geriatric Use Clinical studies of ibutilide fumarate (involving 586 patients) did not include sufficient numbers of subjects less than age 65 (45%) to determine whether they respond differently from older subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Use in Patients With Hepatic or Renal Dysfunction The safety, effectiveness, and pharmacokinetics of CORVERT (ibutilide fumarate injection) have not been established in patients with hepatic or renal dysfunction. However, it is unlikely that dosing adjustments would be necessary in patients with compromised renal or hepatic function based on the following considerations: (1) CORVERT (ibutilide fumarate injection) is indicated for rapid intravenous therapy (duration ≤ 30 minutes) and is dosed to a known, well-defined pharmacologic action (termination of arrhythmia) or to a maximum of two 10-minute infusions; (2) less than 10% of the dose of CORVERT (ibutilide fumarate injection) is excreted unchanged in the urine; and (3) drug distribution appears to be one of the primary mechanisms responsible for termination of the pharmacologic effect. Nonetheless, patients with abnormal liver function should be monitored by telemetry for more than the 4-hour period generally recommended. In 285 patients with atrial fibrillation or atrial flutter who were treated with CORVERT (ibutilide fumarate injection) , the clearance of ibutilide was independent of renal function, as assessed by creatinine clearance (range 21 to 140 mL/min). Last reviewed on RxList: 6/25/2008
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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