Cordarone (Amiodarone HCl)

CORDARONE® CORDARONE® I.V.

Wyeth-Ayerst

Amiodarone HCl

Antiarrhythmic Agent

Action And Clinical Pharmacology: Amiodarone is generally considered a class III antiarrhythmic drug, but it possesses electrophysiologic characteristics of all 4 Vaughan Williams classes. Like Class I drugs, amiodarone blocks sodium channels at rapid pacing frequencies, and like class II drugs, it exerts antisympathetic activity. One of its main effects, with prolonged administration, is to lengthen the cardiac action potential, a class III effect. The negative chronotropic effect of amiodarone in nodal tissues is similar to the effect of class IV drugs. In addition to blocking sodium channels, amiodarone blocks myocardial potassium channels, which contributes to slowing of conduction and prolongation of refractoriness. The antisympathetic action and block of calcium and potassium channels are responsible for the negative dromotropic effects on the sinus node and for the slowing of conduction and prolongation of refractoriness in the atrioventricular (AV) node.

Additionally, amiodarone has vasodilatory action that can decrease cardiac workload and consequently myocardial oxygen consumption.

At higher doses (>10 mg/kg) of amiodarone i.v., prolongation of the ERP RV and modest prolongation of the QRS have been seen. These differences between oral and i.v. administration suggest that the initial acute effects of amiodarone i.v. may be predominantly focused on the AV node, causing an intranodal conduction delay and increased nodal refractoriness due to calcium channel blockade (Class IV activity) and b-adrenoreceptor antagonism (Class II activity).

Pharmacodynamics: Amiodarone has been reported to produce negative inotropic and vasodilating effects in animals and humans. After long-term treatment with oral amiodarone in a dose range of 200 to 600 mg/day, patients with decreased left ventricular ejection fraction (LVEF) show no significant change in mean LVEF.

Clinical Trials: I.V.: A placebo-controlled study of i.v. amiodarone in patients with supraventricular arrhythmias and 2- to 3-consecutive beat ventricular arrhythmias, and a pharmacokinetic/pharmacodynamic study evaluating rapid i.v. loading in patients with recurrent, refractory VT/VF have shown rapid onset of antiarrhythmic activity well before significant blood levels of DEA were present; approximately 1 500 mg/day of i.v. amiodarone were administered using 2- and 3-stage infusion regimens. In the patients with complex ventricular arrhythmias, including sustained and nonsustained VT, amiodarone therapy reduced episodes of VT by 85%.

The acute effectiveness of amiodarone i.v. in suppressing recurrent VF or hemodynamically unstable VT is supported by 2 randomized, parallel, dose-response studies of approximately 300 patients each. In these studies, patients with at least 2 episodes of VF or hemodynamically unstable VT in the preceding 24 hours were randomly assigned to receive doses of approximately 125 or 1 000 mg over the first 24 hours, an 8-fold difference. In one study, a middle dose of approximately 500 mg was evaluated. The dose regimen consisted of an initial rapid loading infusion, followed by a slower 6-hour loading infusion, and then an 18-hour maintenance infusion. The maintenance infusion was continued up to hour 48. Additional supplemental infusions of 150 mg were given for “breakthrough” VT/VF more frequently to the 125-mg dose group, thereby considerably reducing the planned 8-fold differences in total dose to 1.8- and 2.6-fold, respectively, in the 2 studies.

The prospectively defined primary efficacy end point was the rate of VT/VF episodes/hour. For both studies, the median rate was 0.02 episodes/hour in patients receiving the high dose and 0.07 episodes/hour in patients receiving the low dose, or approximately 0.5 versus 1.7 episodes per day (p=0.07, 2-sided, in both studies). In one study, the time to first episode of VT/VF was significantly prolonged (approximately 10 hours in patients receiving the low dose and 14 hours in patients receiving the high dose). In both studies, significantly fewer supplemental infusions were given to patients in the high-dose group. Mortality was not affected in these studies; at the end of double-blind therapy or after 48 hours, all patients were given open access to whatever treatment (including amiodarone i.v.) was deemed necessary.

Pharmacokinetics: The absorption of oral amiodarone is slow and variable, with peak serum amiodarone concentrations being attained at 3 to 12 hours after administration. Absorption may continue for up to 15 hours after oral ingestion. There is extensive intersubject variation: mean oral bioavailability is approximately 50% (mean range, 33% to 65%). First-pass metabolism in the gut wall and liver appears to be an important factor in determining the systemic availability of the drug. The mean terminal half-life after steady-state administration is approximately 50 days and has been found in one study (n=8) to range from 26 to 107 days. Since at least 3 to 4 half-lives are needed to approach steady-state concentrations, loading doses must be administered at the onset of oral amiodarone therapy.

Amiodarone has a very high apparent volume of distribution (approximately 5 000 L) with an extensive accumulation in tissues, especially adipose tissues, and in highly perfused organs such as liver, lung, spleen, heart and kidney. One major metabolite of amiodarone, desethylamiodarone, has been identified, but the pharmacological activity of this metabolite is not known. During chronic treatment, the plasma ratio of metabolite to parent compound approximates 1.

In patients on long-term oral therapy, amiodarone has a biphasic elimination pattern, with an initial decline in plasma levels observed from 2.5 to 10 days after discontinuation of therapy. This initial phase is followed by a marked rebound in plasma levels at 12 to 20 days post-dosing, before settling into a slower terminal elimination phase. In one study (n=8), the plasma elimination half-life of the parent compound ranged from 26 to 107 days (mean: 53 days).

Amiodarone exhibits complex disposition characteristics after i.v. administration. Peak serum concentrations after single 5 mg/kg 15-minute i.v. infusions in healthy subjects range between 5 and 41 mg/L. Peak concentrations after 150 mg supplemental infusions in patients with VF or hemodynamically unstable VT range between 7 and 26 mg/L. Due to rapid disposition, serum concentrations decline to 10% of peak values within 30 to 45 minutes after the end of the infusion. In clinical trials, after 48 hours of continued infusions (125, 500, or 1 000 mg/day) plus supplemental (150 mg) infusions (for recurrent arrhythmias), amiodarone mean serum concentrations between 0.7 to 1.4 mg/L were observed (n=260).

Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion. Desethylamiodarone (DEA) is the major active metabolite of amiodarone. At the usual amiodarone daily maintenance dose of 400 mg, mean steady-state DEA/amiodarone ratios ranged from 0.61 to 0.93. High-dose oral amiodarone loading in patients yielded 24-hour DEA/amiodarone ratios of 0.083 to 0.19. High-dose i.v. loading yielded a mean 24-hour DEA/amiodarone ratio of 0.041. No data are presently available on the activity of DEA in humans, but animal studies have shown that it has significant electrophysiologic and antiarrhythmic properties. The major enzyme responsible for the N-deethylation to DEA is believed to be cytochrome P-450 3A4. Large interindividual variability in CYP-450 3A4 activity may explain the variable systemic availability of amiodarone. DEA is highly lipophilic and has a very large apparent volume of distribution, showing a higher concentration than amiodarone in all tissue except fat at steady state. Myocardial concentrations of DEA are approximately 3- to 4.5-fold greater than those of amiodarone during long-term oral amiodarone therapy. However, after either acute oral or acute i.v. administration, both mean serum and mean myocardial DEA concentrations are quite low compared to those of amiodarone.

There is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable. Amiodarone and DEA cross the placenta and both appear in breast milk.

Table II summarizes the mean ranges of pharmacokinetic parameters of amiodarone reported in single dose i.v. (5 mg/kg over 15 min) and oral (400 or 600 mg) studies of healthy subjects and in in vitro studies. Pharmacokinetics were similar in males and females.

During chronic treatment with oral amiodarone, close monitoring may be prudent for elderly patients and those with severe left ventricular dysfunction. However, during short-term i.v. use, age, sex, renal disease, and hepatic disease (cirrhosis) do not have clinically significant effects on the disposition of amiodarone and DEA. No dosage adjustment is necessary for patients in any of these populations.

There is no well-established relationship between drug concentration and therapeutic response for long-term oral or short-term i.v. use. Steady-state amiodarone concentrations of 1 to 2.5 mg/L, however, have been effective with minimal toxicity following chronic oral amiodarone.

Indications And Clinical Uses:

No antiarrhythmic drug has been shown to reduce the incidence of sudden death in patients with asymptomatic ventricular arrhythmias. Most antiarrhythmic drugs have the potential to cause dangerous arrhythmias; some have been shown to be associated with an increased incidence of sudden death. In light of the above, physicians should carefully consider the risks and benefits of antiarrhythmic therapy for all patients with ventricular arrhythmias.

Amiodarone therapy should be initiated in hospital and continued in a monitored environment until adequate control of the arrhythmia has occurred.

Patients treated with amiodarone should be under the supervision of a cardiologist or a physician with equivalent experience in cardiology.

Oral: Because of its potential for serious toxicity and the substantial management difficulties associated with its oral use, amiodarone is indicated only for the treatment of patients with the following documented, life-threatening, recurrent ventricular arrhythmias refractory to all other treatment or when alternative agents could not be tolerated: hemodynamically unstable ventricular tachycardia (VT); recurrent ventricular fibrillation (VF).

I.V.: For initiation of treatment of documented, life-threatening, frequently recurring ventricular fibrillation and hemodynamically unstable ventricular tachycardia in patients refractory to all other treatment. Additionally, amiodarone i.v. can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with amiodarone i.v., patients may be transferred to oral amiodarone therapy (see Dosage).

Amiodarone i.v. should be used for acute treatment until the patient’s ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but amiodarone i.v. may be administered for longer periods if necessary.

Contra-Indications: In patients with known hypersensitivity to any of the components of oral amiodarone (tablets) or amiodarone i.v., and in patients with cardiogenic shock, marked sinus bradycardia, and second- or third-degree AV block unless a functioning pacemaker is available. In addition, oral amiodarone is contraindicated in patients with evidence of acute hepatitis (see Precautions), thyroid dysfunction (see Warnings), or pulmonary interstitial abnormalities (see Warnings). tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Oral: Mortality: The results of the Cardiac Arrhythmia Suppression Trial (CAST) in postmyocardial infarction patients with asymptomatic ventricular arrhythmias showed a significant increase in mortality and in nonfatal cardiac arrest rate in patients treated with encainide or flecainide compared with a matched placebo-treated group. CAST was continued using a revised protocol with the moricizine and placebo treatment groups only. The trial was prematurely terminated because of a trend towards an increase in mortality in the moricizine-treated group.

The applicability of these results to other populations or other antiarrhythmic agents is uncertain, but at present, it is prudent to consider these results when using any antiarrhythmic agent.

Thyroid Dysfunction: Both hyper- and hypothyroidism may occur during, or soon after treatment with oral amiodarone; its occurrence during i.v. therapy is negligible. Thyroid function should be monitored before, and at regular intervals (e.g., every 3 months ) during long-term oral amiodarone therapy.

Since amiodarone disturbs the classical thyroid function tests, (PBI, I31 specific measurement of plasma thyroxine levels, as well as those of T3 and of TSH must be used.

In most of the patients who developed thyroid dysfunction while taking oral amiodarone, this drug was discontinued. A few patients with clinical manifestations of hyper- or hypothyroidism have been maintained on amiodarone concurrent with therapy for control of thyroid function, but the risk of such treatment must be weighed carefully against the apparent benefit of oral amiodarone therapy.

In a rat carcinogenicity study, at doses of 5, 16 and 50 mg/kg/day, amiodarone produced statistically significant dose-related changes in the thyroid gland, including follicular adenomas and carcinomas. The significance of these changes for the long-term use of amiodarone in humans is unknown.

I.V. and Oral: Pulmonary Toxicity: One of the most serious complications resulting from oral amiodarone therapy is pulmonary toxicity, characterized by pneumonitis. Clinical symptoms include cough, dyspnea, weight loss, and weakness.

On chest x-ray, there is a diffuse interstitial pattern of lung involvement frequently with patchy alveolar infiltrates, particularly in the upper lobe. Predicting which patient will develop pulmonary toxicity has been difficult (see Contraindications). Pulmonary toxicity can appear abruptly either early or late during therapy and it commonly mimics viral or bacterial infection or worsening congestive heart failure. The relationship of pulmonary toxicity to duration of therapy, maintenance dose, and total dose is unclear. Besides an immediate cessation of amiodarone administration, steroid therapy may be beneficial. The majority of patients have recovered with this management, although some fatalities have occurred. Chest x-rays and pulmonary function tests are recommended prior to, and periodically during, the chronic administration of oral amiodarone.

Only 1 of more than 1 000 patients treated with amiodarone i.v. in clinical studies developed pulmonary fibrosis. For that patient, the condition was diagnosed 3 months after treatment with amiodarone i.v., during which time she had received oral amiodarone. Amiodarone i.v. therapy should be discontinued if a diagnosis of pulmonary fibrosis is made.

During clinical studies of amiodarone i.v., 2% of patients were reported to have adult respiratory distress syndrome (ARDS). ARDS is a disorder characterized by bilateral, diffuse pulmonary infiltrates with pulmonary edema and varying degrees of respiratory insufficiency. The clinical and radiographic picture can arise after a variety of lung injuries, such as those resulting from trauma, shock, prolonged cardiopulmonary resuscitation, and aspiration pneumonia, conditions present in many of the patients enrolled in the clinical studies. It is not possible to determine what role, if any, amiodarone i.v. played in causing or exacerbating the pulmonary disorder in those patients.

Proarrhythmia/QT Interval Prolongation: Amiodarone may cause a worsening of the existing arrhythmias or precipitate a new arrhythmia. Amiodarone causes prolongation of the QT interval. Proarrhythmia, primarily torsades de pointes, has been associated with prolongation of the QTc interval to 500 ms or greater. Proarrhythmia has been reported (2 to 5%) with oral amiodarone, especially in the presence of concomitant antiarrhythmic therapy and has included new-onset VF, incessant VT, increased resistance to cardioversion, and paroxysmal polymorphic VT associated with QT prolongation (torsades de pointes). Although QTc prolongation occurred frequently in patients receiving amiodarone i.v., torsades de pointes or new-onset VF occurred infrequently (less than 2% of all patients treated with amiodarone i.v. in controlled clinical trials). Patients should be monitored carefully for QTc prolongation during amiodarone therapy.

Bradycardia and AV Block: In patients treated with oral amiodarone, symptomatic bradycardia or sinus arrest with suppression of escape foci occurred in approximately 2 to 4% of patients. Bradycardia was reported as an adverse drug reaction in 4.9% of patients receiving amiodarone i.v. for life-threatening VT/VF in clinical trials. AV block was reported as an adverse drug reaction in 1.4% of patients receiving amiodarone i.v. There was no dose-related increase in bradycardia or AV block in these studies.

In patients who develop symptomatic bradycardia while taking oral amiodarone, dose reduction or discontinuation, and possibly pacing, may be considered. Due to the large body load of amiodarone that accumulates with chronic dose administration, and the long half-life of the drug, levels may drop slowly after dose reduction or discontinuation.

During amiodarone i.v. therapy, bradycardia should be treated by slowing the infusion rate or discontinuing therapy.

I.V.: Hypotension: Hypotension is the most common adverse event seen with amiodarone i.v. therapy.

Precautions: General: Patients with life-threatening arrhythmias may experience serious adverse events during their treatment and therefore should be properly monitored. Amiodarone should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and adverse events of treatment (see Indications).

Loading Phase: The higher doses of oral amiodarone used in the loading phase may sometimes be associated with adverse effects such as nausea or tremor. The nausea may respond to dividing the total dose into 2 or 3 fractions taken with meals, or by decreasing the total daily dose. The tremor may respond to dose reduction as well.

Oral: Cardiac Disorders: Oral amiodarone should be used with caution in patients with latent or manifest heart failure because this condition may be worsened by its administration. In these cases, oral amiodarone should be given with appropriate concurrent therapy.

Oral amiodarone therapy may be considered in the treatment of patients with Wolff-Parkinson-White (WPW) syndrome, atrial flutter, or atrial fibrillation, when these conditions are complicated by life-threatening ventricular tachyarrhythmias. In such cases, care is required since the effect of oral amiodarone in these conditions does not appear to be uniform. Electrophysiologic studies may be of value in the selection of these patients who may respond to oral amiodarone, particularly in WPW syndrome.

Nervous System Disorders: Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete.

Dermatologic Disorders: Oral amiodarone may induce photosensitization in some patients. Sunscreen preparations or protective clothing may afford some protection to individual patients experiencing photosensitization. Blue-grey discoloration of exposed skin has been reported during long-term treatment. With discontinuation of therapy, the pigmentation regresses slowly over a period of up to several years. The risk of this phenomenon apppears to be related to dose and duration of therapy.

Ocular Abnormalities: Microdeposits appear in the cornea in the majority of patients treated with oral amiodarone. The deposits are usually discernible only by slit-lamp examination and occasionally give rise to symptoms such as visual halos, which are experienced in as many as 10% of patients. Corneal microdeposits are reversible with reduction of dose or termination of treatment.

Cases of optical neuropathy, usually resulting in visual impairment, have been reported in patients treated with oral amiodarone. A causal relationship to the drug has not been clearly established. If such symptoms appear, prompt ophthalmological examination is recommended. Appearance of optic neuropathy calls for re-evaluation of oral amiodarone therapy. The risk of complications of treatment must be weighed against the benefit of therapy in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmological examination, including fundoscopy and slit-lamp examination, is recommended during administration of oral amiodarone.

Postsurgical Disorders: Occurrences of adult respiratory syndrome (ARDS) and low cardiac output syndrome have been reported postoperatively in patients receiving oral amiodarone therapy who have undergone either cardiac or noncardiac surgery. An intra-aortic balloon pump augmentation has been required in some patients with the low cardiac output syndrome at discontinuation of cardiopulmonary bypass. In the case of ARDS, although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. A number of patients who developed ARDS were subjected to a high concentration of oxygen in the inspired air; this could have been a factor in the respiratory complications. Therefore, the operative Fi02 should be kept as close to room air as possible. Caution should also be exercised in considering amiodarone patients for surgery in the presence of pre-operative pulmonary dysfunction.

However, as amiodarone has a very long half-life, withdrawal before surgery implies delaying operations by several weeks and putting patients at increased risk of malignant dysrhythmias. The ARDS in these cases has rarely been fatal. Caution should be used in considering amiodarone patients for surgery in the presence of preoperative pulmonary dysfunction.

Hypotension independent of, or associated with, discontinuation of cardiopulmonary bypass following open-heart surgery has been reported. Blood vessels may respond poorly to adrenoreceptor agonists. Atropine-resistant bradycardia and complete heart block have also been reported in patients being weaned from cardiopulmonary bypass.

Urogenital System Disorders: Oral amiodarone-induced epididymitis has been observed in some patients. This form of epididymitis is rare, benign, self-limited, and requires no treatment. Physicians should be aware of it to protect their patients from unnecessary invasive urologic examinations and antibiotic therapy.

Oral and I.V.: Liver Enzyme Elevations: In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of amiodarone therapy. However, patients receiving oral or i.v. amiodarone should be monitored carefully for evidence of progressive hepatic injury.

Elevations of blood hepatic enzyme values, ALT, AST and GGT are seen commonly in patients with immediately life-threatening VT/VF. Interpreting elevated AST activity can be difficult because the values may be elevated in patients with recent myocardial infarction, congestive heart failure, and in those who have received multiple electrical defibrillations.

Asymptomatic elevations of liver enzymes (AST and ALT) are frequently associated with the use of oral amiodarone. The mechanism whereby this hepatic effect occurs has not been defined. Phospholipidosis and fibrosis of the liver resembling alcoholic hepatitis or cirrhosis, accompanied by only a mild elevation of hepatic enzymes, have been reported in association with the use of oral amiodarone. Rises in hepatic enzymes, especially when associated with clinical signs and symptoms of hepatitis, or with asymptomatic hepatomegaly, may indicate a liver scan and, if needed, a liver biopsy with ultrastructural study. If serum enzyme levels increase significantly, or persist over time, consideration should be given to discontinuation or reducing the dose of amiodarone. Hepatic failure has been a rare cause of death in patients treated with oral amiodarone.

Approximately 54% of patients receiving amiodarone i.v. in clinical studies had baseline elevations in liver enzyme values, and 13% had clinically significant elevations. In 81% of patients with baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment.

Two cases of fatal hepatocellular necrosis after treatment with amiodarone i.v. have been reported. The patients, one 28 years of age and the other 60 years of age, were treated for atrial arrhythmias with an initial infusion of 1 500 mg over 5 hours, a rate much higher than recommended. Both patients developed hepatic and renal failure within 24 hours after the start of amiodarone i.v. treatment and died on day 14 and day 4, respectively. Because these episodes of hepatic necrosis may have been due to the rapid rate of infusion and hypotension is related to the rate of infusion, the initial rate of infusion should be monitored closely and should not exceed that recommended in the Dosage section.

Electrolyte Disturbances: Patients with hypokalemia or hypomagnesemia should have the condition corrected whenever possible before being treated with amiodarone, since these disorders can exaggerate the degree of QTc prolongation and increase the potential for torsades de pointes. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea in patients receiving concomitant diuretics.

Children: The safety and efficacy of amiodarone in children have not been established; therefore, its use in children is not recommended. Experience with the use of oral amiodarone in children is very limited. The following information is provided in order to help the physician who considers that critical and treatment-resistant disease in a pediatric patient makes the use of amiodarone necessary. In a study of 26 patients aged 6 weeks to 29 years (mean 13 years), an amiodarone dose of 5 mg/kg/day, b.i.d. (10 mg/kg/day) was administered for 10 days; the subsequent mean maintenance dose of oral amiodarone was 7.5 mg/kg/day (range 2.5 to 21.5 mg/kg/day).

Pregnancy: Amiodarone has been shown to be embryotoxic in some animal species. In 3 different human case reports, both the parent drug and its DEA metabolite have been shown to pass through the placenta, quantitatively ranging between 10 and 50% of human maternal serum concentrations. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. Therefore, amiodarone should be used during pregnancy only if the potential benefit to the mother justifies the risk to the fetus.

Labor and Delivery: It is not known whether the use of amiodarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect on the duration of gestation or on parturition.

Lactation: Amiodarone and its DEA metabolite are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone have demonstrated reduced viability and reduced body weight gains. The risk of exposing the infant to amiodarone should be weighed against the potential benefit of arrhythmia suppression in the mother. The mother should be advised to discontinue nursing.

Drug Interactions: Amiodarone can inhibit the metabolism mediated by cytochrome P-450 enzymes, probably accounting for the significant effects of oral amiodarone (and presumably amiodarone i.v.) on the pharmacokinetics of various therapeutic agents including digoxin, quinidine, procainamide, warfarin, dextromethorphan, and cyclosporine. Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem, and verapamil. Conversely, agents producing a significant effect on amiodarone pharmacokinetics include phenytoin, cimetidine, and cholestyramine. The potential for drug interactions may persist long after discontinuation of amiodarone administration because of its long half-life. Few data are available on drug interactions with amiodarone i.v. Except as noted, Tables III and IV summarize the key interactions between oral amiodarone and other therapeutic agents.

Beta-Blockers: Since amiodarone has weak beta-blocking activity, use with beta-blocking agents could increase risk of hypotension and bradycardia.

Calcium Channel Blockers: Amiodarone may have additive effects on atrioventricular conduction or myocardial contractility, increasing the risk of hypotension.

In addition to the interactions noted above, chronic (>2 weeks) oral amiodarone administration impairs metabolism of phenytoin, dextromethorphan, and methotrexate.

Adverse Reactions: Oral : Because of the extensive distribution of amiodarone in body tissues, and the prolonged time required for its elimination from the body following discontinuation of long-term therapy, the relationship between adverse reactions and dosage and duration of therapy, has not been fully established. For some adverse reactions – for example, corneal microdeposits – a relationship to dosage and duration of therapy has been established, so that corneal deposits are reversible with dose reduction or with discontinuation of therapy. However, for other adverse reactions – for example, fibrosing alveolitis or peripheral neuropathy – the dose relationship and the reversibility of the adverse reaction have not been established. Certain gastrointestinal reactions (e.g., nausea, vomiting, constipation, and bad taste) and CNS reactions (e.g., fatigue, headaches, vertigo, nightmares, and sleeplessness) occur frequently at the initiation of therapy when high doses are used. These may disappear on reduction of the dose. The time and dose relationship of adverse events are under continued study.

The most serious and potentially life-threatening adverse effects associated with the use of amiodarone are pulmonary fibrosis, the aggravation of arrhythmias, and cirrhotic hepatitis.

Published data reflecting the North American experience with chronic oral amiodarone therapy suggest that amiodarone-associated adverse drug reactions are very common, having occurred in approximately 75% of patients taking 400 mg or more/day; these adverse events have led to the discontinuation of amiodarone treatment in 7 to 18% of patients. The adverse reactions most frequently requiring discontinuation of amiodarone have included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. Other symptoms causing discontinuations less often have included visual disturbances, solar dermatitis, blue skin discoloration, hyperthyroidism, and hypothyroidism.

Ophthalmological Abnormalities: Corneal microdeposits are apparent upon slit-lamp examination in virtually all adult patients who have taken amiodarone for longer than 6 months. These deposits may give rise to symptoms such as visual halos or blurred vision (see Precautions). Other reported amiodarone-associated abnormalities have included corneal degeneration, photosensitivity, eye discomfort, dry eyes, scotoma, lens opacities, and macular degeneration.

Neurological Abnormalities: Occurring in 20 to 40% of patients, these common disorders have included ataxia, tremor, fatigue, dizziness, weakness, sleep disorders, headaches, cognitive disorders, disturbances of alertness, peripheral motor and sensory neuropathies, proximal muscle weakness, and impotence (see Precautions).

Pulmonary Abnormalities: In some studies symptomatic pulmonary disease has been detected at rates as high as 10 to 15%, whereas asymptomatic abnormalities of pulmonary diffusion capacity have been demonstrated at greater than twice that incidence. Pulmonary toxicity has been fatal about 10% of the time (see Warnings).

Cardiovascular Abnormalities: Exacerbation of arrhythmia has had a reported incidence of about 2 to 5% in most series (new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and paroxysmal polymorphic ventricular tachycardia (torsades de pointes). In addition, symptomatic bradycardia or sinus arrest with suppression of escape foci have occurred in 2 to 4% of patients. Congestive heart failure has occurred in approximately 3% of patients. Second degree AV block and left bundle branch block (LBBB) have occurred in less than 1% of patients. Hypotension independent of – as well as associated with – discontinuation of cardiopulmonary bypass following open-heart surgery has also been reported (see Warnings and Precautions).

Gastrointestinal Abnormalities: Complaints of this nature have occurred in about 25% of patients and have included nausea, vomiting, constipation, anorexia, abnormal taste, dyspepsia, abdominal pain, and diarrhea (see Precautions).

Hepatic Abnormalities: Abnormal elevations of serum levels of enzymes associated with hepatic dysfunction have occurred in approximately 15% of patients. Symptomatic hepatitis has occurred in less than 1% of patients (see Precautions).

Dermatologic Abnormalities: These have occurred in approximately 15% of patients, with photosensitivity (10% of patients) being the most common. Blue-grey skin pigmentation has been reported in 2 to 3% of patients. Hair loss (alopecia) has been observed in up to 4% of patients. Other amiodarone-associated phenomena reported with less than 1% incidence have included nonspecific skin eruptions, pruritus, acquired keratoderma, hyperhidrosis, onycholysis, generalized pustular psoriasis, vasculitis and polyserositis, and toxic epidermal necrolysis (see Precautions).

Thyroid Abnormalities: Amiodarone-associated hypothyroidism has been reported in 2 to 4% of patients in most series but in 8 to 10% of patients with other series: hyperthyroidism has been reported in 1 to 3% of patients (see Warnings).

The following adverse events are based upon retrospective multicentre analysis of 241 patients treated at various doses of amiodarone for 2 to 1 515 days (mean duration: 441.3 days) (see Table V).

I.V.: In a total of 1 836 patients in controlled and uncontrolled clinical trials, 14% of patients received amiodarone i.v. for up to 1 week, 5% received it for up to 2 weeks, 2% received it for up to 3 weeks, and 1% received it for more than 3 weeks, without an increased incidence of serious adverse events. The mean duration of therapy in these studies was 5.6 days.

Overall, treatment was discontinued in 9% of the patients because of adverse events. The most common serious adverse events leading to discontinuation of amiodarone i.v. therapy were ventricular tachycardia (2%), hypotension (2%), cardiac arrest (asystole/cardiac arrest/electromechanical dissociation) (1%), and cardiogenic shock (1%).

Table VI lists the most common (incidence ³1%) adverse drug reactions during amiodarone i.v. therapy that were collected from controlled and open-label clinical trials involving 1 836 patients with hemodynamically unstable VT or VF.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Oral: Overdose may lead to severe bradycardia and to conduction disturbances with the appearance of an idioventricular rhythm, particularly in elderly patients or patients on digitalis therapy.

One report of the acute ingestion of a single 8 g dose of oral amiodarone by a healthy 20-year-old female has been reported. At first assessment, the patient was conscious and profuse perspiration and a slight tachycardia were the only abnormal findings on clinical observation. Slight bradycardia was observed during the second and third day; thereafter, QT interval and heart rate returned to normal. No clinical adverse events were documented over the subsequent 3-month monitoring period.

If an overdose should occur, gastric lavage or induced emesis should be employed to reduce absorption, in addition to general supportive measures. The patient’s cardiac rhythm and blood pressure should be monitored, and if clinically significant bradycardia ensues, a temporary pacemaker should be used.

I.V.: The most likely effects of an inadvertent overdose of amiodarone i.v. are hypotension, cardiogenic shock, bradycardia, AV block, and hepatotoxicity. Hypotension and cardiogenic shock should be treated by slowing the infusion rate or with standard therapy: vasopressor drugs, positive inotropic agents and volume expansion. Bradycardia and AV block may require temporary pacing. Hepatic enzyme concentrations should be monitored closely.

Neither amiodarone nor DEA is dialyzable.

Dosage And Administration: Oral: General Considerations: Amiodarone therapy should be initiated in hospital and continued in a monitored environment until adequate control of the arrhythmia has occurred. Patients treated with amiodarone should be under the supervision of a cardiologist or a physician with equivalent experience in cardiology. Dose administration must be individualized, particularly taking into account concomitant antiarrhythmic therapy.

The dosage schedule for amiodarone is still somewhat controversial, probably in part due to its poor absorption, unusually long elimination half-life, and huge volume of distribution. Extensive tissue stores of amiodarone must be established before the effects on the heart of oral dose administration are apparent. Intersubject variability as well as differences in dosage regimens and methods of assessment have made it difficult to precisely define the time of onset of initial and maximal antiarrhythmic effect in an individual patient. In order to ensure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required. Amiodarone’s antiarrhythmic effect after oral administration may be noted in as early as 3 days (72 hours) but more often takes 1 to 3 weeks.

Because of the slow rate of elimination of amiodarone, its antiarrhythmic effects may persist for weeks or months after its discontinuation, but the time of arrhythmia recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established more rapidly relative to the initial response, possibly because tissue stores were not wholly depleted at the time of recurrence.

The combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening arrhythmias who are unresponsive to adequate doses of a single agent (see Precautions, Drug Interactions).

Adults: Ventricular Arrhythmias: Loading Dose: Loading doses of 800 to 1 600 mg/day are required for 1 to 3 weeks (occasionally longer) until therapeutic response occurs. (Administration of amiodarone in divided doses at meals is suggested for total daily doses of 1 000 mg or higher, when gastrointestinal intolerance occurs).

Maintenance Dose: When adequate arrhythmia control has been achieved, or if adverse drug reactions become prominent, the amiodarone dose should be reduced to 600 to 800 mg/day for 1 month and then to the maintenance dose, usually 200 to 400 mg/day (occasionally 600 mg/day). Amiodarone may be administered as a single daily dose, or in patients with severe gastrointestinal intolerance, as a b.i.d. dose. In each patient, the chronic maintenance dose should be determined according to antiarrhythmic effect as assessed by symptoms, Holter recordings, and/or programmed electrical stimulation, and by patient tolerance. Plasma concentrations may be helpful in evaluating nonresponsiveness or unexpectedly severe toxicity.

The lowest effective dose should be used to prevent the occurrence of adverse drug reactions. In all instances, the physician must be guided by the severity of the individual patient’s arrhythmia and response to therapy. When dose adjustments are necessary, the patient should be closely monitored for an extended period of time because of the long and variable half-life of amiodarone and the difficulty in predicting the time required to attain a new steady-state level of drug.

I.V.: See Table VIII. Amiodarone i.v. must be delivered by a volumetric infusion pump. The surface properties of solutions containing injectable amiodarone are altered such that the drop size may be reduced. This reduction may lead to underdosage of the patient by up to 30% if drop counter infusion sets are used.

Amiodarone i.v. should, whenever possible, be administered through a central venous catheter dedicated to that purpose. An in-line filter should be used during administration.

Amiodarone i.v. concentrations greater than 3 mg/mL in D5W have been associated with a high incidence of peripheral vein phlebitis; however, concentrations of 2.5 mg/mL or less appear to be less irritating. Therefore, for infusions longer than 1 hour, amiodarone i.v. concentrations should not exceed 2 mg/mL unless a central venous catheter is used.

Amiodarone i.v. infusions exceeding 2 hours must be administered in glass or polyolefin bottles containing D5W.

It is well known that amiodarone adsorbs to polyvinyl chloride (PVC) tubing and the clinical trial dose administration schedule was designed to account for this adsorption. All of the clinical trials were conducted using PVC tubing and its use is therefore recommended. The concentrations and rates of infusion provided in Dosage reflect doses identified in these studies.

Amiodarone i.v. does not need to be protected from light during administration.

Amiodarone shows considerable interindividual variation in response. Thus, although a starting dose adequate to suppress life-threatening arrhythmias is needed, close monitoring with adjustment of dose is essential. The recommended starting dose of amiodarone i.v. is about 1 000 mg over the first 24 hours of therapy, delivered by the infusion regimen in Table X. It is important that the recommended infusion regimen be followed closely.

After the first 24 hours, the maintenance infusion rate of 0.5 mg/min (720 mg/24 hours) should be continued utilizing a concentration of 1 to 6 mg/mL (amiodarone i.v. concentrations greater than 2 mg/mL should be administered via a central venous catheter). In the event of breakthrough episodes of VF or hemodynamically unstable VT, 150 mg supplemental infusions of amiodarone i.v. mixed in 100 mL of D5W may be administered. Such infusions should be administered over 10 minutes to minimize the potential for hypotension. The rate of the maintenance infusion may be increased to achieve effective arrhythmia suppression.

The first 24-hour dose may be individualized for each patient; however, in controlled clinical trials, mean daily doses above 2 100 mg were associated with an increased risk of hypotension. The initial rate of infusion should not exceed 30 mg/min.

Based on the experience from clinical studies of amiodarone i.v., a maintenance infusion of up to 0.5 mg/min can be cautiously continued for 2 to 3 weeks regardless of the patient’s age, renal function, or left ventricular function. There has been limited experience in patients receiving amiodarone i.v. for longer than 3 weeks.

I.V. to Oral Transition: Patients whose arrhythmias have been suppressed by amiodarone i.v. may be switched to oral amiodarone. The optimal dose for changing from i.v. to oral administration of amiodarone will depend on the dose of amiodarone i.v. already administered as well as the bioavailability of oral amiodarone. When changing to oral amiodarone therapy, clinical monitoring is recommended, particularly for elderly patients.

Table XI provides suggested doses of oral amiodarone to be initiated after varying durations of amiodarone i.v. administration. These recommendations are made on the basis of a comparable total body amount of amiodarone delivered by the i.v. and oral routes, based on a 50% bioavailability of oral amiodarone.

SuppliedSupplied: Oral: Each round, flat, pink tablet with a raised “C” and marked “200” on one side with the reverse side scored contains: amiodarone HCl 200 mg. Nonmedicinal ingredients: colloidal silicon dioxide, cornstarch, lactose, magnesium stearate and povidone. Keep bottle tightly closed. Store at room temperature, 15 to 30°C. Protect from light.

I.V.: Each mL of clear, pale yellow solution contains: amiodarone HCl 50 mg. Nonmedicinal ingredients: benzyl alcohol (20.2 mg), polysorbate 80 (100 mg) and water for injection. Clear type 1 flint glass ampuls of 5 mL containing 3 mL of solution. Store at controlled room temperature, 15 to 25°C. Protect from light and excessive heat. Use carton to protect contents from light until use.

CORDARONE® CORDARONE® I.V. Wyeth-Ayerst Amiodarone HCl Antiarrhythmic Agent

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