Cordarone Information
Cordarone () Description
Cordarone () (amiodarone HCl) is a member of a class of antiarrhythmic drugs with predominantly Class III (Vaughan Williams' classification) effects, available for oral administration as pink, scored tablets containing 200 mg of amiodarone hydrochloride. The inactive ingredients present are colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. Cordarone () is a benzofuran derivative: 2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride.
The structural formula is as follows:
Amiodarone HCl is a white to cream-colored crystalline powder. It is slightly soluble in water, soluble in alcohol, and freely soluble in chloroform. It contains 37.3% iodine by weight.
Cordarone () Clinical Pharmacology
In animals, Cordarone () is effective in the prevention or suppression of experimentally induced arrhythmias. The antiarrhythmic effect of Cordarone () may be due to at least two major properties:
Cordarone () prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. Cordarone () increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15 to 20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave contour. These changes should not require discontinuation of Cordarone () as they are evidence of its pharmacological action, although Cordarone () can cause marked sinus bradycardia or sinus arrest and heart block. On rare occasions, QT prolongation has been associated with worsening of arrhythmia (see ).
Following oral administration in man, Cordarone () is slowly and variably absorbed. The bioavailability of Cordarone () is approximately 50%, but has varied between 35 and 65% in various studies. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Despite this, the onset of action may occur in 2 to 3 days, but more commonly takes 1 to 3 weeks, even with loading doses. Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability. Food increases the rate and extent of absorption of Cordarone () . The effects of food upon the bioavailability of Cordarone () have been studied in 30 healthy subjects who received a single 600-mg dose immediately after consuming a high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (C) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (T) by 37%. The mean AUC and mean C of desethylamiodarone increased by 55% (range 58 to 101%) and 32% (range 4 to 84%), respectively, but there was no change in the T in the presence of food.
Cordarone () has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen. One major metabolite of Cordarone () , desethylamiodarone (DEA), has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA's precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular Class III effects after oral Cordarone () administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation.
Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines.
Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable.
In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 and 440 ml/hr/kg. Age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or DEA. Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of intravenous amiodarone in cirrhotic patients, significantly lower C and average concentration values are seen for DEA, but mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances (about 100 ml/hr/kg) than younger subjects (about 150 ml/hr/kg) and an increase in t from about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition t of DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with Cordarone () , close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction.
Following single dose administration in 12 healthy subjects, Cordarone () exhibited multi-compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, Cordarone () has been shown to have a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 10 days. A much slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to 107 days, with a mean of approximately 53 days and most patients in the 40- to 55-day range. In the absence of a loading-dose period, steady-state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5- to 10-day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat.
The considerable intersubject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Daily maintenance doses of Cordarone () should be based on individual patient requirements (see ).
Cordarone () and its metabolite have a limited transplacental transfer of approximately 10 to 50%. The parent drug and its metabolite have been detected in breast milk.
Cordarone () is highly protein-bound (approximately 96%).
Although electrophysiologic effects, such as prolongation of QTc, can be seen within hours after a parenteral dose of Cordarone () , effects on abnormal rhythms are not seen before 2 to 3 days and usually require 1 to 3 weeks, even when a loading dose is used. There may be a continued increase in effect for longer periods still. There is evidence that the time to effect is shorter when a loading-dose regimen is used.
Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after Cordarone () is discontinued, but the time of recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly compared to the initial response, presumably because tissue stores were not wholly depleted at the time of recurrence.
Predicting the effectiveness of any antiarrhythmic agent in long-term prevention of recurrent ventricular tachycardia and ventricular fibrillation is difficult and controversial, with highly qualified investigators recommending use of ambulatory monitoring, programmed electrical stimulation with various stimulation regimens, or a combination of these, to assess response. There is no present consensus on many aspects of how best to assess effectiveness, but there is a reasonable consensus on some aspects:
Several predictors of success not based on PES have also been suggested, including complete elimination of all nonsustained ventricular tachycardia on ambulatory monitoring and very low premature ventricular-beat rates (less than 1 VPB/1,000 normal beats).
While these issues remain unsettled for Cordarone () , as for other agents, the prescriber of Cordarone () should have access to (direct or through referral), and familiarity with, the full range of evaluatory procedures used in the care of patients with life-threatening arrhythmias.
It is difficult to describe the effectiveness rates of Cordarone () , as these depend on the specific arrhythmia treated, the success criteria used, the underlying cardiac disease of the patient, the number of drugs tried before resorting to Cordarone () , the duration of follow-up, the dose of Cordarone () , the use of additional antiarrhythmic agents, and many other factors. As Cordarone () has been studied principally in patients with refractory life-threatening ventricular arrhythmias, in whom drug therapy must be selected on the basis of response and cannot be assigned arbitrarily, randomized comparisons with other agents or placebo have not been possible. Reports of series of treated patients with a history of cardiac arrest and mean follow-up of one year or more have given mortality (due to arrhythmia) rates that were highly variable, ranging from less than 5% to over 30%, with most series in the range of 10 to 15%. Overall arrhythmia-recurrence rates (fatal and nonfatal) also were highly variable (and, as noted above, depended on response to PES and other measures), and depend on whether patients who do not seem to respond initially are included. In most cases, considering only patients who seemed to respond well enough to be placed on long-term treatment, recurrence rates have ranged from 20 to 40% in series with a mean follow-up of a year or more.
Cordarone () Indications And Usage
Because of its life-threatening side effects and the substantial management difficulties associated with its use (see below), Cordarone () is indicated only for the treatment of the following documented, life-threatening recurrent ventricular arrhythmias when these have not responded to documented adequate doses of other available antiarrhythmics or when alternative agents could not be tolerated.
As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of Cordarone () Tablets favorably affects survival.
Cordarone () should be used only by physicians familiar with and with access to (directly or through referral) the use of all available modalities for treating recurrent life-threatening ventricular arrhythmias, and who have access to appropriate monitoring facilities, including in-hospital and ambulatory continuous electrocardiographic monitoring and electrophysiologic techniques. Because of the life-threatening nature of the arrhythmias treated, potential interactions with prior therapy, and potential exacerbation of the arrhythmia, initiation of therapy with Cordarone () should be carried out in the hospital.
Cordarone () Contraindications
Cordarone () is contraindicated in patients with cardiogenic shock; severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third-degree atrioventricular block; and when episodes of bradycardia have caused syncope (except when used in conjunction with a pacemaker).
Cordarone () is contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine.
Cordarone () Warnings
Cordarone () is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity.
Cordarone () has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10 to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal about 10% of the time. Liver injury is common with Cordarone () , but is usually mild and evidenced only by abnormal liver enzymes. Overt liver disease can occur, however, and has been fatal in a few cases. Like other antiarrhythmics, Cordarone () can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse. This has occurred in 2 to 5% of patients in various series, and significant heart block or sinus bradycardia has been seen in 2 to 5%. All of these events should be manageable in the proper clinical setting in most cases. Although the frequency of such proarrhythmic events does not appear greater with Cordarone () than with many other agents used in this population, the effects are prolonged when they occur.
Even in patients at high risk of arrhythmic death, in whom the toxicity of Cordarone () is an acceptable risk, Cordarone () poses major management problems that could be life-threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first.
The difficulty of using Cordarone () effectively and safely itself poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of Cordarone () is given, and a response generally requires at least one week, usually two or more. Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment. In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15 to 20% overall frequencies of discontinuation due to adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk during this time and may need prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when Cordarone () must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when Cordarone () is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried.
In the National Heart, Lung and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-centered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had had myocardial infarctions more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate was seen in patients treated with encainide or flecainide (56/730) compared with that seen in patients assigned to matched placebo-treated groups (22/725). The average duration of treatment with encainide or flecainide in this study was ten months.
These data are consistent with the results of a pooled analysis of smaller, controlled studies involving patients with structural heart disease (including myocardial infarction).
There have been post-marketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with oral Cordarone () with or without initial I.V. therapy. Findings have included pulmonary infiltrates and/or mass on X-ray, pulmonary alveolar hemorrhage, pleural effusion, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure and/or death. Post-marketing reports describe cases of pulmonary toxicity in patients treated with low doses of Cordarone () ; however, reports suggest that the use of lower loading and maintenance doses of Cordarone () are associated with a decreased incidence of Cordarone () -induced pulmonary toxicity.
Cordarone () Tablets may cause a clinical syndrome of cough and progressive dyspnea accompanied by functional, radiographic, gallium-scan, and pathological data consistent with pulmonary toxicity, the frequency of which varies from 2 to 7% in most published reports, but is as high as 10 to 17% in some reports. Therefore, when Cordarone () therapy is initiated, a baseline chest X-ray and pulmonary-function tests, including diffusion capacity, should be performed. The patient should return for a history, physical exam, and chest X-ray every 3 to 6 months.
Pulmonary toxicity secondary to Cordarone () seems to result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis (including eosinophilic pneumonia) or interstitial/alveolar pneumonitis, respectively.
Patients with preexisting pulmonary disease have a poorer prognosis if pulmonary toxicity develops.
Hypersensitivity pneumonitis
Bronchoalveolar lavage is the procedure of choice to confirm this diagnosis, which can be made when a T suppressor/cytotoxic (CD8-positive) lymphocytosis is noted. Steroid therapy should be instituted and Cordarone () therapy discontinued in these patients.
Interstitial/alveolar pneumonitis
In a patient receiving Cordarone () , any new respiratory symptoms should suggest the possibility of pulmonary toxicity, and the history, physical exam, chest X-ray, and pulmonary-function tests (with diffusion capacity) should be repeated and evaluated. A 15% decrease in diffusion capacity has a high sensitivity but only a moderate specificity for pulmonary toxicity; as the decrease in diffusion capacity approaches 30%, the sensitivity decreases but the specificity increases. A gallium-scan also may be performed as part of the diagnostic workup.
Fatalities, secondary to pulmonary toxicity, have occurred in approximately 10% of cases. However, in patients with life-threatening arrhythmias, discontinuation of Cordarone () therapy due to suspected drug-induced pulmonary toxicity should be undertaken with caution, as the most common cause of death in these patients is sudden cardiac death. Therefore, every effort should be made to rule out other causes of respiratory impairment (i.e., congestive heart failure with Swan-Ganz catheterization if necessary, respiratory infection, pulmonary embolism, malignancy, etc.) before discontinuing Cordarone () in these patients. In addition, bronchoalveolar lavage, transbronchial lung biopsy and/or open lung biopsy may be necessary to confirm the diagnosis, especially in those cases where no acceptable alternative therapy is available.
If a diagnosis of Cordarone () -induced hypersensitivity pneumonitis is made, Cordarone () should be discontinued, and treatment with steroids should be instituted. If a diagnosis of Cordarone () -induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, Cordarone () discontinued or, at a minimum, reduced in dosage. Some cases of Cordarone () -induced interstitial/alveolar pneumonitis may resolve following a reduction in Cordarone () dosage in conjunction with the administration of steroids. In some patients, rechallenge at a lower dose has not resulted in return of interstitial/alveolar pneumonitis; however, in some patients (perhaps because of severe alveolar damage) the pulmonary lesions have not been reversible.
Cordarone () , like other antiarrhythmics, can cause serious exacerbation of the presenting arrhythmia, a risk that may be enhanced by the presence of concomitant antiarrhythmics. Exacerbation has been reported in about 2 to 5% in most series, and has included new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia associated with QTc prolongation (Torsade de Pointes [TdP]). In addition, Cordarone () has caused symptomatic bradycardia or sinus arrest with suppression of escape foci in 2 to 4% of patients.
Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See ).
The need to co-administer amiodarone with any other drug known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient.
A careful assessment of the potential risks and benefits of administering Cordarone () must be made in patients with thyroid dysfunction due to the possibility of arrhythmia breakthrough or exacerbation of arrhythmia in these patients.
Cordarone () can cause fetal harm when administered to a pregnant woman. Although Cordarone () use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. If Cordarone () is used during pregnancy, or if the patient becomes pregnant while taking Cordarone () , the patient should be apprised of the potential hazard to the fetus.
In general, Cordarone () Tablets should be used during pregnancy only if the potential benefit to the mother justifies the unknown risk to the fetus.
In pregnant rats and rabbits, amiodarone HCl in doses of 25 mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose*) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose*) caused abortions in greater than 90% of the animals. In the rat, doses of 50 mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose.*) Adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose*).
*600 mg in a 50 kg patient (doses compared on a body surface area basis)
Cordarone () Precautions
Cordarone () inhibits peripheral conversion of thyroxine (T) to triiodothyronine (T) and may cause increased thyroxine levels, decreased T levels, and increased levels of inactive reverse T (rT) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because of its release of inorganic iodine, or perhaps for other reasons, Cordarone () can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of Cordarone () and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following Cordarone () withdrawal.
Hypothyroidism has been reported in 2 to 4% of patients in most series, but in 8 to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Hypothyroidism is best managed by Cordarone () dose reduction and/or thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue Cordarone () Tablets in some patients.
Hyperthyroidism occurs in about 2% of patients receiving Cordarone () , but the incidence may be higher among patients with prior inadequate dietary iodine intake. Cordarone () -induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and/or arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED.
Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum T RIA, and further elevations of serum T, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany Cordarone () -induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of Cordarone () .
The institution of antithyroid drugs, β-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Cordarone () -induced hyperthyroidism may be followed by a transient period of hypothyroidism (see ).
When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning.
There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with Cordarone () . In some instances hyperthyroidism was also present (see and ).
Elevations in liver enzymes (SGOT and SGPT) can occur. Liver enzymes in patients on relatively high maintenance doses should be monitored on a regular basis. Persistent significant elevations in the liver enzymes or hepatomegaly should alert the physician to consider reducing the maintenance dose of Cordarone () or discontinuing therapy.
Cordarone () alters the results of thyroid-function tests, causing an increase in serum T and serum reverse T, and a decline in serum T levels. Despite these biochemical changes, most patients remain clinically euthyroid.
Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines (see ). Amiodarone is an inhibitor of CYP3A4 and p-glycoprotein. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4 and substrates of p-glycoprotein. While only a limited number of drug-drug interactions with amiodarone have been reported, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. In view of the long and variable half-life of amiodarone, potential for drug interactions exists, not only with concomitant medication, but also with drugs administered after discontinuation of amiodarone.
Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit CYP3A4 may decrease the metabolism and increase serum concentrations of amiodarone. Reported examples include the following:
Amiodarone HCl was associated with a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors was greater than control even at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose*).
Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with Cordarone () were negative.
In a study in which amiodarone HCl was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose*).
*600 mg in a 50 kg patient (dose compared on a body surface area basis)
Cordarone () Adverse Reactions
Adverse reactions have been very common in virtually all series of patients treated with Cordarone () for ventricular arrhythmias with relatively large doses of drug (400 mg/day and above), occurring in about three-fourths of all patients and causing discontinuation in 7 to 18%. The most serious reactions are pulmonary toxicity, exacerbation of arrhythmia, and rare serious liver injury (see ), but other adverse effects constitute important problems. They are often reversible with dose reduction or cessation of Cordarone () treatment. Most of the adverse effects appear to become more frequent with continued treatment beyond six months, although rates appear to remain relatively constant beyond one year. The time and dose relationships of adverse effects are under continued study.
Neurologic problems are extremely common, occurring in 20 to 40% of patients and including malaise and fatigue, tremor and involuntary movements, poor coordination and gait, and peripheral neuropathy; they are rarely a reason to stop therapy and may respond to dose reductions or discontinuation (see ). There have been spontaneous reports of demyelinating polyneuropathy.
Gastrointestinal complaints, most commonly nausea, vomiting, constipation, and anorexia, occur in about 25% of patients but rarely require discontinuation of drug. These commonly occur during high-dose administration (i.e., loading dose) and usually respond to dose reduction or divided doses.
Ophthalmic abnormalities including optic neuropathy and/or optic neuritis, in some cases progressing to permanent blindness, papilledema, corneal degeneration, photosensitivity, eye discomfort, scotoma, lens opacities, and macular degeneration have been reported. (See .)
Asymptomatic corneal microdeposits are present in virtually all adult patients who have been on drug for more than 6 months. Some patients develop eye symptoms of halos, photophobia, and dry eyes. Vision is rarely affected and drug discontinuation is rarely needed.
Dermatological adverse reactions occur in about 15% of patients, with photosensitivity being most common (about 10%). Sunscreen and protection from sun exposure may be helpful, and drug discontinuation is not usually necessary. Prolonged exposure to Cordarone () occasionally results in a blue-gray pigmentation. This is slowly and occasionally incompletely reversible on discontinuation of drug but is of cosmetic importance only.
Cardiovascular adverse reactions, other than exacerbation of the arrhythmias, include the uncommon occurrence of congestive heart failure (3%) and bradycardia. Bradycardia usually responds to dosage reduction but may require a pacemaker for control. CHF rarely requires drug discontinuation. Cardiac conduction abnormalities occur infrequently and are reversible on discontinuation of drug.
The following are based on a retrospective study of 241 patients treated for 2 to 1,515 days (mean 441.3 days).
Cordarone () Overdosage
There have been cases, some fatal, of Cordarone () overdose.
In addition to general supportive measures, the patient's cardiac rhythm and blood pressure should be monitored, and if bradycardia ensues, a β-adrenergic agonist or a pacemaker may be used. Hypotension with inadequate tissue perfusion should be treated with positive inotropic and/or vasopressor agents. Neither Cordarone () nor its metabolite is dialyzable.
The acute oral LD of amiodarone HCl in mice and rats is greater than 3,000 mg/kg.
Cordarone () Dosage And Administration
BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, Cordarone () 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 Cordarone () THERAPY, AND WHO HAVE ACCESS TO LABORATORY FACILITIES CAPABLE OF ADEQUATELY MONITORING THE EFFECTIVENESS AND SIDE EFFECTS OF TREATMENT.
In order to insure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required. A uniform, optimal dosage schedule for administration of Cordarone () has not been determined. Because of the food effect on absorption, Cordarone () should be administered consistently with regard to meals (see ). Individual patient titration is suggested according to the following guidelines:
Cordarone () How Supplied
Cordarone () (amiodarone HCl) Tablets are available in bottles of 60 tablets as follows:
200 mg, NDC 0008-4188-04, round, convex-faced, pink tablets with a raised “C” and marked “200” on one side, with reverse side scored and marked “WYETH” and “4188.”
Manufactured by Sanofi Winthrop Industrie
1, rue de la Vierge
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LAB-0564-1.0
Revised October 2011
Cordarone ()
Cordarone () Package Label.principal Display Panel
NDC 0008-4188-04
60 Tablets
Cordarone ()
(amiodarone HCl)
200 mg
Note to authorized dispenser: Each time Cordarone () Tablets is dispensed, give the patient a medication guide.
SEALED FOR YOUR PROTECTION
Rx only
Wyeth
