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amiodarone hydrochloride tablet
----------Amiodarone Hydrochloride Tablets, 200 mg
Amiodarone hydrochloride tablets are a member of a new class of antiarrhythmic drugs with predominantly Class III (Vaughan Williams’ classification) effects, available for oral administration as yellow, scored tablets. Each tablet for oral administration contains 200 mg of amiodarone hydrochloride. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, povidone, and D&C yellow No. 10 aluminum lake. Amiodarone hydrochloride tablets are a benzofuran derivative: 2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride. It is not chemically related to any other available antiarrhythmic drug.
The structural formula is as follows:
C25H29I2NO3 • HCl Molecular Weight: 681.8
Amiodarone hydrochloride 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.
Electrophysiology/Mechanisms of Action
In animals, amiodarone hydrochloride tablets are effective in the prevention or suppression of experimentally induced arrhythmias. The antiarrhythmic effect of amiodarone hydrochloride tablets may be due to at least two major properties: 1) a prolongation of the myocardial cell-action potential duration and refractory period and 2) noncompetitive α- and β-adrenergic inhibition.
Amiodarone hydrochloride tablets prolong 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. Amiodarone hydrochloride tablets increase 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 amiodarone hydrochloride tablets as they are evidence of its pharmacological action, although amiodarone can cause marked sinus bradycardia or sinus arrest and heart block. On rare occasions, QT prolongation has been associated with worsening of arrhythmia (see WARNINGS).
In animal studies and after intravenous administration in man, amiodarone hydrochloride tablets relax vascular smooth muscle, reduces peripheral vascular resistance (afterload) and slightly increases cardiac index. After oral dosing, however, amiodarone hydrochloride tablets produce no significant change in left ventricular ejection fraction (LVEF), even in patients with depressed LVEF. After acute intravenous dosing in man, amiodarone hydrochloride tablets may have a mild negative inotropic effect.
Following oral administration in man, amiodarone hydrochloride tablets are slowly and variably absorbed. The bioavailability of amiodarone hydrochloride tablets 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 mg/day 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 amiodarone hydrochloride tablets. The effects of food upon the bioavailability of amiodarone hydrochloride tablets 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 (Cmax) 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 (Tmax) by 37%. The mean AUC and mean Cmax of desethylamiodarone increased by 55% (range 58% to 101%) and 32% (range 4% to 84%), respectively, but there was no change in the Tmax in the presence of food.
Amiodarone hydrochloride tablets have 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 amiodarone hydrochloride tablets, 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 lll effects after oral amiodarone hydrochloride tablet 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 mL/hr/kg 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 Cmax 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 t1/2 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 t1/2 of DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic or cardiac abnormalities has been defined during chronic treatment with amiodarone hydrochloride tablets, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction.
Following single dose administration in 12 healthy subjects, amiodarone hydrochloride tablets 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, amiodarone hydrochloride tablets have 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 amiodarone hydrochloride tablets should be based on individual patient requirements (see DOSAGE AND ADMINISTRATION).
Amiodarone hydrochloride tablets 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.
Amiodarone hydrochloride tablets are highly protein-bound (approximately 96%).
Although electrophysiologic effects, such as prolongation of QTc, can be seen within hours after a parenteral dose of amiodarone hydrochloride tablets, 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 amiodarone hydrochloride tablets are 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.
There is no well-established relationship of plasma concentration to effectiveness, but it does appear that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Within individuals dose reductions and ensuing decreased plasma concentrations can result in loss of arrhythmia control. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from a dose increase, or unusually high and who might have dosage reduction in the hope of minimizing side effects. Some observations have suggested a plasma concentration, dose or dose/duration relationship for side effects such as pulmonary fibrosis, liver-enzyme elevations, corneal deposits and facial pigmentation, peripheral neuropathy, gastrointestinal and central nervous system effects.
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 amiodarone hydrochloride tablets, as for other agents, the prescriber of amiodarone hydrochloride tablets 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 amiodarone hydrochloride tablets, 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 amiodarone hydrochloride tablets, the duration of follow-up, the dose of amiodarone hydrochloride tablets, the use of additional antiarrhythmic agents, and many other factors. As amiodarone hydrochloride tablets have 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.
INDICATIONS AND USAGE
Because of its life-threatening side effects and the substantial management difficulties associated with its use (see WARNINGSbelow), amiodarone hydrochloride tablets are 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 amiodarone hydrochloride tablets favorably affects survival.
Amiodarone hydrochloride tablets 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 amiodarone hydrochloride tablets should be carried out in the hospital.
Amiodarone hydrochloride tablets are 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).
Amiodarone hydrochloride tablets are contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine.
Amiodarone hydrochloride tablets are intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity.
Amiodarone hydrochloride tablets have 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 amiodarone hydrochloride tablets, 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, amiodarone hydrochloride tablets 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 amiodarone hydrochloride tablets 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 amiodarone hydrochloride tablets are an acceptable risk, amiodarone hydrochloride tablets pose 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 amiodarone hydrochloride tablets effectively and safely itself poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of amiodarone hydrochloride tablets are 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 amiodarone hydrochloride tablets must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when amiodarone hydrochloride tablets are 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.
Amiodarone hydrochloride tablet therapy was evaluated in two multi-centered, randomized, double-blind, placebo-controlled trials involving 1202 (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial; CAMIAT) and 1486 (European Myocardial Infarction Amiodarone Trial; EMIAT) post-MI patients followed for up to 2 years. Patients in CAMIAT qualified with ventricular arrhythmias, and those randomized to amiodarone received weight- and response-adjusted doses of 200 mg/day to 400 mg/day. Patients in EMIAT qualified with ejection fraction <40%, and those randomized to amiodarone received fixed doses of 200 mg/day. Both studies had weeks-long loading dose schedules. Intent-to-treat all-cause mortality results were as follows:
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 amiodarone hydrochloride tablets 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. cases have progressed to respiratory failure and/or death. Post-marketing reports describe cases of pulmonary toxicity in patients treated with low doses of amiodarone hydrochloride tablets; however, reports suggest that the use of lower loading and maintenance doses of amiodarone hydrochloride tablets are associated with a decreased incidence of amiodarone hydrochloride tablet-induced pulmonary toxicity.
Amiodarone hydrochloride 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 amiodarone hydrochloride tablet 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 amiodarone hydrochloride tablets seem 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 Pneumonitisusually appears earlier in the course of therapy, and rechallenging these patients with amiodarone hydrochloride tablets results in a more rapid recurrence of greater severity.
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 amiodarone hydrochloride tablet therapy discontinued in these patients.
Interstitial/Alveolar Pneumonitismay result from the release of oxygen radicals and/or phospholipidosis and is characterized by findings of diffuse alveolar damage, interstitial pneumonitis or fibrosis in lung biopsy specimens. Phospholipidosis (foamy cells, foamy macrophages), due to inhibition of phospholipase, will be present in most cases of amiodarone hydrochloride tablet-induced pulmonary toxicity; however, these changes also are present in approximately 50% of all patients on amiodarone hydrochloride tablet therapy. These cells should be used as markers of therapy, but not as evidence of toxicity. A diagnosis of amiodarone hydrochloride tablet-induced interstitial/alveolar pneumonitis should lead, at a minimum, to dose reduction or, preferably, to withdrawal of the amiodarone hydrochloride tablets to establish reversibility, especially if other acceptable antiarrhythmic therapies are available. Where these measures have been instituted, a reduction in symptoms of amiodarone-induced pulmonary toxicity was usually noted within the first week, and a clinical improvement was greatest in the first two to three weeks. Chest X-ray changes usually resolve within two to four months. According to some experts, steroids may prove beneficial. Prednisone in doses of 40 mg/day to 60 mg/day or equivalent doses of other steroids have been given and tapered over the course of several weeks depending upon the condition of the patient. In some cases rechallenge with amiodarone hydrochloride tablets at a lower dose has not resulted in return of toxicity.
In a patient receiving amiodarone hydrochloride tablets, 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 amiodarone hydrochloride tablet 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 amiodarone hydrochloride tablets 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 amiodarone hydrochloride tablet-induced hypersensitivity pneumonitis is made, amiodarone hydrochloride tablets should be discontinued and treatment with steroids should be instituted. If a diagnosis of amiodarone-induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, amiodarone hydrochloride tablets discontinued or, at a minimum, reduced in dosage. Some cases of amiodarone-induced interstitial/alveolar pneumonitis may resolve following a reduction in amiodarone hydrochloride tablets 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.
Amiodarone hydrochloride tablets, 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 (torsades de pointes [TdP]). In addition, amiodarone hydrochloride tablets have 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 Drug Interactions, Other reported interactions with amiodarone.)
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 amiodarone hydrochloride tablets must be made in patients with thyroid dysfunction due to the possibility of arrhythmia breakthrough or exacerbation of arrhythmia in these patients.
Implantable Cardiac Devices
In patients with implanted defibrillators or pacemakers, chronic administration of antiarrhythmic drugs may affect pacing or defibrillating thresholds. Therefore, at the inception of and during amiodarone treatment, pacing and defibrillation thresholds should be assessed.
Amiodarone hydrochloride tablet-induced hyperthyroidism may result in thyrotoxicosis and/or the possibility of arrhythmia breakthrough or aggravation. 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 (see PRECAUTIONS, Thyroid Abnormalities).
Elevations of hepatic enzyme levels are seen frequently in patients exposed to amiodarone hydrochloride tablets and in most cases are asymptomatic. If the increase exceeds three times normal, or doubles in a patient with an elevated baseline, discontinuation of amiodarone hydrochloride tablets or dosage reduction should be considered. In a few cases in which biopsy has been done, the histology has resembled that of alcoholic hepatitis or cirrhosis. Hepatic failure has been a rare cause of death in patients treated with amiodarone hydrochloride tablets.
Loss of Vision
Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and/or neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt ophthalmic examination is recommended. Appearance of optic neuropathy and/or neuritis calls for re-evaluation of amiodarone hydrochloride tablet therapy. The risks and complications of antiarrhythmic therapy with amiodarone hydrochloride tablets must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is recommended during administration of amiodarone hydrochloride tablets (see ADVERSE REACTIONS).
Neonatal Hypo- or Hyperthyroidism
Amiodarone hydrochloride tablets can cause fetal harm when administered to a pregnant woman. Although amiodarone hydrochloride tablets use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. If amiodarone hydrochloride tablets are used during pregnancy or if the patient becomes pregnant while taking amiodarone hydrochloride tablets, the patient should be apprised of the potential hazard to the fetus.
In general, amiodarone hydrochloride 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)
Impairment of Vision
Optic Neuropathy and/or Neuritis
Cases of optic neuropathy and optic neuritis have been reported (see WARNINGS).
Corneal microdeposits appear in the majority of adults treated with amiodarone hydrochloride tablets. They are usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment (see ADVERSE REACTIONS).
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.
Amiodarone hydrochloride tablets have induced photosensitization in about 10% of patients; some protection may be afforded by the use of sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy.
Amiodarone hydrochloride tablets inhibit peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased thyroxine levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) 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, amiodarone hydrochloride tablets 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 amiodarone hydrochloride tablets and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following amiodarone hydrochloride tabletswithdrawal.
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 amiodarone hydrochloride tablets dose reduction and/or thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue amiodarone hydrochloride tablets in some patients.
Hyperthyroidism occurs in about 2% of patients receiving amiodarone hydrochloride tablets, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone hydrochloride tablet-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 hydrochloride tablet-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 T3 RIA, and further elevations of serum T4, 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 amiodarone hydrochloride tablet-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone hydrochloride tablets.
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 hydrochloride tablet-induced hyperthyroidism. Amiodarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism (see WARNINGS, Thyrotoxicosis).
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 post-marketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone hydrochloride tablets. In some instances hyperthyroidism was also present (see WARNINGS and ADVERSE REACTIONS).
Volatile Anesthetic Agents
Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics.
Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving amiodarone hydrochloride tablets have been reported. The relationship of this event to amiodarone hydrochloride tablet therapy is unknown.
Adult Respiratory Distress Syndrome (ARDS)
Postoperatively, occurrences of ARDS have been reported in patients receiving amiodarone hydrochloride tablet therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiO2 and the determinants of oxygen delivery to the tissues (e.g., SaO2, PaO2) be closely monitored in patients on amiodarone hydrochloride tablets.
Corneal Refractive Laser Surgery
Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking amiodarone hydrochloride tablets.
Information for Patients
Patients should be instructed to read the accompanying Medication Guide each time they refill their prescription. The complete text of the Medication Guide is reprinted at the end of this document.
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 amiodarone hydrochloride tablets or discontinuing therapy.
Amiodarone hydrochloride tablets alter the results of thyroid-function tests, causing an increase in serum T4 and serum reverse T3 and a decline in serum T3 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 CLINICAL PHARMACOLOGY, Pharmacokinetics). 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 in vivo 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:
Protease inhibitors are known to inhibit CYP3A4 to varying degrees. A case report of one patient taking amiodarone 200 mg and indinavir 800 mg three times a day resulted in increases in amiodarone concentrations from 0.9 mg/L to 1.3 mg/L. DEA concentrations were not affected. There was no evidence of toxicity. Monitoring for amiodarone toxicity and serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy should be considered.
Histamine H1 Antagonists
Loratadine, a non-sedating antihistaminic, is metabolized primarily by CYP3A4. QT interval prolongation and torsade de pointes have been reported with the co-administration of loratadine and amiodarone.
Trazodone, an antidepressant, is metabolized primarily by CYP3A4. QT interval prolongation and torsade de pointes have been reported with the co-administration of trazodone and amiodarone.
Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, and decreased DEA to unquantifiable concentrations. Grapefruit juice inhibits CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when changing from intravenous amiodarone to oral amiodarone (see DOSAGE AND ADMINISTRATION).
Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6 and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates of p-glycoprotein. Reported examples of this interaction include the following:
Cyclosporine (CYP3A4 substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine.
HMG-CoA Reductase Inhibitors
HMG-CoA reductase inhibitors that are CYP3A4 substrates (including simvastatin and atorvastatin) in combination with amiodarone have been associated with reports of myopathy/rhabdomyolysis.
When co-administered with amiodarone, lower starting and maintenance doses of these agents should be considered.
In patients receiving digoxin therapy, administration of oral amiodarone regularly results in an increase in the serum digoxin concentration that may reach toxic levels with resultant clinical toxicity. Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day. On initiation of oral amiodarone, the need for digitalis therapy should be reviewed and the dose reduced by approximately 50% or discontinued. If digitalis treatment is continued, serum levels should be closely monitored and patients observed for clinical evidence of toxicity. These precautions probably should apply to digitoxin administration as well.
Other antiarrhythmic drugs, such as quinidine, procainamide, disopyramide, and phenytoin, have been used concurrently with oral amiodarone.
There have been case reports of increased steady-state levels of quinidine, procainamide, and phenytoin during concomitant therapy with amiodarone. Phenytoin decreases serum amiodarone levels. Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by 33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively. Quinidine and procainamide doses should be reduced by one-third when either is administered with amiodarone. Plasma levels of flecainide have been reported to increase in the presence of oral amiodarone; because of this, the dosage of flecainide should be adjusted when these drugs are administered concomitantly. In general, any added antiarrhythmic drug should be initiated at a lower than usual dose with careful monitoring.
Combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone. During transfer to amiodarone the dose levels of previously administered agents should be reduced by 30% to 50% several days after the addition of amiodarone, when arrhythmia suppression should be beginning. The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established, and discontinuation ordinarily should be attempted. If the treatment is continued, these patients should be particularly carefully monitored for adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose.
Amiodarone should be used with caution in patients receiving β-receptor blocking agents (e.g., propranolol, a CYP3A4 inhibitor) or calcium channel antagonists (e.g., verapamil, a CYP3A4 substrate, and diltiazem, a CYP3A4 inhibitor) because of the possible potentiation of bradycardia, sinus arrest, and AV block; if necessary, amiodarone can continue to be used after insertion of a pacemaker in patients with severe bradycardia or sinus arrest.
Potentiation of warfarin-type (CYP2C9 and CYP3A4 substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3 to 4 days, the dose of the anticoagulant should be reduced by one-third to one-half, and prothrombin times should be monitored closely.
Clopidogrel, an inactive thienopyridine prodrug, is metabolized in the liver by CYP3A4 to an active metabolite. A potential interaction between clopidogrel and amiodarone hydrochloride tablets resulting in ineffective inhibition of platelet aggregation has been reported.
Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A4 (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy. Reported examples of this interaction include the following:
Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with oral amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone.
Other substances, including herbal preparations
St. John’s Wort (Hypericum perforatum) induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that the use of St. John’s Wort in patients receiving amiodarone could result in reduced amiodarone levels.
Other reported interactions with amiodarone
Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.
Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine (CYP3A4 substrate) given for local anesthesia. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant administration of intravenous amiodarone.
Dextromethorphan is a substrate for both CYP2D6 and CYP3A4. Amiodarone inhibits CYP2D6.
Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t1/2.
Disopyramide increases QT prolongation which could cause arrhythmia.
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 WARNINGS, Worsened Arrhythmia).
Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem and verapamil.
Volatile Anesthetic Agents (See PRECAUTIONS, Surgery,Volatile Anesthetic Agents.)
In addition to the interactions noted above, chronic (> 2 weeks) oral amiodarone hydrochloride tablet administration impairs metabolism of phenytoin, dextromethorphan and methotrexate.
Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone hydrochloride tablet therapy. Use caution when co-administering amiodarone hydrochloride tablets with drugs which may induce hypokalemia and/or hypomagnesemia.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Amiodarone hydrochloride 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 amiodarone hydrochloride tablet were negative.
In a study in which amiodarone hydrochloride 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)
Pregnancy Category D
See WARNINGS, Neonatal Hypo- or Hyperthyroidism.
Labor and Delivery
It is not known whether the use of amiodarone hydrochloride tablets during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect of amiodarone hydrochloride tablets on the duration of gestation or on parturition.
Amiodarone hydrochloride tablets and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breastfeeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone hydrochloride tablets have been shown to be less viable and have reduced body-weight gains. Therefore, when amiodarone hydrochloride tablet therapy is indicated, the mother should be advised to discontinue nursing.
The safety and effectiveness of amiodarone hydrochloride tablets in pediatric patients have not been established.
Clinical studies of amiodarone hydrochloride tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger 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.
Adverse reactions have been very common in virtually all series of patients treated with amiodarone hydrochloride tablets 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 WARNINGS), but other adverse effects constitute important problems. They are often reversible with dose reduction or cessation of amiodarone hydrochloride tablet 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 PRECAUTIONS). 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 WARNINGS).
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 amiodarone hydrochloride tablets 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 side-effect rates are based on a retrospective study of 241 patients treated for 2 to 1,515 days (mean 441.3 days).
The following side effects were each reported in 10% to 33% of patients:
Gastrointestinal: Nausea and vomiting.
The following side effects were each reported in 4% to 9% of patients:
Dermatologic: Solar dermatitis/photosensitivity.
Neurologic: Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias.
Gastrointestinal: Constipation, anorexia.
Ophthalmologic: Visual disturbances.
Hepatic: Abnormal liver-function tests.
Respiratory: Pulmonary inflammation or fibrosis.
The following side effects were each reported in 1% to 3% of patients:
Thyroid: Hypothyroidism, hyperthyroidism.
Neurologic: Decreased libido, insomnia, headache, sleep disturbances.
Cardiovascular: Congestive heart failure, cardiac arrhythmias, SA node dysfunction.
Gastrointestinal: Abdominal pain.
Hepatic: Nonspecific hepatic disorders.
Other: Flushing, abnormal taste and smell, edema, abnormal salivation, coagulation abnormalities.
The following side effects were each reported in less than 1% of patients:
Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension and cardiac conduction abnormalities.
In surveys of almost 5,000 patients treated in open U.S. studies and in published reports of treatment with amiodarone hydrochloride tablets, the adverse reactions most frequently requiring discontinuation of amiodarone hydrochloride tablets included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure and elevation of liver enzymes. Other symptoms causing discontinuations less often included visual disturbances, solar dermatitis, blue skin discoloration, hyperthyroidism and hypothyroidism.
In post-marketing surveillance, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, urticaria, eosinophilic pneumonia, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, renal impairment, renal insufficiency, acute renal failure, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pulmonary alveolar hemorrhage, pleural effusion, pleuritis, pseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), syndrome of inappropriate antidiuretic hormone secretion (SIADH), thyroid nodules/thyroid cancer, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, eczema, skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma, myopathy, muscle weakness, rhabdomyolysis, demyelinating polyneuropathy, hallucination, confusional state, disorientation, delirium, epididymitis and impotence, also have been reported with amiodarone therapy.
There have been cases, some fatal, of amiodarone hydrochloride tablets 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 amiodarone hydrochloride tablets nor its metabolite is dialyzable.
The acute oral LD50 of amiodarone hydrochloride in mice and rats is greater than 3,000 mg/kg.
DOSAGE AND ADMINISTRATION
BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, AMIODARONE HYDROCHLORIDE TABLETS 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 HYDROCHLORIDE TABLET 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 amiodarone hydrochloride tablets has not been determined. Because of the food effect on absorption, amiodarone hydrochloride tablets should be administered consistently with regard to meals (see CLINICAL PHARMACOLOGY). Individual patient titration is suggested according to the following guidelines:
For life-threatening ventricular arrhythmias, such as ventricular fibrillation or hemodynamically unstable ventricular tachycardia: Close monitoring of the patients is indicated during the loading phase, particularly until risk of recurrent ventricular tachycardia or fibrillation has abated. Because of the serious nature of the arrhythmia and the lack of predictable time course of effect, loading should be performed in a hospital setting. Loading doses of 800 mg/day to 1,600 mg/day are required for 1 to 3 weeks (occasionally longer) until initial therapeutic response occurs. (Administration of amiodarone hydrochloride tablets in divided doses with meals is suggested for total daily doses of 1,000 mg or higher, or when gastrointestinal intolerance occurs.) If side effects become excessive, the dose should be reduced. Elimination of recurrence of ventricular fibrillation and tachycardia usually occurs within 1 to 3 weeks, along with reduction in complex and total ventricular ectopic beats.
Since grapefruit juice is known to inhibit CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, grapefruit juice should not be taken during treatment with oral amiodarone (see PRECAUTIONS, Drug Interactions).
Upon starting amiodarone hydrochloride tablet therapy, an attempt should be made to gradually discontinue prior antiarrhythmic drugs (see section on PRECAUTIONS, Drug Interactions). When adequate arrhythmia control is achieved, or if side effects become prominent, amiodarone hydrochloride tablets dose should be reduced to 600 mg/day to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day (see CLINICAL PHARMACOLOGY, Monitoring Effectiveness). Some patients may require larger maintenance doses, up to 600 mg/day, and some can be controlled on lower doses. Amiodarone hydrochloride tablets 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 (see CLINICAL PHARMACOLOGY).
The lowest effective dose should be used to prevent the occurrence of side effects. In all instances, the physician must be guided by the severity of the individual patient’s arrhythmia and response to therapy.
When dosage 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 hydrochloride tablets and the difficulty in predicting the time required to attain a new steady-state level of drug. Dosage suggestions are summarized below:
Amiodarone hydrochloride tablets for oral administration are available as:
200 mg: Round, flat-faced, beveled edge, yellow tablets debossed, “E” over bisect “144” below bisect, plain on the reverse side and supplied as:
NDC 0185-0144-60 bottles of 60
NDC 0185-0144-09 bottles of 90
NDC 0185-0144-09 bottles of 90
NDC 0185-0144-05 bottles of 500
Keep tightly closed.
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Protect from light.
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure as required.
Amiodarone Hydrochloride Tablets (a-meé-oh-da-rone)
Read the Medication Guide that comes with Amiodarone Hydrochloride Tablets before you start taking them and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment.
What is the most important information I should know about Amiodarone Hydrochloride Tablets?
Amiodarone Hydrochloride Tablets can cause serious side effects that can lead to death including:
Call your doctor or get medical help right away if you have any symptoms such as the following:
Because of these possible side effects, Amiodarone Hydrochloride Tablets should only be used in adults with life-threatening heartbeat problems called ventricular arrhythmias, for which other treatments did not work or were not tolerated.
Amiodarone Hydrochloride Tablets can cause other serious side effects. See “What are the possible or reasonably likely side effects of Amiodarone Hydrochloride Tablets?” for more information.
If you get serious side effects during treatment with Amiodarone Hydrochloride Tablets you may need to stop Amiodarone Hydrochloride Tablets, have your dose changed, or get medical treatment. Talk with your doctor before you stop taking Amiodarone Hydrochloride Tablets.
You may still have side effects after stopping Amiodarone Hydrochloride Tablets because the medicine stays in your body months after treatment is stopped.
Tell all your healthcare providers that you take or took Amiodarone Hydrochloride Tablets. This information is very important for other medical treatments or surgeries you may have.
What are Amiodarone Hydrochloride Tablets?
Amiodarone Hydrochloride Tablets are a medicine used in adults to treat life-threatening heartbeat problems called ventricular arrhythmias, for which other treatment did not work or was not tolerated. Amiodarone Hydrochloride Tablets have not been shown to help people with life-threatening heartbeat problems live longer. Treatment with Amiodarone Hydrochloride Tablets should be started in a hospital to monitor your condition. You should have regular check-ups, blood tests, chest x-rays and eye exams before and during treatment with Amiodarone Hydrochloride Tablets to check for serious side effects.
Amiodarone Hydrochloride Tablets have not been studied in children.
Who should not take Amiodarone Hydrochloride Tablets?
Do not take Amiodarone Hydrochloride Tablets if you:
What should I tell my doctor before starting Amiodarone Hydrochloride Tablets?
Tell your doctor about all of your medical conditions including if you:
Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements.
Amiodarone Hydrochloride Tablets and certain other medicines can interact with each other causing serious side effects. Sometimes the dose of Amiodarone Hydrochloride Tablets or other medicines must be changed when they are used together. Especially, tell your doctor if you are taking:
Know the medicines you take. Keep a list of them with you at all times and show it to your doctor and pharmacist each time you get a new medicine. Do not take any new medicines while you are taking Amiodarone Hydrochloride Tablets unless you have talked with your doctor.
How should I take Amiodarone Hydrochloride Tablets?
What should I avoid while taking Amiodarone Hydrochloride Tablets?
What are the possible or reasonably likely side effects of Amiodarone Hydrochloride Tablets?
Amiodarone Hydrochloride Tablets can cause serious side effects that lead to death including lung damage, liver damage, worse heartbeat problems, and thyroid problems. See “What is the most important information I should know about Amiodarone Hydrochloride Tablets?”
Some other serious side effects of Amiodarone Hydrochloride Tablets include:
Other side effects of Amiodarone Hydrochloride Tablets include nausea, vomiting, constipation and loss of appetite.
Call your doctor about any side effect that bothers you.
These are not all the side effects with Amiodarone Hydrochloride Tablets. For more information, ask your doctor or pharmacist.
How should I store Amiodarone Hydrochloride Tablets?
General information about Amiodarone Hydrochloride Tablets
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Amiodarone Hydrochloride Tablets for a condition for which it was not prescribed. Do not share Amiodarone Hydrochloride Tablets with other people, even if they have the same symptoms that you have. It may harm them.
If you have any questions or concerns about Amiodarone Hydrochloride Tablets, ask your doctor or healthcare provider. This Medication Guide summarizes the most important information about Amiodarone Hydrochloride Tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Amiodarone Hydrochloride Tablets that was written for healthcare professionals.
What are the ingredients in Amiodarone Hydrochloride Tablets?
Active Ingredient: amiodarone hydrochloride
Inactive Ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, povidone and D&C yellow No. 10 aluminum lake.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Tagamet® is a registered trademark of SmithKline Beecham Pharmaceuticals Co.
Claritin® is a registered trademark of Schering Corporation.
Alavert®is a registered trademark of Wyeth.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Princeton, NJ 08540
Amiodarone hydrochloride tablets, 200 mg are available from Cardinal Health in unit dose cartons of 30.
Cardinal Health Zanesville, OH 43701
Principal Display Panel - 200 mg Carton
NDC 0185-0144-05 (SANDOZ)
Revised: 04/2011 Cardinal Health
Reproduced with permission of U.S. National Library of Medicine
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