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Pacerone
Overview
What is Pacerone?
Pacerone (amiodarone hydrochloride) tablets are a member of a class of antiarrhythmic drugs with predominantly Class III (Vaughan Williams' classification) effects, available for oral administration as light yellow, scored tablets. Each tablet for oral administration contains 400 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, the active ingredient in Pacerone Tablets, is a benzofuran derivative: 2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride.
The structural formula is as follows:
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.
What does Pacerone look like?
What are the available doses of Pacerone?
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What should I talk to my health care provider before I take Pacerone?
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How should I use Pacerone?
Because of its life-threatening side effects and the substantial management difficulties associated with its use (see below), Pacerone (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.
Pacerone (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 Pacerone (amiodarone hydrochloride) tablets should be carried out in the hospital.
BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, PACERONE 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 Pacerone Tablets has not been determined. Because of the food effect on absorption, Pacerone Tablets should be administered consistently with regard to meals (see ). Individual patient titration is suggested according to the following guidelines:
What interacts with Pacerone?
Pacerone (amiodarone hydrochloride) 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).
Pacerone (amiodarone hydrochloride) is contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine.
What are the warnings of Pacerone?
Pacerone (amiodarone hydrochloride) is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity.
Amiodarone hydrochloride 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 amiodarone hydrochloride, 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 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 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 is an acceptable risk, Pacerone 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 Pacerone effectively and safely itself poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of Pacerone 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 Pacerone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when amiodarone hydrochloride is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried.
Mortality
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 therapy was evaluated in two multi-centered, randomized, double-blind, placebo-controlled trials involving 1,202 (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial; CAMIAT) and 1,486 (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).
| Placebo | Amiodarone | Relative Risk | ||||
|---|---|---|---|---|---|---|
| N | Deaths | N | Deaths | 95% CI | ||
| EMIAT | 743 | 102 | 743 | 103 | 0.99 | 0.76–1.31 |
| CAMIAT | 596 | 68 | 606 | 57 | 0.88 | 0.58–1.16 |
Pulmonary Toxicity
There have been post-marketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with oral amiodarone hydrochloride 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 amiodarone hydrochloride; however, reports suggest that the use of lower loading and maintenance doses of amiodarone hydrochloride are associated with a decreased incidence of amiodarone hydrochloride-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 Pacerone 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 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 Pacerone therapy discontinued in these patients.
Interstitial/Alveolar Pneumonitis
In a patient receiving Pacerone, 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 Pacerone 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 Pacerone 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-induced hypersensitivity pneumonitis is made, Pacerone should be discontinued, and treatment with steroids should be instituted. If a diagnosis of amiodarone hydrochloride-induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, Pacerone discontinued or, at a minimum, reduced in dosage. Some cases of amiodarone hydrochloride-induced interstitial/alveolar pneumonitis may resolve following a reduction in Pacerone 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.
Worsened Arrhythmia
Amiodarone hydrochloride, like other antiarrhythmics, can cause serious exacerbation of the presenting arrhythmia and 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, amiodarone hydrochloride has caused symptomatic bradycardia or sinus arrest with suppression of escape foci in 2% to 4% of patients. The risk of exacerbation may be increased when other risk factors are present such as electrolytic disorders or use of concomitant antiarrhythmics or other interacting drugs (see ).
Correct hypokalemia, hypomagnesemia or hypocalcemia whenever possible before initiating treatment with amiodarone hydrochloride, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics and laxatives, systemic corticosteroids, amphotericin B (IV) or other drugs affecting electrolyte levels.
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.
Serious Symptomatic Bradycardia When Co-administered with Ledipasvir/Sofosbuvir or with Sofosbuvir with Simeprevir
Postmarketing cases of symptomatic bradycardia, some requiring pacemaker insertion and at least one fatal, have been reported when ledipasvir/sofosbuvir or sofosbuvir with simeprevir were initiated in patients on amiodarone. Bradycardia generally occurred within hours to days, but in some cases up to 2 weeks after initiating antiviral treatment. Bradycardia generally resolved after discontinuation of antiviral treatment. The mechanism for this effect is unknown. Monitor heart rate in patients taking or recently discontinuing amiodarone when starting antiviral treatment.
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.
Thyrotoxicosis
Amiodarone hydrochloride-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 ).
Liver Injury
Elevations of hepatic enzyme levels are seen frequently in patients exposed to amiodarone hydrochloride and in most cases are asymptomatic. If the increase exceeds three times normal, or doubles in a patient with an elevated baseline, discontinuation of Pacerone 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.
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 Pacerone therapy. The risks and complications of antiarrhythmic therapy with Pacerone 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 Pacerone (see ).
Neonatal Injury
Amiodarone can cause fetal harm when administered to a pregnant woman. Fetal exposure may increase the potential for adverse experiences including cardiac, thyroid, neurodevelopmental, neurological and growth effects in neonate. Inform the patient of the potential hazard to the fetus if amiodarone hydrochloride is administered during pregnancy or if the patient becomes pregnant while taking amiodarone hydrochloride.
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).
What are the precautions of Pacerone?
Impairment of Vision
Optic Neuropathy and/or Neuritis
Cases of optic neuropathy and optic neuritis have been reported (see ).
Corneal Microdeposits
Corneal microdeposits appear in the majority of adults treated with amiodarone hydrochloride. 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 ).
Neurologic
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.
Photosensitivity
Amiodarone hydrochloride has 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.
Thyroid Abnormalities
Amiodarone hydrochloride 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, amiodarone hydrochloride 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 and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following Pacerone (amiodarone hydrochloride) withdrawal.
Hypothyroidism has been reported in 2% to 10% of patients receiving amiodarone and may be primary or subsequent to resolution of preceding amiodarone-induced hyperthyroidism. This condition may be identified by clinical symptoms and elevated serum TSH levels. Cases of severe hypothyroidism and myxedema coma, sometimes fatal, have been reported in association with amiodarone therapy. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the dose of or discontinuing Pacerone and considering the need for thyroid hormone supplement.
Hyperthyroidism occurs in about 2% of patients receiving amiodarone hydrochloride, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone hydrochloride-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 amiodarone hydrochloride-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of Pacerone.
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. Amiodarone hydrochloride-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 post-marketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone hydrochloride. In some instances hyperthyroidism was also present (see and ).
Surgery
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.
Hypotension Postbypass
Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving amiodarone hydrochloride have been reported. The relationship of this event to Pacerone therapy is unknown.
Adult Respiratory Distress Syndrome (ARDS)
Postoperatively, occurrences of ARDS have been reported in patients receiving amiodarone hydrochloride 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 FiO and the determinants of oxygen delivery to the tissues (e.g., SaO, PaO) be closely monitored in patients on Pacerone.
Corneal Refractive Laser Surgery
Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking Pacerone.
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.
Laboratory Tests
Elevations in liver enzymes (aspartate aminotransferase and alanine aminotransferase) 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 Pacerone or discontinuing therapy.
Amiodarone hydrochloride 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.
Drug Interactions
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.
Pharmacodynamic Interactions
Pharmacokinetic Interactions
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 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).
Pregnancy
See .
- neonatal bradycardia, QT prolongation, and periodic ventricular extrasystoles
- neonatal hypothyroidism (with or without goiter) detected antenatally or in the newborn and reported even after a few days of exposure
- neonatal hyperthyroxinemia
- neurodevelopmental abnormalities independent of thyroid function, including speech delay and difficulties with written language and arithmetic, delayed motor development, and ataxia.
- jerk nystagmus with synchronous head titubation
- fetal growth retardation
- premature birth
Amiodarone and desethylamiodarone cross the placenta.
Reported risks include:
Labor and Delivery
It is not known whether the use of Pacerone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect of amiodarone hydrochloride on the duration of gestation or on parturition.
Nursing Mothers
Amiodarone and one of its major metabolites, DEA, are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone have been shown to be less viable and have reduced body-weight gains. The risk of exposing the infant to amiodarone and DEA must be weighed against the potential benefit of arrhythmia suppression in the mother. Advise the mother to discontinue nursing.
Pediatric Use
The safety and effectiveness of Pacerone (amiodarone hydrochloride) in pediatric patients have not been established.
Geriatric Use
Clinical studies of amiodarone hydrochloride 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.
What are the side effects of Pacerone?
Adverse reactions have been very common in virtually all series of patients treated with amiodarone hydrochloride 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 amiodarone hydrochloride 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 amiodarone hydrochloride 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
The following side effects were each reported in 4% to 9% of patients:
Dermatologic
Neurologic
Gastrointestinal
Ophthalmologic
Hepatic
Respiratory
The following side effects were each reported in 1% to 3% of patients:
Thyroid
Neurologic
Cardiovascular
Gastrointestinal
Hepatic
Other
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, the adverse reactions most frequently requiring discontinuation of amiodarone hydrochloride 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.
PostMarketing Reports
In postmarketing surveillance, serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with ledipasvir/sofosbuvir or with sofosbuvir with simeprevir, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, urticaria, eosinophilic pneumonia, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, acute pancreatitis, renal impairment, renal insufficiency, acute renal failure, acute respiratory distress syndrome in the post-operative setting, 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, bullous dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), 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, impotence, dry mouth and lupus-like syndrome, also have been reported with amiodarone therapy.
What should I look out for while using Pacerone?
Pacerone (amiodarone hydrochloride) 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).
Pacerone (amiodarone hydrochloride) is contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine.
What might happen if I take too much Pacerone?
There have been cases, some fatal, of amiodarone hydrochloride 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 nor its metabolite is dialyzable.
The acute oral LD of amiodarone hydrochloride in mice and rats is greater than 3,000 mg/kg.
How should I store and handle Pacerone?
Vials should be stored in a refrigerator at 2° to 8°C (36° to 46°F). Vials may be transferred to 25°C (77°F) [see USP Controlled Room Temperature]; for up to 2 months. Upon transfer, vial cartons must be marked by the dispensing pharmacist with a "DISCARD BY" date (2 months from the transfer date or the labeled expiration date, whichever comes first). Pacerone (Amiodarone Hydrochloride) Tablets, 400 mg, are available in unit dose cartons of 100 tablets (10 cards containing 10 tablets each) (NDC 0245-0145-01). The 400 mg tablets are light yellow, oval-shaped, scored, uncoated tablets, debossed with "P400" on the unscored side, and "01" to the left and "45" to the right of the score on the reverse side.
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
In animals, amiodarone hydrochloride is effective in the prevention or suppression of experimentally induced arrhythmias. The antiarrhythmic effect of amiodarone hydrochloride may be due to at least two major properties:
Amiodarone hydrochloride 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. Amiodarone hydrochloride 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 Pacerone as there is evidence of its pharmacological action, although amiodarone hydrochloride can cause marked sinus bradycardia or sinus arrest and heart block. On rare occasions, QT prolongation has been associated with worsening of arrhythmia (see ).
Non-Clinical Toxicology
Pacerone (amiodarone hydrochloride) 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).Pacerone (amiodarone hydrochloride) is contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine.
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.
Adverse reactions have been very common in virtually all series of patients treated with amiodarone hydrochloride 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 amiodarone hydrochloride 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 amiodarone hydrochloride 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
The following side effects were each reported in 4% to 9% of patients:
Dermatologic
Neurologic
Gastrointestinal
Ophthalmologic
Hepatic
Respiratory
The following side effects were each reported in 1% to 3% of patients:
Thyroid
Neurologic
Cardiovascular
Gastrointestinal
Hepatic
Other
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, the adverse reactions most frequently requiring discontinuation of amiodarone hydrochloride 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.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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