Data from FDA - Curated by EPG Health - Last updated 22 December 2016

Indication(s)

INDICATIONS AND USAGE Because of its life-threatening side effects and the substantial management difficulties associated with its use (see " WARNINGS " below), Cordarone is indicated only for the treatment of the following documented, life-threatening recurrent ventricular arrhythmias when these have not responded to documented adequate doses of other available antiarrhythmics or when alternative agents could not be tolerated.

Recurrent ventricular fibrillation.

Recurrent hemodynamically unstable ventricular tachycardia.

As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of Cordarone Tablets favorably affects survival.

Cordarone should be used only by physicians familiar with and with access to (directly or through referral) the use of all available modalities for treating recurrent life-threatening ventricular arrhythmias, and who have access to appropriate monitoring facilities, including in-hospital and ambulatory continuous electrocardiographic monitoring and electrophysiologic techniques.

Because of the life-threatening nature of the arrhythmias treated, potential interactions with prior therapy, and potential exacerbation of the arrhythmia, initiation of therapy with Cordarone should be carried out in the hospital.

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Advisory information

contraindications

CONTRAINDICATIONS Cordarone is contraindicated in patients with cardiogenic shock; severe sinus-node dysfunction, causing marked sinus bradycardia; second - or third-degree atrioventricular block; and when episodes of bradycardia have caused syncope (except when used in conjunction with a pacemaker).

Cordarone is contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine.

Special warnings and precautions

PRECAUTIONS Impairment of Vision Optic Neuropathy and/or Neuritis Cases of optic neuropathy and optic neuritis have been reported (see " WARNINGS ").

Corneal Microdeposits Corneal microdeposits appear in the majority of adults treated with Cordarone.

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 ").

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 Cordarone 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 Cordarone inhibits 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, Cordarone can cause either hypothyroidism or hyperthyroidism.

Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction.

Because of the slow elimination of Cordarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following Cordarone withdrawal.

Hypothyroidism has been reported in 2 to 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 Cordarone and considering the need for thyroid hormone supplement.

Hyperthyroidism occurs in about 2 % of patients receiving Cordarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake.

Cordarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and/or arrhythmia breakthrough or aggravation, all of which may result in death.

There have been reports of death associated with amiodarone-induced thyrotoxicosis.

IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED. Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum 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 Cordarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of Cordarone.

The institution of antithyroid drugs,?

-adrenergic blockers and/or temporary corticosteroid therapy may be necessary.

The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland.

Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism.

Cordarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism (see " WARNINGS, Thyrotoxicosis ").

When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone can not be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option.

Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm.

Therefore, surgical and anesthetic management require careful planning.

There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with

Cordarone.

In some instances hyperthyroidism was also present (see " WARNINGS " and " ADVERSE REACTIONS ").

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 Cordarone have been reported.

The relationship of this event to Cordarone therapy is unknown.

Adult Respiratory Distress Syndrome (ARDS) Postoperatively, occurrences of ARDS have been reported in patients receiving Cordarone 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 Cordarone.

Corneal Refractive Laser Surgery Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking Cordarone.

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 Cordarone or discontinuing therapy.

Cordarone alters 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.

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 Drugs inducing TdP or prolonging QT Co-administration of amiodarone with drugs known to prolong the QT interval (such as class I and III antiarrhythmics, lithium, certain phenothiazines, tricyclic antidepressants, certain fluoroquinolone and macrolide antibiotics, IV pentamidine, and azole antifungals) increases the risk of Torsades de Points.

Avoid concomitant use of drugs that prolong the QT interval.

Drugs lowering heart rate or causing automaticity or conduction disorders Concomitant use of drugs with depressant effects on the sinus and AV node (e.g., digoxin, beta blockers, verapamil, diltiazem, clonidine) can potentiate the electrophysiologic and hemodynamic effects of amiodarone, resulting in bradycardia, sinus arrest, and AV block.

Monitor heart rate in patients on amiodarone and concomitant drugs that slow heart rate.

Pharmocokinetic interactions Effects of other medicinal products on amiodarone Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit CYP3A (e.g., certain protease inhibitors, loratadine, cimetidine, trazodone) may decrease the metabolism and increase serum concentrations of amiodarone.

Concomitant use of CYP3A inducers (rifampin, St. John 's Wort), may lead to decreased serum concentrations and loss of efficacy.

Consider serial measurement of amiodarone serum concentration during concomitant use of drugs affecting CYP3A activity.

Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50 % and Cmax by 84 %, and decreased DEA to unquantifiable concentrations.

Grapefruit juice inhibits

CYP3A-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 transitioning from intravenous to oral amiodarone.

Cholestyramine reduces enterohepatic circulation of amiodarone thereby increasing its elimination.

This results in reduced amiodarone serum levels and half-life.

Effects of amiodarone on other medicinal products Amiodarone inhibits P-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A.

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 (CYP3A 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.

Monitor cyclosporine drug levels and renal function in patients taking both drugs.

HMG-CoA reductase inhibitors The use of HMG-CoA reductase inhibitors that are CYP3A substrates in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis.

Limit the dose of simvastatin in patients on amiodarone to 20 mg daily.

Limit the daily dose of lovastatin to 40 mg.

Lower starting and maintenance doses of other CYP3A substrates (e.g., atorvastatin) may be required as amiodarone may increase the plasma concentration of these drugs.

Digoxin In patients receiving digoxin therapy, administration of oral amiodarone results in an increase in the serum digoxin concentration.

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.

Antiarrhythmics The metabolism of quinidine, procainamide, flecainide can be inhibited by amiodarone.

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.

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 transition 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.

Metabolism of lidocaine (CYP3A substrate) can be inhibited by amiodarone resulting in increased lidocaine concentrations.

Sinus bradycardia and seizure has been reported in patients receiving concomitant lidocaine and amiodarone.

Anticoagulants Potentiation of warfarin-type (CYP2C9 and CYP3A 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.

A potential interaction between clopidogrel and amiodarone resulting in ineffective inhibition of platelet aggregation has been reported.

Dabigatran etexilate when taken concomitantly with amiodarone may result in elevated serum concentration of dabigatran.

Fentanyl (CYP3A substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.

Increased steady-state levels of phenytoin during concomitant therapy with amiodarone have been reported.

Monitor phenytoin levels in patients taking both drugs.

Dextromethorphan is a substrate for both CYP2D6 and CYP3A. Amiodarone inhibits

CYP2D6 and CYP3A. Chronic (>2 weeks) amiodarone treatment impairs metabolism of dextromethorphan leading to increased serum concentration.

Carcinogenesis, Mutagenesis, Impairment of Fertility Amiodarone HCl was associated with a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats.

The incidence of thyroid tumors was greater than control even at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose600 mg in a 50 kg patient (dose compared on a body surface area basis)).

Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with Cordarone were negative.

In a study in which amiodarone HCl was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose).

Pregnancy See " WARNINGS, Neonatal

Injury ".

Teratogenic Effects Amiodarone and desethylamiodarone cross the placenta.

Reported risks include: 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 Labor and Delivery It is not known whether the use of Cordarone during labor or delivery has any immediate or delayed adverse effects.

Preclinical studies in rodents have not shown any effect of Cordarone 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 Cordarone Tablets in pediatric patients have not been established.

Geriatric Use Clinical studies of Cordarone 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

ADVERSE REACTIONS Adverse reactions have been very common in virtually all series of patients treated with Cordarone for ventricular arrhythmias with relatively large doses of drug (400 mg/day and above), occurring in about three-fourths of all patients and causing discontinuation in 7 to 18 %.

The most serious reactions are pulmonary toxicity, exacerbation of arrhythmia, and rare serious liver injury (see " WARNINGS "), but other adverse effects constitute important problems.

They are often reversible with dose reduction or cessation of Cordarone treatment.

Most of the adverse effects appear to become more frequent with continued treatment beyond six months, although rates appear to remain relatively constant beyond one year.

The time and dose relationships of adverse effects are under continued study.

Neurologic problems are extremely common, occurring in 20 to 40 % of patients and including malaise and fatigue, tremor and involuntary movements, poor coordination and gait, and peripheral neuropathy; they are rarely a reason to stop therapy and may respond to dose reductions or discontinuation (see " 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 Cordarone occasionally results in a blue-gray pigmentation.

This is slowly and occasionally incompletely reversible on discontinuation of drug but is of cosmetic importance only.

Cardiovascular adverse reactions, other than exacerbation of the arrhythmias, include the uncommon occurrence of congestive heart failure (3 %) and bradycardia.

Bradycardia usually responds to dosage reduction but may require a pacemaker for control.

CHF rarely requires drug discontinuation.

Cardiac conduction abnormalities occur infrequently and are reversible on discontinuation of drug.

The following 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 Cordarone, the adverse reactions most frequently requiring discontinuation of Cordarone 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 and dry mouth, also have been reported with amiodarone therapy.

Usage information

Dosing and administration

DOSAGE AND ADMINISTRATION BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, CORDARONE SHOULD BE ADMINISTERED ONLY BY PHYSICIANS WHO ARE EXPERIENCED IN THE TREATMENT OF LIFE-THREATENING ARRHYTHMIAS WHO ARE THOROUGHLY FAMILIAR WITH THE RISKS AND BENEFITS OF CORDARONE THERAPY, AND WHO HAVE ACCESS TO LABORATORY FACILITIES CAPABLE OF ADEQUATELY MONITORING THE EFFECTIVENESS AND SIDE EFFECTS OF TREATMENT.

In order to insure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required.

A uniform, optimal dosage schedule for administration of Cordarone has not been determined.

Because of the food effect on absorption, Cordarone should be administered consistently with regard to meals (see " 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 to 1,600 mg/day are required for 1 to 3 weeks (occasionally longer) until initial therapeutic response occurs.

(Administration of Cordarone 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 Cordarone therapy, an attempt should be made to gradually discontinue prior antiarrhythmic drugs (see section on " Drug Interactions ").

When adequate arrhythmia control is achieved, or if side effects become prominent, Cordarone dose should be reduced to 600 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.

Cordarone 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 Cordarone and the difficulty in predicting the time required to attain a new steady-state level of drug.

Dosage suggestions are summarized below: Loading Dose (Daily) Adjustment and Maintenance Dose (Daily) Ventricular Arrhythmias 1 to 3 weeks ~1 month usual maintenance 800 to 1,600 mg 600 to 800 mg 400 mg

Pregnancy and lactation

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.

More information

Category Value
Authorisation number NDA018972
Orphan designation No
Product NDC 0008-4188
Date Last Revised 16-05-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 833530
Storage and handling Keep tightly closed. Store at Controlled Room Temperature, 20° to 25°C (68° to 77°F). Protect from light. Dispense in a light-resistant, tight container.
Marketing authorisation holder Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.
Warnings

Cordarone is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity.

Cordarone has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10 to 17 % in some series of patients with ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients.

Pulmonary toxicity has been fatal about 10 % of the time.

Liver injury is common with Cordarone, but is usually mild and evidenced only by abnormal liver enzymes.

Overt liver disease can occur, however, and has been fatal in a few cases.

Like other antiarrhythmics, Cordarone can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse.

This has occurred in 2 to 5 % of patients in various series, and significant heart block or sinus bradycardia has been seen in 2 to 5 %.

All of these events should be manageable in the proper clinical setting in most cases.

Although the frequency of such proarrhythmic events does not appear greater with Cordarone than with many other agents used in this population, the effects are prolonged when they occur.

Even in patients at high risk of arrhythmic death, in whom the toxicity of Cordarone is an acceptable risk, Cordarone poses major management problems that could be life-threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first.

The difficulty of using Cordarone effectively and safely itself poses a significant risk to patients.

Patients with the indicated arrhythmias must be hospitalized while the loading dose of Cordarone is given, and a response generally requires at least one week, usually two or more.

Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment.

In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15 to 20 % overall frequencies of discontinuation due to adverse reactions.

The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months.

The patient is obviously at great risk during this time and may need prolonged hospitalization.

Attempts to substitute other antiarrhythmic agents when Cordarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden.

A similar problem exists when Cordarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried.