CORDARONE® (amiodarone) tablets

CORDARONE® (amiodarone) tablets

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CORDARONE® (amiodarone) tablets

CORDARONE (amiodarone HCl) is an antiarrhythmic drug, available for oral administration as pink, scored tablets containing 200 mg of amiodarone hydrochloride. The inactive ingredients present are colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and FD&C Red 40. CORDARONE is a benzofuran derivative: 2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]- 3,5-diiodophenyl ketone hydrochloride.

Indications and usage

CORDARONE is indicated for the treatment of documented, life-threatening recurrent ventricular fibrillation and life-threatening recurrent hemodynamically unstable tachycardia in adults who have not responded to adequate doses of other available antiarrhythmics or when alternative agents cannot be tolerated.

Mechanism of Action

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

CORDARONE prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. CORDARONE increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15 to 20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave contour. These changes should not require discontinuation of CORDARONE as they are evidence of its pharmacological action, although CORDARONE can cause marked sinus bradycardia or sinus arrest and heart block

Dosage and administration

Dosage must be individualized based on severity of arrhythmia and response. Use the lowest effective dose. Obtain baseline chest x-ray, pulmonary function tests, thyroid function tests, and liver aminotransferases. Correct hypokalemia, hypomagnesemia, and hypocalcemia before initiating treatment

Recommended Dosage: Initiate treatment with a loading doses of 800 to 1600 mg/day until initial therapeutic response occurs (usually 1 to 3 weeks). Once adequate arrhythmia control is achieved, or if side effects become prominent, reduce CORDARONE dose to 600 to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day.

Administration: Administer CORDARONE consistently with regard to meals. Administration of CORDARONE in divided doses with meals is suggested for total daily doses of 1000 mg or higher, or when gastrointestinal intolerance occurs.

Contraindications

  • Cardiogenic shock.
  • Sick sinus syndrome, second- or third-degree atrioventricular block, bradycardia leading to syncope without a functioning pacemaker.
  • Known hypersensitivity to the drug or to any of its components, including iodine.

Warnings and precautions

Persistence of Adverse Effects: Because of the long half-life of amiodarone (15 to 142 days) and its active metabolite desethylamiodarone (14 to 75 days), adverse reactions and drug interactions can persist for several weeks following amiodarone discontinuation.

Pulmonary Toxicity: CORDARONE may cause a clinical syndrome of cough and progressive dyspnea accompanied by functional, radiographic, gallium-scan, and pathological data consistent with pulmonary toxicity. Pulmonary toxicity secondary to CORDARONE may result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis (including eosinophilic pneumonia) or interstitial/alveolar pneumonitis, respectively.

Consider alternative antiarrhythmic therapy if the patient experiences signs or symptoms of pulmonary toxicity. Prednisone 40 to 60 mg/day tapered over several weeks may be helpful in treating pulmonary toxicity.

Hepatic Injury: Asymptomatic elevations of hepatic enzyme levels are seen frequently, but CORDARONE can cause life-threatening hepatic injury. Histology has resembled that of alcoholic hepatitis or cirrhosis. Obtain baseline and periodic liver transaminases. If transaminases exceed three times normal, or doubles in a patient with an elevated baseline, discontinue or reduce dose of CORDARONE, obtain follow-up tests and treat appropriately.

Worsened Arrhythmia: CORDARONE can exacerbate the presenting arrhythmia in about 2 to 5% of patients or cause new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia associated with QTc prolongation (Torsade de Pointes [TdP]).

Correct hypokalemia, hypomagnesemia, and hypocalcemia before initiating treatment with CORDARONE, 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 receiving drugs affecting electrolyte levels, such as diuretics, laxatives, systemic corticosteroids, or amphotericin B.

Optic Neuropathy and Optic Neuritis: Cases of optic neuropathy and optic neuritis, usually resulting in visual impairment and sometimes permanent blindness, have been reported in patients treated with amiodarone and may occur at any time during therapy. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, consider discontinuing CORDARONE and promptly refer for ophthalmic examination

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.

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. CORDARONE can cause either hypothyroidism (reported in up to 10% of patients) or hyperthyroidism (occurring in about 2% of patients). Monitor thyroid function 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.

Bradycardia: CORDARONE causes symptomatic bradycardia or sinus arrest with suppression of escape foci in 2 to 4% of patients. The risk is increased by electrolytic disorders or use of concomitant antiarrhythmics or negative chronotropes. Bradycardia may require a pacemaker for rate control.

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Implantable Cardiac Devices: In patients with implanted defibrillators or pacemakers, chronic administration of antiarrhythmic drugs may affect pacing or defibrillation thresholds. Therefore, at the inception of and during amiodarone treatment, pacing and defibrillation thresholds should be assessed.

Fetal Toxicity: CORDARONE may cause fetal harm when administered to a pregnant woman. Fetal exposure may increase the potential for cardiac, thyroid, neurodevelopmental, neurological, and growth effects in neonate

Peripheral Neuropathy: Chronic administration of CORDARONE may lead to peripheral neuropathy, which may not resolve when CORDARONE is discontinued.

Photosensitivity and Skin Discoloration: CORDARONE induces photosensitization in about 10% of patients; some protection may be afforded 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. Some reversal of discoloration may occur upon drug discontinuation.

Volatile Anesthetic Agents: Patients on CORDARONE therapy may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics.

Side effects

Hematologic: hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma.

Immune: anaphylactic/anaphylactoid reaction (including shock), angioedema.

Neurologic: pseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), demyelinating polyneuropathy.

Psychiatric: hallucination, confusional state, disorientation, delirium.

Cardiac: hypotension (sometimes fatal), sinus arrest.

Respiratory: eosinophilic pneumonia, acute respiratory distress syndrome in the post-operative setting, bronchospasm, bronchiolitis obliterans organizing pneumonia, pulmonary alveolar hemorrhage, pleural effusion, pleuritis.

Gastrointestinal: pancreatitis, acute pancreatitis.

Hepatic: hepatitis, cholestatic hepatitis, cirrhosis.

Skin and Subcutaneous Tissue Disorders: urticaria, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, bullous dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, pruritus, skin cancer, lupus-like syndrome.

Musculoskeletal: myopathy, muscle weakness, rhabdomyolysis.

Renal: renal impairment, renal insufficiency, acute renal failure.

Reproductive: epididymitis, impotence.

Body as a whole: fever, dry mouth.

Endocrine and metabolic: thyroid nodules/ thyroid cancer, syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Vascular: vasculitis.

Drug interactions

QT Prolonging Drugs: class I and III antiarrhythmics, lithium, certain phenothiazines, tricyclic antidepressants, certain fluoroquinolone and macrolide antibiotics, azole antifungals, halogenated inhalation anesthetic agents. Increased risk of Torsade de Pointes. Avoid concomitant use.

Negative Chronotropes: digoxin, beta blockers, verapamil, diltiazem, clonidine, ivabradine. Potentiates the electrophysiologic and hemodynamic effects of amiodarone, resulting in bradycardia, sinus arrest, and AV block. Monitor heart rate.

CYP450 Inhibitors: grapefruit juice, certain fluoroquinolone and macrolide antibiotics, azole antifungals, cimetidine, certain protease inhibitors. Increased exposure of amiodarone. Avoid concomitant use.

CYP450 Inducers: St. John’s Wort. Reduced amiodarone serum levels.

Cyclosporine: Increased plasma levels of cyclosporine have been reported resulting in elevated creatinine, despite reduction of cyclosporine dose. Monitor cyclosporine drug levels and renal function with concomitant use.

Antiarrhythmics: quinidine, procainamide, flecainide. Reserve concomitant use for patients who are unresponsive to a single agent. Antiarrhythmic metabolism inhibited by amiodarone. Initiate antiarrhythmic at a lower than usual dose and monitor patient carefully. Reduce dose levels of previously administered antiarrhythmic by 30 to 50% for several days after transitioning to oral amiodarone. Evaluate continued need for antiarrhythmic.

Digoxin: Increased digoxin concentration. Reduce digoxin by half or discontinue. If continued, monitor for evidence of toxicity.

HMG-CoA Reductase Inhibitors: simvastatin, lovastatin, atorvastatin. Increased plasma concentration of HMGCoA reductase inhibitor. Limit the dose of lovastatin to 40 mg. Limit the coadministered dose of simvastatin to 20 mg. Lower starting dose of other CYP3A4 substrates may be required.

Warfarin: Potentiates anticoagulant response and can result in serious or fatal bleeding. Coadministration increases prothrombin time by 100% after 3 to 4 days. Reduce warfarin dose by one-third to one-half and monitor prothrombin times

Phenytoin: Increased steady-state levels of phenytoin. Monitor phenytoin levels.

Hepatitis C Direct Acting Antiviral: sofosbuvir. Cases of symptomatic bradyarrhythmia requiring pacemaker insertion have been reported in patients on oral maintenance amiodarone who initiated therapy with sofosbuvir.

CYP3A Substrate: lidocaine. Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine given for local anesthesia. Monitor heart rate. A lower starting dose of lidocaine may be required.

CYP3A Substrate: fentanyl. Fentanyl in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.

Use in specific populations

Pregnancy: Available data from postmarketing reports and published case series indicate that amiodarone use in pregnant women may increase the risk for fetal adverse effects including neonatal hypo- and hyperthyroidism, neonatal bradycardia, neurodevelopmental abnormalities, preterm birth and fetal growth restriction. Amiodarone and its metabolite, desethylamiodarone (DEA), cross the placenta.

The incidence of ventricular tachycardia is increased and may be more symptomatic during pregnancy. Ventricular arrhythmias most often occur in pregnant women with underlying cardiomyopathy, congenital heart disease, valvular heart disease, or mitral valve prolapse. Most tachycardia episodes are initiated by ectopic beats and the occurrence of arrhythmia episodes may therefore, increase during pregnancy due to the increased propensity to ectopic activity. Breakthrough arrhythmias may also occur during pregnancy, as therapeutic treatment levels may be difficult to maintain due to the increased volume of distribution and increased drug metabolism inherent in the pregnant state.

Lactation: Amiodarone and one of its major metabolites, DEA, are present in breastmilk at between 3.5% and 45% of the maternal weightadjusted dosage of amiodarone. There are cases of hypothyroidism and bradycardia in breastfed infants, although it is unclear if these effects are due to amiodarone exposure in breastmilk. Breastfeeding is not recommended during treatment with CORDARONE

Pediatric Use: The safety and effectiveness of CORDARONE in pediatric patients have not been established.

Overdosage

There have been cases, some fatal, of CORDARONE overdose. Monitor the patient’s cardiac rhythm and blood pressure, and, if bradycardia ensues, a β-adrenergic agonist or a pacemaker may be used. Treat hypotension with inadequate tissue perfusion with positive inotropic and vasopressor agents. Neither CORDARONE nor its metabolite is dialyzable.

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