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 amiodarone. 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:
Amiodarone 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 inhibits peripheral conversion of thyroxine (T 4) to triiodothyronine (T 3) and may cause increased thyroxine levels, decreased T 3 levels, and increased levels of inactive reverse T 3 (rT 3) 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 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 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 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 amiodarone hydrochloride and considering the need for thyroid hormone supplement.
Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-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 3 RIA, and further elevations of serum T 4, 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-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone.
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-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 postmarketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone. 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.
Hypotension Postbypass:
Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving amiodarone have been reported. The relationship of this event to amiodarone therapy is unknown.
Adult Respiratory Distress Syndrome (ARDS):
Postoperatively, occurrences of ARDS have been reported in patients receiving amiodarone 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 2 and the determinants of oxygen delivery to the tissues (e.g., SaO 2, PaO 2) be closely monitored in patients on amiodarone.
Corneal Refractive Laser Surgery:
Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking amiodarone.
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 amiodarone or discontinuing therapy.
Amiodarone alters the results of thyroid-function tests, causing an increase in serum T 4 and serum reverse T 3, and a decline in serum T 3 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, ivabradine, 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 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 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:
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 amiodarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect of amiodarone 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 amiodarone hydrochloride tablets in pediatric patients have not been established.
Geriatric Use:
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.
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