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AMIODARON (A to Z Drug Information)

(A-MEE-oh-duh-rone) Cordarone Tablets: 200 mg, Injection: 50 mg/mL, Pacerone, Tablets: 200 mg, Tablets: 400 mg Class: Antiarrhythmic Action Prolongs action potential duration and refractory period in myocardial cells; acts as noncompetitive inhibitor of alpha- and beta-adrenergic receptors. Indications Oral Treatment of life-threatening, recurrent ventricular arrhythmias (ie, ventricular fibrillation and hemodynamically unstable ventricular tachycardia) that do not respond to other antiarrhythmic agents. Use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity. Parenteral Initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation and hemodynamically unstable ventricular tachycardia in patients refractory to other therapy; treatment of ventricular tachycardia and fibrillation when oral amiodarone is indicated but patient is unable to take oral medication. Conversion of atrial fibrillation and maintenance of sinus rhythm; treatment of supraventricular tachycardia; IV amiodarone has been used to treat AV nodal reentry tachycardia. Contraindications Oral Severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third-degree atrioventricular (AV) block; when bradycardia produces syncope, unless used with pacemaker; hypersensitivity to the drug. Parenteral Marked sinus bradycardia; second- and third-degree atrioventricular block unless functioning pacemaker is available; cardiogenic shock. Route/Dosage Life-Threatening Recurrent Ventricular Arrhythmias Loading dose: PO 800 to 1600 mg/day for 1 to 3 wk. Reduce doses of other antiarrhythmic agents gradually. When adequate arrhythmia control is achieved, reduce dose to 600 to 800 mg/day for 1 mo. Usual maintenance dose: PO 400 mg/day. Adults: IV Recommended starting dose is 1000 mg over the first 24 hr administered as follows: rapid administration of 150 mg over first 10 min (15 mg/min), followed by 360 mg over next 6

hr (1 mg/min), then 540 mg over remaining 18 hr (0.5 mg/min). After first 24 hr, continue maintenance infusion rate of 0.5 mg/min (720 mg/24 hr). Paroxysmal Atrial Fibrillation, PSVT, Symptomatic Atrial Flutter PO 600 to 800 mg/day for 7 to 10 days, then 200 to 400 mg/day. Arrhythmias in Patients with CHF PO 200 mg/day. IV to Oral Transition Adults: Clinical monitoring is recommended when changing from IV to oral therapy. PO 800 to 1600 mg amiodarone if duration of IV infusion < 1 wk; 600 to 800 mg amiodarone if duration of IV infusion 1 to 3 wk; 400 mg amiodarone if duration of IV infusion > 3 wk. Interactions Anticoagulants: Effect of anticoagulant may be increased. Use of product may require 30% to 50% decrease in anticoagulant dose. Beta-Blockers: Increased risk of hypotension and bradycardia as well as increased effect of beta blockers eliminated by hepatic metabolism. Calcium Channel Blockers: Increased risk of atrioventricular block with verapamil or diltiazem as well as hypotension with other calcium blockers. Cisapride, Disopyramide, Fluoroquinolones (eg, gatifloxacin, moxifloxacin, sparfloxacin): Possible prolongation of the QT interval, increasing the risk of life-threatening cardiac arrhythmias (including torsades de pointes). Cholestyramine, Rifamycins (eg, rifampin): Amiodarone plasma levels may be reduced, decreasing the pharmacologic effect. Cimetidine, Ritonavir: Amiodarone plasma levels may be elevated, increasing the risk of side effects. Cyclosporine: Elevated plasma concentrations of cyclosporine resulting in elevated creatinine. Dextromethorphan: Increased dextromethorphan plasma levels. Digoxin: Serum digoxin levels may be increased. Fentanyl: Increased risk of hypotension and bradycardia and decreased cardiac output. Flecainide: Serum levels of flecainide may be increased. Hydantoins (eg, phenytoin): Serum concentrations of hydantoins may be increased with potential for symptoms of hydantoin toxicity; also, amiodarone levels may be decreased. Methotrexate, Theophylline: Amiodarone may elevate plasma levels of these agents, increasing the risk of toxicity. Procainamide: Serum levels of procainamide may be increased. Quinidine: Serum quinidine levels may increase, creating potential for fatal cardiac arrhythmias. Lab Test Interferences May alter results of thyroid and LFTs. Adverse Reactions

CARDIOVASCULAR: Exacerbation of arrhythmias, CHF, bradycardia, sinoatrial node dysfunction, heart block, sinus arrest, flushing (oral); hypotension, asystole/cardiac arrest, cardiogenic shock, ventricular tachycardia, atrioventricular block (parenteral). CNS: Fatigue; malaise; tremor/abnormal involuntary movements; lack of coordination; abnormal gait/ataxia; dizziness; paresthesias; decreased libido; insomnia; headache; sleep disturbances; abnormal sense of smell. DERMATOLOGIC: Photosensitivity, solar dermatitis, blue discoloration of skin (oral); Stevens-Johnson syndrome (parenteral). EENT: Visual disturbances; visual impairment; blindness; reversible asymptomatic corneal microdeposits; photophobia; abnormal taste. GI: Nausea, vomiting, constipation, anorexia, abdominal pain, abnormal salivation (oral); diarrhea (parenteral). HEMATOLOGIC: Coagulation abnormalities (oral); thrombocytopenia (parenteral). HEPATIC: Nonspecific hepatic disorders. RESPIRATORY: Pulmonary inflammation or fibrosis, progressive dyspnea, pulmonary toxicosis and death (oral); lung edema, respiratory disorder (parenteral). OTHER: Edema, hyperthyroidism or hypothyroidism (oral); fever (parenteral). Precautions Pregnancy: Category D. Lactation: Excreted in breast milk. Children: Safety and efficacy not established. Adult Respiratory Distress Syndrome (ARDS): ARDS has been reported. Benzyl Alcohol: Benzyl alcohol, contained in some of these products as a preservative, has been associated with fatal gasping syndrome in children. Ophthalmic Effects: Optic neuropathy or neuritis, resulting in visual impairment may occur. Potential Fatal Toxicities: Pulmonary toxicity and arrhythmias have been reported.

Amiodarone (Goodman and Gillman) Amiodarone. Amiodarone (CORDARONE, PACERONE) exerts a multiplicity of pharmacological effects, none of which is clearly linked to its arrhythmia-suppressing properties (Mason, 1987). Amiodarone is a structural analog of thyroid hormone, and some of its antiarrhythmic actions and its toxicity may be attributable to interaction with nuclear thyroid hormone receptors. Amiodarone is highly lipophilic, is concentrated in many tissues, and is eliminated extremely slowly; consequently, adverse effects may resolve very slowly. In the United States, the drug is indicated for oral therapy in patients with recurrent ventricular tachycardia or fibrillation resistant to other drugs. Oral amiodarone also is effective in maintaining sinus rhythm in patients with atrial fibrillation (Connolly, 1999). An intravenous form is indicated for acute termination of ventricular tachycardia or fibrillation (Kowey et al., 1995) and is supplanting lidocaine as first-line therapy for out-of-hospital cardiac arrest (Dorian et al., 2002). Trials of oral amiodarone have shown a modest beneficial effect on mortality after acute myocardial infarction (Amiodarone Trials Meta-Analysis Investigators, 1997). Despite uncertainties about its mechanisms of action and the potential for serious toxicity, amiodarone now is used very widely in the treatment of common arrhythmias such as atrial fibrillation (Roy et al., 2000). Pharmacological Effects. Studies of the acute effects of amiodarone in in vitro systems are complicated by its insolubility in water, necessitating the use of solvents such as dimethyl sulfoxide. Amiodarone's effects may be mediated by perturbation of the lipid environment of the ion channels (Herbette et al., 1988). Amiodarone blocks inactivated Na+ channels and has a relatively rapid rate of recovery (time constant 1.6 s) from block. It also decreases Ca2+ current and transient outward delayed rectifier and inward rectifier K+ currents and exerts a noncompetitive adrenergic blocking effect. Amiodarone potently inhibits abnormal automaticity and, in most tissues, prolongs action potential duration. Amiodarone decreases conduction velocity by Na+ channel block and by a poorly understood effect on cell-cell coupling that may be especially important in diseased tissue (Levine et al., 1988). Prolongations of the PR, QRS, and QT intervals and sinus bradycardia are frequent during chronic therapy. Amiodarone prolongs refractoriness in all cardiac tissues; Na+ channel block, delayed repolarization owing to K+ channel block, and inhibition of cell-cell coupling all may contribute to this effect. Adverse Effects. Hypotension owing to vasodilation and depressed myocardial performance are frequent with the intravenous form of amiodarone and may be due in part to the solvent. While depressed contractility can occur during long-term oral therapy, it is unusual. Despite administration of high doses that would cause serious toxicity if continued long-term, adverse effects are unusual during oral drug-loading regimens, which typically require several weeks. Occasional patients develop nausea during the loading phase, which responds to a decrease in daily dose. Adverse effects during long-term therapy reflect both the size of daily maintenance doses and the cumulative dose (i.e., to duration of therapy), suggesting that tissue accumulation may be responsible. The most serious adverse effect during chronic amiodarone therapy is pulmonary fibrosis, which can be rapidly progressive and fatal. Underlying lung disease, doses of 400 mg/day or more, and recent pulmonary insults such as pneumonia appear to be risk factors (Dusman et al., 1990). Serial chest X-rays or pulmonary function studies may detect early amiodarone toxicity, but monitoring plasma concentrations has not been useful. With low doses, such as 200 mg/day or less used in atrial fibrillation, pulmonary toxicity is unusual. Other adverse effects during long-term therapy include corneal microdeposits (which often are asymptomatic), hepatic dysfunction, neuromuscular symptoms (most commonly peripheral neuropathy or proximal muscle weakness), photosensitivity, and hypo- or hyperthyroidism. The multiple effects of amiodarone on thyroid function are discussed further in Chapter 56. Treatment consists of withdrawal of the drug and supportive measures, including corticosteroids, for life-threatening pulmonary toxicity; reduction of dosage may be sufficient if the drug is deemed necessary and the adverse effect is not life-threatening. Despite the marked QT prolongation and bradycardia typical of chronic amiodarone therapy, torsades de pointes and other drug-induced tachyarrhythmias are unusual. Clinical Pharmacokinetics. Amiodarone's oral bioavailability is approximately 30% presumably because of poor absorption. This incomplete bioavailability is important in calculating equivalent dosing regimens when converting from intravenous to oral therapy. The drug is distributed in lipid; e.g., hearttissue-to-plasma concentration ratios of greater than 20:1 and lipid-to-plasma ratios of greater than

300:1 have been reported. After the initiation of amiodarone therapy, increases in refractoriness, a marker of pharmacological effect, require several weeks to develop. Amiodarone undergoes hepatic metabolism by CYP3A4 to desethyl-amiodarone, a metabolite with pharmacological effects similar to those of the parent drug. When amiodarone therapy is withdrawn from a patient who has been receiving therapy for several years, plasma concentrations decline with a half-life of weeks to months. The mechanism whereby amiodarone and desethyl-amiodarone are eliminated is not well established. A therapeutic plasma amiodarone concentration range of 0.5 to 2 g/ml has been proposed. However, efficacy apparently depends as much on duration of therapy as on plasma concentration, and elevated plasma concentrations do not predict toxicity (Dusman et al., 1990). Because of amiodarone's slow accumulation in tissue, a high-dose oral loading regimen (e.g., 800 to 1600 mg/day) usually is administered for several weeks before maintenance therapy is started. Maintenance dose is adjusted based on adverse effects and the arrhythmias being treated. If the presenting arrhythmia is lifethreatening, dosages of more than 300 mg/day normally are used unless unequivocal toxicity occurs. On the other hand, maintenance doses of 200 mg/day or less are used if recurrence of an arrhythmia would be tolerated, as in patients with atrial fibrillation. Because of its very slow elimination, amiodarone is administered once daily, and omission of one or two doses during chronic therapy rarely results in recurrence of arrhythmia. Dosage adjustments are not required in hepatic, renal, or cardiac dysfunction. Amiodarone potently inhibits the hepatic metabolism or renal elimination of many compounds. Mechanisms identified to date include inhibition of CYP3A4 and CYP2C9 and P-glycoprotein (see Chapter 3). Dosages of warfarin, other antiarrhythmics (e.g., flecainide, procainamide, and quinidine), or digoxin usually require reduction during amiodarone therapy.

Amiodaron (Handbook Of Clinical Drug Data, hal 298-299) Pharmacology. Amiodarone is a type III antiarrhythmic that prolongs the effective refractory period of atrial and ventricular tissue by blocking potassium conductance. It decreases sinus rate and slows conduction through the AV node by A-adrenergic blockade. Amiodarone also blocks sodium and calcium channels. The antiarrhythmic actions can be caused by interruption of reentrant substrate or abolition of premature beats that trigger re-entry. Administration and Adult Dosage. PO loading dosage 8001600 mg/day in divided doses for 12 weeks. Loading dosages are usually toward the lower end of this range for atrial arrhythmias and toward the upper end of the range for ventricular arrhythmias. PO maintenance dosage 100 600 mg/day (usually 300400 mg/day for recurrent ventricular tachycardia and 100200 mg/day for supraventricular tachycardias such as atrial fibrillation). Some suggest a 600800 mg/day priming dosage for 12 months after the initial loading period and before maintenance therapy.5 IV for treatment or prevention of refractory ventricular tachycardia or fibrillation 150 mg over 10 min 360 mg over the next 6 hr, and 540 mg over the next 18 hr. In one study, amiodarone was administered as a 300 mg IV bolus for cardiac arrest.6 Initiate amiodarone only during hospitalization for the first several days of the loading phase. Special Populations. Pediatric Dosage. Safety and efficacy not established. PO 10.15 mg/kg/day for 10 days and then 5 mg/kg/day maintenance therapy has been used.7 IV 5 mg/kg in 1 mg/kg increments over 5.10 min each; an additional 1 to 5 mg/kg may be given in 30 min if needed. Geriatric Dosage. Same as adult dosage. Dosage Forms. Tab 200 mg; Inj 50 mg/mL. Patient Instructions. Report any shortness of breath, tiredness, abdominal discomfort, or visual abnormalities. Avoid intense sunlight; use sunscreen. Divided doses during loading or maintenance dosage phases can reduce intestinal upset. Missed Doses. Take this drug at regular intervals. If you miss a dose, do not take it. If it is about time for the next dose, take that dose only. Do not double the dose or take extra. Pharmacokinetics. Onset and Duration. Onset is variable, from several days to a month; full effect might not occur for several months.8 Serum Levels. 1.2.5 mg/L (1.6.4 mol/L) proposed but not well established. Desethylamiodarone accumulates to serum levels similar to or greater than the parent drug. Fate. Oral absorption is erratic and incomplete; bioavailability is 46 } 22%. Peak serum concentrations occur in 3.7 hr. The drug is 99.9% plasma protein bound;8,10 Vd is 66 } 44 L/kg; Cl is 0.11 } 0.024 L/hr/kg.8,10,11 Amiodarone is primarily hepatically eliminated with at least one active metabolite, desethylamiodarone. No unchanged amiodarone or desethylamiodarone is found in urine. t1... phase 4.12 hr; phase changes with duration of therapy and study sampling. Reported variously as 25 } 12 days and 53 } 23 days.8,10,11 Similar for desethylamiodarone. Adverse Reactions. Corneal microdeposits occur in virtually all patients and are no reason for stopping treatment; however, visual disturbances are reported in about 5%.11 Neurologic effects occur frequently and include tremor, ataxia, paresthesias, and nightmares, which can be more common during the loading phase. Anorexia, nausea, vomiting, and/or constipation occur frequently. Transient elevations in hepatic enzymes occur in more than 50% of patients, but clinical hepatitis occurs only occasionally.12 Photosensitivity occurs frequently, and a blue-gray skin pigmentation (sometimes irreversible) develops in 24% of patients.11 Hypothyroidism

(low-T3 syndrome) or hyperthyroidism occurs frequently. Occasional proximal muscle weakness and myopathy have been reported. Symptomatic pulmonary fibrosis has been reported in 16% of patients; it is probably not immunologic in etiology and seems to occur more often in patients with underlying lung disease. Pulmonary symptoms usually improve with drug discontinuation, but up to 10% of cases result in death. Aggravation of ventricular tachycardia and drug-induced torsades de pointes can occur. Occasional severe sinus bradycardia (requiring a pacemaker) or AV block has been reported. Contraindications. Sick sinus syndrome or second- or third-degree heart block in the absence of a ventricular pacemaker; patients in whom bradycardia has caused syncope; long-QT syndrome. Precautions. Electrophysiologic studies may not predict the long-term efficacy of amiodarone.16 The benzyl alcohol preservative can be hazardous in infants. Drug Interactions. Amiodarone inhibits a wide array of cytochrome P450 enzymes including CYP1A2, 2C9, 2D6, and 3A4; it also inhibits p-glycoprotein. Amiodarone increases serum levels of cyclosporine, digoxin, flecainide, phenytoin, procainamide, and quinidine. It potentiates the anticoagulant effects of warfarin; reduce the initial dosage of warfarin by one-third to one-half. Parameters to Monitor. Monitor ECG daily during loading phase for heart rate, PR, QRS, and QT duration. Baseline and periodic thyroid function tests and liver enzymes (especially if symptoms present). Obtain baseline pulmonary function tests; repeat chest x-ray and clinical examination q 36 months.11,14 Notes. Because of the results of the Cardiac Arrhythmia Suppression Trial (CAST),18 many clinicians use type III antiarrhythmics (eg, amiodarone, sotalol) as first-line therapy for supraventricular and ventricular arrhythmias. A noniodinated analogue of amiodarone under clinical investigation is dronedarone.

Amiodarone (Martindale, hal 1211) C25H29I2NO3 = 645.3. CAS 1951-25-3. ATC C01BD01. ATC Vet QC01BD01.

Amiodarone Hydrochloride. A white or almost white, fine crystalline powder. Very slightly soluble in water; sparingly soluble in alcohol; freely soluble in dichloromethane; soluble in methyl alcohol. Store at a temperature not exceeding 30. Protect from light. Adsorption. Amiodarone is known to be adsorbed by PVC, although the amount of adsorption has varied in different studies. A study using amiodarone hydrochloride 600 micrograms/mL in glucose 5% found that the concentration fell by 10% in 3 hours followed by a steady decrease to 60% of the initial concentration after 5 days when stored in flexible PVC bags at ambient temperature. However, another study2 using amiodarone hydrochloride 1.8 to 2 mg/mL in glucose 5% found only that the concentration remained 97.3% of the initial value after 24 hours in PVC infusion bags. In the first study, perfusion of the solution through PVC giving sets resulted in the concentration falling to 82% after 15 minutes, whereas the second study found the concentration fell to 95.1% after 1 hour but then returned to the initial value. No loss was noted in either study when glass or rigid PVC containers were used, suggesting that the losses were caused by the plasticiser, di-2-ethylhexylphthalate (DEHP). Amiodarone may also leach out DEHP and other plasticisers, and it has been suggested that bags and tubing containing DEHP should not be used for giving amiodarone in order to minimise patient exposure. Incompatibility. Amiodarone injection has been reported to be incompatible with aminophylline, flucloxacillin, heparin, and sodium bicarbonate. A further study reported incompatibility with ampicillin/sulbactam sodium, ceftazidime sodium, digoxin, furosemide, imipenem/cilastatin sodium, magnesium sulfate, piperacillin sodium, piperacillin/tazobactam sodium, potassium phosphate, and sodium phosphate. UK licensed product information states that it is incompatible with sodium chloride solutions. Stability. An oral suspension prepared from tablets1 and containing amiodarone hydrochloride 5 mg/mL was stable for 3 months at 4 and 6 weeks at 25. Adverse Effects and Treatment Adverse effects are common with amiodarone. Many are dose-related and reversible with reduction in dose; however, because of its long half-life this can take some time and adverse effects may develop after treatment is stopped.

Adverse cardiovascular effects associated with amiodarone include severe bradycardia, sinus arrest, and conduction disturbances. Severe hypotension may follow intravenous use, particularly (though not exclusively) at rapid infusion rates. Amiodarone may also produce ventricular tachyarrhythmias; torsade de pointes has been reported but appears to be less of a problem with amiodarone than other antiarrhythmics. Rarely, heart failure may be precipitated or aggravated. Amiodarone reduces the peripheral transformation of thyroxine (T4) to tri-iodothyronine (T3) and increases the formation of reverse-T3. It can affect thyroid function and may induce hypo- or hyperthyroidism. There have been reports of severe pulmonary toxicity including pulmonary fibrosis and interstitial pneumonitis. These effects are usually reversible on withdrawal of amiodarone but are potentially fatal. Amiodarone can adversely affect the liver. There may be abnormal liver function tests and cirrhosis or hepatitis; fatalities have been reported. Prolonged use of amiodarone causes the development of benign yellowish-brown corneal microdeposits in the majority of patients, sometimes associated with coloured haloes of light; these are reversible on stopping therapy. Photosensitivity reactions are also common and more rarely blue-grey discoloration of the skin may occur. Other adverse effects reported include benign intracranial hypertension, haemolytic or aplastic anaemia, peripheral neuropathy, paraesthesias, myopathy, ataxia, tremor, nausea, vomiting, a metallic taste, nightmares, headaches, sleeplessness, fatigue, and epididymitis. Thrombophlebitis can occur if amiodarone is injected regularly or infused for prolonged periods into a peripheral vein. Rapid intravenous injection has been associated with anaphylactic shock, hot flushes, sweating, and nausea. It has been suggested that amiodarone-induced phospholipidosis may explain some of its adverse effects. Amiodarones iodine content contributes to its thyrotoxicity. Effects on electrolyte balance. Hyponatraemia associated with the syndrome of inappropriate secretion of antidiuretic hormone has been reported1-4 in patients taking amiodarone. In each case, the hyponatraemia improved when the dose was reduced or amiodarone was stopped. Effects on the eyes. Slit-lamp examination showed corneal abnormalities in 103 of 105 patients treated with amiodarone for 3 months to 7 years.1 The most advanced abnormality comprised whorled patterns with uniform granular opacities. The corneal deposits became denser if amiodarone dosage was increased and regressed if dosage was reduced. Ocular symptoms were reported in only 12 patients. Photophobia was reported in 3 patients, while 2 had visual haloes, 1 had blurring of vision, and a further 6 had lid irritation. However, lid irritation was considered a photosensitive skin reaction and blurred vision was probably not due to amiodarone. No patient had any deterioration in visual acuity attributable to amiodarone. In 16 patients amiodarone was withdrawn with complete clearing of corneal abnormalities within 7 months and routine ophthalmological monitoring was considered unnecessary in patients without ocular symptoms. However, optic neuropathy2-4 and neuritis with visual impairment have been reported with amiodarone and UK licensed product information recommends that annual ophthalmological examinations should be performed. A sicca syndrome with diminished tear and saliva production has been reported during amiodarone treatment. Effects on the genitalia. Epididymal swelling and scrotal pain have been reported with amiodarone.1-3 Time to onset varied from 7 to 71 months after starting treatment, and resolution occurred within 10 weeks despite continuation of amiodarone in some patients. The mechanism of the reaction is unknown, but in 1 patient2 the concentration of desethylamiodarone in semen was fivefold that in serum. Effects on the heart. Amiodarone has the potential to provoke arrhythmias; it prolongs the QT interval and there have been reports of torsade de pointes. However, a review of the literature1 indicated that the frequency of proarrhythmic events was low. The risk of torsade de pointes also appears to be lower with amiodarone than with other class III antiarrhythmics, possibly due to additional actions of amiodarone such as blockade of calcium channels.

Effects on lipid metabolism. Amiodarone increases phospholipid concentrations in tissues and this may be responsible for some of its adverse effects. Although hyperlipidaemia may result from hypothyroidism, amiodarone can also increase serumcholesterol concentrations independently of any effect on the thyroid. The effect on triglyceride concentrations is not clear. Effects on the liver. Plasma concentrations of liver enzymes are often increased in patients taking amiodarone but this is usually asymptomatic. However, there have been reports of hepatic injury, including hepatitis and cirrhosis, with histological changes resembling alcoholic liver disease.1 Fatal cirrhosis has been reported, usually in patients receiving high doses or longterm therapy,3-8 and may develop after stopping amiodarone. However, rapidly progressive fatal hepatic failure has occurred only one month after starting treatment. There have also been reports of severe cholestasis, including a case that was reversible, and another that was fatal, despite amiodarone being stopped. Acute hepatitis occurring within 24 hours of intravenous amiodarone has been reported, but in case did not recur with subsequent oral therapy, suggesting that the reaction may have been related to the vehicle used in the intravenous formulation. Effects on the lungs. Pulmonary toxicity is one of the most severe adverse effects associated with amiodarone therapy. Reviews have suggested that it may occur in up to 10% of patients (although the incidence in controlled studies appears to be lower) and fatalities have been reported. The onset is usually chronic, and patients often present several months after starting amiodarone with increasing dyspnoea, cough, and pleuritic chest pain; however, the onset may also be more acute, and in one patient occurred within days of starting amiodarone. Acute reactions have also developed in patients undergoing surgery or other procedures; two patients with amiodarone pulmonary toxicity died less than 1 hour and 24 hours, respectively after pulmonary angiography. Different forms of toxicity have been reported, including interstitial and alveolar infiltration, fibrosis, and pneumonitis; amiodarone-induced asthma has also been reported Although there is some evidence that toxicity is doserelated, it has also occurred at low doses,11 and different mechanisms may be involved; some patients have evidence of direct toxicity, while in others an immunological reaction appears to be involved. Most patients recover gradually if amiodarone is stopped, but treatment with corticosteroids may be given if necessary, and has been particularly recommended in acute lung injury. Effects on mental state. There have been isolated reports of patients (age range 54 to 80 years) developing delirium within about 4 to 17 days of starting amiodarone therapy. Mental status improved on withdrawal of amiodarone. Precautions Amiodarone should not be given to patients with bradycardia, sino-atrial block, AV block or other severe conduction disorders (unless the patient has a pacemaker), severe hypotension, or severe respiratory failure. It may be used, but with caution, in patients with heart failure. Electrolyte disorders should be corrected before starting treatment. The use of amiodarone should be avoided in patients with iodine sensitivity, or evidence or history of thyroid disorders. Patients taking amiodarone should avoid exposure to sunlight. Thyroid function should be monitored regularly in order to detect amiodarone-induced hyper- or hypothyroidism. Thyroxine, tri-iodothyronine, and thyrotrophin (thyroid-stimulating hormone; TSH) concentrations should be measured; clinical assessment is important but is unreliable alone. See also Effects on Thyroid Function under Adverse Effects and Treatment, above. Tests of liver and pulmonary function should also be carried out regularly in patients on long-term therapy. Ophthalmological examinations should be performed annually. Although urinary excretion is not a major route for the elimination of amiodarone or its metabolites, there is a possibility of iodine accumulation in renal impairment. Intravenous injections of amiodarone should be given slowly: if prolonged or repeated infusions are envisaged, the use of a central venous catheter should be considered. Some of the contra-indications for amiodarone may not apply when it is given intravenously in emergency situations.

Administration. For the problems of controlling the delivery rate of amiodarone by intravenous infusion, see under Uses and Administration, below. Breast feeding. Amiodarone is distributed into breast milk and significant amounts may be ingested if infants are breast fed. Licensed product information therefore contra-indicates the use of amiodarone during breast feeding, and the American Academy of Pediatrics considers3 that the use of amiodarone may be of concern due to the risk of hypothyroidism in the infant. In one study, amiodarone was still detectable in breast milk several weeks after amiodarone was stopped, suggesting that caution is still required. However, there has been a report of an infant who was successfully breast fed with close monitoring of thyroid function; the mother stopped amiodarone at delivery. Pharmacokinetics Amiodarone is absorbed variably and erratically from the gastrointestinal tract; the average bioavailability is about 50%, but varies widely, and both the rate and extent of absorption are increased by food. It is extensively distributed to body tissues and accumulates notably in fat as well as in skeletal muscles and highly perfused tissues such as liver, lungs, and spleen; it has been reported to be about 96% bound to plasma proteins. The terminal elimination half-life is about 50 days with a range of about 20 to 100 days due to its extensive tissue distribution. On stopping prolonged amiodarone therapy a pharmacological effect is evident for a month or more. A major metabolite, desethylamiodarone, has antiarrhythmic properties. There is very little urinary excretion of amiodarone or its metabolites, the major route of excretion being in faeces via the bile; some enterohepatic recycling may occur. Amiodarone and desethylamiodarone are reported to cross the placenta and to be distributed into breast milk. After intravenous injection the maximum effect is achieved within 1 to 30 minutes and persists for 1 to 3 hours. Uses and Administration Amiodarone is an antiarrhythmic with mainly class III properties (see p.1153). It is used in the control of ventricular and supraventricular arrhythmias, including arrhythmias associated with Wolff-Parkinson-White syndrome. It has been tried for the prevention of arrhythmias in patients with myocardial infarction or heart failure. Amiodarone hydrochloride is given orally in initial doses of 200 mg three times daily for a week, then 200 mg twice daily for a week, and then a usual maintenance dosage of 200 mg or less daily, according to response. In the USA, amiodarone is only licensed for ventricular arrhythmias and higher doses are used: loading doses of amiodarone hydrochloride are up to 1.6 g daily for 1 to 3 weeks, followed by 600 to 800 mg daily for a month, then a usual maintenance dose of 400 mg daily. Consideration should be given to potential adverse effects, and patients should be given the minimum effective dose. Amiodarone hydrochloride may be given intravenously where facilities for close monitoring of cardiac function and resuscitation are available. It is usually given as a dilute solution in glucose 5%. Solutions containing less than 600 micrograms/mL are unstable but high concentrations are irritating to the veins, and solutions containing more than 2 mg/mL should be given via a central catheter; a central catheter is also preferred if repeated or continuous infusion is required. The usual dose is 1 to 1.2 g over 24 hours, given by intermittent or continuous infusion as follows: in the UK, an initial infusion of 5 mg/kg in 250 mL of glucose 5% is given over 20 to 120 minutes; the infusion may be repeated if required, up to a total dose of 1.2 g in 24 hours, diluted in up to 500 mL of glucose 5% in the USA, an initial dose of 150 mg in 100 mL of glucose 5% is given over 10 minutes, followed by 900 mg in 500 mL of glucose 5% over 24 hours, given at a rate of 1 mg/minute for 6 hours and then 500 micrograms/minute for 18 hours; if necessary the maintenance infusion may be continued at a rate of 500 micrograms/minute using a 1 to 6 mg/mL solution

In emergencies, amiodarone hydrochloride may be given in doses of 150 to 300 mg in 10 to 20 mL of glucose 5% by slow intravenous injection over a period of not less than 3 minutes; a second injection should not be given until at least 15 minutes after the first

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