a) PREVALENCE: 1.4% to 40% of patients (Moorthy & Valluri, 1999).

a) Intravenous amiodarone produces both negative inotropic effects and peripheral vasodilatory effects and has been associated with severe hypotension, cardiovascular collapse, and congestive heart failure, primarily in patients with left ventricular dysfunction. Hypotension is the most common adverse effect seen with intravenous amiodarone, occurring in 16% of patients. Hypotension is most often seen in the first several hours of intravenous administration and does not seem to be dose related, but appears to be related to the rate of infusion. Initial infusion rates should not exceed 30 mg/minutes. Significant impairment of left ventricular performance and fatalities have occurred following intravenous (IV) bolus administration in patient with preexisting left ventricular dysfunction. However, IV amiodarone has been used safely in some patients with mild left ventricular dysfunction. IV amiodarone is generally well-tolerated in patients with good left ventricular function (Prod Info Cordarone(R) oral tablets, 2011; Kosinski et al, 1984; Schwartz et al, 1983; Installe et al, 1981; Benaim & Uzan, 1978; Barillon, 1977; Michat et al, 1976).

a) There have been sporadic reports of dose-dependent polymorphic ventricular tachycardia associated with recurrent syncope during chronic therapy. In reported cases, the QT interval was prolonged (0.58 to 0.60 seconds) (Raehl et al, 1985). This is thought to be an idiosyncratic reaction (Brown et al, 1986; Bajaj et al, 1991).
b) Amiodarone can cause serious exacerbation of the presenting dysrhythmia, with a potentially greater risk when used concomitantly with antiarrhythmics. Exacerbation was reported in about 2% to 5% in most series, and has included new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia associated with QTc prolongation (torsade de pointes) (Prod Info Cordarone(R) oral tablets, 2011).
c) CASE REPORT: Polymorphous ventricular tachycardia with increased QT interval has been reported with therapeutic amiodarone serum levels in a 77-year-old man. Amiodarone was discontinued and magnesium sulfate infusion corrected the dysrhythmia (Winters et al, 1997).

a) CASE REPORT: A 71-year-old man with bipolar disorder ingested 4 g of amiodarone and developed a QTc interval of 446 ms 3 days after admission. The serum concentrations of amiodarone and desethylamiodarone peaked on day 2 (358 ng/mL) and day 6 (81 ng/mL), respectively. Following supportive therapy, including 10 g of activated charcoal 3 hours postingestion, he gradually recovered. A year after this episode, he ingested 11.4 g of amiodarone with phenobarbital and developed a QTc interval of 447 ms 2 days after admission. The amiodarone serum concentration was 1839 ng/mL on day 1, which decreased rapidly following supportive care, including 50 g of activated charcoal 8.5 hours postingestion and 20 g at 2 and 6 hours later. The desethylamiodarone serum concentration was 158 ng/mL on day 1, which decreased slowly over the next few days (Takei et al, 2011).
b) CASE REPORTS: QTc prolongation without evidence of torsades de pointes has been reported in 2 overdose cases after ingestion of 3.4 and 2.6 grams (Leatham et al, 1993).
c) CASE REPORT: A 20-year-old woman ingested 8 g of amiodarone and unknown amounts of diazepam and lorazepam. She presented 12 hours post-ingestion with profuse perspiration and normal blood pressure, heart rate and QT interval. Follow-up for 13 days of hospitalization revealed slight bradycardia (nadir 48 beats/min), and prolonged QT interval on days 2 and 3, which normalized by day 4. No symptoms developed nor was treatment required. The elimination half-life (31.5 hours) is consistent with that seen with single IV dosing (Bonati et al, 1983; Fortunati et al, 1983).
d) CASE REPORT: A 67-year-old woman receiving amiodarone therapeutically at 200 mg/day for one week took 2.6 g in an overdose. The ECG on admission, 6 hours post-ingestion was unchanged from baseline. The next morning the QT interval was prolonged (0.61 seconds), T wave inversion was present and R waves disappeared transiently. Return of repolarization to baseline occurred 10 days after discharge. The heart rate remained normal and no symptoms were noted (Oreto et al, 1980).

a) Prolongation of the QTc interval to 500 milliseconds or longer by amiodarone hydrochloride injection has been associated with torsade de pointes. Torsade de pointes or new onset ventricular fibrillation have occurred with amiodarone hydrochloride injection, but infrequently, in less than 2% of patients (Prod Info amiodarone HCl IV injection, 2008).
b) CASE REPORTS: Two patients developed torsade de pointes while on chronic amiodarone therapy (Foley et al, 2008).

a) Symptomatic sinus bradycardia and AV block have been seen in patients receiving amiodarone chronically. Bradycardia typically responds to dosage reduction, but may require a pacemaker for control. Dysrhythmias are usually reversible upon discontinuation of the drug. (Prod Info Cordarone(R) oral tablets, 2011; Boriani et al, 1996; Hohnloser et al, 1994; Staubli et al, 1985; Aravanis et al, 1982).

a) Asymptomatic bradycardia was noted in an overdose of 8 g in an adult from 2 to 4 hours after ingestion. Bradycardia was accompanied by a prolonged QT interval (Bonati et al, 1983).
b) Sinus bradycardia and first degree heart block were noted in a patient who took 15 grams (Garson et al, 1984a).

a) A brief episode of ventricular tachycardia was the only effect observed after ingestion of 3.4 grams by an 18-year-old woman (Goddard & Whorwell, 1989).

a) CASE REPORT: A neonate with complex congenital cardiac anomalies developed supraventricular tachycardia (SVT) post-operatively that was treated with amiodarone 15 mg/kg/day with restoration of sinus rhythm and a normal QTc on ECG. On his 10th postoperative day he developed recurrent SVT, and was converted with adenosine and given an additional 3 mg/kg dose of amiodarone. Three hours later he developed sudden bradycardia (75 beats/min) with an atrial rate of 150 and 2 to 1 atrioventricular conduction and a prolonged QTc of 650 msec. He was treated with isoproterenol with resolution of bradycardia and AV block. Prolongation of the QTc, without recurrent dysrhythmias, persisted for another 14 days, and amiodarone was discontinued(McMahon et al, 2003).

a) CASE REPORT: A neonate, born at 37 weeks gestation with atrial flutter, was given amiodarone as an intravenous infusion at a dosage of 15 mg/kg to be given over an hour, instead of the prescribed dose of 5 mg/kg. Within 30 minutes, the patient developed 2:1 and 3:1 AV block with an accompanying decrease in heart rate and blood pressure. After 45 minutes, the infusion was discontinued following detection of the error. Following cardiac resuscitative measures, including epinephrine administration, electrical cardioversion, and extracorporeal membrane oxygenation (ECMO), the infant gradually recovered and was discharged approximately 10 days after the amiodarone overdose (Haas et al, 2008).

a) SUMMARY: One of the most serious extracardiac side effects of amiodarone is pulmonary toxicity, which occurs in 10% to 17% of patients. A lower incidence of 1.6% has been reported in patients receiving daily amiodarone doses of 400 mg or less. However, amiodarone-induced pulmonary toxicity including fatalities have been reported after only 8 to 14 days of treatment. Pulmonary toxicity has been fatal from 1% to 33% of the time (Prod Info Cordarone(R) oral tablets, 2011; Kharabsheh et al, 2002; Kaushik et al, 2001; Sunderji et al, 2000; Chendrasekhar et al, 1996; Rotmensch et al, 1980; Heger et al, 1981; Riley et al, 1982; Olson et al, 1984); (Pollack & Sami, 1984; Zandwijk et al, 1983)(Israel-Biet et al, 1987; Myers et al, 1987; Gonzalez-Rothi et al, 1987; Kennedy et al, 1987; Zipes et al, 1984; Joelson et al, 1984; Jirik et al, 1983; Russell et al, 1983a; Rakita et al, 1983; Darmanata et al, 1984; Akoun et al, 1984; Gefter et al, 1983; Schlaeffer et al, 1982; Leech et al, 1984; Kudenchuk et al, 1984; Wright & Brackenridge, 1982; Sobol & Rakita, 1982; Liss & Leachman, 1984; Adams et al, 1986a). Amiodarone pulmonary toxicity may be reversible upon discontinuation of the drug. Clinical symptoms tend to resolve within 2 to 4 weeks after discontinuation of amiodarone, whereas the radiographic findings clear up more slowly, over about 3 to 18 months (Vernhet et al, 2001).
b) Interstitial pneumonitis/alveolitis and pulmonary fibrosis have been reported in up to 15% of patients receiving chronic therapy with doses of 400 to 1400 mg/day (usually greater than 600 mg/day) for 1 to 72 months (Kanji et al, 1999).
c) In one patient, symptoms began in as little as 15 days from the start of therapy; the patient died on day 26 after a lack of respiratory improvement and a clinical course that was complicated by sepsis, cardiac ischemia, and inotrope dependence (Kanji et al, 1999).
d) Clinical and radiologic findings have included exertional or progressive dyspnea, tachypnea, cough, pleuritic chest pain, fever, malaise, elevated ESR, leukocytosis, hypoxemia, decreased total lung capacity, diffuse interstitial or alveolar infiltrates, and pleural thickening (Marchlinski et al, 1982; Kennedy et al, 1987a) Myers et al, 1989; Kuhlman et al, 1990; (Olshansky, 1997; Kanji et al, 1999).
e) Unusual presentations on chest tomography (CT) include unilateral alveolar consolidation, pleural effusion and pleural parenchymal lesions with potential pleural thickening (McNeil et al, 1992; Verswijvel et al, 1998). Pulmonary function studies have shown a decrease in carbon monoxide diffusing capacity (DCO) (Verswijvel et al, 1998).
f) Radiological findings typical in amiodarone-induced pulmonary toxicity include asymmetric bilateral alveolar opacification, solitary or multiple masses and lobar or segmental consolidation. Pleural effusions are rarely seen alone, but may be seen in conjunction with other findings. A restrictive pattern with reduced diffusing capacity is normally seen on lung function tests, and obstructive patterns are unusual (Leonard et al, 1997).
g) Hemoptysis, an unusual adverse effect of amiodarone therapy, is associated with amiodarone-induced pulmonary toxicity (Ravishankar et al, 1998).
h) INCIDENCE: A frequency of 3% or less has been reported for therapeutic use; the most common form being interstitial pneumonitis-fibrosis. Other forms include: acute respiratory distress syndrome, bronchiolitis obliterans with organizing pneumonia (BOOP), and a solitary pulmonary mass (Kanji et al, 1999).
i) CASE SERIES: A review of 1020 cases of amiodarone-induced toxicity that were reported to the Australian Adverse Drug Reaction Advisory Committee (ADRAC) identified 116 cases (11.4%) of pulmonary toxicity. Of those 116 cases, pulmonary fibrosis was reported as the most frequent amiodarone-induced pulmonary complication, at 55 cases (47.4%), with 31 cases (26.7%) of pulmonary infiltrates and 13 cases of interstitial lung disease (11.2%). From the Center for Drug Evaluation and Research (CDER) in the United States, 121 amiodarone-induced pulmonary toxicity cases were identified from a total of 1196 patients who reported an amiodarone-related adverse effect. Of the 121 pulmonary toxicity cases, interstitial lung disease occurred in 38 patients (31.4%), followed by pulmonary fibrosis and pleural effusion, identified in 31 (25.6%) and 30 (24.8%) patients, respectively (Ernawati et al, 2008).
j) CASE REPORTS

a) Rarely, amiodarone has been associated with exacerbations of bronchial asthma, thought due to its antiadrenergic effects (Fraser, 1986).

a) Although adult respiratory distress syndrome (ARDS) has been reported in patients receiving amiodarone after cardiovascular surgery, the causal relationship has not been determined (Fraser, 1986).

a) CASE REPORT: A 62-year-old man developed a unilateral, exudative pleural effusion 5 years after starting amiodarone 400 mg/day. There was no concomitant pulmonary parenchymal disease. Corticosteroids were successfully used to treat the pleural effusion while continuing amiodarone (Carmichael & Newman, 1996).

a) Neurologic problems, including malaise, fatigue, tremor, poor coordination and gait, and peripheral neuropathy, are extremely common, occurring in 20% to 40% of patients on amiodarone therapy (Prod Info Cordarone(R) oral tablets, 2011). In one study, 45% (n=102) of patients treated with amiodarone therapy developed neurotoxicity (Burns et al, 2000).
b) Age (except advanced age) or total cumulative dose was NOT found to be risk factors for the development of neuromuscular toxicity (Burns et al, 2000).
c) CHARACTERISTICS: Common manifestations or clinical symptoms have included: tremor, peripheral neuropathy, ataxia and proximal myopathy. Other effects described: dyskinesia, myoclonic jerks, extrapyramidal hypertony, and altered mental status. In many cases, toxic effects resolved with discontinuation of therapy (Burns et al, 2000).
d) RISK FACTORS: Advanced age, significant co-morbidity (e.g., diabetes mellitus, renal failure, and alcoholism) appear to be risk factors for the development of neurotoxicity (Burns et al, 2000).

a) Dizziness was reported in 4% to 9% of patients treated with amiodarone for a mean duration of 441.3 days (range, 2 to 1515 days) in a retrospective study (n=241) (Prod Info Cordarone(R) oral tablets, 2011).

a) Paresthesia was reported in 4% to 9% of patients treated with amiodarone for a mean duration of 441.3 days (range, 2 to 1515 days) in a retrospective study (n=241) (Prod Info Cordarone(R) oral tablets, 2011).

a) Neurologic problems, including peripheral neuropathy, are extremely common, occurring in 20% to 40% of patients on amiodarone therapy (Prod Info Cordarone(R) oral tablets, 2011).
b) Symmetrical distal neuropathy has been described following doses of 600 to 2000 mg/day for 6 to 12 months. Proximal muscle weakness, ataxia, tremors, and abnormal nerve conduction have been noted and may occur during treatment with usual maintenance doses (Lin et al, 1984; (Meier et al, 1979; Lustman & Monseu, 1974; Jacobs & Costa-Jussa, 1985; Fraser, 1986; Burns et al, 2000).

a) Tremors have been noted during chronic therapy (Lustman & Monseu, 1974; Burns et al, 2000).
b) In postmarketing surveillance, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy) have been reported with amiodarone therapy (Prod Info Cordarone(R) oral tablets, 2011).
c) Neurologic problems, including tremor, involuntary movements, and poor coordination and gait, are extremely common, occurring in 20% to 40% of patients on amiodarone therapy. Tremor, ataxia, abnormal involuntary movements, and lack of coordination were reported in 4% to 9% of patients treated with amiodarone for a mean duration of 441.3 days (range, 2 to 1515 days) in a retrospective study (n=241). Rarely does therapy need to be stopped for these problems and they may respond to dose reductions or discontinuation (Prod Info Cordarone(R) oral tablets, 2011).

a) In postmarketing surveillance, pseudotumor cerebri (benign intracranial hypertension) has been reported (Prod Info Cordarone(R) oral tablets, 2011)
b) CASE REPORT: A 58-year-old man developed pseudotumor cerebri secondary to amiodarone therapy (Fikkers et al, 1986).

a) Nausea was reported in 10% to 33% of patients treated with amiodarone for a mean duration of 441.3 days (range, 2 to 1515 days) in a retrospective study (n=241) (Prod Info Cordarone(R) oral tablets, 2011).

a) Nausea occurs frequently within ingestions of large doses. Single doses of more than 1 g will usually produce nausea.

a) Constipation was reported in 4% to 9% of patients treated with amiodarone for a mean duration of 441.3 days (range, 2 to 1515 days) in a retrospective study (n=241) (Prod Info Cordarone(R) oral tablets, 2011).

a) Anorexia was reported in 4% to 9% of patients treated with amiodarone for a mean duration of 441.3 days (range, 2 to 1515 days) in a retrospective study (n=241) (Prod Info Cordarone(R) oral tablets, 2011).

a) Vomiting was reported in 10% to 33% of patients treated with amiodarone for a mean duration of 441.3 days (range, 2 to 1515 days) in a retrospective study (n=241) (Prod Info Cordarone(R) oral tablets, 2011).

a) A metallic or salty taste may occur during chronic therapy.

a) CASE REPORT: Amiodarone-induced acute pancreatitis developed in a 66-year-old woman who was taking amiodarone. The patient, who had a long history of rheumatic heart disease involving mitral and aortic valves and had received a cardiac pacemaker, presented with epigastralgia radiating to both flanks for 2 months. Three months prior to presentation, she was prescribed amiodarone 200 mg/day for recurrent paroxysmal atrial fibrillation which was subsequently reduced to 100 mg/day one month prior to presentation. One month following amiodarone therapy initiation, she experienced constant, dull, epigastric pain which was not alleviated by changing body positions and worsened slightly after meals. Although no nausea/vomiting or diarrhea were present, she suffered from loss of appetite and had a weight loss of 2 kg in 1 month. At current presentation, no fever or jaundice were present and urinalysis, CBC, liver and renal functions were within normal limits. Serum lipase was elevated (395 units/liter (L)) and serum amylase was normal (109 units/L). Endoscopic ultrasonography revealed a reticular pattern over the whole pancreas, leading to a diagnosis of pancreatitis. Despite stopping all oral intake, with the exception oral medications including amiodarone, and 3 weeks of conventional treatment for pancreatitis, abdominal symptoms and elevated serum lipase levels persisted. No known causal factors for pancreatitis were identified. Subsequently, amiodarone was replaced by propafenone (400 mg) after a 3-day overlap which led to resolution of abdominal symptoms and a gradual decline in serum lipase levels. At a 3-month follow-up, the patients was completely free of abdominal symptoms, and serum lipase and amylase levels were normal (Chen et al, 2007).
b) CASE REPORT: Acute pancreatitis developed in a 46-year-old woman who presented with nausea, vomiting, and abdominal pain 4 days after beginning therapeutic doses of amiodarone. Laboratory evaluation revealed serum amylase of 1480 Units/mL and serum lipase of 946 Units/mL. Pancreatic function returned to normal after stopping amiodarone therapy. Clinical and laboratory evidence of pancreatitis recurred on re-challenge (Bosch & Bernadich, 1997).

a) Liver injury is common with amiodarone, but is usually mild and evidenced only by abnormal liver enzymes. Increased liver enzymes was reported in 4% to 9% of patients treated with amiodarone for a mean duration of 441.3 days (range, 2 to 1515 days) in a retrospective study (n=241) (Prod Info Cordarone(R) oral tablets, 2011).
b) Transient 1.5 to 3 times elevations in liver enzymes (aspartate aminotransferase, LDH, alkaline phosphatase, SGOT, SGPT) have been noted with therapeutic use in 5 to 20% of patients (Adams et al, 1986). Abnormalities may be related to higher mean daily dose and plasma concentrations of the parent compound (Greenberg et al, 1987). Both toxic and hypersensitivity liver injury can occur (Rigas et al, 1986).
c) OTHER: CT scan of the liver and spleen may also indicate a high attenuation lesion or density similar to findings in the lung parenchyma (Burns et al, 2000).
d) An increase in liver and spleen density were reported in an elderly woman following prolonged use of a high daily dose of amiodarone (600 mg daily for one year); elevated liver enzymes were not reported (Verswijvel et al, 1998).
e) After open heart surgery, three patients developed acute hepatocellular injury with an elevation of transaminases up to 17,000 U/L (up to more than 100-fold of the upper limit of normal) within 24 hours after starting intravenous amiodarone loading. Following the discontinuation of intravenous amiodarone and other potentially hepatotoxic drugs, liver parameters improved significantly or returned to normal. Oral amiodarone were reintroduced in 2 of the patients without further liver test abnormalities. It was proposed that acute liver damage was possibly induced by the solubilizer polysorbate 80 (Bravo et al, 2005).
f) CASE REPORT: A 79-year-old woman with congestive heart failure developed markedly elevated liver enzyme levels within 24 hours after receiving an intravenous bolus dose of amiodarone of 180 mg over a 60-minute period followed by an infusion of 360 mg over the next 5 hours for treatment of atrial tachyfibrillation (>130 bpm). Her AST and ALT levels peaked at 4202 international units/L and 3387 international units/L, respectively, 2 days after cessation of amiodarone therapy, and then progressively decreased thereafter (Rizzioli et al, 2007).

a) CASE REPORT: Acute hepatitis was reported in a 59-year-old after a loading dose of 1200 mg of amiodarone (Simon et al, 1990).

a) CASE REPORT: An 84-year-old woman treated with amiodarone therapy developed abnormal liver function. Clinical symptoms and elevated liver enzymes gradually improved following drug withdrawal, but 4 months later she developed an increase in bilirubin level, and a CT scan of the abdomen showed a diffuse hyperdense liver; biopsy was consistent with amiodarone-induced cholestatic hepatotoxicity. Despite antioxidant therapy with acetylcysteine and vitamin E no significant improvement in liver function tests were noted. The patient died several weeks after discharge; autopsy was not performed (Chang et al, 1999).

a) Chronic amiodarone therapy may induce alcohol-like cirrhotic liver changes (Simon et al, 1984; Tordjman et al, 1985) Lin et al, 1984; (Rigas et al, 1986).
b) CASE REPORT: Following 8 months of amiodarone therapy, a 72-year-old man developed hepatic dysfunction, deteriorating to hepatic coma. Autopsy revealed advanced hepatic fibrosis with near total hepatic infarction, consistent with hepatic amiodarone toxicity. His liver function was reported as normal prior to initiation of amiodarone therapy (Pierce & Skaehill, 1997).

a) Noninfectious epididymitis occurs in 3% to 11% of men receiving amiodarone. Epididymitis has been reported following 4 months to 6 years of treatment in patients receiving 200 to 800 mg/day of amiodarone. Discontinuation or a reduction in the dose of amiodarone usually results in resolution of pain and testicular swelling within 1 to 2 weeks, but may take as long as 3 months. In 1 case, upon reinstitution of amiodarone therapy, epididymal symptoms returned within 2 months. Amiodarone-induced epididymitis has been associated with high serum or epididymal levels of amiodarone and desethylamiodarone. Anti-amiodarone antibodies may also be involved in the pathogenesis of epididymitis. Focal epididymal fibrosis and lymphocytic infiltration have been reported following histological examination of amiodarone- induced epididymitis (Gabal-Shehab & Monga, 1999; Hamoud et al, 1996; Sadek et al, 1993; Kirkah, 1988; Ward et al, 1988; Gasparich et al, 1985).
b) Two cases of amiodarone-induced epididymitis in children have been reported. The 2 boys (13 and 15 years old) had been taking amiodarone 300 to 400 mg/day for 1 to 2 years prior to onset (Hutcheson et al, 1998).

a) BONE MARROW TOXICITY: A bone marrow biopsy indicated that a 63-year-old man with atrial fibrillation had developed bone marrow granulomas after 17 months of therapy with amiodarone. Initial symptoms included: intermittent fever, night sweats and fatigue. Several other cases have been reported in the literature following amiodarone therapy (Yamreudeewong et al, 2000).

a) Rare cases of neutropenia, pancytopenia, aplastic anemia, and hemolytic anemia have been reported in patients treated with amiodarone (Lossos & Matzner, 1992; Weinberger et al, 1987). Neutropenia, thrombocytopenia, pancytopenia, aplastic anemia, and hemolytic anemia have also been reported during postmarketing use of amiodarone (Prod Info Cordarone(R) oral tablets, 2011).

a) Urticaria has been reported during postmarketing use of amiodarone (Prod Info Cordarone(R) oral tablets, 2011).

a) Vasculitis has been associated with the therapeutic use of amiodarone (Sun et al, 1994) and has been reported during postmarketing use of amiodarone (Prod Info Cordarone(R) oral tablets, 2011).
b) Cutaneous leukocytoclastic vasculitis and polyserositis occurred at different times in a 34-year-old man receiving oral amiodarone for supraventricular tachycardia (Staubli et al, 1985).

a) Toxic epidermal necrolysis (sometimes fatal) has been reported during postmarketing use of amiodarone (Prod Info Cordarone(R) oral tablets, 2011; Jafari-Fesharaki & Scheinman, 1998; Kounis et al, 1996; Waitzer et al, 1987; Roupe et al, 1987; Raeder et al, 1985; Bencini et al, 1985; Ferguson et al, 1984; Marcus et al, 1981).

a) Photosensitization has been reported in approximately 10% of patients treated with amiodarone (Prod Info Cordarone(R) oral tablets, 2011).
b) This effect may be enhanced by concomitant administration of pyridoxine (Mulrow et al, 1985).

a) Stevens-Johnson syndrome has been reported during postmarketing use of amiodarone (Prod Info Cordarone(R) oral tablets, 2011).

a) Prolonged exposure to sunlight after 6 to 39 months of chronic amiodarone therapy may result in blue or purple skin discoloration (pseudocyanosis). The reaction is often preceded by photosensitivity reactions and is more common in patients receiving high doses (400 to 800 mg per day) and chronic therapy (Trimble et al, 1983).

a) Cutaneous hyperpigmentation occurs in 1% to 5% of patients taking therapeutic doses of amiodarone (Sun et al, 1994a; Rogers & Wolfe, 2000). The skin may develop a blue-gray appearance.

a) Pruritic rash has been infrequently reported with amiodarone (Jafari-Fesharaki & Scheinman, 1998; Kounis et al, 1996).
b) Other dermatologic effects associated with therapeutic use of amiodarone include psoriasis, erythema nodosum, vasculitis, exfoliative dermatitis, and toxic epidermal necrolysis (Sun et al, 1994a).
c) INCIDENCE: Amiodarone-induced photodermatitis occurs in approximately 2% to 24% of patients with exposure to sunlight. It appears more commonly at doses of greater than 200 milligrams/day (Rogers & Wolfe, 2000).
d) PATHOPHYSIOLOGY: results from dermal macrophages phagocytosing the highly lipid-soluble amiodarone molecules (Rogers & Wolfe, 2000).

a) Alopecia develops in less than 1% of patients on therapeutic doses (Sun et al, 1994a).

a) Proximal muscle weakness has been noted in conjunction with neuropathy.

a) Myalgia and muscle weakness developed in one patient with steady-state serum amiodarone levels of 5.7 mcm/L (Staubel et al, 1983).

a) Myopathy has also been described in patients receiving amiodarone (Carella, 1989).

a) Both hypo- and hyperthyroidism have been reported during chronic therapy (Gammage & Franklyn, 1986; Aghini-Lombardi et al, 1993; Kothari et al, 1999).
b) Hyperthyroidism and hypothyroidism were reported in 1% to 3% of patients treated with amiodarone for a mean duration of 441.3 days (range, 2 to 1515 days) in a retrospective study (n=241) (Prod Info Cordarone(R) oral tablets, 2011).
c) Most patients remain clinically euthyroid despite abnormalities in thyroid function tests. The amiodarone molecule is similar to thyroxine and contains 75 mg of iodine per 200 mg tablet.
d) CASE SERIES: Thyrotoxicosis was reported in 10 out of 120 patients treated with maintenance doses of 200 mg/day (Dickstein et al, 1984).
e) CASE REPORT: A 65-year old man treated with maintenance doses of 600 mg/day for 24 days developed hypothyroidism and subsequently died of myxedema coma (Mazonson et al, 1984).
f) INCIDENCE: Subclinical hypothyroidism can occur in up to 18% of patients on chronic therapy (Greenberg et al, 1987).

a) An elderly patient receiving low doses of amiodarone developed hyperglycemia, glycosuria, hypercholesterolemia and hypertriglyceridemia after one year of amiodarone therapy (Politi et al, 1984).

a) Anaphylaxis, including anaphylactic shock, has been reported during postmarketing use of amiodarone (Prod Info Cordarone(R) oral tablets, 2011).
b) CASE REPORT: A 55-year-old man experienced lip swelling and tingling within 1 hour of receiving oral amiodarone 400 mg for atrial fibrillation prophylaxis. Symptoms completely resolved upon administration of IV promethazine 12.5 mg. Suspecting an allergic reaction, the amiodarone was discontinued, and no further symptoms were noted (Stafford, 2007).

a) Institute continuous cardiac monitoring and obtain an ECG.

a) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) ATROPINE/DOSE

a) ISOPROTERENOL INDICATIONS

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).

a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).

a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).

a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).

a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

a) The role of steroids is somewhat controversial; no controlled trials evaluating the use of steroids are available. They may be of benefit in patients in whom amiodarone must be continued despite pulmonary toxicity (Pitcher, 1992) (McNeil et al, 1992) (Carmichael & Newman, 1996).

a) In an in vitro study, alpha tocopherol (at 10, 20 and 40 micromolar concentrations) reduced amiodarone toxicity to pulmonary artery endothelial cells (Kachel et al, 1990). Other antioxidants (catalase, superoxide dismutase, ascorbic acid, dimethyl sulfoxide, ethanol) had no effect.

a) In a hamster model of amiodarone induced pulmonary toxicity treatment with niacin and/or taurine decreased amiodarone-induced collagen accumulation (Wang et al, 1992).

a) LOADING DOSE: 800 to 1600 mg/day for 1 to 3 weeks (Prod Info Cordarone(R) oral tablets, 2013).
b) MAINTENANCE DOSE: Decrease dose to 600 to 800 mg/day for 1 month; then decrease to 400 mg/day given either in single or divided doses (Prod Info Cordarone(R) oral tablets, 2013).

a) The recommended initial dose is 1000 mg over the first 24 hours using the following infusion regimen:

a) LOADING DOSE: 10 to 20 mg/kg/day orally given once daily or in divided doses twice daily for 7 to 10 days, followed by maintenance dose (Drago et al, 2008; Burri et al, 2003; Etheridge et al, 2001; Drago et al, 1998; Luedtke et al, 1997; Luedtke et al, 1997a; Pongiglione et al, 1991; Guccione et al, 1990; Kannan et al, 1987; Bucknall et al, 1986).
b) MAINTENANCE DOSE: 5 to 10 mg/kg/day orally given once daily or in divided doses twice daily (Drago et al, 2008; Burri et al, 2003; Etheridge et al, 2001; Drago et al, 1998; Luedtke et al, 1997; Luedtke et al, 1997a; Pongiglione et al, 1991; Guccione et al, 1990; Kannan et al, 1987; Bucknall et al, 1986). Higher maintenance doses (15 to 20 mg/kg/day) may be required in infants (less than 1 year of age) (Burri et al, 2003; Drago et al, 1998; Bucknall et al, 1986). When stable, maintenance dose may also be given on a 5 days per week schedule (Luedtke et al, 1997a; Guccione et al, 1990; Kannan et al, 1987; Garson et al, 1984).

a) LOADING DOSE: 5 mg/kg IV infusion given over 20 to 60 minutes; maximum 300 mg/dose; preferably in a central vein. Boluses of 5 mg/kg may be repeated up to 2 times (15 mg/kg total) (Kovacikova et al, 2009; Haas & Camphausen, 2008; Haas & Camphausen, 2008a; Burri et al, 2003; Laird et al, 2003; Perry et al, 1996; Soult et al, 1995; Figa et al, 1994)
b) MAINTENANCE DOSE: 5 to 15 mcg/kg/minute IV (7 to 20 mg/kg/day) (Kovacikova et al, 2009; Haas & Camphausen, 2008; Haas & Camphausen, 2008a; Plumpton et al, 2005; Burri et al, 2003; Laird et al, 2003; Perry et al, 1996; Soult et al, 1995; Figa et al, 1994). Maximum effective doses up to 20 to 25 mcg/kg/minute (29 to 36 mg/kg/day) have been used in infants (Burri et al, 2003). Duration of maintenance infusion is usually 24 to 72 hours, followed by oral maintenance therapy if indicated (Plumpton et al, 2005; Laird et al, 2003; Bucknall et al, 1986).
c) Safety and efficacy of IV amiodarone have not been established in pediatric patients; use is NOT recommended (Prod Info NEXTERONE(R) intravenous injection, 2008).
d) The following dose is suggested by the American Heart Association for the treatment of ventricular dysrhythmias:

a) Antemortem and postmortem femoral vein amiodarone and its active desethylmetabolite levels were measured in an 18-year-old man with a history of congenital heart disease who had taken 200 mg/day prior to his death. Levels in mg/liter are as follows (O'Sullivan et al, 1995):

a) Toxic effects have been observed with plasma levels of 2.5 to 6.7 micrograms/milliliter for amiodarone and adverse effects were observed at 2.9 to 9.9 micrograms/milliliter for desethylamiodarone (major metabolite). In addition, reverse triiodothyronine (rT3) levels, considered predictive of toxicity, were 102 to 149 nanograms/deciliter (Gillis & Kates, 1984).
b) Plasma levels (either of the parent compound or the active metabolite) may not accurately predict toxicity (Greenberg et al, 1987).
c) CASE REPORT: A 71-year-old man with bipolar disorder ingested 4 g of amiodarone and developed a QTc interval of 446 ms 3 days after admission. The serum concentrations of amiodarone and desethylamiodarone peaked on day 2 (358 ng/mL) and day 6 (81 ng/mL), respectively. Following supportive therapy, including 10 g of activated charcoal 3 hours postingestion, he gradually recovered. A year after this episode, he ingested 11.4 g of amiodarone with phenobarbital and developed a QTc interval of 447 ms 2 days after admission. The amiodarone serum concentration was 1839 ng/mL on day 1, which decreased rapidly following supportive care, including 50 g of activated charcoal 8.5 hours postingestion and 20 g at 2 and 6 hours later. The desethylamiodarone serum concentration was 158 ng/mL on day 1, which decreased slowly over the next few days (Takei et al, 2011).

a) Maintenance plasma levels above 4 micromoles/liter were associated with vision deterioration and polyserositis in a study of 17 patients receiving chronic therapy (Staubli et al, 1983).

a) A serum amiodarone level of 2.3 milligrams/liter was associated with pulmonary toxicity following 2 months of therapy with 400 milligrams/day in a 59-year-old male (Olshansky, 1997).

a) 254 mg/kg (RTECS , 2001)

a) >4 gm/kg (RTECS , 2001)

a) 885 mg/kg (RTECS , 2001)