Amiodarone hydrochloride

681.77

681.000366

243-293-2

976728SY6Z

759560|85442

DTXSID7037185

C236

White

29322090

242nm(MeOH)(lit.)

42.7

1.58 g/cm3

154-158°C

9℃

Soluble in chloroform, methanol.

2-8°C

dog,LD50,intravenous,5gm/kg (5000mg/kg),Iyakuhin Kenkyu. Study of Medical Supplies. Vol. 23, Pg. 682, 1992.

pH= 3.4 to 3.9 (5%) soln.

pKa (25°C) 6.56 ±0.06

pKa = 6.56

226.3 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

White to cream colored, crystalline powder and has solubilities of approx 0.72 mg/ml in water and 12.8 mg/ml in alcohol at 25 °C. The drug is highly lipophilic.

2-8°C

UN1230 - class 3 - PG 2 - Methanol, solution

3

Xn,T,F

36-45-36/37-16-7

OB1361000

Xn,T,F

Store at +4°C

Amiodarone Hydrochloride 0.6 mg/ml in dextrose 5% in water is stable for five days at room temperature. Solutions containing less than 0.6 mg/ml of amiodarone hydrochloride in dextrose 5% in water are unstable and should not be used.

P210-P260-P280-P301 + P310-P311

20/21/22-39/23/24/25-23/24/25-11

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl amiodarone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.|Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

UN1230 - class 3 - PG 2 - Methanol, solution

|Warning|H312 (89.62%): Harmful in contact with skin [Warning Acute toxicity, dermal]|P261, P271, P280, P302+P352, P304+P312, P304+P340, P312, P322, P363, and P501|Aggregated GHS information provided by 106 companies from 12 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Concomitant use of amiodarone and procainamide may result in increased plasma procainamide and N-acetylprocainamide (NAPA) concentrations and subsequent toxicity.|Plasma flecainide concentrations adjusted for daily dosage increased by an average of about 60% (range: 5-190%) when amiodarone therapy was initiated in a limited number of patients receiving flecainide.|Limited data indicate that administration of cholestyramine resin following a single oral dose amiodarone may decrease the elimination half-life and plasma concentrations of amiodarone, possibly by interfering with enterohepatic circulation of the antiarrhythmic agent.|Potentially serious adverse cardiovascular and cardiac effects have occurred in some amiodarone treated patients undergoing general anesthesia, suggesting the possibility of an interaction between the antiarrhythmic agent and various anesthetic agents.|For more Interactions (Complete) data for AMIODARONE HYDROCHLORIDE (11 total), please visit the HSDB record page.

LD50 Mouse oral>3,000 mg/kg|LD50 Rat oral >3,000 mg/kg

Amiodarone and its major metabolite are distributed into milk in concentrations substantially higher than concurrent maternal plasma concentrations. Limited data in a lactating woman indicate amiodarone and N-desethylamiodarone milk-to-plasma ratios ranging from 2.3-9.1 and 0.8-3.8, respectively.

Amiodarone and its major metabolite are distributed into milk in concentrations substantially higher than concurrent maternal plasma concentrations. Limited data in a lactating woman indicate amiodarone and N-desethylamiodarone milk-to-plasma ratios ranging from 2.3-9.1 and 0.8-3.8, respectively.

Anti-Arrhythmia Agents; Enzyme Inhibitors; Vasodilator Agents|Anti-arrhythmic class III|Amiodarone in the oral dosage form is indicated only in the treatment of recurrent hemodynamically unstable ventricular tachycardia and recurrent ventricular fibrillation unresponsive to documented adequate doses of other available antiarrythmic medications or when alternative agents cannot be tolerated. In patients from whom the oral form of amiodarone is indicated, but who are unable to take oral medication, the intravenous form may be used.|Amiodarone is used to suppress and prevent recurrence of supraventricular arrythmias refractory to conventional treatment, especially when associated with Wolff-Parkinson-White (W-P-W) syndrome, including paroxysmal atrial fibrillation, atrial fibrillation, atrial flutter, ectopic atrial tachycardia, and paroxysmal supraventricular tachycardia from both atriovantricular (AV) nodal re-entrant and AV re-entrant tachycardia in patients with W-P-W syndrome.|Amiodarone has been used in a limited number of patients for the management of chronic stable angina pectoris.

Pulmonary toxicity, which is potentially fatal, is the most severe adverse effect associated with oral amiodarone therapy. Amiodarone induced pulmonary toxicity may result from pulmonary interstitial pneumonitis (or alveolitis) or from hypersensitivity pneumonitis. Clinically apparent interstitial pneumonitis (or alveolitis), hypersensitivity pneumonitis, and pulmonary fibrosis have occurred in up to 10-17% of patients with ventricular arrhythmias receiving amiodarone hydrochloride therapy at oral dosages of about 400 mg daily, and an abnormal diffusion capacity without symptoms occurs in a much higher percentage of patients. ... Amiodarone induced pulmonary toxicity has been fatal in about 10% of cases. Rarely, amiodarone has been associated with exacerbation of bronchial asthma, possibly because of its antiadrenergic effects in at least one patient receiving aminodarone. Hemoptysis was reported.|Amiodarone induced peripheral neuropathy ... is usually symmetrical and involves all four limbs; the neurologic deficit is usually more marked in the lower limbs than in the upper limbs. Signs and symptoms may include distal sensory loss, sensory ataxia, loss of vibratory sensation, paresthesia, and/or decreased tendon reflexes. Proximal muscle weakness may also be present. Nerve biopsies in patients with amiodarone induced peripheral neuropathy have demonstrated complete loss of a large myelinated fibers, marked reduction of small myelinated and unmyelinated axons, and evidence of lysosomal inclusion bodies within Schwann cells. Nerve conduction studies have demonstrated normal or reduced nerve conduction velocities.|Amiodarone induced hypothyroidism has been reported in about 2-4% of patients receiving oral drug therapy in most clinical studies, although this effect may occur more frequently. Limited data suggest that hypothyroidism may be more likely to occur in females and in patients with a prior history of thyroid dysfunction.|Arrhythmogenic effects associated with amiodarone have occurred in approximately 2-5% of patients and have included progression of ventricular tachycardia to ventricular fibrillation, sustained ventricular tachycardia, increased resistance to cardioversion, atrial fibrillation, nodal arrhythmia, and atypical ventricular tachycardia (torsade de pointes). Transient exacerbation of preexisting cardiac arrhythmias with subsequent control during continued therapy has also been reported. ... Acceleration of ventricular rate was reported in a patient receiving IV amiodarone for the treatment of atrial fibrillation associated with Wolff-Parkinson-White syndrome.|For more Drug Warnings (Complete) data for AMIODARONE HYDROCHLORIDE (28 total), please visit the HSDB record page.

Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP2C9. (See all compounds classified as Cytochrome P-450 CYP2C9 Inhibitors.)|A class of drugs that act by inhibition of potassium efflux through cell membranes. Blockade of potassium channels prolongs the duration of ACTION POTENTIALS. They are used as ANTI-ARRHYTHMIA AGENTS and VASODILATOR AGENTS. (See all compounds classified as Potassium Channel Blockers.)|Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP1A2. (See all compounds classified as Cytochrome P-450 CYP1A2 Inhibitors.)|Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP3A. (See all compounds classified as Cytochrome P-450 CYP3A Inhibitors.)|A class of drugs that act by inhibition of sodium influx through cell membranes. Blockade of sodium channels slows the rate and amplitude of initial rapid depolarization, reduces cell excitability, and reduces conduction velocity. (See all compounds classified as Sodium Channel Blockers.)|Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade. (See all compounds classified as Anti-Arrhythmia Agents.)|Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP2D6. (See all compounds classified as Cytochrome P-450 CYP2D6 Inhibitors.)|Drugs used to cause dilation of the blood vessels. (See all compounds classified as Vasodilator Agents.)

Plasma concentration of amiodarone appear to decline in at least a biphasic manner, although more complex, multicompartmental pharmacokinetics have been described. Following a single IV dose in healthy adults, the half-life of the drug in the terminal elimination phase has been reported to average 25 days (range 9-47 days). The elimination half-life of the major metabolite, N-desethylamiodarone, is equal to or longer than that of the parent drug. Following single dose admin of amiodarone in a limited number of healthy individuals, amiodarone exhibits multicompartmental pharmacokinetics; the mean apparent terminal plasma elimination half-life of amiodarone and N-desethylamiodarone were 58 (range: 15-142) and 36 (range: 14-75) days, respectively. The half-life of amiodarone appears to be substantially more prolonged following multiple rather than single doses. It has been suggested that differences in reported elimination half-lives may result in part from misinterpretation of slow distribution phases as elimination phases following IV administration of the drug. Following chronic oral administration of amiodarone hydrochloride in patients with cardiac arrhythmias (200-600 mg daily for 2-52 months), the drug appears to be eliminated in a biphasic manner with an initial elimination half-life of about 2.5-10 days, which is followed by a terminal elimination half-life averaging 53 days (range: 26-107 days), with most patients exhibiting a terminal elimination half-life in the range of 40-55 days. The elimination half-life of the major metabolite, N-desethylamiodarone, averages 57-61 days (range 20-118 days) following long-term oral administration of amiodarone. The elimination profile of amiodarone may reflect an initial elimination of the drug from well-perfused tissues followed by prolonged elimination from poorly perfused tissues such as adipose tissue.|Following iv administration of amiodarone in healthy individuals, total plasma clearance of the drug averages approximately 1.9 ml/min/kg (range: 1.4-2.5 ml/min/kg). Although not clearly established, total apparent plasma clearance of the drug appears to decrease with time. Clinical experience suggests that clearance of amiodarone may be more rapid in pediatric patients; however, further studies are needed to fully determine the effects of age on clearance of the drug. Factors of age, gender, or renal or hepatic disease appear to have no effect on the disposition of amiodarone or its major metabolite, N-desethylamiodarone.|Amiodarone hydrochloride is slowly and variably absorbed from the GI tract following oral administration. The absolute bioavailability of commercially available amiodarone hydrochloride tablets averages approximately 50%, but varies considerably, ranging from 22-86%.|Following oral administration, peak plasma amiodarone concentrations usually occur within 3-7 hours (range: 2-12 hours). Following oral administration of a single 400 mg dose of amiodarone hydrochloride in fasting, healthy adults, peak plasma amiodarone concentration of approximately 0.15-0.7 ug/ml are attained. Within the oral dosage range of 100-600 mg daily, steady state plasma concentrations of the drug are approximately proportional to dosage, increasing by an average of 0.5 ug/ml per 100 mg increment in dosage; however, there is considerable interindividual variation in plasma concentrations attained with a given dosage. Following continuous oral administration of the drug in the absence of an initial loading dose regimen, steady state plasma amiodarone concentrations would not be attained for at least 1 month and generally not for up to 5 months or longer. Following chronic oral administration of amiodarone, plasma concentrations of N-desethylamiodarone, the major metabolite of the drug, are approximately 0.5-2 times those of unchanged drug.|For more Absorption, Distribution and Excretion (Complete) data for AMIODARONE HYDROCHLORIDE (11 total), please visit the HSDB record page.

The drug appears to be extensively metabolized, probably in the liver and possibly in the intestinal lumen and/or GI mucosa, to at least one major metabolite. The major metabolite, N-desethylamiodarone, is formed by N-deethylation. Although not clearly established, limited data in animals indicate that the desethyl metabolite may possess some antiarrhythmic activity. ... A minor metabolite of amiodarone, di-N-desethylamiodarone, has been identified in animals following chronic administration of the drug. Amiodarone and N-desethylamiodarone may undergo deiodination to form deiodoamiodarone and deiodo-N-desethylamiodarone, respectively; iodine (in the form of iodide); and possibly other iodine containing metabolites. It is not known whether deiodinated metabolites are pharmacologically active.|Amiodarone undergoes hepatic metabolism by cytochrome P450 3A4 to desethyl-amiodarone.

Following a single IV dose in healthy adults, the half-life of the drug in the terminal elimination phase has been reported to average 25 days (range 9-47 days). The elimination half-life of the major metabolite, N-desethylamiodarone, is equal to or longer than that of the parent drug.|Following single dose admin of amiodarone in a limited number of healthy individuals, amiodarone exhibits multicompartmental pharmacokinetics; the mean apparent terminal plasma elimination half-life of amiodarone and N-desethylamiodarone were 58 (range: 15-142) and 36 (range: 14-75) days, respectively.|Following chronic oral administration of amiodarone hydrochloride in patients with cardiac arrhythmias (200-600 mg daily for 2-52 months), the drug appears to be eliminated in a biphasic manner with an initial elimination half-life of about 2.5-10 days, which is followed by a terminal elimination half-life averaging 53 days (range: 26-107 days), with most patients exhibiting a terminal elimination half-life in the range of 40-55 days.|The elimination half-life of the major metabolite, N-desethylamiodarone, averages 57-61 days (range 20-118 days) following long-term oral administration of amiodarone.

Amiodarone prolongs the action potential duration of myocardial cells without altering the resting membrane potential. Consequently the drug alters repolarization (QT prolongation) without affecting spontaneous (phase 4) depolarization. Since neither class I nor class II antiarrhythmic drugs possess both these properties, amiodarone is classified as a class III antiarrhythmic agent. The effect of amiodarone on thyroid metabolism remains unclear but probably involves an intracellular rather than a central or peripheral action.|Although several investigators have suggested that the myocardial effects observed during chronic amiodarone therapy are comparable to those associated with hypothyroidism and may be related to competitive inhibition of sodium-potassium-activated adenosine triphosphatase (Na+ -K+ -ATPase) activity, other data suggest that amiodarone's effects on thyroid function contribute minimally, if at all, to the overall electrophysiologic effects of the drug.|The drug also appears to inhibit transmembrane influx of extracellular sodium ions via fast sodium channels, as indicated by a decrease in the maximal rate of depolarization of phase O of the action potential. Like class I antiarrhythmic agents, amiodarone is believed to combine with fast sodium channels in their inactive state and thereby inhibit recovery after repolarization in a time- and voltage-dependent manner which is associated with subsequent dissociation of the drug from the sodium channels. Amiodarone appears to have little affinity for activated fast sodium channels.|Amiodarone has mild negative inotropic effect that is more prominent with intravenous than with oral administration but that usually does not depress left ventrical function. Amiodarone causes coronary and peripheral vasodialation and, therefore, decrease peripheral vascular resistance but only causes hypotension in large doses.

The ability of activated charcoal to prevent the absorption of amiodarone was studied in 18 healthy volunteers, divided into three groups of six subjects. All subjects were administered a single dose of 400 mg amiodarone; one group ingested the drug with water only (control) and the second with 25 g of activated charcoal as a water suspension. The subjects in the third group were given 25 g of charcoal immediately after the 1.5 hr blood sample. The extent of amiodarone absorption was reduced by about 98% by simultaneously administered charcoal (p < 0.001); taking charcoal 1.5 hr after amiodarone still resulted in a 50% reduction in amiodarone bioavailability (p < 0.05). These results indicate that activated charcoal should be effective in preventing amiodarone absorption in acute poisoning.|Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. 2. Treat coma, seizures, hypotension, and arrhythmias if they occur. Note: Type Ia antiarrhythmic agents should not be used to treat cardiotoxicity caused by type Ia, type Ic, or type III drugs. 3. Continuously monitor vital signs and ECG for a minimum of 6 hours after exposure, and admit the patient for 24 hours of intensive monitoring if there is evidence of toxicity. /Amiodarone, Antiarrhythmic drugs/|Specific drugs and antidotes. In patients with intoxication by type Ia or type Ic drugs, QRS prolongation, bradyarrhythmias, and hypotension may respond to sodium bicarbonate, 1-2 mEq/kg IV. The sodium bicarbonate reverses cardiac-depressant effects caused by inhibition of the fast sodium channel. /Amiodarone, Antiarrhythmic drugs/|Decontamination. 1. Prehospital. Administer activated charcoal, if available. 2. Hospital. Administer activated charcoal. Consider gastric lavage for large ingestions. /Amiodarone, Antiarrhythmic drugs/|For more Antidote and Emergency Treatment (Complete) data for AMIODARONE HYDROCHLORIDE (7 total), please visit the HSDB record page.

/HUMAN EXPOSURE STUDIES/ Pulmonary toxicity, which is potentially fatal, is the most severe adverse effect associated with oral amiodarone therapy. Amiodarone induced pulmonary toxicity may result from pulmonary interstitial pneumonitis (or alveolitis) or from hypersensitivity pneumonitis. Clinically apparent interstitial pneumonitis (or alveolitis), hypersensitivity pneumonitis, and pulmonary fibrosis have occurred in up to 10-17% of patients with ventricular arrhythmias receiving amiodarone hydrochloride therapy at oral dosages of about 400 mg daily, and an abnormal diffusion capacity without symptoms occurs in a much higher percentage of patients. ... Amiodarone induced pulmonary toxicity has been fatal in about 10% of cases. Rarely, amiodarone has been associated with exacerbation of bronchial asthma, possibly because of its antiadrenergic effects in at least one patient receiving aminodarone. Hemoptysis was reported.|/HUMAN EXPOSURE STUDIES/ A patient taking an overdose of 3.4 g of amiodarone is described. Consciousness and physical examination remained normal throughout. Continuous electrocardiographic monitoring for 48 hr after admission revealed only a self limiting episode of ventricular tachycardia, despite high serum levels of the drug (serum desethylamiodarone levels 4.4 mg/L).|/SIGNS AND SYMPTOMS/ Pulmonary toxicity, which is potentially fatal, is the most severe adverse effect associated with oral amiodarone therapy. Amiodarone induced pulmonary toxicity may result from pulmonary interstitial pneumonitis (or alveolitis) or from hypersensitivity pneumonitis. Clinically apparent interstitial pneumonitis (or alveolitis), hypersensitivity pneumonitis, and pulmonary fibrosis have occurred in up to 10-17% of patients with ventricular arrhythmias receiving amiodarone hydrochloride therapy at oral dosages of about 400 mg daily, and an abnormal diffusion capacity without symptoms occurs in a much higher percentage of patients. ... Amiodarone induced pulmonary toxicity has been fatal in about 10% of cases. Rarely, amiodarone has been associated with exacerbation of bronchial asthma, possibly because of its antiadrenergic effects in at least one patient receiving aminodarone. Hemoptysis was reported.|/CASE REPORTS/ Two fatal cases of amiodarone induced acute, confluent, necrotic hepatitis are described. The patients, aged 28 and 60, had received a high loading dose of amiodarone and after the first and second day respectively, the patients developed jaundice, hepatomegaly, high serum transaminases, a prolonged prothrombin time, and low cholesterol concentration. They died of hepatic coma and acute renal failure on the fourteenth and fourth day respectively. Needle liver biopsy, performed immediately after death, revealed lesions of acute drug induced hepatitis with confluent and bridging necrosis. It is proposed that rapid administration of a high loading dose of amiodarone can cause acute confluent necrotic hepatitis. The mode of administration and the dosage of the drug should be reconsidered.|/CASE REPORTS/ A 45 year old man had severe blue-gray cutaneous discoloration during amiodarone therapy for atrial fibrillation. Therefore, this drug regimen was discontinued, and long term anticoagulation and digoxin therapy were used. The patient was advised to avoid exposure of his skin to sunlight, and a bleaching agent was prescribed. After 18 months of follow-up, the blue-gray hyperpigmentation had diminished. Although photosensitivity reactions from amiodarone occur in more than 50% of patients, blue-gray cutaneous discoloration occurs in less than 10% of patients on prolonged therapy with amiodarone. The presence of high concentrations of iodine, detected by electron probe analysis, suggests that the cutaneous deposits are amiodarone itself or a metabolite. The slow rate of elimination of amiodarone and a high uptake by fat associated tissues may explain the delayed disappearance of cutaneous photosensitivity and late resolution of the blue-gray discoloration. Current case supports the reversibility of these adverse effects on long term follow-up.

Amiobeta

Amiodar, Ancaron, Cordarex, Cordarone, Ortacrone, Pacerone, Tachydaron, Trangorex|Oral tablets 200 mg Cordarone (with povidone; scored); Wyeth-Ayerst; Pacerone (with providone; scored), Upsher-Smith; 400 mg Pacerone (with povidone, scored), Upsher-Smith.

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