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Amiodarone information from DrugsUpdate  

See Available Brands of Amiodarone in India

P - Contraindicated in pregnancy
L - Contraindicated in lactation

Amiodarone is an antiarrhythmic agent (medication used for irregular heart beat) used for various types of tachyarrhythmias (fast forms of irregular heart beat), both ventricular and supraventricular (atrial) arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985. Despite relatively common side-effects, it is used in arrhythmias that are otherwise difficult to treat with medication. Related newer compounds, such as dronedarone, have lower efficacy but a reduced rate of side-effects.

Pharmacodynamics

There is no well-established relationship of plasma concentration to effectiveness, but it does appear that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Within individuals dose reductions and ensuing decreased plasma concentrations can result in loss of arrhythmia control. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from a dose increase, or unusually high, and who might have dosage reduction in the hope of minimizing side effects. Some observations have suggested a plasma concentration, dose, or dose/duration relationship for side effects such as pulmonary fibrosis, liver-enzyme elevations, corneal deposits and facial pigmentation, peripheral neuropathy, gastrointestinal and central nervous system effects.

Pharmacokinetics

Following oral administration in man, Amiodarone is slowly and variably absorbed. The bioavailability of Amiodarone is approximately 50%, but has varied between 35 and 65% in various studies. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Despite this, the onset of action may occur in 2 to 3 days, but more commonly takes 1 to 3 weeks, even with loading doses. Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability.
Amiodarone has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen. One major metabolite of Amiodarone, desethylAmiodarone (DEA), has been identified in man; it accumulates to an even greater extent in almost all tissues.
Amiodarone is metabolized to desethylAmiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines.
Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of Amiodarone or DEA in urine. Neither Amiodarone nor DEA is dialyzable.
In clinical studies of 2 to 7 days, clearance of Amiodarone after intravenous administration in patients with VT and VF ranged between 220 and 440 mL/hr/kg. Age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of Amiodarone or DEA. Renal impairment does not influence the pharmacokinetics of Amiodarone. After a single dose of intravenous Amiodarone in cirrhotic patients, significantly lower Cmax and average concentration values are seen for DEA, but mean Amiodarone levels are unchanged.
 Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with Amiodarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction.
Following single dose administration in 12 healthy subjects, Amiodarone exhibited multi-compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for Amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, Amiodarone has been shown to have a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 10 days. A much slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to 107 days, with a mean of approximately 53 days and most patients in the 40 to 55 day range. In the absence of a loading-dose period, steady-state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5 to 10 day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat.

Amiodarone Indications / Amiodarone Uses

Ventricular arrhythmia and ventricular tachycardia.

Amiodarone Adverse Reactions / Amiodarone Side Effects

Blue-grey discolouration of skin, photosensitivity, peripheral neuropathy, paraesthesia, myopathy, ataxia, tremor, nausea, vomiting, metallic taste, hypothyroidism, hyperthyroidism, alopoecia, sleep disturbances, corneal microdeposits, hot flushes, sweating. Heart block, bradycardia, sinus arrest, hepatotoxicity, heart failure.
Potentially Fatal: Pulmonary toxicity including pulmonary fibrosis and interstitial pneumonitis, hepatotoxicity, thyrotoxicity. Ventricular arrhythmias, pulmonary alveolitis, exacerbation of arrhythmias and rare serious liver injury. Generally in patients with high doses and having preexisting abnormalities of diffusion capacity.

Precautions

Information Not Available

Special Precautions

Close monitoring is recommended as amiodarone may worsen arrhythmia especially when used concurrently with other anti-arrhythmic drugs or drugs that prolong QT interval. May cause hypotension and bradycardia. May increase risk of liver toxicity. May cause visual disturbance/impairment; corneal refractive laser surgery is not recommended in patients on amiodarone treatment. May cause lung damage; monitor for pulmonary toxicity e.g. acute respiratory distress syndrome. Monitor liver functions regularly. May affect defibrillation or pacing thresholds of cardiac devices. Correct electrolyte imbalance before starting treatment. Caution when used in patients undergoing surgery. Avoid excessive sunlight exposure due to increased risk of photosensitivity. Hepatic impairment, thyroid disease,

Other Drug Interactions

Potentiation of antiarrhythmic drugs. Possible increased risk of adverse effects when used with anaesthetic agents. Monitor plasma levels of amiodarone when used with HIV protease inhibitors.
Cimetidine may increase serum levels of amiodarone. Concurrent use may increase serum levels of ciclosporin. May increase risk of myopathy or rhabdomyolysis when used with HMG-CoA reductase inhibitors. Rifampin may reduce the serum levels of amiodarone.
Potentially Fatal: Potentiates the effect of warfarin and other anticoagulants hence dose of warfarin generally needs to be reduced approx half. Raised plasma concentrations of digoxin, phenytoin and quinidine. Additive effect with beta-blockers and calcium-channel blockers (e.g. verapamil and diltiazem).

Other Interactions

Food: St. John's wort may reduce serum levels of amiodarone. Grapefruit juice may increase serum levels of amiodarone.

Dosage

Oral: Ventricular arrhythmias
Adult- 800-1,600 mg/day in 1-2 divided doses for 1-3 wk until initial therapeutic response is achieved, then reduce dose to 600-800 mg/day in 1-2 divided doses for 1 mth. Maintenance: 400 mg/day; lower doses may be used for supraventricular arrhythmias. Daily doses may be divided. Close monitoring of the patient is recommended. Use the minimum effective dose.
 Hepatic impairment: Dosage reduction may be necessary.
Intravenous:
Life-threatening ventricular arrhythmias
Adult: Recommended starting dose: About 1 g over 1st 24 hr. Dose is given in a 3-phase sequence. Initial rapid loading dose: Infuse 150 mg at a rate of 15 mg/minute (initial infusion rate should not exceed 30 mg/minute); followed by the slow loading phase: Infuse 360 mg at a rate of 1 mg/minute; followed by the first maintenance phase: Infuse 540 mg at a rate of 0.5 mg/minute. After the 1st 24 hr, maintain infusion rate at 0.5 mg/minute (i.e. 720 mg over 24 hr); rate may be increased to achieve effective suppression of arrhythmia. For breakthrough episodes, supplemental doses of 150 mg may be given at 15 mg/minute; may repeat supplemental doses up to a max IV dose of 2.2 g/24 hr. Maintenance infusion at up to 0.5 mg/minute may be continued for up to 2-3 wk with caution. Concentrate for inj should be diluted prior to admin. Conversion to oral therapy will depend on the administered dose of the IV therapy and the bioavailability of the oral drug.

Hepatic impairment: Dosage reduction may be necessary.
Intravenous
Pulseless ventricular fibrillation or ventricular tachycardia.
Adult- Initial: 300 mg (diluted in 20-30 ml dextrose 5% or normal saline) if VF or VT recurs, to be given as a single dose by rapid IV inj. Supplemental dose: 150 mg followed by an infusion of 1 mg/minute for 6 hr, then 0.5 mg/minute. Max: 2.1 g daily.
Hepatic impairment: Dosage reduction may be necessary.

Reconstitution: To make solution for 1st rapid loading infusion or supplemental infusion: Add 3 ml of amiodarone HCl concentrate (50 mg/ml) to 100 ml of dextrose 5% to give a final conc of 1.5 g/ml; for slow infusion: Add 18 ml of amiodarone HCl concentrate (50 mg/ml) to 500 ml of dextrose 5% to give a final conc of 1.8 mg/ml; for subsequent maintenance infusions, diluted solutions with conc ranging from 1-6 mg/ml may be used. Solutions with conc ≥ 2 mg/ml should be administered via a central venous catheter.

Incompatibility: Y-site incompatibility: Cefamandole, sodium bicarbonate, heparin, aminophylline. Syringe incompatibility: Heparin. Admixture incompatibility (amiodarone conc: 4 mg/ml): Cefazolin sodium, cefamandole, mezlocillin sodium, sodium bicarbonate, heparin sodium, aminophylline.

Food(before/after)

May be taken with or without food. (Take consistently w/ or without meals. Take w/ meals if high dose or to reduce GI discomfort).

List of Contraindications

Amiodarone and Pregnancy

Teratogenic Effects
Pregnancy category D, Neonatal Hypo- or Hyperthyroidism

Amiodarone and Lactation

Teratogenic Effects
Pregnancy category D, Neonatal Hypo- or HyperthyroidismAmiodarone and one of its major metabolites, desethylAmiodarone (DEA), are excreted in human milk, suggesting that breastfeeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered Amiodarone have been shown to be less viable and have reduced body-weight gains. Therefore, when Amiodarone therapy is indicated, the mother should be advised to discontinue nursing.

Amiodarone and Children

The safety and effectiveness of Amiodarone hydrochloride tablets in pediatric patients have not been established.

Amiodarone and Geriatic

Clinical studies of Amiodarone hydrochloride tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Amiodarone and Other Contraindications

Amiodarone hydrochloride tablets are contraindicated in patients with cardiogenic shock; severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third-degree atrioventricular block; and when episodes of bradycardia have caused syncope (except when used in conjunction with a pacemaker).
Amiodarone hydrochloride tablets are contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine.

Storage

Intravenous: Store at 15-25°C. Oral: Store at 20-25°C.

Lab interference

Intravenous: Store at 15-25°C. Oral: Store at 20-25°C.

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