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Intravenous Dilution Guidelines

Amiodarone - Cordarone ®

The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.  PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.

Usual Diluents

D5W

Standard Dilutions   [Amount of drug] [Infusion volume] [Infusion rate]

[150 mg / 100 ml] [10 minutes]

(Glass bottle or polyolefin container)
[720 mg / 500 ml ] [See comments]
[900 mg / 500 ml ] [See comments]
(an inline 0.22 micron filter should be used).

Stability / Miscellaneous

Recommended concentration: 1-6 mg/ml.
Central line is required for concentrations > 2 mg/ml.
[Supplied: 3 ml amp (50 mg/ml)].

Infusion: whenever possible administer through a central venous catheter. Also, an in-line filter should be used during administration. Cordarone I.V. concentrations greater than 3 mg/mL in D5W have been associated with a high incidence of peripheral vein phlebitis; however, concentrations of 2.5 mg/mL or less appear to be less irritating. Therefore, for infusions longer than 1 hour, Cordarone I.V. concentrations should not exceed 2 mg/mL unless a central venous catheter is used. Cordarone I.V. infusions exceeding 2 hours must be administered in glass or polyolefin bottles containing D5W. Use of evacuated glass containers for admixing Cordarone I.V. is not recommended as incompatibility with a buffer in the container may cause precipitation.

AmiodaroneI.V. DOSE RECOMMENDATIONS -- FIRST 24 HOURS -- Loading infusions. The recommended starting dose of Cordarone I.V. is about 1000 mg over the first 24 hours of therapy, delivered by the following infusion regimen:

First Rapid: 150 mg over the FIRST - 10 minutes (15 mg/min). Add 3 mL of Cordarone I.V. (150 mg) to 100 mL D5W. Infuse 100 mL over 10 minutes.

Followed by Slow: 360 mg over the NEXT 6 hours (1 mg/min). Add 18 mL of Cordarone I.V. (900 mg) to 500 mL D5W (conc = 1.8 mg/mL).

Maintenance infusion: 540 mg over the REMAINING 18 hours (0.5 mg/min).


After the first 24 hours, the maintenance infusion rate of 0.5 mg/min (720 mg/24 hours) should be continued utilizing a concentration of 1 to 6 mg/mL (Cordarone I.V. concentrations greater than 2 mg/mL should be administered via a central venous catheter). In the event of breakthrough episodes of VF or hemodynamically unstable VT, Give 150-mg/100 ml D5W over 10 minutes to minimize potential for hypotension. The rate of the maintenance infusion may be increased to achieve effective arrhythmia suppression. The initial infusion rate should not exceed 30 mg/min. The maintenance infusion of up to 0.5 mg/min can be cautiously continued for 2 to 3 weeks regardless of the patient's age, renal function, or Left-ventricular function. There is limited experience in patients receiving Cordarone I.V. > 3 weeks.

RECOMMENDATIONS FOR ORAL DOSAGE AFTER I.V. INFUSION
Duration of Cordarone I.V. Infusion*: <1 week
Initial Daily Dose of Oral Cordarone : 800-1600 mg

Duration of Cordarone I.V. Infusion: 1 to 3 weeks
Initial Daily Dose of Oral Cordarone : 600-800 mg

Duration of Cordarone I.V. Infusion: >3 weeks
Initial Daily Dose of Oral Cordarone : 400 mg
*Assuming a 720 mg/day infusion (0.5 mg/min). Cordarone I.V is not intended for maint therapy.

Restated: Duration of IV infusion < 1 week: 800-1600mg/day po initially x 1-2 weeks or complete current week; 1-3 weeks: 600-800mg/day po initially - total therapy ~ 1 month counting IV infusion ; >3 weeks: 400mg po qd initially.

Oral Loading - Half-life elimination: 40-55 days (range: 26-107 days);
Administration of Cordarone in divided doses with meals is suggested for total daily doses of 1,000 mg or higher, or when gastrointestinal intolerance occurs.) If side effects become excessive, the dose should be reduced.
Loading Dose (Daily): (Ventricular Arrhythmias) 800 to 1,600 mg x 1-3 weeks, then 600 to 800 mg x ~1 month, then start maintenance of 400mg/day.


Recommendations for conversion to intravenous amiodarone after oral administration: During long-term amiodarone therapy (ie, 4 months), the mean plasma-elimination half-life of the active metabolite of amiodarone is 61 days. Replacement therapy may not be necessary in such patients if oral therapy is discontinued for a period <2 weeks, since any changes in serum amiodarone concentrations during this period may not be clinically significant.


Mechanisms of Action
Amiodarone is generally considered a class III antiarrhythmic drug, but it possesses electrophysiologic characteristics of all four Vaughan Williams classes. Like class I drugs, amiodarone blocks sodium channels at rapid pacing frequencies, and like class II drugs, it exerts a noncompetitive antisympathetic action. One of its main effects, with prolonged administration, is to lengthen the cardiac action potential, a class III effect. The negative chronotropic effect of amiodarone in nodal tissues is similar to the effect of class IV drugs. In addition to blocking sodium channels, amiodarone blocks myocardial potassium channels, which contributes to slowing of conduction and prolongation of refractoriness. The antisympathetic action and the block of calcium and potassium channels are responsible for the negative dromotropic effects on the sinus node and for the slowing of conduction and prolongation of refractoriness in the atrioventricular (AV) node. Its vasodilatory action can decrease cardiac workload and consequently myocardial oxygen consumption.

Intravenous amiodarone administration prolongs intranodal conduction (Atrial-His, AH) and refractoriness of the atrioventricular node (ERP AVN), but has little or no effect on sinus cycle length (SCL), refractoriness of the right atrium and right ventricle (ERP RA and ERP RV), repolarization (QTc), intraventricular conduction (QRS), and infranodal conduction (His-ventricular, HV).


Pharmacokinetics and Metabolism
Amiodarone exhibits complex disposition characteristics after intravenous administration. Peak serum concentrations after single 5 mg/kg 15-minute intravenous infusions in healthy subjects range between 5 and 41 mg/L. Peak concentrations after 10-minute infusions of 150 mg intravenous amiodarone in patients with ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT) range between 7 and 26 mg/L. Due to rapid distribution, serum concentrations decline to 10% of peak values within 30 to 45 minutes after the end of the infusion. In clinical trials, after 48 hours of continued infusions (125, 500, or 1000 mg/day) plus supplemental (150 mg) infusions (for recurrent arrhythmias), amiodarone mean serum concentrations between 0.7 to 1.4 mg/L were observed (n=260).

N-desethylamiodarone (DEA) is the major active metabolite of amiodarone in humans. DEA serum concentrations above 0.05 mg/L are not usually seen until after several days of continuous infusion but with prolonged therapy reach approximately the same concentration as amiodarone. 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. The highly variable systemic availability of oral amiodarone may be attributed potentially to large interindividual variability in CYP3A4 activity.

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. Amiodarone and DEA cross the placenta and both appear in breast milk.


The systemic availability of oral amiodarone in healthy subjects ranges between 33% and 65%. From in vitro studies, the protein binding of amiodarone is >96%.

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/h/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. Normal subjects over 65 years of age show lower clearances (about 100 mL/hr/kg) than younger subjects (about 150 mL/hr/kg) and an increase in t1/2 from about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition t1/2 of DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with oral amiodarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction.

There is no established relationship between drug concentration and therapeutic response for short-term intravenous use. Steady-state amiodarone concentrations of 1 to 2.5 mg/L have been associated with antiarrhythmic effects and acceptable toxicity following chronic oral amiodarone therapy.


CONTRAINDICATIONS
Amiodarone injection is contraindicated in patients with known hypersensitivity to any of the components of amiodarone injection, including iodine, or in patients with cardiogenic shock, marked sinus bradycardia, and second- or third-degree AV block unless a functioning pacemaker is available.

WARNINGS
Hypotension
Hypotension is the most common adverse effect seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse effect in 288 (16%) of 1836 patients treated with intravenous amiodarone. Clinically significant hypotension during infusions was seen most often in the first several hours of treatment and was not dose related, but appeared to be related to the rate of infusion. Hypotension necessitating alterations in intravenous amiodarone therapy was reported in 3% of patients, with permanent discontinuation required in less than 2% of patients.

Hypotension should be treated initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion. The initial rate of infusion should be monitored closely and should not exceed that prescribed in DOSAGE AND ADMINISTRATION.

In some cases, hypotension may be refractory resulting in fatal outcome (see package insert for ADVERSE REACTIONS, Postmarketing Reports).

Bradycardia and AV Block
Drug-related bradycardia occurred in 90 (4.9%) of 1836 patients in clinical trials while they were receiving intravenous amiodarone for life-threatening VT/VF; it was not dose-related. Bradycardia should be treated by slowing the infusion rate or discontinuing amiodarone. In some patients, inserting a pacemaker is required. Despite such measures, bradycardia was progressive and terminal in 1 patient during the controlled trials. Patients with a known predisposition to bradycardia or AV block should be treated with intravenous amiodarone in a setting where a temporary pacemaker is available.

Long-Term Use
See labeling for oral amiodarone. There has been limited experience in patients receiving intravenous amiodarone for longer than 3 weeks.

Neonatal Hypo- or Hyperthyroidism
Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism associated with its oral administration. If intravenous amiodarone is administered during pregnancy, the patient should be apprised of the potential hazard to the fetus.


HOW SUPPLIED ----------------------
Amiodarone Hydrochloride Injection, 50 mg/mL is supplied in:
3 mL (150 mg) 10 Single-dose vials per carton (NDC 60505-0722-0).

Store at 20° to 25°C (68° to 77°F)

Protect from light. Avoid excessive heat.
Use carton to protect contents from light until used.
Disclaimer
The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.  PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.
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