Amiodarone Hydrochloride (Page 6 of 7)

Postmarketing Reports

In postmarketing surveillance, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, renal impairment, renal insufficiency, acute renal failure, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pleuritis, pseudotumor cerebri, syndrome of inappropriate antidiuretic hormone secretion (SIADH), thyroid nodules/thyroid cancer, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma, myopathy, muscle weakness, rhabdomyolysis, hallucination, confusional state, disorientation, delirium, epididymitis, and impotence also have been reported with amiodarone therapy.

Also, in patients receiving recommended dosages of amiodarone HCl injection, there have been postmarketing reports of the following injection site reactions: pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing (see DOSAGE AND ADMINISTRATION).

OVERDOSAGE

There have been cases, some fatal, of amiodarone overdose. Effects of an inadvertent overdose of amiodarone HCl injection include hypotension, cardiogenic shock, bradycardia, AV block, and hepatotoxicity. Hypotension and cardiogenic shock should be treated by slowing the infusion rate or with standard therapy: vasopressor drugs, positive inotropic agents, and volume expansion. Bradycardia and AV block may require temporary pacing. Hepatic enzyme concentrations should be monitored closely. Amiodarone is not dialyzable.

DOSAGE AND ADMINISTRATION

Amiodarone shows considerable interindividual variation in response. Thus, although a starting dose adequate to suppress life-threatening arrhythmias is needed, close monitoring with adjustment of dose as needed is essential. The recommended starting dose of amiodarone HCl injection is about 1000 mg over the first 24 hours of therapy, delivered by the following infusion regimen:

AMIODARONE HCL INJECTION DOSE RECOMMENDATIONS– FIRST 24 HOURS –

Loading infusions

First Rapid:

150 mg over the FIRST 10 minutes (15 mg/min). Add 3 mL of Amiodarone HCl Injection (150 mg) to 100 mL D 5 W (concentration = 1.5 mg/mL). Infuse 100 mL over 10 minutes.

Followed by Slow:

360 mg over the NEXT 6 hours (1 mg/min). Add 18 mL of Amiodarone HCl Injection (900 mg) to 500 mL D 5 W (concentration = 1.8 mg/mL).

Maintenance infusion

540 mg over the REMAINING 18 hours (0.5 mg/min). Decrease the rate of the slow loading infusion to 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 (Amiodarone HCl Injection 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, 150 mg supplemental infusions of amiodarone HCl injection mixed in 100 mL of D 5 W may be administered. Such infusions should be administered over 10 minutes to minimize the potential for hypotension. The rate of the maintenance infusion may be increased to achieve effective arrhythmia suppression.

The first 24-hour dose may be individualized for each patient; however, in controlled clinical trials, mean daily doses above 2100 mg were associated with an increased risk of hypotension. The initial infusion rate should not exceed 30 mg/min.

Based on the experience from clinical studies of amiodarone HCl injection, a 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 has been limited experience in patients receiving amiodarone HCl injection for longer than 3 weeks.

The surface properties of solutions containing injectable amiodarone are altered such that the drop size may be reduced. This reduction may lead to underdosage of the patient by up to 30% if drop counter infusion sets are used. Amiodarone HCl injection must be delivered by a volumetric infusion pump.

Amiodarone HCl injection should, whenever possible, be administered through a central venous catheter dedicated to that purpose. An in-line filter should be used during administration. Amiodarone HCl injection loading infusions at much higher concentrations and rates of infusion much faster than recommended have resulted in hepatocellular necrosis and acute renal failure, leading to death (see PRECAUTIONS, Liver Enzyme Elevations).

Amiodarone HCl injection concentrations greater than 3 mg/mL in D 5 W 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, amiodarone HCl injection concentrations should not exceed 2 mg/mL unless a central venous catheter is used (see ADVERSE REACTIONS, Postmarketing Reports).

Amiodarone HCl injection infusions exceeding 2 hours must be administered in glass or polyolefin bottles containing D 5 W. Use of evacuated glass containers for admixing amiodarone HCl injection is not recommended as incompatibility with a buffer in the container may cause precipitation.

It is well known that amiodarone adsorbs to polyvinyl chloride (PVC) tubing and the clinical trial dose administration schedule was designed to account for this adsorption. All of the clinical trials were conducted using PVC tubing and its use is therefore recommended. The concentrations and rates of infusion provided in DOSAGE AND ADMINISTRATION reflect doses identified in these studies. Amiodarone HCl injection has been found to leach out plasticizers, including DEHP [di-(2-ethylhexyl)phthalate] from intravenous tubing (including PVC tubing). The degree of leaching increases when infusing amiodarone HCl injection at higher concentrations and lower flow rates than provided in DOSAGE AND ADMINISTRATION. In addition, polysorbate 80, a component of amiodarone HCl injection, is also known to leach DEHP from PVC (see DESCRIPTION). Therefore, it is important that the recommendations in DOSAGE AND ADMINISTRATION be followed closely.

Amiodarone HCl injection does not need to be protected from light during administration.

Note: Parenteral drug products should be inspected visually for particulate matter, whenever solution and container permit.

AMIODARONE HCL INJECTION SOLUTION STABILITY

Solution

Concentration (mg/mL)

Container

Comments

5% Dextrose in Water (D 5 W)

1 to 6

PVC

Physically compatible, with amiodarone loss <10% at 2 hours at room temperature.

5% Dextrose in Water (D 5 W)

1 to 6

Polyolefin, Glass

Physically compatible, with no amiodarone loss at 24 hours at room temperature.


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