Amiodarone Hydrochloride

AMIODARONE HYDROCHLORIDE- amiodarone hydrochloride injection
Wockhardt USA LLC.

1 INDICATIONS AND USAGE

Amiodarone injection is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. Amiodarone also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with amiodarone, patients may be transferred to oral amiodarone therapy [see Dosage and Administration (2)].

Use amiodarone for acute treatment until the patient’s ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but amiodarone may be safely administered for longer periods if necessary.

2 DOSAGE AND ADMINISTRATION

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

Table 1: AMIODARONE DOSE RECOMMENDATIONS: FIRST 24 HOURS
Loading infusions First Rapid: 150 mg over the FIRST 10 minutes (15 mg/min). Add 3 mL of amiodarone (150 mg) to 100 mL D5 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 (900 mg) to 500 mL D5 W (concentration = 1.8 mg/mL). Infuse 200 mL at a rate of 0.556 mL/min.
Maintenance infusion 540 mg over the REMAINING 18 hours (0.5 mg/min). Decrease the rate of the slow loading infusion to 0.278 mL/min.

After the first 24 hours, continue the maintenance infusion rate of 0.5 mg/min (720 mg per 24 hours) utilizing a concentration of 1 to 6 mg/mL (Use a central venous catheter for amiodarone concentrations greater than 2 mg/mL). The rate of the maintenance infusion may be increased to achieve effective arrhythmia suppression.

In the event of breakthrough episodes of VF or hemodynamically unstable VT, use 150 mg supplemental infusions of amiodarone (mixed in 100 mL of D5 W and infused over 10 minutes to minimize the potential for hypotension).

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. Do not exceed an initial infusion rate of 30 mg/min.

Based on the experience from clinical studies of intravenous amiodarone, a maintenance infusion of up to 0.5 mg/min can be 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 intravenous amiodarone 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 must be delivered by a volumetric infusion pump.

Administer amiodarone, whenever possible, through a central venous catheter dedicated to that purpose. Use an in-line filter during administration.

Intravenous amiodarone 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 Warnings and Precautions (5.3)].

Intravenous amiodarone concentrations greater than 3 mg/mL in D5 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, do not exceed amiodarone concentrations of 2 mg/mL, unless a central venous catheter is used [see Adverse Reactions (6.2)].

Amiodarone infusions exceeding 2 hours must be administered in glass or polyolefin bottles containing D5 W. Do not use evacuated glass containers for admixing, as incompatibility with a buffer in the container may cause precipitation.

Amiodarone adsorbs to polyvinyl chloride (PVC) tubing, but all of the clinical experience has been with PVC tubing and the concentrations and rates of infusion provided in DOSAGE AND ADMINISTRATION reflect dosing in these studies.

Amiodarone 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 at higher concentrations and lower flow rates than provided in DOSAGE AND ADMINISTRATION. Polysorbate 80, a component of amiodarone injection, is also known to leach DEHP from PVC [see Description (11)].

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

NOTE: Inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit — solution should be clear.

CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before the administration of the fluid from the secondary container is complete.

Table 2: AMIODARONE HCl SOLUTION STABILITY
Concentration
Solution (mg/mL) Container Comments
5% Dextrose in Water (D5W) 1 to 6 PVC Physically compatible, with amiodarone loss <10% at 2 hours at room temperature.
5% Dextrose in Water (D5W) 1 to 6 Polyolefin, Glass Physically compatible, with no amiodarone loss at 24 hours at room temperature.

Admixture Incompatibility

Amiodarone in D5 W Injection forms precipitates with the drugs shown in Table 3. If co-administration of the following drugs is necessary, use separate intravenous administration lines.

Table 3: Y-SITE INJECTION INCOMPATIBILITY

D5 W = Dextrose 5% in Sterile Water, NS = Normal Saline

Drug Vehicle Amiodarone Concentration
Aminophylline D5 W; NS 4 mg/mL
Amoxicillin Sodium-Clavulanic Acid Unknown 12.5 mg/mL
Ampicillin Sodium-Sulbactam Sodium NS 6 mg/mL
Argatroban D5 W 1.8 mg/mL
Bivalirudin D5 W 4 mg/mL
Cefamandole Nafate D5 W 4 mg/mL
Cefazolin Sodium D5 W 4 mg/mL
Ceftazidime D5 W 6 mg/mL
Digoxin D5 W 6 mg/mL
Furosemide (10 mg/mL) D5 W 6 mg/mL
Mezlocillin Sodium D5 W 4 mg/mL
Heparin Sodium D5 W
Imipenem-Cilastin Sodium D5 W 6 mg/mL
Magnesium Sulfate (500 mg/mL) D5 W 6 mg/mL
Micafungin NS 4 mg/mL
Piperacillin Sodium — TazobactamSodium D5 W 6 mg/mL
Potassium Phosphates D5 W 6 mg/mL
Sodium Bicarbonate D5 W 3 mg/mL
Sodium Nitroprusside D5 W 1.5, 6 and 15 mg/mL
Sodium Phosphates D5 W 6 mg/mL

Intravenous to Oral Transition

Patients whose arrhythmias have been suppressed by amiodarone may be switched to oral amiodarone. The optimal dose for changing from intravenous to oral administration of amiodarone will depend on the dose of intravenous amiodarone already administered, as well as the bioavailability of oral amiodarone. When changing to oral amiodarone therapy, clinical monitoring is recommended, particularly for elderly patients. See package insert for oral amiodarone.

Since grapefruit juice is known to inhibit CYP3A-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, do not drink grapefruit juice during treatment with oral amiodarone [see Drug Interactions (7)].

Table 4 provides suggested doses of oral amiodarone to be initiated after varying durations of amiodarone administration. These recommendations are made on the basis of a similar total body amount of amiodarone delivered by the intravenous and oral routes, based on 50% bioavailability of oral amiodarone.

Table 4: RECOMMENDATIONS FOR ORAL DOSAGE AFTER INTRAVENOUS INFUSION

# Assuming a 720 mg/day infusion (0.5 mg/min).

* Intravenous amiodarone is not intended for maintenance treatment.

Duration of Amiodarone Infusion# Initial Daily Dose of Oral Amiodarone
< 1 week 800 to 1600 mg
1 to 3 weeks 600 to 800 mg
> 3 weeks* 400 mg

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