AMIODARONE HYDROCHLORIDE

AMIODARONE HYDROCHLORIDE- amiodarone hydrochloride injection, solution
HF Acquisition Co LLC, DBA HealthFirst

HIGHLIGHTS OF PRESCRIBING INFORMATION


These highlights do not include all the information needed to use Amiodarone Hydrochloride Injection safely and effectively. See full prescribing information for Amiodarone Injection.
AMIODARONE Hydrochloride Injection for intravenous use
Initial U.S. Approval: 1995

INDICATIONS AND USAGE

Amiodarone Hydrochlroide Injection is an antiarrhythmic agent 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. ( 1)

DOSAGE AND ADMINISTRATION

The recommended starting dose is about 1000 mg over the first 24 hours of therapy, delivered by the following infusion regimen ( 2):

-Initial Load: 150 mg per 100 mL (in D5W) infused over 10 minutes
-Followed by: 1 mg/min for 6 hours
-Followed by: 0.5 mg/min thereafter

In the event of breakthrough episodes of VF or hemodynamically unstable VT ( 2):

-Repeat the Initial Load described above as needed (infused over 10 minutes)

Increase the rate of the maintenance infusion to achieve effective arrhythmia suppression. ( 2)

DOSAGE FORMS AND STRENGTHS

Injection, 50 mg/mL ( 3)

CONTRAINDICATIONS

Amiodarone is contraindicated in patients with ( 4):

Known hypersensitivity to any of the components of amiodarone, including iodine
Cardiogenic shock
Marked sinus bradycardia
Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available.

WARNINGS AND PRECAUTIONS

Hypotension: Treat initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion. 5-(5.1)
Bradycardia and AV block: Treat by slowing the infusion rate or discontinuing amiodarone. 5-(5.2)

ADVERSE REACTIONS

The most common adverse reactions (1-2%) leading to discontinuation of intravenous amiodarone therapy are hypotension, asystole/cardiac arrest/pulseless electrical activity, VT, and cardiogenic shock. ( 6)
Other important adverse reactions are, torsade de pointes (TdP), congestive heart failure, and liver function test abnormalities. ( 6)

To report SUSPECTED ADVERSE REACTIONS, contact West-ward Pharmaceuticals Corp. at 1-877-233-2001, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone.
Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs that are metabolized by those CYP450 enzymes or are substrates for p-glycoprotein.
Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. ( 7)

USE IN SPECIFIC POPULATIONS

Pregnancy: Use amiodarone during pregnancy only if the potential benefit to the mother justifies the risk to the fetus 8-(8.1).
Nursing mothers: Amiodarone 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. Advise mothers to discontinue breastfeeding 8-(8.3).
Pediatric use: The safety and efficacy of amiodarone in the pediatric population have not been established ( 8-8.4).

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 7/2016

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hypotension
5.2 Bradycardia and Atrio-ventricular Block
5.3 Liver Enzyme Elevations
5.4 Proarrhythmia
5.5 Pulmonary Disorders
5.6 Loss of Vision
5.7 Long-Term Use
5.8 Thyroid Abnormalities
5.9 Surgery
5.10 Corneal Refractive Laser Surgery
5.11 Electrolyte Disturbances
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Labor and Delivery
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/ STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS & USAGE

Amiodarone Hydrochloride 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 Hydrochloride Injection 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 Hydrochloride Injection, patients may be transferred to oral amiodarone therapy [see Dosage and Administration ( 2)].

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

2 DOSAGE & 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

DOSAGE 1
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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 D5W 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-(5.3)].

Intravenous amiodarone 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, do not exceed amiodarone concentrations of 2 mg/mL, unless a central venous catheter is used [see Adverse Reactions 6-(6.2)].

Amiodarone infusions exceeding 2 hours must be administered in glass or polyolefin bottles containing D5W. 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.

Table 2: AMIODARONE HCl SOLUTION STABILITY

DOSAGE 2
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Admixture Incompatibility

Amiodarone in D5W is incompatible with the drugs shown in Table 3.

Table 3: Y-SITE INJECTION INCOMPATIBILITY

DOSAGE 3
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Intravenous to Oral Transition

Patients whose arrhythmias have been suppressed by amiodarone may be switched to 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

DOSAGE 4
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*
Assuming a 720 mg/day infusion (0.5 mg/min).

Intravenous amiodarone is not intended for maintenance treatment.

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