Authors: Allie K. Wasik, PharmD, and Kristin Watson, PharmD, BCPS-AQ Cardiology

Amiodarone is one of the most widely used antiarrhythmic agents in both the inpatient and outpatient settings.1 Amiodarone is also one of the few antiarrhythmics routinely used for both atrial and ventricular arrhythmias, even though it is only approved for use in life-threatening recurrent ventricular arrhythmias.2,3 Amiodarone is unique in its multifarious properties, as it blocks sodium, calcium, and potassium channels in the myocardium while also possessing alpha- and beta-blocking properties, albeit to a lesser extent.4 Because of the large volume of distribution of amiodarone and its long half-life, a loading dose is necessary to accelerate the onset of action and shorten the time to steady state concentrations.4

Did You Know?
Amiodarone distributes into lipophilic tissue and can exhibit a half-life of nearly 90 days with repeated exposure. Without the use of a loading dose, it can take 265 days on average (range 130-535 days) to achieve steady state!

Recommendations for amiodarone loading doses typically range from 6 to 10 g. Table 1 highlights recommended loading dose strategies. 2,3,5 A loading dose of 6 to 8 g has been used in many clinical trials, particularly when being used for atrial fibrillation (AF). On the contrary, an 8 to 10 g load has been used in trials involving patients with ventricular arrhythmias. The time to completion of the loading regimen has also varied. The aim of this blog is to discuss the evidence that supports the use of a specific loading dose of amiodarone.

Table 1. Recommended Strategies for Loading with Amiodarone

Reference Recommendations
2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation AF rate control: 300 mg IV over 1 hour, then 10 – 50 mg/h over 24 hours; followed by oral maintenance dose of 100-200 mg/d

 

AF pharmacological cardioversion:

Oral: 600 – 800 mg daily (in divided doses) to a total load of up to 10 g; then 200 mg/d maintenance dose

 

IV: 150 mg over 10 min, then 1 mg/min for 6 hours, then 0.5 mg/min for 18 hours or change to oral dosing

 

AF maintenance of sinus:

Oral: 400 – 600 mg/d (in divided doses) for 2-4 wk; maintenance dose is typically 100 – 200 mg/d

 

IV: 150 mg over 10 min; then 1 mg/min for 6 hours; then 0.5 mg/min for 18 hours or change to oral dosing; after 24 hours, consider decreasing dose to 0.25 mg/min

2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death Ventricular arrhythmias:

 

IV: 300 mg bolus for VF/ pulseless VT arrest; 150-mg bolus for stable VT; 1 mg/min x 6 h, then 0.5 mg/min x 18 hours

 

Oral: 400 mg* every 8 to 12 hours for 1 – 2 wk, then 300 – 400 mg/d; reduce dose to 200 mg/d, if possible

North American Society of Pacing and Electrophysiology Practical Guide for Clinicians Who Treat Patients with Amiodarone Ventricular arrhythmias

 

IV: 150 mg for 10 minutes, followed by 1 mg/min for 6 hrs then 0.5 mg/min; supplemental doses of 150 mg may be given every 10 to 30 minutes (limited to 6-8 supplemental boluses in 24 hours)

 

Oral: Following the initial IV load, 800 – 1600 mg/d (in divided doses) for up to 2 to 3 weeks; reduce the dose to 400 – 600 mg/d. Further dose reductions to 200 – 300 mg/d in some patients.

 

AF:

Oral: 600 – 800 mg/d (in 2 divided doses) for 2 to 4 weeks; the dose can then be reduced to 400 mg/d. Further reduce to 100 to 300 mg/d at 3 to 6 months based on efficacy and development of side effects.

Abbreviations: AF atrial fibrillation, IV intravenous, VF ventricular fibrillation, VT ventricular tachycardia

Amiodarone dosing strategies and routes of administration for recent-onset AF vary greatly in clinical trials. A meta-analysis that evaluated amiodarone in new-onset AF demonstrated greater conversion to normal sinus rhythm (NSR) with intravenous (IV) doses greater than 1500 mg/day. In a randomized controlled trial of 100 patients with new-onset AF, a bolus dose of 5 mg/kg  followed by continuous infusion of 1200 mg over 24 hours was not superior to placebo in conversion to NSR at 24 hours (68 versus 60%, p=0.532). There was also no difference in time to achieve NSR or maintenance of NSR at 15 days.6

However, other trials evaluating higher doses of IV amiodarone have shown benefit in the rates of conversion to NSR. Hou et al. assigned patients with recent-onset, persistent AF or atrial flutter to amiodarone 5 mg/min for 1 hour, 3 mg/min for the next 3 hours, 1 mg/min for 6 hours followed by 0.5 mg/min (for a 70 kg patient) for the remaining 14 hours (n = 26) versus digoxin (n=24). Ninety-two percent of patients receiving this high dose regimen (mean 24 hour dose 1383 +250 mg) converted to NSR versus 72% in placebo group, p=0.0048.7

Despite the suggested efficacy of high-dose IV regimens, this route of administration may be limited by hemodynamic adverse events. Therefore, high-dose oral regimens have also been studied. A high-dose oral loading regimen (mean dose 2020 +70 mg) was compared to IV continuous infusion (mean dose 1038 +62 mg) in 72 patients with sustained atrial tachyarrhythmias. There was no difference in conversion rates to NSR between the oral and IV groups (64.4 versus 66.7% respectively).8 These analyses suggest that successful rates of cardioversion for recent-onset AF are dependent on the dose administered rather than the route of administration.

Amiodarone suppresses ventricular arrhythmias, but the optimal dose and route of administration has yet to be elucidated. Current evidence suggests a dose-response relationship, with higher doses prolonging time to recurrent events.9 One study randomized patients to dose tertiles (IV 125 mg/24 hours, 500 mg/24 hours or 1000 mg/24 hours) and found that patients in the highest dose tertile had lower ventricular arrhythmia event rates (125-mg dose group, 1.68; 500-mg dose group, 0.96; and 1000-mg dose group, 0.48; p=0.067) after 48 hours of treatment. Supplemental doses of 150 mg IV boluses were permitted for breakthrough ventricular tachycardia (VT) or ventricular fibrillation (VF). The mean number of supplemental doses decreased with increasing amiodarone dose (125 mg dose group, 2.44±3.1; 500 mg dose group, 2.49±4.0; and 1000 mg dose group, 1.75±2.6; p=0.038), supporting the notion that amiodarone possesses dose-dependent antiarrhythmic effects.10

In another study, amiodarone 600 mg PO twice daily for 10 days (mean total loading dose 12 g) was compared to an oral weight-based regimen for 10 days (mean total loading dose 23.3 g) in 32 patients with inducible, sustained monomorphic VT. There was no difference in inducible VT between the two dosing strategies at day 3 (mean 1.6 +1.1 versus 1.3 +0.7 events in low and high dose groups respectively) and day 10 (mean 1.5 +0.8  versus 1.6 +0.9  events).11 This trial suggests that a high-dose oral loading regimen for VT is no more efficacious than a conventional oral loading regimen.

In our experience, it is common to use IV amiodarone for 24 hours for ventricular arrhythmias before switching to the oral route of administration. Certainly, IV dosing remains first line for patients in pulseless VT and VF, those who have no enteral access, and those who are hemodynamically unstable. The oral route can be used in most patients with AF, as no difference has been seen in achieving NSR compared to IV amiodarone in this population. In many cases, the oral form may be preferred as it is less expensive and does not carry the same risk for hemodynamic compromise as IV amiodarone.12 Rapid administration of an IV bolus can cause hypotension in up to 15% of patients.4,5 This effect is thought to be due to polysorbate 80 /benzyl alcohol, the diluent used in several commercially available glass vials used to prepare infusions, rather than the drug itself.13 This formulation has been shown to lower mean arterial pressure by up to 23% in the 12-18 hours after IV administration.14

The use of the oral formulation does not carry the same risk of lowering mean arterial pressure and thus amiodarone should be converted to the oral formulation whenever appropriate. However, in some patients conversion to oral therapy is not possible. Slowing the rate of the infusion may mitigate some of the hypotensive effects associated with formulations containing polysorbate 80 /benzyl alcohol. Alternatively, Nexterone®, a premixed amiodarone injection diluted in 5% dextrose in water with excipients/surfactants that do not cause hypotension, may also be considered when an IV formulation is needed.13 Amiodarone has also been associated with thrombophlebitis in up to 40% of patients, and the incidence is higher among those receiving continuous infusion, especially when administered via peripheral line.15

While patients are being loaded with a high-dose oral regimen, it is important to be mindful of the risk for gastrointestinal (GI) intolerance. Patients completing a loading dose in the outpatient setting should be counseled to notify their prescriber if GI effects occur rather than stopping therapy on their own. Additionally, the plan for completion of the loading regimen and the transition to a maintenance dose should be clearly communicated to patients and outpatient providers to ensure that loading doses are not continued for longer than necessary. Regarding maintenance doses, patients should receive the lowest effective dose possible (typically 200 – 400 mg/d) to minimize dose-related adverse events.

In summary, given the pharmacokinetic properties of amiodarone, a loading dose can be advantageous in several ways. Data suggest that a number of loading dose strategies can be used; however, the magic of number of 10 grams is yet to be validated in a randomized controlled trial. Current recommendations for amiodarone loading doses stem from anecdotal experience in clinical trials, but the best dosing strategy is yet to be independently studied. Until then, it important that we acknowledge the variability in amiodarone and recognize that current recommendations stem from trial experience. Additionally there is little evidence to provide a compelling reason to use IV over oral amiodarone in new-onset AF, particularly when the potential risks of IV amiodarone are considered.

 

Allie K. Wasik, PharmD

At the time of writing, Dr. Allie Wasik was a PGY2 Cardiology Resident at the University of Maryland.

 
Kristin Watson, PharmD, BCPS-AQ Cardiology

Kristin Watson is an associate professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in the ambulatory heart failure clinic at the Veterans Affairs Medical Center in Baltimore, MD. Follow her on Twitter @cards_pharm_gal

 

References

  1. ClinCalc DrugStats Database Amiodarone Hydrochloride Drug Usage and Statistics, United States. Available at: http://clincalc.com/drugstats/Drugs/AmiodaroneHydrochlorideAccessed June 6, 2018.
  2. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2017.
  3. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1-76.
  4. Amiodarone [package insert]. Lake Forest, IL: Bioniche Pharma USA LLC; June 2008.
  5. Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Archives of Internal Medicine 2000;160:1741-8.
  6. Galve E, Rius T, Ballester R, et al. Intravenous amiodarone in treatment of recent-onset atrial fibrillation: results of a randomized, controlled study. J Am Coll Cardiol 1996;27:1079-82.
  7. Hou ZY, Chang MS, Chen CY, et al. Acute treatment of recent-onset atrial fibrillation and flutter with a tailored dosing regimen of intravenous amiodarone. A randomized, digoxin-controlled study. European heart journal 1995;16:521-8.
  8. Andrivet P, Boubakri E, Dove PJ, Mach V, Vu Ngoc C. A clinical study of amiodarone as a single oral dose in patients with recent-onset atrial tachyarrhythmia. European heart journal 1994;15:1396-402.
  9. Levine JH, Massumi A, Scheinman MM, et al. Intravenous amiodarone for recurrent sustained hypotensive ventricular tachyarrhythmias. Intravenous Amiodarone Multicenter Trial Group. J Am Coll Cardiol 1996;27:67-75.
  10. Scheinman MM, Levine JH, Cannom DS, et al. Dose-Ranging Study of Intravenous Amiodarone in Patients With Life-Threatening Ventricular Tachyarrhythmias. Circulation 1995;92:3264-72.
  11. Kalbfleisch SJ, Williamson B, Man KC, et al. Prospective, randomized comparison of conventional and high dose loading regimens of amiodarone in the treatment of ventricular tachycardia. Journal of the American College of Cardiology 1993;22:1723-9.
  12. Xanthos T, Bassiakou E, Vlachos IS, et al. Intravenous and oral administration of amiodarone for the treatment of recent onset atrial fibrillation after digoxin administration. Int J Cardiol 2007;121:291-5.
  13. Cushing DJ, Kowey PR, Cooper WD, Massey BW, Gralinski MR, Lipicky RJ. PM101: a cyclodextrin-based intravenous formulation of amiodarone devoid of adverse hemodynamic effects. Eur J Pharmacol 2009;607:167-72.
  14. Lindquist DE, Rowe AS, Heidel E, Fleming T, Yates JR. Evaluation of the Hemodynamic Effects of Intravenous Amiodarone Formulations During the Maintenance Phase Infusion. Ann Pharmacother 2015;49:1317-21.
  15. Norton L, Ottoboni LK, Varady A, et al. Phlebitis in amiodarone administration: incidence, contributing factors, and clinical implications. Am J Crit Care 2013;22:498-505.
10 Grams or Bust: What is the Appropriate Loading Dose of Amiodarone?
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