amiodarone (Pacerone, Cordarone, Nexterone)

Dosing and uses of Pacerone, Cordarone (amiodarone)

• Adult
• Pediatric
• Geriatric

 

Adult dosage forms and strengths

injectable solution

• 50mg/mL
• 150mg/100mL (Nexterone)
• 360mg/200mL (Nexterone)
• Conventional IV preparation contains polysorbate 80 and benzyl alcohol
• Newer IV formulation (Nexterone) does not contain polysorbate 80 or benzyl alcohol

tablet

• 100mg
• 200mg
• 400mg

 

Stable Monomorphic or Polymorphic Ventricular Tachycardia (Off-label)

150 mg IV bolus in 10 minutes; may repeat q10min as necessary, THEn

1 mg/min IV for 6 hours, THEn

0.5 mg/min IV for 18 hours; not to exceed 2.2 g/24hr

For breakthrough episodes of VF or hemodynamically unstable VT , repeat the initial Load

Dosing considerations

• Initiate in hospital with experienced personnel

 

ACLS, Pulseless Ventricular Fibrillation/Ventricular Tachycardia (Off-label)

300 mg IV or intraosseous push after dose epinephrine if no initial response to defibrillation

May follow initial dose with 150 mg IV q3-5min

Dosing considerations

• Rapid IV push if pulseless/no BP

 

Ventricular Arrhythmias

PO

• Load: 800-1600 mg PO qDay for 1-3 weeks until response; once adequate arrhythmia control achieved, reduce dose to 600-800 mg/day for 1 mo; THEN reduce to maintenance dose
• Maintenance dose: 400 mg PO qDay

IV

• 150 mg over first 10 min (15mg/min), followed by 360 mg over next 6 hr (1 mg/min), THEN 540 mg over remaining 18 hr (0.5 mg/min), for a total of 1000 mg over 24 hr before administering maintenance infusion
• Maintenance: 0.5 mg/min for a total 720 mg/24hr at a concentration of 1-6 mg/mL (360 mg/200mL), or 1.8 mg/mL Nexterone at rate of 278 mL/min
• Duration of therapy: May continue to administer 0.5 mg/min for 2-3 weeks regardless of patient's age, renal function or ventricular function

 

Conversion to oral amiodarone after IV administration

<1 week IV infusion: 800-1600 mg/day

1-3 week IV infusion: 600-800 mg/day

>3 week IV infusion: 400 mg/day

 

Pediatric dosage forms and strengths

injectable solution

• 50mg/mL
• 150mg/100mL (Nexterone)
• 360mg/200mL (Nexterone)
• Note: Conventional IV preparation contains polysorbate 80 and benzyl alcohol
• Newer IV formulation (Nexterone) does not contain polysorbate 80 or benzyl alcohol

tablet

• 100mg
• 200mg
• 400mg

 

Drug Resistant Refractory Cardiac Arrhythmias (Off-label)

PO

• Age <1 year: 600-800 mg/1.73 m² q24hr or divided q12hr; continue therapy for 4-14 days and/or until adequate control achieved; if initial treatment effective, decrease dosage to 200-400 mg/1.73 m² q24hr or divided q12hr
• Age >1 year: Until adequate control, 10-15 mg/kg/day PO qDay or divided q12hr; if effective, reduce to 5 mg/kg/day PO qDay or divided q12hr

IV

• Loading dose (limited data): 5 mg/kg IV over 30-60 min
• Maintenance dose: 0.005 mg/kg/min IV infusion; may increase to 20 mcg/kg/min per 24 hr; consider converting to oral therapy within 24-48 hr

 

Pulseless Ventricular Tachycardia or Ventricular Fibrillation (PALS dosing) (Off-label)

5 mg/kg IV/IO rapid bolus; not to exceed 300 mg/dose; may repeat twice to maximum 15 mg/kg during acute treatment

 

Supraventricular Tachycardia (Off-label)

Infants/children/adolescents: 5 mg/kg IV over 1 hr initially; follow with 5 mg/kg/day for 47 hr

Maintenance: 10-20 mg/kg/day for 7-10 days; follow with 3-20 mg/kg/day

 

Dosing Considerations

In a pediatric trial of 61 patients, aged 30 days to 15 years, hypotension (36%), bradycardia (20%), and atrioventricular block (15%) were common dose-related adverse events and were severe or life-threatening in some cases

Injection site reactions were seen in 5 (25%) of the 20 patients receiving amiodarone HCI injection through a peripheral vein, irrespective of dose regimen

Conventional IV amiodarone contains the preservative benzyl alcohol; there have been reports of fatal “gasping syndrome” in neonates (children aged less than 1 month) following the administration of IV solutions containing the preservative benzyl alcohoL

Nexterone does not contain benzyl alcohoL

 

Geriatric dosage forms and strengths

Recommended to start dosing at the lower end of the dosing range because elderly may be predisposed to toxicity

 

Pacerone, Cordarone (amiodarone) adverse (side) effects

>10%

Increased liver AST or ALT levels (3-20%; as high as 40-50% in some studies)

Hypotension (16%)

Dizziness (3-40%)

Headache (3-40%)

Malaise (3-40%)

Abnormal gait/ataxia (3-40%)

Fatigue (3-40%)

Impaired memory (3-40%)

Involuntary movement (3-40%)

Sleep disturbances (3-40%)

Photosensitivity (10-75%)

Hypothyroidism (1-22%)

Constipation (10-33%)

Anorexia (10-33%)

 

1-10%

CHF (3%)

Bradycardia (3-5%)

AV block (5%)

SA node dysfunction (1-3%)

Hyperthyroidism (3-10%)

Hepatitis and cirrhosis (<3%)

Visual disturbances (2-9%)

Optic neuritis (1%)

 

Frequency not defined

Corneal microdeposits

Demyelinating polyneuropathy

 

Postmarketing Reports

Hypersensitivity: Anaphylactic/anaphylactoid reaction (including shock), angioedema, urticaria

Pulmonary: Eosinophilic pneumonia, ARDS (in postoperative setting), 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, pulmonary alveolar hemorrhage, pleural effusion, pleuritis

Gastrointestinal: Hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, dry mouth

Nephrology: Renal impairment, renal insufficiency, acute renal failure

Neurology: Pseudotumor cerebri, parkinsonian symptoms, such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy)

Endocrine: SIADH, thyroid nodules/thyroid cancer

Dermatology: Toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, skin cancer, vasculitis, pruritus, bullous dermatitis

Hematology: Hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma

Musculoskeletal: Myopathy, muscle weakness, rhabdomyolysis, demyelinating polyneuropathy

Psychiatric: Hallucination, confusional state, disorientation, delirium

Genitourinary: Epididymitis, impotence

 

Warnings

Black box warnings

Indicated only for life-threatening arrhythmias

• Indicated only for life-threatening arrhythmias because of risk for substantial toxicity; poses major management problems that could be life-threatening in patients at risk of sudden death; therefore, make every effort to utilize alternative agents first
• Difficulty of using amiodarone effectively and safely poses significant risk to patients
• Patients must be hospitalized while IV loading dose administered; response generally requires at least 1 wk
• Absorption and elimination variable, maintenance dosing difficult, and often requires dosage decrease or temporary discontinuation
• Retrospective survey of 192 patients with ventricular tachyarrhythmias showed 84 patients required dose reduction and 18 required at least temporary discontinuation (because of adverse reactions); several trials have reported 15-20% overall frequencies of discontinuation because of adverse reactions
• Time to recurrence of previously controlled life-threatening arrhythmia after discontinuation or dose adjustment is unpredictable (ranges from weeks to months); patient is at great risk during this transition and may require hospitalization
• Fatal toxicities: Fatal toxicities may be caused by pulmonary toxicity, hepatotoxicity, and proarrhythmic effect

Pulmonary toxicity

• Presents as hypersensitivity pneumonitis or interstitial/alveolar pneumonitis (10-17% incidence with 400 mg/day)
• May present without symptoms as abnormal diffusion capacity in a much higher percentage of patients
• Fatal in ~10% of cases

Liver injury

• Common but usually mild and evidenced only by abnormal liver enzymes
• Overt liver disease can occur and has been fatal in a few cases

Proarrhythmic effect

• Like other antiarrhythmics, can exacerbate the arrhythmia (eg, by making the arrhythmia less well tolerated or more difficult to reverse)
• 2-5% incidence; includes significant heart block or sinus bradycardia
• Manage arrhythmias in proper clinical setting
• Effects are prolonged when they occur because of long drug half-life

 

Contraindications

Hypersensitivity

Severe sinus node dysfunction, 2°/3° AV block or bradycardia causing syncope (except with functioning artificial pacemaker), cardiogenic shock

Avoid during breastfeeding

 

Cautions

To be administered only by physicians experienced in treatment of life-threatening arrhythmias, who are thoroughly familiar with risks and benefits of amiodarone therapy, and have access to facilities adequate for monitoring effectiveness and side effects of treatment; because of long half-life of amiodarone and its metabolite desethylamiodarone, the potential for adverse reactions or interactions, as well as observed adverse effects, can persist following amiodarone withdrawaL

Adjust dosage based on adverse reaction and therapeutic response

Avoid excessive exposure to sunlight; may cause photosensitivity

Attempts to substitute other antiarrhythmic agents when amiodarone must be stopped is difficult due to the complex pharmacokinetics of the drug, including prolonged duration of action and half-life and difficulties predicting them, which in turn increases risk for drug interactions

Hypothyroidism has been reported in 2 to 10% of patients receiving amiodarone and may be primary or subsequent to resolution of preceding amiodarone-induced hyperthyroidism; manage hypothyroidism by reducing the dose of or discontinuing amiodarone and considering the need for thyroid hormone supplement

Risks of acute MI, AV block, cardiomegaly; especially with IV administration

Bradycardia and atrio-ventricular block reported; treat bradycardia by slowing infusion rate or discontinuing therapy; in some patients, inserting a pacemaker is required; treat patients with a known predisposition to bradycardia or AV block in a setting where a temporary pacemaker is available

Hypotension is the most common adverse reaction; in some cases, hypotension may be refractory and result in a fatal outcome; treat hypotension initially by slowing the infusion; additional standard therapy may include vasopressor drugs, positive inotropic agents, and volume expansion; monitor initial rate of infusion closely, not to exceed recommended rate

Chronic administration of antiarrhythmic drugs may affect defibrillation or pacing thresholds in patients with implanted defibrillators, pacemakers; assess when therapy is initiated and throughout

Correct hypokalemia, hypomagnesemia or hypocalcemia before initiating treatment as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP; give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics and laxatives, systemic corticosteroids, amphotericin B (IV) or other drugs affecting electrolyte levels

May increase risks of pulmonary fibrosis; liver disease; hypotension, bradycardia, hyperthyroidism; optic neuropathy; pleural effusion; pneumonitis (including eosinophilic pneumonia)

Acute-onset (days to weeks) pulmonary injury reported in patients treated with IV amiodarone; findings have included pulmonary infiltrates and masses on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia; some cases have progressed to respiratory failure or death

Postoperatively, occurrences of adult respiratory distress syndrome reported in patients receiving amiodarone therapy who have undergone either cardiac or noncardiac surgery; although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal; until further studies performed, monitor FiO2 and determinants of oxygen delivery to tissues (e.g., SaO2, PaO2) while taking amiodarone

Use caution when administering concomitantly with drugs that prolong QTc intervaL

Corneal microdeposits appear in majority of adults treated; usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision up to 10% of patients; corneal microdeposits are reversible upon reduction of dose or termination of treatment; asymptomatic microdeposits alone are not reason to reduce dose or discontinue treatment

Causes increased INR; use caution when initiating therapy in patients treated with warfarin

Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to myocardial depressant and conduction effects of halogenated inhalational anesthetics

Fatal cutaneous reactions reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis; discontinue therapy if symptoms of progressive skin rash occur

Monitor hepatic enzymes regularly in patients receiving relatively high maintenance doses

Peripheral neuropathy reported rarely with chronic administration; may resolve upon discontinuation of therapy

Bradycardia, some requiring pacemaker insertion reported when ledipasvir/sofosbuvir or sofosbuvir with simeprevir initiated in patients on amiodarone; bradycardia generally occurred within hours to days, but in some cases up to 2 weeks after initiating antiviral treatment; monitor heart rate in patients taking or recently discontinuing amiodarone when starting antiviral treatment

Amiodarone can cause fetal harm when administered to a pregnant woman; fetal exposure may increase potential for adverse experiences including cardiac, thyroid, neurodevelopmental, neurological and growth effects in neonate; inform patient of potential hazard to fetus if amiodarone administered during pregnancy or if patient becomes pregnant while taking amiodarone

 

Pregnancy and lactation

Pregnancy category: d

Lactation: Excreted into breast milk; not recommended

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Pacerone, Cordarone (amiodarone)

Mechanism of action

Class III antiarrhythmic agent, which inhibits adrenergic stimulation; affects sodium, potassium, and calcium channels; markedly prolongs action potential and repolarization; decreases AV conduction and sinus node function

 

Absorption

Bioavailability: 35-65%

Onset (PO): Initial response 2 days to 3 wk; peak response takes 1 week to 5 months

Duration (PO): Up to 50 days after discontinuation of therapy

Peak serum time: 3-7 hr (PO)

Therapeutic range: 0.8-2.8 mcg/mL

Toxicity range: >2-2.5 mcg/mL

 

Distribution

Protein bound: 96%

Vd: 66 L/kg

 

Metabolism

Liver with enterohepatic recirculation; hepatic CYP2C8 and CYP3A3/4 isozymes

Metabolites: N-desethylamiodarone (DEA) (active)

Enzymes inhibited: CYP2C9, CYP2D6, CYP3A3/4

 

Elimination

Half-life: 26-107 days (parent drug); 61 days (DEA metabolite)

Dialyzable: Not dialyzable by hemodialysis or peritoneal dialysis

Excretion: Feces; urine

 

Administration

IV Incompatibilities

Additive: Floxacillin, quinidine

Syringe: Heparin

Y-site: Aminophylline, ampicillin/sulbactam, bivalirudin, cefamandole, cefazolin, ceftazidime, digoxin, furosemide(?), heparin, imipenem/cilastatin, mezlocillin, piperacillin, piperacillin/tazobactam, K phosphates, Na bicarb, Na nitroprusside(?), Na phosphates

 

IV Compatibilities

Solution: D5W (incomp in 24 hr), NS (incomp in 24 hr)

Additive: dobutamine, furosemide (incomp at high conc), lidocaine, KCl, procainamide, propafenone, verapamiL

Y-site (partial list): amphotericin B, atracurium, atropine, CaCl2, ciprofloxacin, clarithromycin, dobutamine, dopamine, epinephrine, eptifibatide, erythromycin, esmolol, fentanyl, fluconazole, gentamicin, labetalol, lorazepam, lidocaine, Mg sulfate (incomp at high conc), milrinone, morphine sulfate, nitroglycerin, norepinephrine, KCl, vancomycin

 

IV Preparation

Loading IV infusion: Dilute 150 mg (3 mL) in 100 mL to form 1.5 mg/mL concentration

Slow/maintenance infusion: Dilute 900 mg (18 mL) of amiodarone with 500 mL to form 1.8 mg/mL concentration

Conventional amiodarone: Dilute only with D5W

Nexterone: May dilute with either D5W or 0.9% NaCL

For subsequent maintenance infusion, may use 1-6 mg/mL concentrations

 

IV Administration

Concentrations >2 mg mL associated with venous irritation

If concentration >2 mg/mL, administer via central venous catheter; in-line filter should be used during administration

Administer IV via volumetric infusion pump

Do not use evacuated glass containers for admixing, as incompatibility with a buffer in the container may cause precipitation

Does not need to be protected from light during administration

See dosing for bolus/infusion times

Conventional amiodarone

• Administer in glass/polyolefin bottles for infusions >2 hr

Nexterone

• First product to successfully overcome solubility issues of amiodarone by removing the original cosolvents polysorbate 80 and benzyl alcohol
• As a result, Nexterone does not have many of the product administration limitations regarding compatibility and stability with plastics and ionic infusion fluids, which are included in the labeling of conventional IV amiodarone
• May be diluted in D5W or 0.9% NaCl and administered in polyvinyl chloride (PVC), polyolefin, or glass containers

 

Storage

Store at room temp; protect from light and excessive heat