NEODOSE

INDICATIONS

Arrhythmias: Treatment of life-threatening or drug-resistant refractory supraventricular(SVT) , ventricular tachyarrhythmias (VT) , and postoperative junctional ectopic tachycardia(JET) (see Adverse Effects).

CONTRAINDICATIONS

Hypersensitivity to amiodarone including iodine, cardiogenic shock, bradycardia leading to syncope without a functioning pacemaker, sick sinus syndrome or marked sinus bradycardia, second- or third-degree atrioventricular block unless a functioning pacemaker is available .

PRECAUTIONS

• Administration:
  • The IV formulation should only be administered when access to facilities equipped to monitor for effectiveness and side effects are available, and by physicians experienced in the treatment of life-threatening arrhythmias
• Due to the long half-life, adverse events can persist for several weeks following discontinuation:
  • Due to the long half-life, adverse events can persist for several weeks following discontinuation.
• Cardiovascular:
  • Hypotension, including some refractory and fatal cases, has been reported, particularly with IV administration; monitoring recommended.
  • Exacerbation of presenting arrhythmia, new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia with QTc prolongation (Torsade de Pointes) may occur.
  • Bradycardia or sinus arrest has been reported, especially with concomitant use of drugs that slow heart rate (eg, digoxin, beta blockers, verapamil, diltiazem, ivabradine, clonidine) or by presence of electrolyte disorders) and with concomitant use of ledipasvir/sofosbuvir or sofosbuvir with simeprevir . Monitoring recommended with concomitant use or recent discontinuation of amiodarone when starting antiviral treatment.
  • Preexisting implanted defibrillator or pacemaker may result in changes to electrical conduction properties (pacing or defibrillating thresholds) of heart; monitoring recommended with oral administration.
• Concomitant Use:
  • Avoid drugs that prolong the QT interval.
  • Avoid grapefruit juice.
• dermatologic:
  • Photosensitivity has been reported and may be reduced with sun-barrier creams or protective clothing. Blue-gray skin discoloration may occur with prolonged use; ome reversal of discoloration may occur upon discontinuation.
• Endocrine & Metabolic:
  • Thyroid abnormalities, including hypothyroidism, hyperthyroidism and myxedema coma (sometimes fatal), thyroid nodules, and thyroid cancer, have been reported; increased risk for potentially fatal thyrotoxicosis and arrhythmia breakthrough or exacerbation; monitoring recommended and dosage adjustment or discontinuation may be necessary.
  • Preexisting hypokalemia or hypomagnesemia may exaggerate degree of QT prolongation and increase potential for torsade de pointes; increased risk in patients with severe or prolonged diarrhea or those receiving diuretics, laxatives, systemic corticosteroids, or amphotericin B. Correct prior to treatment when possible.
  • Prior inadequate dietary iodine intake may increase incidence of amiodarone-induced hyperthyroidism.
• Hepatic:
  • Elevation of liver enzymes has been reported; life-threatening hepatic injury may occur with histology similar to alcoholic hepatitis or cirrhosis. Monitoring recommended and discontinuation or dose reduction may be necessary.
  • Hepatocellular necrosis leading to hepatic coma, acute renal failure, and death have occurred with IV administration at higher than recommended loading dose concentration and rate of infusion.
• Immunologic:
  • Potentially fatal anaphylactic or anaphylactoid reactions have been reported with IV administration, including shock (sometimes fatal), cardiac arrest, and the following manifestations: hypotension, tachycardia, hypoxia, cyanosis, rash, flushing, hyperhidrosis, and cold sweat.
• Neurologic:
  • Chronic administration may lead to peripheral neuropathy, which may not resolve when therapy is discontinued.
• Ophthalmic:
  • Optic neuritis and optic neuropathy, in some cases resulting in visual impairment that led to blindness, have been reported and may occur at any time during therapy. Discontinuation may be required; monitoring recommended.
  • Corneal microdeposits have been reported and may result in visual halos or blurred vision; usually resolve upon dose reduction or discontinuation but asymptomatic microdeposits do not require dose change or discontinuation.
  • Corneal refractive laser surgery is contraindicated by most manufacturers of corneal refractive laser surgery devices.
• Respiratory:
  • Pulmonary toxicity, sometimes fatal, may occur presenting with cough and progressive dyspnea and resulting from either indirect (hypersensitivity pneumonitis, including eosinophilic pneumonia) or direct toxicity (interstitial/alveolar pneumonitis). Monitoring recommended. Consider alternative antiarrhythmic therapy if the patient experiences signs or symptoms of pulmonary toxicity.
• Surgery:
  • Increases sensitivity to myocardial depressant and conduction effects of halogenated inhalational anesthetics; perioperative monitoring recommended.

ADVERSE EFFECTS

• Common: In adult clinical trials: hypo- or hyperthyroidism, congestive heart failure, cardiac arrhythmias, SA node dysfunction, nausea, vomiting, constipation, anorexia, abdominal pain, solar dermatitis/photosensitivity, malaise/fatigue, tremor/abnormal involuntary movements and other neurologic adverse events, visual disturbances, abnormal liver function tests, pulmonary infiltration or fibrosis, flushing, coagulation abnormalities. Blue skin discoloration, rash, hypotension, and cardiac conduction abnormalities were reported less commonly.
• short-term Toxicity: Bradycardia and hypotension (possibly associated with rapid rates of infusion) may occur. Hypotension may be due, in part, to the co-solvents, polysorbate 80 and benzyl alcohol, which are components of the original amiodarone product. In a study of pediatric patients (n=61), ages 30 days to 15 years, hypotension and bradycardia were reported in 36% and 20% of patients, respectively. AV block was reported in 15% of patients. Polymorphic ventricular tachycardia may occur. Irritating to the peripheral vessels (concentrations greater than 2 mg/mL). Administration through central vein preferred.
• Long-term Toxicity: Hyperthyroidism (due to inhibition of T4 to T3) and hypothyroidism (due to high concentration of inorganic iodine). Generic formulation contains 2% benzyl alcohol (20 mg/mL). Hepatitis and cholestatic hepatitis (rare). Photosensitivity (10%), nausea and vomiting (10%), optic neuritis (4% to 9%), and pulmonary fibrosis (4% to 9%) have been reported with prolonged oral use in adults.

BLACK BOX WARNING

Warning: Warning: Pulmonary, Hepatic and Cardiac Toxicity.

Amiodarone oral tablet is intended for use only in patients with the indicate life-threatening arrhythmias because its use is accompanied by substantial toxicity. Amiodarone can cause pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 17% in some series of patients. Pulmonary toxicity has been fatal about 10% of the time. Obtain a baseline chest X-ray and pulmonary-function tests, including diffusion capacity, when therapy is initiated. Repeat history, physical exam, and chest X-ray every 3 to 6 months. Amiodarone can cause hepatoxicity, which can be fatal. Obtain baseline and periodic liver transaminases and discontinue or reduce dose if the increase exceeds three times normal, or doubles in a patient with an elevated baseline. Discontinue if the patient experiences signs or symptoms of clinical liver injury. Amiodarone can exacerbate arrhythmias. Initiate in a clinical setting where continuous electrocardiograms and cardiac resuscitation are available.

ADMINISTRATION

Dilute the IV loading dose to 1.5 mg/mL and infusing over 20 to 60 minutes . For IV infusion, dilute to a concentration of 1 to 6 mg/mL in compatible diluent. For infusions lasting longer than 1 hour (eg, continuous infusion), amiodarone IV concentrations should not exceed 2 mg/mL unless using a central line. When infusing the original amiodarone product, infusions lasting longer than 2 hours should be administered in glass or polyolefin bottles containing D5W; use of evacuated glass containers is not recommended as precipitation may occur from the buffer. An in-line filter should be used during administration. Administration central catheter is preferred. Extravasation Management: Neonatal data are limited to pooled data from 10 case reports/case series (n=237) and are not specific to amiodarone extravasation; subcutaneous saline irrigation with or without hyaluronidase infiltration was commonly used. No standardized management was established. An option for more severe injuries (stages 3 and 4) is subcutaneous irrigation with saline, but this is not advocated as standard treatment. Conservative management is appropriate for mild extravasation (stages 1 and 2). Although not neonatal-specific, the following are recommendations for extravasation of acidic or alkaline agents (amiodarone is acidic with a pH ranging from 3.5 to 4.5):

General

• Stop and disconnect infusion; do not remove the cannula or needle
• Attempt to gently aspirate as much extravasated agent as possible; avoid manual pressure
• Remove cannula or needle
• Dry heat and elevation
• Closely monitor for signs of coagulation and ischemia
• Avoid attempt at pH neutralization (amiodarone – pH 3.5 to 4.5)
• Monitor and consider the need for surgical management such as surgical flushing with normal saline or debridement and excision of necrotic tissue (especially if pain persists for 1 to 2 weeks). In cases of compartment syndrome, surgical decompression may be required

Refractory Events:

• Hyaluronidase 15 units intradermally along injection site and edematous area. Give as five, 0.2-mL intradermal injections along extravasation site and edematous tissue.

Inadvertent Intraarterial Administration:

• Leave inadvertent intraarterial line in place for diagnostics
• Systemic heparin titrated to therapeutic anticoagulant effect
• Stellate ganglion block

MONITORING

• Obtain baseline chest x-ray, pulmonary function tests, thyroid function tests, and liver aminotransferases.
• Continuous EKG and blood pressure (for IV). Follow AST and ALT. Monitor T3, T4, and TSH. Observe IV site for extravasation.