NEXTERONE (amiodarone HCl) Premixed Injection

NEXTERONE (amiodarone HCl) Premixed Injection

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NEXTERONE (amiodarone HCl) Premixed Injection

NEXTERONE contains amiodarone HCl (C25H29I2NO3•HCl), a class III antiarrhythmic drug. Amiodarone HCl is (2-butyl-3-benzo-furanyl)[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]methanone hydrochloride.

Amiodarone HCl is a white to slightly yellow crystalline powder and is very slightly soluble in water. It has a molecular weight of 681.78 and contains 37.3% iodine by weight. NEXTERONE Premixed Injection is a sterile clear, colorless to slightly yellow solution visually free from particulates. NEXTERONE Premixed Injection is available as a ready-to-use, nonpyrogenic, isoosmotic solution for intravenous administration in 100-mL GALAXY containers with 150 mg of amiodarone HCl, USP (1.5mg/mL) in dextrose, and 200-mL GALAXY containers with 360 mg of amiodarone HCl, USP (1.8 mg/mL) in dextrose.

Indications and usage

NEXTERONE 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.

Mechanism of Action

Amiodarone is considered a class III antiarrhythmic drug, but it possesses electrophysiologic characteristics of all four Vaughan Williams classes. Like class I drugs, amiodarone blocks sodium channels at rapid pacing frequencies, and like class II drugs, amiodarone exerts a noncompetitive antisympathetic action. One of its main effects, with prolonged administration, is to lengthen the cardiac action potential, a class III effect. The negative chronotropic effect of amiodarone in nodal tissues is similar to the effect of class IV drugs.

In addition to blocking sodium channels, amiodarone blocks myocardial potassium channels, which contributes to slowing of conduction and prolongation of refractoriness. The antisympathetic action and the block of calcium and potassium channels are responsible for the negative dromotropic effects on the sinus node and for the slowing of conduction and prolongation of refractoriness in the atrioventricular (AV) node. Its vasodilatory action can decrease cardiac workload and consequently myocardial oxygen consumption.

Intravenous amiodarone administration prolongs intranodal conduction (Atrial-His, AH) and refractoriness of the atrioventricular node (ERP AVN) but has little or no effect on sinus cycle length (SCL), refractoriness of the right atrium and right ventricle (ERP RA and ERP RV), repolarization (QTc), intraventricular conduction (QRS), and infra-nodal conduction (Hisventricular, HV).

At higher doses (>10 mg/kg) of intravenous amiodarone, prolongation of the ERP RV and modest prolongation of the QRS have been seen. These differences between oral and IV administration suggest that the initial acute effects of intravenous amiodarone may be predominately focused on the AV node, causing an intranodal conduction delay and increased nodal refractoriness due to slow channel blockade (class IV activity) and noncompetitive adrenergic antagonism (class II activity).

Dosage and administration

Inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit, solution should be clear. Visually inspect the container. If the administration port protector is damaged, detached or not present, discard the container as the solution path sterility may be compromised. Check for minute leaks prior to use by squeezing the bag firmly. If leaks are detected, discard solution as sterility may be impaired. Protect from light until ready to use.

NEXTERONE Premixed Injection is available in GALAXY containers as a single-use, ready-touse, iso-osmotic solution in dextrose for intravenous administration. No further dilution is required. Discard any unused portion after use.

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

Recommended dosage

Loading Infusion

First Rapid: 150 mg over the FIRST 10 minutes (15 mg/min). Directly infuse NEXTERONE Premixed Injection (150 mg/100mL; 1.5 mg/mL) at a rate of 10 mL/min.

Followed by Slow: 360mg over the NEXT 6 hours (1 mg/min). Directly infuse NEXTERONE Premixed Injection (360 mg/ 200 mL; 1.8 mg/mL) at a rate of 0.556 mL/min.

540 mg over the REMAINING 18 hours (0.5mg/min).

Decrease the rate to 0.278 mL/min.

Maintenance Infusion

After the first 24 hours, continue the maintenance infusion 720 mg per 24 hour period (0.5 mg/min)

Directly infuse NEXTERONE Premixed Injection (360 mg/200 mL; 1.8 mg/mL) at a rate of 0.278 mL/min).

Breakthrough VF or Hemodynamically Unstable VT

150 mg supplemental infusion over 10 minutes (15 mg/min). Directly infuse NEXTERONE Premixed Injection (150 mg/100mL; 1.5 mg/mL) at a rate of 10 mL/min.

Contraindications

NEXTERONE is contraindicated in patients with:

  • Known hypersensitivity to any of the components of NEXTERONE Premixed Injection, including iodine.
  • Cardiogenic shock.
  • Marked sinus bradycardia.
  • Second- or third-degree atrioventricular (AV) block unless a functioning pacemaker is available.

Warnings and precautions

Persistence of Adverse Effects: Because of the long half-life of amiodarone (9 to 36 days) and its metabolite desethylamiodarone (9 to 30 days), adverse reactions or interactions, as well as observed adverse effects, can persist following amiodarone withdrawal.

Hypotension: Hypotension, the most common adverse reaction seen with intravenous amiodarone seen most often in the first several hours of treatment and is likely related to the rate of infusion. In some cases, hypotension may be refractory and result in a fatal outcome. Hypotension necessitating alterations in intravenous amiodarone therapy was reported in 3% of patients, with permanent discontinuation required in less than 2% of patients.

Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion. Monitor the initial rate of infusion closely and do not exceed the recommended rate

Bradycardia and Atrioventricular Block: NEXTERONE causes bradycardia and AV block which may require slowing the infusion rate or discontinuing NEXTERONE. In some patients, inserting a pacemaker is required. Have a temporary pacemaker available when treating a patient predisposed to bradycardia or AV block.

Hepatic Injury: Acute hepatocellular necrosis leading to hepatic coma, acute renal failure, and death has been associated with the administration of intravenous amiodarone. Intravenous infusions at much higher concentrations and rates of infusion than those recommended appear to increase this risk

Carefully monitor patients receiving NEXTERONE for evidence of progressive hepatic injury. Consider reducing the rate of administration or withdrawing NEXTERONE if hepatic injury occurs.

Proarrhythmia: NEXTERONE may cause a worsening of existing arrhythmias or precipitate a new arrhythmia, sometimes leading to fatal outcomes. Proarrhythmia, primarily torsade de pointes (TdP), has been associated with prolongation, by intravenous amiodarone. Monitor patients for QTc prolongation during infusion with NEXTERONE. Reserve the combination of amiodarone with other antiarrhythmic therapies that prolong the QTc to patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent.

Correct hypokalemia, hypomagnesemia or hypocalcemia whenever possible before initiating treatment with NEXTERONE, 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

Pulmonary Injury: There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with intravenous amiodarone. Findings have included pulmonary infiltrates and masses on X-ray, pulmonary fibrosis, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Two percent (2%) of patients were reported to have adult respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy.

Some cases have progressed to respiratory failure or death. Monitor for new respiratory symptoms and evaluate appropriately. Obtain a baseline chest X-ray and pulmonary function tests in patients who are expected to be receiving amiodarone chronically

Loss of Vision: Cases of optic neuropathy and optic neuritis, usually resulting in visual impairment, have been reported in patients treated with oral amiodarone or intravenous amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and neuritis may occur at any time following initiation of therapy. Perform an ophthalmic examination if symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision. Reevaluate the necessity of amiodarone therapy if optic neuropathy or neuritis is suspected.

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Thyroid Abnormalities: Nexterone inhibits peripheral conversion of throxine (T4) to triiodothyronine (T3) and may cause increased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. Monitor thyroid function prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction.

Hyperthyroidism may induce arrhythmia breakthrough. If any new signs of arrhythmia appear, the possibility of hyperthyroidism should be considered.

Antithyroid drugs, β-adrenergic blockers, temporary corticosteroid therapy may be necessary to treat the symptoms of hyperthyroidism. The action of antithyroid drugs may be delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism.

Neonatal Injury: Amiodarone can cause fetal harm when administered to a pregnant woman. Fetal exposure may increase the potential for adverse experiences including cardiac, thyroid, neurodevelopmental, neurological and growth effects in neonate. Inform the patient of the potential hazard to the fetus if NEXTERONE is administered during pregnancy or if the patient becomes pregnant while taking NEXTERONE.

Hypersensitivity Reactions: Anaphylactic/anaphylactoid reactions have been reported with intravenous amiodarone including shock (sometimes fatal), cardiac arrest, and the following manifestations: hypotension, tachycardia, hypoxia, cyanosis, rash, Stevens-Johnson syndrome, flushing, hyperhidrosis and cold sweat

Phlebitis: Infusion site phlebitis has occurred in patients receiving intravenous amiodarone. Intravenous amiodarone concentrations greater than 3 mg/mL have been associated with a high incidence of peripheral vein phlebitis.

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.

Other important adverse reactions are torsade de pointes, congestive heart failure, and liver function test abnormalities.

Drug interactions

QT Prolonging Drugs: class I and III antiarrhythmics, lithium, certain phenothiazines, tricyclic antidepressants, certain fluoroquinolone and macrolide antibiotics, azole antifungals, halogenated inhalation anesthetic agents.

Increased risk of Torsade de Pointes. Avoid concomitant use.

Negative Chronotropes: digoxin, beta blockers, verapamil, diltiazem, clonidine, ivabradine

Potentiates the electrophysiologic and hemodynamic effects of amiodarone, resulting in bradycardia, sinus arrest and AV block. Monitor heart rate.

CYP450 Inhibitors: Grapefruit juice, certain fluoroquinolone and macrolide antibiotics, azole antifungals, cimetidine.

Increased exposure of amiodarone. Avoid concomitant use.

CYP450 Inducers: St. John’s Wort.

Reduced amiodarone serum levels

Cyclosporine: Increased plasma levels of cyclosporine have been reported resulting in elevated creatinine, despite reduction of cyclosporine dose. Monitor cyclosporine drug levels and renal function with concomitant use.

Cholestyramine: Reduced amiodarone serum levels

Antiarrhythmics: quinidine, procainamide, flecainide.

Reserve concomitant use for patients who are unresponsive to a single agent. Antiarrhythmic metabolism inhibited by amiodarone. Initiate antiarrhythmic at a lower than usual dose and monitor patient carefully. Reduce dose levels of previously administered antiarrhythmic by 30 to 50% for several days after transitioning to oral amiodarone. Evaluate continued need for antiarrhythmic

Digoxin: Increased digoxin concentration. Reduce digoxin by half or discontinue. If continued, monitor for evidence of toxicity.

HMG-CoA Reductase Inhibitors: simvastatin, lovastatin, atorvastatin.

Increased plasma concentration of HMG-CoA reductase inhibitor.

Limit the dose of lovastatin to 40 mg.

Limit the coadministered dose of simvastatin to 20 mg.

Lower starting dose of other CYP3A4 substrates may be required.

Warfarin: Potentiates anticoagulant response and can result in serious or fatal bleeding. Coadministration increases INR by 100% after 3 to 4 days. Reduce warfarin dose by one-third to one-half and monitor INR.

Phenytoin: Increased steady state levels of phenytoin. Monitor phenytoin levels.

Hepatitis C direct acting antiviral: Sofosbuvir.

Cases of symptomatic bradyarrhythmia requiring pacemaker insertion have been reported in patients on oral maintenance amiodarone who initiated therapy with Sofosbuvir.

Use in specific populations

Pregnancy: Available data from postmarketing reports and published case series indicate that amiodarone use in pregnant women may increase the risk for fetal adverse effects including neonatal hypo- and hyperthyroidism, neonatal bradycardia, neurodevelopmental abnormalities, preterm birth and fetal growth restriction. Amiodarone and its metabolite, desethylamiodarone (DEA), cross the placenta. Untreated underlying arrhythmias, including ventricular arrhythmias, during pregnancy pose a risk to the mother and fetus.

The incidence of ventricular tachycardia is increased and may be more symptomatic during pregnancy. Ventricular arrhythmias most often occur in pregnant women with underlying cardiomyopathy, congenital heart disease, valvular heart disease, or mitral valve prolapse. Most tachycardia episodes are initiated by ectopic beats and the occurrence of arrhythmia episodes may therefore, increase during pregnancy due to the increased propensity to ectopic activity. Breakthrough arrhythmias may also occur during pregnancy, as therapeutic treatment levels may be difficult to maintain due to the increased volume of distribution and increased drug metabolism inherent in the pregnant state.

Amiodarone and its metabolite have been shown to cross the placenta. Adverse fetal effects associated with maternal amiodarone use during pregnancy may include neonatal bradycardia, QT prolongation, and periodic ventricular extrasystoles, neonatal hypothyroidism (with or without goiter) detected antenatally or in the newborn and reported even after a few days of exposure, neonatal hyperthyroxinemia, neurodevelopmental abnormalities independent of thyroid function, including speech delay and difficulties with written language and arithmetic, delayed motor development, and ataxia, jerk nystagmus with synchronous head titubation, fetal growth restriction, and premature birth. Monitor the newborn for signs and symptoms of thyroid disorder and cardiac arrhythmias.

Risk of arrhythmias may increase during labor and delivery.

Lactation: Amiodarone and one of its major metabolites, DEA, are present in breastmilk at between 3.5% and 45% of the maternal weight-adjusted dosage of amiodarone. There are cases of hypothyroidism and bradycardia in breastfed infants, although it is unclear if these effects are due to amiodarone exposure in breastmilk. Breastfeeding is not recommended during treatment with NEXTERONE.

Pediatric Use: The safety and effectiveness of amiodarone in pediatric patients have not been established. In a pediatric trial of 61 patients, aged 30 days to 15 years, hypotension (36%), bradycardia (20%), and AV block (15%) were common dose-related adverse reactions and were severe or life-threatening in some cases. Injection site reactions were seen in 5 (25%) of the 20 patients receiving intravenous amiodarone through a peripheral vein irrespective of dose regimen.

Geriatric Use: Clinical studies of amiodarone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Carefully consider dose selection in an elderly patient. In general, start at the low end of the dosing range in the elderly to reflect the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy.

Overdosage

There have been cases, some fatal, of amiodarone overdose. Effects of an inadvertent overdose of intravenous amiodarone include hypotension, cardiogenic shock, bradycardia, AV block, and hepatotoxicity. Treat hypotension and cardiogenic shock by slowing the infusion rate or with standard therapy: vasopressor drugs, positive inotropic agents, and volume expansion. Bradycardia and AV block may require temporary pacing. Monitor hepatic enzyme concentrations closely. Neither amiodarone nor DEA is dialyzable.

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