Amiodarone Drug Information

Amiodarone 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 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, patients may be transferred to oral amiodarone therapy.

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

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 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 D 5 W 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. Intravenous amiodarone concentrations greater than 3 mg/mL in D 5 W 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. Amiodarone infusions exceeding 2 hours must be administered in glass or polyolefin bottles containing D 5 W. 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 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 hydrochloride injection, is also known to leach DEHP from PVC. 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 – solution should be clear.

CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before the administration of the fluid from the secondary container is complete. Discard unused portion.

Table 2: Amiodarone HCl SOLUTION STABILITY Admixture Incompatibility Amiodarone in D 5 W Injection forms precipitates with the drugs shown in Table 3. If coadministration of the following drugs is necessary, use separate intravenous administration lines. Table 3: Y-SITE INJECTION INCOMPATIBILITY Intravenous to Oral Transition Patients whose arrhythmias have been suppressed by amiodarone may be switched to oral amiodarone.

The optimal dose for changing from intravenous to oral administration of amiodarone will depend on the dose of intravenous amiodarone already administered, as well as the bioavailability of 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. 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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The mean duration of therapy in these studies was 5.6 days; median exposure was 3.7 days. The most important adverse reactions were hypotension, asystole/cardiac arrest/pulseless electrical activity (PEA), cardiogenic shock, congestive heart failure, bradycardia, liver function test abnormalities, VT, and AV block.

Overall, treatment was discontinued for about 9% of the patients because of adverse reactions. Table 5 lists the most common (incidence ≥ 2%) adverse reactions during intravenous amiodarone therapy considered at least possibly drug-related. These data were collected in clinical trials involving 1836 patients with life-threatening VT/VF.

Data from all assigned treatment groups are pooled because none of the adverse reactions appeared to be dose-related. Other adverse reactions reported in less than 2% of patients receiving intravenous amiodarone in controlled and uncontrolled studies included the following: abnormal kidney function, atrial fibrillation, diarrhea, increased ALT, increased AST, lung edema, nodal arrhythmia, prolonged QT interval, respiratory disorder, shock, sinus bradycardia, Stevens-Johnson syndrome, thrombocytopenia, VF, and vomiting.

Post-Marketing Experience

The following adverse reactions have been reported in the post-marketing experience during or in close temporal relationship to intravenous amiodarone administration. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: pancytopenia, neutropenia, hemolytic anemia, aplastic anemia, thrombocytopenia, and agranulocytosis.

Cardiac Disorders: sinus node dysfunction (sinus arrest, sinoatrial block), intraventricular conduction disorders including bundle branch block and infra-HIS block, bradycardia (sometimes fatal), ventricular extrasystoles, and antegrade conduction via an accessory pathway. Endocrine Disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH). Eye Disorders: visual field defect and blurred vision.

Gastrointestinal Disorders: pancreatitis. General Disorders and Administration Site Conditions: infusion site reactions, including thrombosis, phlebitis, thrombophlebitis, cellulitis, pain, induration, edema, inflammation, urticaria, pruritus, erythema, pigment changes, hypoesthesia, skin sloughing, extravasation possibly leading to venous/infusion site necrosis, intravascular amiodarone deposition/mass (developed in the superior vena cava around a central venous catheter after long-term amiodarone therapy administered through a central line), and granuloma. Hepatobiliary Disorders: cholestasis, cirrhosis, jaundice, alkaline phosphatase and blood lactate dehydrogenase increase.

Musculoskeletal and Connective Tissue Disorders: myopathy, muscle weakness, rhabdomyolysis, muscle spasms, and back pain. Neoplasms Benign, Malignant and Unspecified (incl Cysts and Polyps) Disorders: thyroid nodules/thyroid cancer. Nervous System Disorders: intracranial pressure increased, pseudotumor cerebri, tremor, dizziness and hypoesthesia.

Psychiatric Disorders: confusional state, hallucination, disorientation, and delirium. Renal and Urinary Disorders: acute renal failure (sometimes fatal), renal impairment, renal insufficiency, and blood creatinine increased. Reproductive Disorders and Breast Disorders: Epididymitis Respiratory, Thoracic and Mediastinal Disorders: interstitial pneumonitis, bronchiolitis obliterans organizing pneumonia (possibly fatal), pulmonary alveolar hemorrhage, pulmonary phospholipidoisis, pleural effusion, bronchospasm, dyspnea, cough, hemoptysis, wheezing, and hypoxia.

Skin and Subcutaneous Tissue Disorders: toxic epidermal necrolysis (sometimes fatal), Stevens-Johnson syndrome, exfoliative dermatitis, erythema multiforme, skin cancer, pruritus, angioedema, and urticaria. Vascular Disorders: vasculitis and flushing.

Pharmacodynamic Interactions Drugs Prolonging the QT Interval Co-administration of drugs prolonging the QT interval (such as class I and III antiarrhythmics, lithium, certain phenothiazines, tricyclic antidepressants, certain fluoroquinolone and macrolide antibiotics, azole antifungals, halogenated inhalation anesthetic agents) increases the risk of Torsade de Pointes. In general, avoid concomitant use of drugs that prolong the QT interval. Drugs That Slow Heart Rate Concomitant use of drugs with depressant effects on the sinus and AV nodes (e.g., digoxin, beta blockers, verapamil, diltiazem, ivabradine, clonidine) can potentiate the electrophysiologic and hemodynamic effects of amiodarone, resulting in bradycardia, sinus arrest, and AV block.

Monitor heart rate in patients on amiodarone and concomitant drugs that slow heart rate.

Pharmacokinetic Interactions Effect of Other Drugs on Amiodarone Amiodarone is metabolized to the active metabolite desethylamiodarone (DEA) by the cytochrome P450 (CYP450) enzyme group, specifically CYP3A and CYP2C8. Amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP450 enzymes (e.g., inhibitors such as protease inhibitors, grapefruit juice, certain fluoroquinolone and macrolide antibiotics, azole antifungals and inducers such as St. John’s Wort ) or P-glycoprotein.

In view of the long and variable half- life of amiodarone, potential for drug interactions exists not only with concomitant medications but also with drugs administered after discontinuation of amiodarone. Patients should avoid grapefruit juice beverages while taking amiodarone because exposure to amiodarone is significantly increased. Effect of amiodarone on other drugs Amiodarone and DEA are inhibitors of P-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A.

Antiarrhythmics The metabolism of quinidine, procainamide, and flecainide can be inhibited by amiodarone. In general, initiate any added antiarrhythmic drug at a lower than usual dose and monitor the patient carefully. During transfer to oral amiodarone, reduce the dose levels of previously administered antiarrhythmic agents by 30% to 50% several days after the addition of oral amiodarone.

Review the continued need for the other antiarrhythmic agent after the effects of amiodarone have been established, and attempt discontinuation. Digoxin In patients receiving digoxin therapy, administration of oral amiodarone results in an increase in serum digoxin concentration. Reduce dose of digoxin by half or discontinue digoxin.

If digitalis treatment is continued, monitor serum levels closely and observe patients for clinical evidence of toxicity. HMG-CoA Reductase Inhibitors Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg.

Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as amiodarone may increase the plasma concentration of these drugs. Anticoagulants Potentiation of warfarin -type (CYP2C9 and CYP3A substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases INR by 100% after 3 to 4 days, reduce the dose of the anticoagulant by one-third to one-half, and monitor INR closely.

Cyclosporine (CYP3A Substrate) Administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine. Monitor cyclosporine drug levels and renal function in patients taking both drugs. Increased steady-state levels of phenytoin during concomitant therapy with amiodarone have been reported.

Monitor phenytoin levels in patients taking both drugs.

Serious Symptomatic Bradycardia When Co-administered with Ledipasvir/Sofosbuvir or with Sofosbuvir with Simeprevir Postmarketing cases of symptomatic bradycardia, some requiring pacemaker insertion and at least one fatal, have been reported when ledipasvir/sofosbuvir or sofosbuvir with simeprevir were initiated in patients on amiodarone. Bradycardia generally occurred within hours to days, but in some cases up to 2 weeks after initiating antiviral treatment. Bradycardia generally resolved after discontinuation of antiviral treatment.

The mechanism for this effect is unknown. Monitor heart rate in patients taking or recently discontinuing amiodarone when starting antiviral treatment.

• Pregnancy Teratogenic Effects Amiodarone and desethylamiodarone cross the placenta. Reported risks 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 retardation
• Premature birth Amiodarone has caused a variety of adverse effects in animals. The incidence of maternal deaths increased with increasing dose and occurred in all treated groups, and controls. Mean fetal weights were significantly decreased in the low and middle dose groups and embryotoxicity (as manifested by fewer full- term fetuses and increased resorptions) occurred at dosages of 10 mg/kg and above. There were no significant differences in the number of minor fetal abnormalities and no major fetal abnormalities were observed. Maternal toxicity (manifest as reduced weight gain and food consumption) and embryotoxicity (manifest as increased resorptions, decreased live litter size and fetal body weights, and delayed sternal and metacarpal ossification) were observed in the 100 mg/kg group. The delayed ossification was reversible and related to decreased fetal weight. Fetal thyroid tissues appeared normal in all groups. Nonteratogenic Effects Very high concentrations of amiodarone and desethylamiodarone may be found in testes. Elevated follicle-stimulating hormone and luteinizing hormone levels, suggestive of testicular dysfunction, have been reported in men on long-term amiodarone treatment. While planning pregnancy after discontinuation of amiodarone treatment, consider the long half-life of amiodarone and its metabolite DEA.

Pediatric Use The safety and effectiveness of amiodarone in pediatric patients have not been established; therefore, the use of amiodarone in pediatric patients is not recommended. Injection site reactions were seen in 5 (25%) of the 20 patients receiving intravenous amiodarone through a peripheral vein irrespective of dose regimen. Amiodarone hydrochloride injection contains the preservative benzyl alcohol.

There have been reports of fatal "gasping syndrome" in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse.

• Amiodarone is contraindicated in patients with:
• Known hypersensitivity to any of the components of Amiodarone Hydrochloride Injection, USP, including iodine. Hypersensitivity reactions may involve rash, angioedema, cutaneous/mucosal hemorrhage (bleeding), fever, arthralgias (joint pains), eosinophilia (abnormal blood counts), urticaria (hives), thrombotic thrombocytopenic purpura, or severe periateritis (inflammation around blood vessels)
• Cardiogenic shock
• Marked sinus bradycardia
• Second- or third-degree atrio-ventricular (AV) block unless of a functioning pacemaker is available. Amiodarone is contraindicated in patients with:
• 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 of a functioning pacemaker is available.

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.