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NEXTERONE(amiodarone hydrochloride)injection, solution
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HIGHLIGHTS OF PRESCRIBING INFORMATION |
These highlights do not include all the information needed to use NEXTERONE® safely and effectively. See full prescribing information for NEXTERONE.
NEXTERONE (amiodarone HCl) Premixed Injection for intravenous use
Initial U.S. Approval: 2008
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INDICATIONS AND USAGE
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NEXTERONE is an antiarrhythmic agent 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. (1)
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DOSAGE AND ADMINISTRATION
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The recommended starting dose is about 1000 mg over the first 24 hours of therapy, delivered by the following infusion regimen (2):
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Initial Load: 150 mg per 100 mL infused over 10 minutes
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Followed by: 1 mg/min for 6 hours
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Followed by: 0.5 mg/min thereafter
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In the event of breakthrough episodes of VF or hemodynamically unstable VT (2):
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Repeat the Initial Load described above as needed (infused over 10 minutes)
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Increase the rate of the maintenance infusion to achieve effective arrhythmia suppression. (2)
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DOSAGE FORMS AND STRENGTHS
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Injection, 1.5 mg/mL (150 mg/100 mL) Premixed in Dextrose (3)
Injection, 1.8 mg/mL (360 mg/200 mL) Premixed in Dextrose (3)
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CONTRAINDICATIONS
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NEXTERONE is contraindicated in patients with (4):
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Known hypersensitivity to any of the components of NEXTERONE, including iodine
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Cardiogenic shock
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Marked sinus bradycardia
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Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available.
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WARNINGS AND PRECAUTIONS
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Hypotension: Treat initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion.(5.1)
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Bradycardia and AV block: Treat by slowing the infusion rate or discontinuing NEXTERONE.(5.2)
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ADVERSE REACTIONS
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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. (6)
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Other important adverse reactions are, torsade de pointes (TdP), congestive heart failure, and liver function test abnormalities. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Prism Pharmaceuticals at 610-265-7710 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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DRUG INTERACTIONS
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Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone.
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Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates for p-glycoprotein.
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Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly.
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USE IN SPECIFIC POPULATIONS
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Pregnancy: Use NEXTERONE during pregnancy only if the potential benefit to the mother justifies the risk to the fetus (8.1).
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Nursing mothers: Amiodarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Advise mothers to discontinue breast feeding (8.3).
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Pediatric use: The safety and efficacy of amiodarone in the pediatric population have not been established (8.4).
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See 17 for PATIENT COUNSELING INFORMATION |
Revised: 11/2010 |
Back to Highlights and Tabs
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FULL PRESCRIBING INFORMATION: CONTENTS* |
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1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hypotension
5.2 Bradycardia and Atrio-ventricular Block
5.3 Liver Enzyme Elevations
5.4 Proarrhythmia
5.5 Pulmonary Disorders
5.6 Loss of Vision
5.7 Long-Term Use
5.8 Thyroid Abnormalities
5.9 Surgery
5.10 Corneal Refractive Laser Surgery
5.11 Electrolyte Disturbances
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Post-Marketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Labor and Delivery
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
18 PACKAGE LABELING - PRINCIPAL DISPLAY PANEL
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FULL PRESCRIBING INFORMATION
1 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. NEXTERONE 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 NEXTERONE, patients may be transferred to oral amiodarone therapy [see Dosage and Administration (2)].
Use NEXTERONE for acute treatment until the patient's ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary.
2 DOSAGE AND ADMINISTRATION
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 recommended starting dose of NEXTERONE is about 1000 mg over the first 24 hours of therapy, delivered by the following infusion regimen:
Table 1: NEXTERONE PREMIXED INJECTION DOSE RECOMMENDATIONS: FIRST 24 HOURS
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Loading infusions |
First Rapid: |
150 mg over the FIRST 10minutes (15 mg/min).
Directly infuse NEXTERONE Premixed Injection (150 mg/100 mL; 1.5mg/mL) at a rate of 10mL/min.
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Followed by
Slow: |
360 mg over the NEXT 6hours (1 mg/min).
Directly infuse NEXTERONE Premixed Injection (360 mg/200 mL; 1.8 mg/mL) at a rate of 0.556 mL/min.
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Maintenance infusion |
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540 mg over the REMAINING 18 hours (0.5 mg/min). Decrease the rate of the slow loading infusion to 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. |
After the first 24 hours, continue the maintenance infusion rate of 0.5 mg/min (720 mg per 24 hours) by directly infusing NEXTERONE Premixed Injection (360 mg/200 mL; 1.8 mg/mL) at a rate of 0.278 mL/min. 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 NEXTERONE (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.
Administer NEXTERONE, 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 [see Warnings and Precautions (5.3)].
Intravenous amiodarone concentrations greater than 3 mg/mL 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 NEXTERONE concentrations of 2 mg/mL, unless a central venous catheter is used [see Adverse Reactions (6.2)].
NEXTERONE Premixed Injection is available in GALAXY® containers as a single-use, ready-to-use, iso-osmotic solution in dextrose for intravenous administration. No further dilution is required. NEXTERONE Premixed Injection should not be combined with any product in the same intravenous line or premixed container. Protect from light until ready to use.
NEXTERONE does not need to be protected from light during administration.
Since the premixed container is for single-use only, any unused portion should be discarded.
NOTE: Inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Check for minute leaks prior to use by squeezing the bag firmly. If leaks are detected, discard solution as sterility may be impaired.
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.
Preparation of NEXTERONE Premixed Injection for administration:
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Suspend container from eyelet support.
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Remove protector from outlet port at bottom of container.
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Attach administration set. Refer to complete directions accompanying set.
Admixture Incompatibility
NEXTERONE in D5W is incompatible with the drugs shown in Table 2.
Table 2: Y-SITE INJECTION INCOMPATIBILITY
Drug |
Vehicle |
Amiodarone
Concentration |
Comments |
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Aminophylline |
D5W |
4 mg/mL |
Precipitate |
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Cefamandole Nafate |
D5W |
4 mg/mL |
Precipitate |
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Cefazolin Sodium |
D5W |
4 mg/mL |
Precipitate |
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Mezlocillin Sodium |
D5W |
4 mg/mL |
Precipitate |
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Heparin Sodium |
D5W |
-- |
Precipitate |
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Sodium Bicarbonate |
D5W |
3 mg/mL |
Precipitate |
Intravenous to Oral Transition
Patients whose arrhythmias have been suppressed by NEXTERONE may be switched to oral amiodarone. The optimal dose for changing from intravenous to oral administration of amiodarone will depend on the dose of NEXTERONE 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 [see Drug Interactions (7)].
Table 3 provides suggested doses of oral amiodarone to be initiated after varying durations of NEXTERONE 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.
Table 3: RECOMMENDATIONS FOR ORAL DOSAGE AFTER INTRAVENOUS INFUSION
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Duration of NEXTERONE Infusion* |
Initial Daily Dose of
Oral Amiodarone |
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< 1 week |
800-1600 mg |
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1-3 weeks |
600-800 mg |
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> 3 weeks† |
400 mg |
3 DOSAGE FORMS AND STRENGTHS
Injection, 1.5 mg/mL (150 mg/100 mL) Premixed in Dextrose
Injection, 1.8 mg/mL (360 mg/200 mL) Premixed in Dextrose
4 CONTRAINDICATIONS
NEXTERONE is contraindicated in patients with:
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Known hypersensitivity to any of the components of NEXTERONE Premixed Injection, including iodine. Hypersensitivity reactions may involve rash, angioedema, cutaneous/mucosal hemorrhage (bleeding), fever, arthralgias (joint pains), eosinophilia (abnormal blood counts), uritcaria (hives), thrombotic thrombocytopenic purpura, or severe periarteritis (inflammation around blood vessels).
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Cardiogenic shock.
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Marked sinus bradycardia.
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Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available.
5 WARNINGS AND PRECAUTIONS
NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment.
5.1 Hypotension
Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse effect in 288 (16%) of 1836 patients treated with intravenous amiodarone. Clinically significant hypotension during infusions was seen most often in the first several hours of treatment and was not dose related, but appeared to be related to the rate of infusion. 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 [see Dosage and Administration (2)].
In some cases, hypotension may be refractory and result in a fatal outcome [see Adverse Reactions (6.2)].
5.2 Bradycardia and Atrio-ventricular Block
In 90 (4.9%) of 1836 patients in clinical trials, drug-related bradycardia that was not dose-related occurred while they were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. In some patients, inserting a pacemaker is required. Despite such measures, bradycardia was progressive and terminal in 1 patient during the controlled trials. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available.
5.3 Liver Enzyme Elevations
Elevations of blood hepatic enzyme values [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)] are commonly seen in patients with immediately life-threatening VT/VF. Interpreting elevated AST activity can be difficult because the values may be elevated in patients who have had recent myocardial infarction, congestive heart failure, or multiple electrical defibrillations. Approximately 54% of patients receiving intravenous amiodarone in clinical studies had baseline liver enzyme elevations, and 13% had clinically significant elevations. In 81% of patients with both baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment.
Acute, centrolobular confluent hepatocellular necrosis leading to hepatic coma, acute renal failure, and death has been associated with the administration of intravenous amiodarone at a much higher loading dose concentration and much faster rate of infusion than recommended (see Dosage and Administration (2)).
In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of NEXTERONE therapy. Carefully monitor patients receiving NEXTERONE for evidence of progressive hepatic injury. In such cases, consider reducing the rate of administration or withdrawing NEXTERONE.
5.4 Proarrhythmia
Like all antiarrhythmic agents, NEXTERONE may cause a worsening of existing arrhythmias or precipitate a new arrhythmia. Proarrhythmia, primarily torsade de pointes (TdP), has been associated with prolongation, by intravenous amiodarone, of the QTc interval to 500 ms or greater. Although QTc prolongation occurred frequently in patients receiving intravenous amiodarone, TdP or new-onset VF occurred infrequently (less than 2%). 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.
Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly [see Drug Interactions (7)].
Amiodarone causes thyroid dysfunction in some patients, which may lead to potentially fatal breakthrough or exacerbated arrhythmias.
5.5 Pulmonary Disorders
Early-onset Pulmonary Toxicity
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, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure or death.
ARDS
Two percent (2%) of patients were reported to have adult respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy.
Pulmonary Fibrosis
Only 1 of more than 1000 patients treated with intravenous amiodarone in clinical studies developed pulmonary fibrosis. In that patient, the condition was diagnosed 3 months after treatment with intravenous amiodarone, during which time the patient received oral amiodarone. Pulmonary toxicity is a well-recognized complication of long-term amiodarone use (see package insert for oral amiodarone).
5.6 Loss of Vision
Cases of optic neuropathy and optic neuritis, usually resulting in visual impairment, have been reported in patients treated with oral amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. Perform an ophthalmic examination if symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision. Re-eva luate the necessity of amiodarone therapy if optic neuropathy or neuritis is suspected. Perform regular ophthalmic examination, including fundoscopy and slit-lamp examination, during administration of NEXTERONE.
5.7 Long-Term Use
There has been limited experience in patients receiving intravenous amiodarone for longer than 3 weeks. See package insert for oral amiodarone.
5.8 Thyroid Abnormalities
Amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased T4 levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. Amiodarone is also a potential source of large amounts of inorganic iodine and can cause either hypothyroidism or hyperthyroidism. eva luate 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. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following NEXTERONE withdrawal.
There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone. In some instances hyperthyroidism was also present [see Adverse Reactions (6.2)].
Hyperthyroidism and Thyrotoxicosis
Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. Consider the possibility of hyperthyroidism if any new signs of arrhythmia appear.
Identify hyperthyroidism by relevant clinical signs and symptoms, subnormal serum levels of thyroid stimulating hormone (TSH), abnormally elevated serum free T4, and elevated or normal serum T3. Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone. Amiodarone hyperthyroidism may be followed by a transient period of hypothyroidism.
The institution of antithyroid drugs, β-adrenergic blockers or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially 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.
When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning.
Neonatal Hypo- or Hyperthyroidism
Amiodarone can cause fetal harm when administered to a pregnant woman. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism associated with oral administration. Inform the patient of the potential hazard to the fetus if NEXTERONE is administered during pregnancy or if the patie |
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