Amiodarone hydrochloride 400 MG Oral Tablet
WARNINGS
DRUG INTERACTIONS
Drug Interactions In view of the long and variable half-life of amiodarone, potential for drug interactions exists, not only with concomitant medication, but also with drugs administered after discontinuation of amiodarone.
Pharmacodynamic interactions Drugs inducing TdP or prolonging QT Co-administration of amiodarone with drugs known to prolong the QT interval (such as class I and III antiarrhythmics, lithium, certain phenothiazines, tricyclic antidepressants, certain fluoroquinolone and macrolide antibiotics, IV pentamidine, and azole antifungals) increases the risk of Torsades de Points.
Avoid concomitant use of drugs that prolong the QT interval.
Drugs lowering heart rate or causing automaticity or conduction disorders Concomitant use of drugs with depressant effects on the sinus and AV node (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 Effects of other medicinal products on amiodarone Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit CYP3A (e.g., certain protease inhibitors, loratadine, cimetidine, trazodone) may decrease the metabolism and increase serum concentrations of amiodarone.
Concomitant use of CYP3A inducers (rifampin, St.
John’s Wort), may lead to decreased serum concentrations and loss of efficacy.
Consider serial measurement of amiodarone serum concentration during concomitant use of drugs affecting CYP3A activity.
Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and C max by 84%, and decreased DEA to unquantifiable concentrations.
Grapefruit juice inhibits CYP3A-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone; therefore, grapefruit juice should not be taken during treatment with oral amiodarone.
This information should be considered when transitioning from intravenous to oral amiodarone Cholestyramine reduces enterohepatic circulation of amiodarone thereby increasing its elimination.
This results in reduced amiodarone serum levels and half-life.
Effects of amiodarone on other medicinal products 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 of P-glycoprotein.
Reported examples of this interaction include the following: 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.
HMG-CoA reductas e inhibitors: The use of HMG-CoA reductase inhibitors that are CYP3A substrates in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis.
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 CYP3A substrates (e.g., atorvastatin) may be required as amiodarone may increase the plasma concentration of these drugs.
Digoxin : In patients receiving digoxin therapy, administration of oral amiodarone results in an increase in the serum digoxin concentration.
Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day.
On initiation of oral amiodarone, the need for digitalis therapy should be reviewed and the dose reduced by approximately 50% or discontinued.
If digitalis treatment is continued, serum levels should be closely monitored and patients observed for clinical evidence of toxicity.
Antiarrhythmics: The metabolism of quinidine, procainamide, flecainide can be inhibited by amiodarone.
Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by 33% after two days.
Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively.
In general, any added antiarrhythmic drug should be initiated at a lower than usual dose with careful monitoring.
Combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone.
During transition to amiodarone the dose levels of previously administered agents should be reduced by 30 to 50% several days after the addition of amiodarone, when arrhythmia suppression should be beginning.
The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established, and discontinuation ordinarily should be attempted.
If the treatment is continued, these patients should be particularly carefully monitored for adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued.
In amiodarone-treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose.
Metabolism of lidocaine (CYP3A substrate) can be inhibited by amiodarone resulting in increased lidocaine concentrations.
Sinus bradycardia and seizure has been reported in patients receiving concomitant lidocaine and amiodarone.
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 the prothrombin time by 100% after 3 to 4 days, the dose of the anticoagulant should be reduced by one-third to one-half, and prothrombin times should be monitored closely.
A potential interaction between clopidogrel and amiodarone resulting in ineffective inhibition of platelet aggregation has been reported.
Dabigatran etexilate when taken concomitantly with amiodarone may result in elevated serum concentration of dabigatran.
Fentanyl (CYP3A substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.
Increased steady-state levels of phenytoin during concomitant therapy with amiodarone have been reported.
Monitor phenytoin levels in patients taking both drugs.
Dextromethorphan is a substrate for both CYP2D6 and CYP3A.
Amiodarone inhibits CYP2D6 and CYP3A.
Chronic (>2 weeks) amiodarone treatment impairs metabolism of dextromethorphan leading to increased serum concentration.
OVERDOSAGE
There have been cases, some fatal, of amiodarone overdose.
In addition to general supportive measures, the patient’s cardiac rhythm and blood pressure should be monitored, and if bradycardia ensues, a β-adrenergic agonist or a pacemaker may be used.
Hypotension with inadequate tissue perfusion should be treated with positive inotropic and/or vasopressor agents.
Neither amiodarone nor its metabolite is dialyzable.
The acute oral LD 50 of amiodarone HCl in mice and rats is greater than 3,000 mg/kg.
DESCRIPTION
Amiodarone is a member of a class of antiarrhythmic drugs with predominantly Class III (Vaughan Williams’ classification) effects, available for oral administration, as yellow, round, flat faced beveled edge tablets containing 100 mg of amiodarone hydrochloride, and yellow, round, flat beveled edge, scored tablets containing 200 mg of amiodarone hydrochloride, and yellow, oval, biconvex, scored tablets containing 400 mg of amiodarone hydrochloride.
The inactive ingredients present in 100 mg, 200 mg, and 400 mg tablets are: lactose monohydrate, sodium starch glycolate, povidone, colloidal silicon dioxide, magnesium stearate, and Pigment D&C Yellow 10 Aluminum Lake.
Amiodarone is a benzofuran derivative: 2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride.
The structural formula is as follows: Amiodarone HCl is a white to cream-colored crystalline powder.
It is slightly soluble in water, soluble in alcohol, and freely soluble in chloroform.
It contains 37.3% iodine by weight.
Amiodarone structural formula
HOW SUPPLIED
Amiodarone HCl Tablets, 100 mg, are yellow colored, round, flat faced beveled edge tablets with debossings of “AS” on one side and “100” on the other side.
Bottles of 30 tablets NDC 51862-154-30 Amiodarone HCl Tablets, 200 mg, are yellow colored, round, flat beveled edge tablets with “AS” and “200” debossed on either side of the break line on one side and plain on the other side.
Bottles of 60 tablets NDC 51862-155-60 Amiodarone HCl Tablets, 400 mg, are yellow colored, oval, biconvex tablets with “AS” and “400” debossed on either side of the break line on one side and plain on the other side.
Bottles of 30 tablets NDC 51862-156-30 Keep tightly closed.
Store at Controlled Room Temperature, 20 ° to 25 ° C (68 ° to 77 ° F) (see USP Controlled Room Temperature).
Protect from light and moisture.
Dispense in a light-resistant, tight container with a child-resistant closure.
This product’s label may have been revised after this copy was produced.
For more information about the current full prescribing information, please visit www.maynepharma.com.
Distributed by: MAYNE PHARMA GREENVILLE, NC 27834 Manufactured by: MURTY PHARMACEUTICALS, INC.
LEXINGTON, KY 40509 Issued: October 2017 P069- 08
GERIATRIC USE
Geriatric Use Clinical studies of amiodarone HCl tablets 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.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
INDICATIONS AND USAGE
Because of its life-threatening side effects and the substantial management difficulties associated with its use (see “ WARNINGS ” below), amiodarone is indicated only for the treatment of the following documented, life-threatening recurrent ventricular arrhythmias when these have not responded to documented adequate doses of other available antiarrhythmics or when alternative agents could not be tolerated.
Recurrent ventricular fibrillation.
Recurrent hemodynamically unstable ventricular tachycardia.
As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of amiodarone favorably affects survival.
Amiodarone should be used only by physicians familiar with and with access to (directly or through referral) the use of all available modalities for treating recurrent life-threatening ventricular arrhythmias, and who have access to appropriate monitoring facilities, including in-hospital and ambulatory continuous electrocardiographic monitoring and electrophysiologic techniques.
Because of the life-threatening nature of the arrhythmias treated, potential interactions with prior therapy, and potential exacerbation of the arrhythmia, initiation of therapy with amiodarone should be carried out in the hospital.
PEDIATRIC USE
Pediatric Use The safety and effectiveness of amiodarone HCl tablets in pediatric patients have not been established.
PREGNANCY
Pregnancy: See “ WARNINGS, Neonatal Injury ”.
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
NUSRING MOTHERS
Nursing Mothers Amiodarone and one of its major metabolites, DEA, are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug.
Nursing offspring of lactating rats administered amiodarone have been shown to be less viable and have reduced body-weight gains.
The risk of exposing the infant to amiodarone and DEA must be weighed against the potential benefit of arrhythmia suppression in the mother.
Advise the mother to discontinue nursing.
BOXED WARNING
Amiodarone is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity.
Amiodarone has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10 to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients.
Pulmonary toxicity has been fatal about 10% of the time.
Liver injury is common with amiodarone, but is usually mild and evidenced only by abnormal liver enzymes.
Overt liver disease can occur, however, and has been fatal in a few cases.
Like other antiarrhythmics, amiodarone can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse.
This has occurred in 2 to 5% of patients in various series, and significant heart block or sinus bradycardia has been seen in 2 to 5%.
All of these events should be manageable in the proper clinical setting in most cases.
Although the frequency of such proarrhythmic events does not appear greater with amiodarone than with many other agents used in this population, the effects are prolonged when they occur.
Even in patients at high risk of arrhythmic death, in whom the toxicity of amiodarone is an acceptable risk, amiodarone poses major management problems that could be life-threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first.
The difficulty of using amiodarone effectively and safely itself poses a significant risk to patients.
Patients with the indicated arrhythmias must be hospitalized while the loading dose of amiodarone is given, and a response generally requires at least one week, usually two or more.
Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment.
In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15 to 20% overall frequencies of discontinuation due to adverse reactions.
The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months.
The patient is obviously at great risk during this time and may need prolonged hospitalization.
Attempts to substitute other antiarrhythmic agents when amiodarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden.
A similar problem exists when amiodarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried.
INFORMATION FOR PATIENTS
Information for Patients Patients should be instructed to read the accompanying Medication Guide each time they refill their prescription.
The complete text of the Medication Guide is reprinted at the end of this document.
DOSAGE AND ADMINISTRATION
BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, AMIODARONE 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 LABORATORY FACILITIES CAPABLE OF ADEQUATELY MONITORING THE EFFECTIVENESS AND SIDE EFFECTS OF TREATMENT.
In order to insure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required.
A uniform, optimal dosage schedule for administration of amiodarone has not been determined.
Because of the food effect on absorption, amiodarone should be administered consistently with regard to meals (see “ CLINICAL PHARMACOLOGY ” ).
Individual patient titration is suggested according to the following guidelines: For life-threatening ventricular arrhythmias, such as ventricular fibrillation or hemodynamically unstable ventricular tachycardia: Close monitoring of the patients is indicated during the loading phase, particularly until risk of recurrent ventricular tachycardia or fibrillation has abated.
Because of the serious nature of the arrhythmia and the lack of predictable time course of effect, loading should be performed in a hospital setting.
Loading doses of 800 to 1,600 mg/day are required for 1 to 3 weeks (occasionally longer) until initial therapeutic response occurs.
(Administration of amiodarone in divided doses with meals is suggested for total daily doses of 1,000 mg or higher, or when gastrointestinal intolerance occurs.) If side effects become excessive, the dose should be reduced.
Elimination of recurrence of ventricular fibrillation and tachycardia usually occurs within 1 to 3 weeks, along with reduction in complex and total ventricular ectopic beats.
Since grapefruit juice is known to inhibit CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, grapefruit juice should not be taken during treatment with oral amiodarone (see “ PRECAUTIONS, Drug Interactions ” ).
Upon starting amiodarone therapy, an attempt should be made to gradually discontinue prior antiarrhythmic drugs (see section on “ Drug Interactions ” ).
When adequate arrhythmia control is achieved, or if side effects become prominent, amiodarone dose should be reduced to 600 to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day (see “ CLINICAL PHARMACOLOGY–Monitoring Effectiveness ” ).
Some patients may require larger maintenance doses, up to 600 mg/day, and some can be controlled on lower doses.
Amiodarone may be administered as a single daily dose, or in patients with severe gastrointestinal intolerance, as a b.i.d.
dose.
In each patient, the chronic maintenance dose should be determined according to antiarrhythmic effect as assessed by symptoms, Holter recordings, and/or programmed electrical stimulation and by patient tolerance.
Plasma concentrations may be helpful in evaluating nonresponsiveness or unexpectedly severe toxicity (see “ CLINICAL PHARMACOLOGY ” ).
The lowest effective dose should be used to prevent the occurrence of side effects.
In all instances, the physician must be guided by the severity of the individual patient’s arrhythmia and response to therapy.
When dosage adjustments are necessary, the patient should be closely monitored for an extended period of time because of the long and variable half-life of amiodarone and the difficulty in predicting the time required to attain a new steady-state level of drug.
Dosage suggestions are summarized below: Loading Dose (Daily) Adjustment and Maintenance Dose (Daily) Ventricular 1 to 3 Weeks ~ 1 month Usual Maintenance Arrhythmias 800 to 1,600 mg 600 to 800 mg 400 mg