Pacerone

Pronunciation

Generic Name: amiodarone hydrochloride
Dosage Form: tablet

Pacerone®(Amiodarone Hydrochloride) Tablets, 400 mg

Pacerone Description

Pacerone® (amiodarone hydrochloride) Tablets are a member of a class of antiarrhythmic drugs with predominantly Class III (Vaughan Williams’ classification) effects, available for oral administration as light yellow, scored tablets. Each tablet for oral administration contains 400 mg of amiodarone hydrochloride. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, povidone, and D&C yellow No. 10 aluminum lake. Amiodarone hydrochloride, the active ingredient in Pacerone® Tablets, is a benzofuran derivative: 2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride.

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The structural formula is as follows:

C25H29I2NO3•HCl Molecular Weight: 681.8

Amiodarone hydrochloride 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.

Pacerone - Clinical Pharmacology

Electrophysiology/Mechanisms of Action

In animals, amiodarone hydrochloride is effective in the prevention or suppression of experimentally induced arrhythmias. The antiarrhythmic effect of amiodarone hydrochloride may be due to at least two major properties:

1) a prolongation of the myocardial cell-action potential duration and refractory period and

2) noncompetitive α- and β-adrenergic inhibition.

Amiodarone hydrochloride prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. Amiodarone hydrochloride increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15% to 20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave contour. These changes should not require discontinuation of Pacerone® as there is evidence of its pharmacological action, although amiodarone hydrochloride can cause marked sinus bradycardia or sinus arrest and heart block. On rare occasions, QT prolongation has been associated with worsening of arrhythmia (see WARNINGS).

Hemodynamics

In animal studies and after intravenous administration in man, amiodarone hydrochloride relaxes vascular smooth muscle, reduces peripheral vascular resistance (afterload), and slightly increases cardiac index. After oral dosing, however, amiodarone hydrochloride produces no significant change in left ventricular ejection fraction (LVEF), even in patients with depressed LVEF. After acute intravenous dosing in man, amiodarone hydrochloride may have a mild negative inotropic effect.

Pharmacokinetics

Following oral administration in man, amiodarone hydrochloride is slowly and variably absorbed. The bioavailability of amiodarone hydrochloride is approximately 50%, but has varied between 35% and 65% in various studies. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Despite this, the onset of action may occur in 2 to 3 days, but more commonly takes 1 to 3 weeks, even with loading doses. Plasma concentrations with chronic dosing at 100 mg/day to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability. Food increases the rate and extent of absorption of amiodarone hydrochloride. The effects of food upon the bioavailability of amiodarone hydrochloride have been studied in 30 healthy subjects who received a single 600-mg dose immediately after consuming a high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (Tmax) by 37%. The mean AUC and mean Cmax of desethylamiodarone increased by 55% (range 58% to 101%) and 32% (range 4% to 84%), respectively, but there was no change in the Tmax in the presence of food.

Amiodarone hydrochloride has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen. One major metabolite of amiodarone hydrochloride, desethylamiodarone (DEA), has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA’s precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular Class lll effects after oral amiodarone hydrochloride administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation.

Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines.

Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable.

In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 mL/hr/kg and 440 mL/hr/kg. Age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or DEA. Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of intravenous amiodarone in cirrhotic patients, significantly lower Cmax and average concentration values are seen for DEA, but mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances (about 100 mL/hr/kg) than younger subjects (about 150 mL/hr/kg) and an increase in t1/2 from about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition t1/2 of DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic or cardiac abnormalities has been defined during chronic treatment with amiodarone hydrochloride, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction.

Following single dose administration in 12 healthy subjects, amiodarone hydrochloride exhibited multi-compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, amiodarone hydrochloride has been shown to have a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 10 days. A much slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to 107 days, with a mean of approximately 53 days and most patients in the 40- to 55-day range. In the absence of a loading-dose period, steady-state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5- to 10-day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat.

The considerable intersubject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Daily maintenance doses of Pacerone® should be based on individual patient requirements (see DOSAGE AND ADMINISTRATION).

Amiodarone hydrochloride and its metabolite have a limited transplacental transfer of approximately 10% to 50%. The parent drug and its metabolite have been detected in breast milk.

Amiodarone hydrochloride is highly protein-bound (approximately 96%).

Although electrophysiologic effects, such as prolongation of QTc, can be seen within hours after a parenteral dose of amiodarone hydrochloride, effects on abnormal rhythms are not seen before 2 to 3 days and usually require 1 to 3 weeks, even when a loading dose is used. There may be a continued increase in effect for longer periods still. There is evidence that the time to effect is shorter when a loading-dose regimen is used.

Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after Pacerone® is discontinued, but the time of recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly compared to the initial response, presumably because tissue stores were not wholly depleted at the time of recurrence.

Pharmacodynamics

There is no well-established relationship of plasma concentration to effectiveness, but it does appear that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Within individuals dose reductions and ensuing decreased plasma concentrations can result in loss of arrhythmia control. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from a dose increase, or unusually high, and who might have dosage reduction in the hope of minimizing side effects. Some observations have suggested a plasma concentration, dose, or dose/duration relationship for side effects such as pulmonary fibrosis, liver-enzyme elevations, corneal deposits and facial pigmentation, peripheral neuropathy, gastrointestinal and central nervous system effects.

Monitoring Effectiveness

Predicting the effectiveness of any antiarrhythmic agent in long-term prevention of recurrent ventricular tachycardia and ventricular fibrillation is difficult and controversial, with highly qualified investigators recommending use of ambulatory monitoring, programmed electrical stimulation with various stimulation regimens, or a combination of these, to assess response. There is no present consensus on many aspects of how best to assess effectiveness, but there is a reasonable consensus on some aspects:

1. If a patient with a history of cardiac arrest does not manifest a hemodynamically unstable arrhythmia during electrocardiographic monitoring prior to treatment, assessment of the effectiveness of amiodarone hydrochloride requires some provocative approach, either exercise or programmed electrical stimulation (PES).

2. Whether provocation is also needed in patients who do manifest their life-threatening arrhythmia spontaneously is not settled, but there are reasons to consider PES or other provocation in such patients. In the fraction of patients whose PES-inducible arrhythmia can be made noninducible by amiodarone hydrochloride (a fraction that has varied widely in various series from less than 10% to almost 40%, perhaps due to different stimulation criteria), the prognosis has been almost uniformly excellent, with very low recurrence (ventricular tachycardia or sudden death) rates. More controversial is the meaning of continued inducibility. There has been an impression that continued inducibility in amiodarone hydrochloride patients may not foretell a poor prognosis but, in fact, many observers have found greater recurrence rates in patients who remain inducible than in those who do not. A number of criteria have been proposed, however, for identifying patients who remain inducible but who seem likely nonetheless to do well on Pacerone®. These criteria include increased difficulty of induction (more stimuli or more rapid stimuli), which has been reported to predict a lower rate of recurrence, and ability to tolerate the induced ventricular tachycardia without severe symptoms, a finding that has been reported to correlate with better survival but not with lower recurrence rates. While these criteria require confirmation and further study in general, easier inducibility or poorer tolerance of the induced arrhythmia should suggest consideration of a need to revise treatment.

Several predictors of success not based on PES have also been suggested, including complete elimination of all nonsustained ventricular tachycardia on ambulatory monitoring and very low premature ventricular-beat rates (less than 1 VPB/1,000 normal beats).

While these issues remain unsettled for amiodarone hydrochloride, as for other agents, the prescriber of Pacerone® should have access to (direct or through referral), and familiarity with, the full range of evaluatory procedures used in the care of patients with life-threatening arrhythmias.

It is difficult to describe the effectiveness rates of Pacerone®, as these depend on the specific arrhythmia treated, the success criteria used, the underlying cardiac disease of the patient, the number of drugs tried before resorting to Pacerone®, the duration of follow-up, the dose of amiodarone hydrochloride, the use of additional antiarrhythmic agents, and many other factors. As amiodarone hydrochloride has been studied principally in patients with refractory life-threatening ventricular arrhythmias, in whom drug therapy must be selected on the basis of response and cannot be assigned arbitrarily, randomized comparisons with other agents or placebo have not been possible. Reports of series of treated patients with a history of cardiac arrest and mean follow-up of one year or more have given mortality (due to arrhythmia) rates that were highly variable, ranging from less than 5% to over 30%, with most series in the range of 10% to 15%. Overall arrhythmia-recurrence rates (fatal and nonfatal) also were highly variable (and, as noted above, depended on response to PES and other measures), and depend on whether patients who do not seem to respond initially are included. In most cases, considering only patients who seemed to respond well enough to be placed on long-term treatment, recurrence rates have ranged from 20% to 40% in series with a mean follow-up of a year or more.

Indications and Usage for Pacerone

Because of its life-threatening side effects and the substantial management difficulties associated with its use (see WARNINGSbelow), Pacerone® (amiodarone hydrochloride) Tablets are 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.

1. Recurrent ventricular fibrillation.

2. 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 hydrochloride tablets favorably affects survival.

Pacerone® (amiodarone hydrochloride) Tablets 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 Pacerone® (amiodarone hydrochloride) Tablets should be carried out in the hospital.

Contraindications

Pacerone® (amiodarone hydrochloride) is contraindicated in patients with cardiogenic shock; severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third-degree atrioventricular block; and when episodes of bradycardia have caused syncope (except when used in conjunction with a pacemaker).

Pacerone® (amiodarone hydrochloride) is contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine.

Warnings

Pacerone® (amiodarone hydrochloride) is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity.

Amiodarone hydrochloride 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 hydrochloride, 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 hydrochloride 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 hydrochloride 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 hydrochloride is an acceptable risk,Pacerone® 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 Pacerone® effectively and safely itself poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of Pacerone® 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 Pacerone® must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when amiodarone hydrochloride is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried.

Precautions

Impairment of Vision

Optic Neuropathy and/or Neuritis

Cases of optic neuropathy and optic neuritis have been reported (see WARNINGS).

Corneal Microdeposits

Corneal microdeposits appear in the majority of adults treated with amiodarone hydrochloride. They are usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment (see ADVERSE REACTIONS).

Neurologic

Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete.

Photosensitivity

Amiodarone hydrochloride has induced photosensitization in about 10% of patients; some protection may be afforded by the use of sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy.

Thyroid Abnormalities

Amiodarone hydrochloride inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased thyroxine levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because of its release of inorganic iodine, or perhaps for other reasons, amiodarone hydrochloride can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored 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 hydrochloride and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following Pacerone® (amiodarone hydrochloride) withdrawal.

Hypothyroidism has been reported in 2% to 4% of patients in most series, but in 8% to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Hypothyroidism is best managed by Pacerone® dose reduction and/or thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue Pacerone® in some patients.

Hyperthyroidism occurs in about 2% of patients receiving amiodarone hydrochloride, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone hydrochloride-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and/or arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone hydrochloride-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED.

Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum T3 RIA, and further elevations of serum T4, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany amiodarone hydrochloride-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of Pacerone®.

The institution of antithyroid drugs, β-adrenergic blockers and/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. Amiodarone hydrochloride-induced hyperthyroidism may be followed by a transient period of hypothyroidism (see WARNINGS, Thyrotoxicosis).

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.

There have been post-marketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone hydrochloride. In some instances hyperthyroidism was also present (see WARNINGSand ADVERSE REACTIONS).

Surgery

Volatile Anesthetic Agents

Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics.

Hypotension Postbypass

Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving amiodarone hydrochloride have been reported. The relationship of this event to Pacerone® therapy is unknown.

Adult Respiratory Distress Syndrome (ARDS)

Postoperatively, occurrences of ARDS have been reported in patients receiving amiodarone hydrochloride therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiO2 and the determinants of oxygen delivery to the tissues (e.g., SaO2, PaO2) be closely monitored in patients on amiodarone hydrochloride.

Corneal Refractive Laser Surgery

Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking amiodarone hydrochloride.

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.

Laboratory Tests

Elevations in liver enzymes (SGOT and SGPT) can occur. Liver enzymes in patients on relatively high maintenance doses should be monitored on a regular basis. Persistent significant elevations in the liver enzymes or hepatomegaly should alert the physician to consider reducing the maintenance dose of Pacerone® or discontinuing therapy.

Amiodarone hydrochloride alters the results of thyroid-function tests, causing an increase in serum T4 and serum reverse T3, and a decline in serum T3 levels. Despite these biochemical changes, most patients remain clinically euthyroid.

Drug Interactions

Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Amiodarone is an inhibitor of CYP3A4 and p-glycoprotein. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4 and substrates of p-glycoprotein. While only a limited number of in vivo drug-drug interactions with amiodarone have been reported, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. 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.

Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit CYP3A4 may decrease the metabolism and increase serum concentrations of amiodarone. Reported examples include the following:

Protease Inhibitors

Protease inhibitors are known to inhibit CYP3A4 to varying degrees. A case report of one patient taking amiodarone 200 mg and indinavir 800 mg three times a day resulted in increases in amiodarone concentrations from 0.9 mg/L to 1.3 mg/L. DEA concentrations were not affected. There was no evidence of toxicity. Monitoring for amiodarone toxicity and serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy should be considered.

Histamine H1 Antagonists

Loratadine, a non-sedating antihistaminic, is metabolized primarily by CYP3A4. QT interval prolongation and Torsade de Pointes have been reported with the co-administration of loratadine and amiodarone.

Histamine H2 Antagonists

Cimetidine inhibits CYP3A4 and can increase serum amiodarone levels.

Antidepressants

Trazodone, an antidepressant, is metabolized primarily by CYP3A4. QT interval prolongation and Torsade de Pointes have been reported with the co-administration of trazodone and amiodarone.

Other Substances

Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, and decreased DEA to unquantifiable concentrations. Grapefruit juice inhibits CYP3A4-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 changing from intravenous amiodarone to oral amiodarone (see DOSAGE AND ADMINISTRATION).

Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6 and CYP3A4. 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:

Immunosuppressives

Cyclosporine (CYP3A4 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.

HMG-CoA Reductase Inhibitors

The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with amiodarone have 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 CYP3A4 substrates (e.g., atorvastatin) may be required as amiodarone may increase the plasma concentration of these drugs.

Cardiovasculars

Cardiac Glycosides: In patients receiving digoxin therapy, administration of oral amiodarone regularly results in an increase in the serum digoxin concentration that may reach toxic levels with resultant clinical toxicity. 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. These precautions probably should apply to digitoxin administration as well.

Antiarrhythmics:

Other antiarrhythmic drugs, such as quinidine, procainamide, disopyramide, and phenytoin, have been used concurrently with oral amiodarone.

There have been case reports of increased steady-state levels of quinidine, procainamide, and phenytoin during concomitant therapy with amiodarone. Phenytoin decreases serum amiodarone levels. 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. Quinidine and procainamide doses should be reduced by one-third when either is administered with amiodarone. Plasma levels of flecainidehave been reported to increase in the presence of oral amiodarone; because of this, the dosage of flecainide should be adjusted when these drugs are administered concomitantly. 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 transfer 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.

Antihypertensives:

Amiodarone should be used with caution in patients receiving β-receptor blocking agents (e.g., propranolol, a CYP3A4 inhibitor) or calcium channel antagonists (e.g., verapamil, a CYP3A4 substrate, and diltiazem, a CYP3A4 inhibitor) because of the possible potentiation of bradycardia, sinus arrest, and AV block; if necessary, amiodarone can continue to be used after insertion of a pacemaker in patients with severe bradycardia or sinus arrest.

Anticoagulants:

Potentiation of warfarin-type (CYP2C9 and CYP3A4 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.

Clopidogrel, an inactive thienopyridine prodrug, is metabolized in the liver by CYP3A4 to an active metabolite. A potential interaction between clopidogrel and amiodarone hydrochloride resulting in ineffective inhibition of platelet aggregation has been reported.

Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A4 (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy. Reported examples of this interaction include the following:

Antibiotics

Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with oral amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone.

Other substances, including herbal preparations

St. John’s Wort(Hypericum perforatum) induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that the use of St. John’s Wort in patients receiving amiodarone could result in reduced amiodarone levels.

Other reported interactions with amiodarone

Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.

Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine (CYP3A4 substrate) given for local anesthesia. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant administration of intravenous amiodarone.

Dextromethorphan is a substrate for both CYP2D6 and CYP3A4. Amiodarone inhibits CYP2D6.

Cholestyramineincreases enterohepatic elimination of amiodarone and may reduce its serum levels and t1/2.

Disopyramideincreases QT prolongation which could cause arrhythmia.

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 WARNINGS, Worsened Arrhythmia).

Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem, and verapamil.

Volatile Anesthetic Agents (See PRECAUTIONS, Surgery, Volatile Anesthetic Agents.)

In addition to the interactions noted above, chronic (>2 weeks) oral amiodarone hydrochloride administration impairs metabolism of phenytoin, dextromethorphan, and methotrexate.

Electrolyte Disturbances

Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during Pacerone® (amiodarone hydrochloride) therapy. Use caution when co-administering Pacerone® with drugs which may induce hypokalemia and/or hypomagnesemia.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Amiodarone hydrochloride was associated with a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors was greater than control even at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose*).

Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with amiodarone hydrochloride were negative.

In a study in which amiodarone hydrochloride was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose*).

*600 mg in a 50 kg patient (dose compared on a body surface area basis)

Pregnancy

Pregnancy Category D

See WARNINGS, Neonatal Hypo- or Hyperthyroidism.

Labor and Delivery

It is not known whether the use of Pacerone® during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect of amiodarone hydrochloride on the duration of gestation or on parturition.

Nursing Mothers

Amiodarone hydrochloride and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breastfeeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone hydrochloride have been shown to be less viable and have reduced body-weight gains. Therefore, when Pacerone® therapy is indicated, the mother should be advised to discontinue nursing.

Pediatric Use

The safety and effectiveness of Pacerone® (amiodarone hydrochloride) in pediatric patients have not been established.

Geriatric Use

Clinical studies of amiodarone hydrochloride 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.

Adverse Reactions

Adverse reactions have been very common in virtually all series of patients treated with amiodarone hydrochloride for ventricular arrhythmias with relatively large doses of drug (400 mg/day and above), occurring in about three-fourths of all patients and causing discontinuation in 7% to 18%. The most serious reactions are pulmonary toxicity, exacerbation of arrhythmia, and rare serious liver injury (see WARNINGS), but other adverse effects constitute important problems. They are often reversible with dose reduction or cessation of amiodarone hydrochloride treatment. Most of the adverse effects appear to become more frequent with continued treatment beyond six months, although rates appear to remain relatively constant beyond one year. The time and dose relationships of adverse effects are under continued study.

Neurologic problems are extremely common, occurring in 20% to 40% of patients and including malaise and fatigue, tremor and involuntary movements, poor coordination and gait, and peripheral neuropathy; they are rarely a reason to stop therapy and may respond to dose reductions or discontinuation (see PRECAUTIONS). There have been spontaneous reports of demyelinating polyneuropathy.

Gastrointestinal complaints, most commonly nausea, vomiting, constipation, and anorexia, occur in about 25% of patients but rarely require discontinuation of drug. These commonly occur during high-dose administration (i.e., loading dose) and usually respond to dose reduction or divided doses.

Ophthalmic abnormalities including optic neuropathy and/or optic neuritis, in some cases progressing to permanent blindness, papilledema, corneal degeneration, photosensitivity, eye discomfort, scotoma, lens opacities, and macular degeneration have been reported (see WARNINGS).

Asymptomatic corneal microdeposits are present in virtually all adult patients who have been on drug for more than 6 months. Some patients develop eye symptoms of halos, photophobia, and dry eyes. Vision is rarely affected and drug discontinuation is rarely needed.

Dermatological adverse reactions occur in about 15% of patients, with photosensitivity being most common (about 10%). Sunscreen and protection from sun exposure may be helpful, and drug discontinuation is not usually necessary. Prolonged exposure to amiodarone hydrochloride occasionally results in a blue-gray pigmentation. This is slowly and occasionally incompletely reversible on discontinuation of drug but is of cosmetic importance only.

Cardiovascular adverse reactions, other than exacerbation of the arrhythmias, include the uncommon occurrence of congestive heart failure (3%) and bradycardia. Bradycardia usually responds to dosage reduction but may require a pacemaker for control. CHF rarely requires drug discontinuation. Cardiac conduction abnormalities occur infrequently and are reversible on discontinuation of drug.

The following side-effect rates are based on a retrospective study of 241 patients treated for 2 to 1,515 days (mean 441.3 days).

The following side effects were each reported in 10% to 33% of patients:

Gastrointestinal: Nausea and vomiting.

The following side effects were each reported in 4% to 9% of patients:

Dermatologic: Solar dermatitis/photosensitivity.

Neurologic: Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias.

Gastrointestinal: Constipation, anorexia.

Ophthalmologic: Visual disturbances.

Hepatic: Abnormal liver-function tests.

Respiratory: Pulmonary inflammation or fibrosis.

The following side effects were each reported in 1% to 3% of patients:

Thyroid: Hypothyroidism, hyperthyroidism.

Neurologic: Decreased libido, insomnia, headache, sleep disturbances.

Cardiovascular: Congestive heart failure, cardiac arrhythmias, SA node dysfunction.

Gastrointestinal: Abdominal pain.

Hepatic: Nonspecific hepatic disorders.

Other: Flushing, abnormal taste and smell, edema, abnormal salivation, coagulation abnormalities.

The following side effects were each reported in less than 1% of patients:

Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension, and cardiac conduction abnormalities.

In surveys of almost 5,000 patients treated in open U.S. studies and in published reports of treatment with amiodarone hydrochloride, the adverse reactions most frequently requiring discontinuation of amiodarone hydrochloride included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. Other symptoms causing discontinuations less often included visual disturbances, solar dermatitis, blue skin discoloration, hyperthyroidism, and hypothyroidism.

Post-Marketing Reports

In post-marketing surveillance, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, urticaria, eosinophilic pneumonia, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, renal impairment, renal insufficiency, acute renal failure, acute respiratory distress syndrome in the post-operative setting, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pulmonary alveolar hemorrhage, pleural effusion, pleuritis, pseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), syndrome of inappropriate antidiuretic hormone secretion (SIADH), thyroid nodules/thyroid cancer, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma, myopathy, muscle weakness, rhabdomyolysis, demyelinating polyneuropathy, hallucination, confusional state, disorientation, delirium, epididymitis, and impotence, also have been reported with amiodarone therapy.

Overdosage

There have been cases, some fatal, of amiodarone hydrochloride 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 hydrochloride nor its metabolite is dialyzable.

The acute oral LD50 of amiodarone hydrochloride in mice and rats is greater than 3,000 mg/kg.

Pacerone Dosage and Administration

BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, Pacerone® TABLETS 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 HYDROCHLORIDE TABLET 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 Pacerone® Tablets has not been determined. Because of the food effect on absorption, Pacerone® Tablets 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 mg/day to 1,600 mg/day are required for 1 to 3 weeks (occasionally longer) until initial therapeutic response occurs. (Administration of Pacerone® Tablets 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 Pacerone® Tablet therapy, an attempt should be made to gradually discontinue prior antiarrhythmic drugs (see section on PRECAUTIONS, Drug Interactions). When adequate arrhythmia control is achieved, or if side effects become prominent, Pacerone® Tablets dose should be reduced to 600 mg/day 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.

Pacerone® Tablets 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 hydrochloride tablets and the difficulty in predicting the time required to attain a new steady-state level of drug. Dosage suggestions are summarized below:

Ventricular

Arrhythmias

Loading Dose

(Daily)

Adjustment and Maintenance Dose

(Daily)

1 to 3 weeks

~1 month

usual

maintenance

800 mg to 1,600 mg

600 mg to 800 mg

400 mg

How is Pacerone Supplied

Pacerone® (Amiodarone Hydrochloride) Tablets, 400 mg, are available in bottles of 30 tablets (NDC 0245-0145-30), bottles of 100 tablets (NDC 0245-0145-11), bottles of 500 tablets (NDC 0245-0145-15) and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each) (NDC 0245-0145-01). The 400 mg tablets are light yellow, oval-shaped, scored, uncoated tablets, debossed with “P400” on the unscored side, and “01” to the left and “45” to the right of the score on the reverse side.

Store at 20° to 25°C (68° to 77°F). Excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Protect from light.

Dispense in a tight, light-resistant container with a child-resistant closure.

This product’s label may have been updated. For current full prescribing information, please visit www.Pacerone.com or www.upsher-smith.com or call 1-888-650-3789.

Medication Guide

Pacerone® (PAS- r-on) Tablets

(Amiodarone Hydrochloride)

Rx only

Read the Medication Guide that comes with Pacerone® Tablets before you start taking them and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about Pacerone® Tablets?

Pacerone® Tablets can cause serious side effects that can lead to death including:

lung damage

liver damage

worse heartbeat problems

thyroid problems

Call your doctor or get medical help right away if you have any symptoms such as the following:

• shortness of breath, wheezing, or any other trouble breathing; coughing, chest pain or spitting up of blood

• nausea or vomiting; passing brown or dark-colored urine; feel more tired than usual; your skin and whites of your eyes get yellow; or have stomach pain

• heart pounding, skipping a beat, beating very fast or very slowly; feel light-headed or faint

• weakness, weight loss or weight gain, heat or cold intolerance, hair thinning, sweating, changes in your menses, swelling of your neck (goiter), nervousness, irritability, restlessness, decreased concentration, depression in the elderly, or tremor.

Because of these possible side effects, Pacerone® Tablets should only be used in adults with life-threatening heartbeat problems called ventricular arrhythmias, for which other treatments did not work or were not tolerated.

Pacerone® Tablets can cause other serious side effects. See "What are the possible or reasonably likely side effects of Pacerone® Tablets?" for more information.

If you get serious side effects during treatment with Pacerone® Tablets you may need to stop Pacerone® Tablets, have your dose changed, or get medical treatment. Talk with your doctor before you stop taking Pacerone® Tablets.

You may still have side effects after stopping Pacerone® Tablets because the medicine stays in your body months after treatment is stopped.

Tell all your healthcare providers that you take or took Pacerone® Tablets. This information is very important for other medical treatments or surgeries you may have.

What are Pacerone® Tablets?

Pacerone® Tablets are a medicine used in adults to treat life-threatening heartbeat problems called ventricular arrhythmias, for which other treatment did not work or was not tolerated. Pacerone® Tablets have not been shown to help people with life-threatening heartbeat problems live longer. Treatment with Pacerone® Tablets should be started in a hospital to monitor your condition. You should have regular check-ups, blood tests, chest x-rays, and eye exams before and during treatment with Pacerone® Tablets to check for serious side effects.

Pacerone® Tablets have not been studied in children.

Who should not take Pacerone® Tablets?

Do not take Pacerone®Tablets if you:

have certain heart conditions (heart block, very slow heart rate, or slow heart rate with dizziness or light-headedness)

have an allergy to amiodarone, iodine, or any of the other ingredients in Pacerone® Tablets. See the end of this Medication Guide for a complete list of ingredients in Pacerone® Tablets.

What should I tell my doctor before starting Pacerone®Tablets?

Tell your doctor about all of your medical conditions including if you:

• have lung or breathing problems

• have liver problems

• have or had thyroid problems

• have blood pressure problems

• are pregnant or planning to become pregnant. Pacerone® Tablets can harm your unborn baby. Pacerone® Tablets can stay in your body for months after treatment is stopped. Therefore, talk with your doctor before you plan to get pregnant.

• are breastfeeding. Pacerone® Tablets pass into your milk and can harm your baby. You should not breastfeed while taking Pacerone® Tablets. Also, Pacerone® Tablets can stay in your body for months after treatment is stopped.

Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Pacerone® Tablets and certain other medicines can interact with each other causing serious side effects. Sometimes the dose of Pacerone® Tablets or other medicines must be changed when they are used together. Especially, tell your doctor if you are taking:

• antibiotic medicines used to treat infections

• depression medicines

• blood thinner medicines

• HIV or AIDS medicines

• cimetidine (Tagamet®), a medicine for stomach ulcers or indigestion

• loratadine (for example: Claritin®, Alavert®), a medicine for allergy symptoms

• seizure medicines

• diabetes medicines

• cyclosporine, an immunosuppressive medicine

• dextromethorphan, a cough medicine

• medicines for your heart, circulation, or blood pressure

• water pills (diuretics)

• high cholesterol or bile medicines

• narcotic pain medicines

• St. John’s Wort

Know the medicines you take. Keep a list of them with you at all times and show it to your doctor and pharmacist each time you get a new medicine. Do not take any new medicines while you are taking Pacerone® Tablets unless you have talked with your doctor.

How should I take Pacerone® Tablets?

Take Pacerone® Tablets exactly as prescribed by your doctor.

• The dose of Pacerone® Tablets you take has been specially chosen for you by your doctor and may change during treatment. Keep taking your medicine until your doctor tells you to stop. Do not stop taking it because you feel better. Your condition may get worse. Talk with your doctor if you have side effects.

• Your doctor will tell you to take your dose of Pacerone® Tablets with or without meals. Make sure you take Pacerone® Tablets the same way each time.

Do not drink grapefruit juice during treatment with Pacerone® Tablets. Grapefruit juice affects how Pacerone® Tablets are absorbed in the stomach.

• Taking too many Pacerone® Tablets can be dangerous. If you take too many Pacerone® Tablets, call your doctor or go to the nearest hospital right away. You may need medical care right away.

• If you miss a dose, do not take a double dose to make up for the dose you missed. Continue with your next regularly scheduled dose.

What should I avoid while taking Pacerone® Tablets?

• Do not drink grapefruit juice during treatment with Pacerone® Tablets. Grapefruit juice affects how Pacerone® Tablets are absorbed in the stomach.

• Avoid exposing your skin to the sun or sun lamps. Pacerone® Tablets can cause a photosensitive reaction. Wear sun-block cream or protective clothing when out in the sun.

• Avoid pregnancy during treatment with Pacerone® Tablets. Pacerone® Tablets can harm your unborn baby.

• Do not breastfeed while taking Pacerone® Tablets. Pacerone® Tablets pass into your milk and can harm your baby.

What are the possible or reasonably likely side effects of Pacerone® Tablets?

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Pacerone® Tablets can cause serious side effects that lead to death including lung damage, liver damage, worse heartbeat problems, and thyroid problems. See "What is the most important information I should know about Pacerone® Tablets?"

Some other serious side effects of Pacerone® Tablets include:

vision problems that may lead to permanent blindness. You should have regular eye exams before and during treatment with Pacerone® Tablets. Call your doctor if you have blurred vision, see halos, or your eyes become sensitive to light.

nerve problems. Pacerone® Tablets can cause a feeling of "pins and needles" or numbness in the hands, legs, or feet, muscle weakness, uncontrolled movements, poor coordination, and trouble walking.

thyroid problems. Pacerone® Tablets can cause thyroid problems, including low thyroid function or overactive thyroid function. Your doctor may arrange regular blood tests to check your thyroid function during treatment with Pacerone® Tablets. Call your doctor if you have weakness, weight loss or weight gain, heat or cold intolerance, hair thinning, sweating, changes in your menses, swelling of your neck (goiter), nervousness, irritability, restlessness, decreased concentration, depression in the elderly, or tremor.

skin problems. Pacerone® Tablets can cause your skin to be more sensitive to the sun or to turn a bluish-gray color. In most patients, skin color slowly returns to normal after stopping Pacerone® Tablets. In some patients, skin color does not return to normal.

Other side effects of Pacerone® Tablets include nausea, vomiting, constipation, and loss of appetite.

Call your doctor about any side effect that bothers you.

These are not all the side effects with Pacerone® Tablets. For more information, ask your doctor or pharmacist.

How should I store Pacerone® Tablets?

• Store Pacerone® Tablets at room temperature. Protect from light. Keep Pacerone® Tablets in a tightly closed container.

• Safely dispose of Pacerone® Tablets that are out-of-date or no longer needed.

Keep Pacerone® Tablets and all medicines out of the reach of children.

General information about Pacerone® Tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Pacerone® Tablets for a condition for which it was not prescribed. Do not share Pacerone® Tablets with other people, even if they have the same symptoms that you have. It may harm them.

If you have any questions or concerns about Pacerone® Tablets, ask your doctor or healthcare provider. This Medication Guide summarizes the most important information about Pacerone® Tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Pacerone® Tablets that was written for healthcare professionals.

This product's Medication Guide may have been updated. For current Medication Guide, please visit www.Pacerone.com or www.upsher-smith.com.

What are the ingredients in Pacerone® Tablets?

Active Ingredient: amiodarone hydrochloride, 400 mg

Inactive Ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, povidone and D&C yellow No. 10 aluminum lake.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Rx only

Manufactured for

UPSHER-SMITH LABORATORIES, INC.

Maple Grove, MN 55369

Tagamet is a registered trademark of SmithKline Beecham Pharmaceuticals Co.

Claritin is a registered trademark of Schering Corporation.

Alavert is a registered trademark of Wyeth.

OS7841

Revised 05/14

MF0145REV05/14

MG #34342

Pacerone 400 mg x 30 Tablets - Label

NDC 0245-0145-30

Pacerone®

(Amiodarone HCl) Tablets

400 mg

PHARMACIST: PLEASE DISPENSE WITH MEDICATION GUIDE PROVIDED SEPARATELY.

30 Tablets

Rx only

UPSHER-SMITH

Pacerone 
amiodarone hydrochloride tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0245-0145
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Amiodarone Hydrochloride (Amiodarone) Amiodarone Hydrochloride 400 mg
Inactive Ingredients
Ingredient Name Strength
SILICON DIOXIDE  
STARCH, CORN  
LACTOSE MONOHYDRATE  
MAGNESIUM STEARATE  
POVIDONES  
D&C YELLOW NO. 10  
Product Characteristics
Color YELLOW (light yellow) Score 2 pieces
Shape OVAL Size 16mm
Flavor Imprint Code P400;01;45
Contains         
Packaging
# Item Code Package Description
1 NDC:0245-0145-30 30 TABLET in 1 BOTTLE
2 NDC:0245-0145-11 100 TABLET in 1 BOTTLE
3 NDC:0245-0145-15 500 TABLET in 1 BOTTLE
4 NDC:0245-0145-01 10 BLISTER PACK in 1 CARTON
4 NDC:0245-0145-89 10 TABLET in 1 BLISTER PACK
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA075315 06/30/2000
Labeler - Upsher-Smith Laboratories, Inc. (047251004)
Revised: 06/2014
 
Upsher-Smith Laboratories, Inc.
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