Sandoz Amiodarone Product Monograph

Recent Major Label Changes

Table of Contents

Sections or subsections that are not applicable at the time of authorization are not listed.

Recent Major Label Changes .................................................................................................. 2

Table of Contents ................................................................................................................... 2

Part 1: Healthcare Professional Information ........................................................................... 4

1 Indications ................................................................................................................. 4

1.1 Pediatrics ................................................................................................................. 4

1.2 Geriatrics ................................................................................................................. 4

2 Contraindications ....................................................................................................... 4

3 Serious Warnings and Precautions Box ....................................................................... 5

4 Dosage and Administration ......................................................................................... 6

4.1 Dosing Considerations ............................................................................................ 6

4.2 Recommended Dose and Dosage Adjustment ....................................................... 7

4.4 Administration ........................................................................................................ 7

4.5 Missed Dose ............................................................................................................ 8

5 Overdose.................................................................................................................... 8

6 Dosage Forms, Strengths, Composition, and Packaging ............................................... 9

7 Warnings and Precautions .......................................................................................... 9

7.1 Special Populations ............................................................................................... 21

7.1.1 Pregnancy .......................................................................................................... 21

7.1.2 Breastfeeding .................................................................................................... 22

7.1.3 Pediatrics ........................................................................................................... 22

7.1.4 Geriatrics ........................................................................................................... 22

8 Adverse Reactions .................................................................................................... 22

8.1 Adverse Reaction Overview .................................................................................. 22

8.2 Clinical Trial Adverse Reactions ............................................................................. 23

8.3 Less Common Clinical Trial Adverse Reactions ..................................................... 27

8.5 Post-Market Adverse Reactions ............................................................................ 27

9 Drug Interactions ...................................................................................................... 28

9.2 Drug Interactions Overview .................................................................................. 28

9.3 Drug-Behaviour Interactions ................................................................................. 31

9.4 Drug-Drug Interactions ......................................................................................... 31

9.5 Drug-Food Interactions ......................................................................................... 32

9.6 Drug-Herb Interactions ......................................................................................... 33

9.7 Drug-Laboratory Test interactions ........................................................................ 33

10 Clinical Pharmacology............................................................................................... 33

10.1 Mechanism of Action ............................................................................................ 33

10.2 Pharmacodynamics ............................................................................................... 34

10.3 Pharmacokinetics .................................................................................................. 34

11 Storage, Stability, and Disposal ................................................................................. 36

Part 2: Scientific Information ............................................................................................... 37

13 Pharmaceutical Information ..................................................................................... 37

14 Clinical Trials ............................................................................................................ 38

14.1 Clinical Trials .......................................................................................................... 38

14.2 Comparative Bioavailability Studies ...................................................................... 40

15 Microbiology ............................................................................................................ 41

16 Non-Clinical Toxicology ............................................................................................. 41

17 Supporting Product Monographs .............................................................................. 59

Patient Medication Information ........................................................................................... 60

Part 1: Healthcare Professional Information

1 Indications

Considering its potential for life-threatening side effects and the substantial management difficulties associated with its oral use, SANDOZ AMIODARONE (amiodarone hydrochloride) is indicated only for the treatment of patients with 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:

• Hemodynamically unstable ventricular tachycardia (VT).
• Recurrent ventricular fibrillation (VF).

As is the case for other antiarrhythmic agents, there is no evidence from controlled clinical trials that the use of amiodarone hydrochloride tablets favourably affects survival.

Because the life-threatening nature of arrhythmias treated, potential interaction with prior therapy, and potential exacerbation of arrhythmia, initiation of therapy with SANDOZ AMIODARONE should be carried out in the hospital.

SANDOZ AMIODARONE should be used only by healthcare professionals familiar with and with access to (directly or 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 technique.

1.1 Pediatrics

Pediatrics (<18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of SANDOZ AMIODARONE in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (> 65 years of age): Clinical studies of amiodarone tablets did not include sufficient number of subjects aged 65 years 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.

2 Contraindications

SANDOZ AMIODARONE is contraindicated in:

• Patients with known hypersensitivity to any of the components of oral amiodarone hydrochloride (tablets) including iodine, and in patients with cardiogenic shock.
• Severe sinus-node dysfunction, causing bradycardia; second- or third-degree V block, and when episodes of bradycardia have caused syncope (except when used in conjunction with a pacemaker).
• Patients with evidence of hepatitis (see 7 Warnings and Precautions, Hepatic/Biliary/Pancreatic), thyroid dysfunction (see 7 Warnings and Precautions, Thyroid Dysfunction), or pulmonary interstitial abnormalities (see 7 Warnings and Precautions, Pulmonary Toxicity).

3 Serious Warnings and Precautions Box

Serious Warnings and Precautions

4 Dosage and Administration

4.1 Dosing Considerations

See 7 Warnings and Precautions, Monitoring and Laboratory Tests and Monitoring Effectiveness.

General Considerations:

BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, SANDOZ AMIODARONE (AMIODARONE HYDROCHLORIDE) THERAPY SHOULD BE INITIATED IN HOSPITAL AND CONTINUED IN A MONITORED ENVIRONMENT UNTIL ADEQUATE CONTROL OF THE ARRHYTHMIA HAS OCCURRED. PATIENTS TREATED WITH SANDOZ AMIODARONE SHOULD BE UNDER THE SUPERVISION OF A CARDIOLOGIST OR A HEALTHCARE PROFESSIONAL WITH EQUIVALENT EXPERIENCE IN CARDIOLOGY WHO IS EXPERIENCED IN THE TREATMENT OF LIFE-THREATENING ARRHYTHMIAS, WHO IS THOROUGHLY FAMILIAR WITH THE RISK AND BENEFIT OF SANDOZ AMIODARONE THERAPY, AND WHO HAS ACCESS TO LABORATORY FACILITIES CAPABLE OF ADEQUATELY MONITORING EFFECTIVENESS AND SIDE EFFECTS OF TREATMENT. DOSE ADMINISTRATION MUST BE INDIVIDUALIZED, PARTICULARLY TAKING INTO ACCOUNT CONCOMITANT ANTIARRHYTHMIC THERAPY.

The dosage schedule for amiodarone hydrochloride is still somewhat controversial, probably in part due to its poor absorption, unusually long elimination half-life, and huge volume of distribution. Extensive tissue stores of amiodarone hydrochloride must be established before the effects on the heart of oral dose administration are apparent. Intersubject variability as well as differences in dosage regimens and methods of assessment have made it difficult to precisely define the time of onset of initial and maximal antiarrhythmic effect in an individual patient. In order to ensure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required. A uniform, optimal dosage schedule for administration of amiodarone hydrochloride has not been determined. Because of the food effect on the absorption of amiodarone hydrochloride, administration of Sandoz Amiodarone should be consistent with regard to meals (see 10.3 Pharmacokinetics section of 10 Clinical Pharmacology). Amiodarone hydrochloride's antiarrhythmic effect after oral administration may be noted in as early as 3 days (72 hours) but more often takes 1 to 3 weeks.

Because of the slow rate of elimination of amiodarone hydrochloride, its antiarrhythmic effects may persist for weeks or months after its discontinuation, but the time of arrhythmia recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established more rapidly relative to the initial response, possibly because tissue stores were not wholly depleted at the time of recurrence.

The combination of SANDOZ AMIODARONE with other antiarrhythmic therapy should be reserved for patients with life-threatening arrhythmias who are unresponsive to adequate doses of a single agent (see 9 Drug Interactions).

Since grapefruit juice is known to inhibit CYP3A4-mediated metabolism of oral amiodarone hydrochloride in the intestinal mucosa, resulting in significant increased plasma levels of amiodarone hydrochloride, grapefruit juice should not be taken during treatment with oral SANDOZ AMIODARONE (see 9 Drug Interactions ).

4.2 Recommended Dose and Dosage Adjustment

Adult Dosage:

Ventricular Arrhythmias

Loading Dose: Loading doses of 800 to 1600 mg/day are required for 1 to 3 weeks (occasionally longer) until therapeutic response occurs. (Administration of SANDOZ AMIODARONE in divided doses at meals is suggested for total daily doses of 1000 mg or higher, when gastrointestinal intolerance occurs). If side effects become excessive, the dose should be reduced.

Maintenance Dose: When adequate arrhythmia control has been achieved, or if adverse drug reactions become prominent, the SANDOZ AMIODARONE dose should be reduced to 600 to 800 mg/day for one month and then to the maintenance dose, usually 200 to 400 mg/day (occasionally 600 mg/day). SANDOZ 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.

The lowest effective dose should be used to prevent the occurrence of adverse drug reactions. In all instances, the healthcare professional must be guided by the severity of the individual patient's arrhythmia and response to therapy. When dose 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 and the difficulty in predicting the time required to attain a new steady-state level of drug. Dosage suggestions are summarized below:

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Geriatric 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.

Health Canada has not authorized an indication for pediatric use.

4.4 Administration

SANDOZ AMIODARONE may be administered as a single daily dose, or in patients with severe gastrointestinal intolerance, as a b.i.d. dose.

Food increases the rate and extent of absorption of amiodarone hydrochloride. Because of the food effect on the absorption of amiodarone hydrochloride, administration of SANDOZ AMIODARONE should be consistent with regard to meals.

Administration of SANDOZ AMIODARONE in divided doses at meals is suggested for total daily doses of 1000 mg or higher, when gastrointestinal intolerance occurs. If side effects become excessive, the dose should be reduced.

4.5 Missed Dose

If you miss a dose of SANDOZ AMIODARONE, you do not need to make up the missed dose. Skip the missed dose and continue with your next scheduled dose. Do NOT take two doses to make up for the missed dose.

5 Overdose

There have been cases, some fatal, of amiodarone hydrochloride overdose. Overdose may lead to severe bradycardia and to conduction disturbances with the appearance of an idioventricular rhythm, particularly in elderly patients or patients on digitalis therapy.

One report of the acute ingestion of a single 8 g dose of oral amiodarone hydrochloride by a healthy 20 year old female has been reported. At first assessment, the patient was conscious and profuse perspiration and a slight tachycardia were the only abnormal findings on clinical observation. Slight bradycardia was observed during the second and third day; thereafter, QT interval and heart rate returned to normal. No clinical adverse events were documented over the subsequent 3-month monitoring period.

The acute oral LD50 of amiodarone hydrochloride in mice and rats is greater than 3000 mg/kg.

Intravenous Amiodarone

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

Overdosage Management

If an overdose should occur, gastric lavage or induced emesis should be employed to reduce absorption, in addition to general supportive measures. The patient's cardiac rhythm and blood pressure should be monitored, and if clinically significant bradycardia ensues, a ß-adrenergic agonist or a temporary pacemaker should 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.

6 Dosage Forms, Strengths, Composition, and Packaging

Table 2 – Dosage Forms, Strengths, Composition and Packaging

Description

Each SANDOZ AMIODARONE tablet 200 mg is pink, round, biconvex with a single score notch on one side and "R-200" on the other, contains 200 mg of amiodarone hydrochloride and is available in HDPE bottles of 100 tablets.

7 Warnings and Precautions

See 3 Serious Warnings and Precautions Box.

General

Mortality

The results of the Cardiac Arrhythmia Suppression Trial (CAST) in post myocardial infarction patients with asymptomatic non-life threatening ventricular arrhythmias who had a myocardial infarction more than six days but less than two years previously showed a significant increase in mortality and non-fatal cardiac arrest rate in patients treated with encainide or flecainide (56/730) compared with a matched placebo treatment group (22/725). CAST was continued using a revised protocol with moricizine and placebo treatment groups only. The trial was prematurely terminated because of the trend towards an increase in mortality in the moricizine-treated group.

The applicability of these results to other populations or other anti-arrhythmic agents is uncertain, but at present, it is prudent to consider these results when using any anti-arrhythmic agent.

Amiodarone hydrochloride therapy was evaluated in two multi-center, randomized, double-blind, placebo-controlled trials involving 1202 (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial; CAMIAT) and 1486 (European Myocardial Infarction Amiodarone Trial; EMIAT) post-MI patients followed for up to 2 years. Patients in CAMIAT qualified with ventricular arrhythmias, and those randomized to amiodarone hydrochloride received weight- and response-adjusted doses of 200 to 400 mg/day. Patients in EMIAT qualified with ejection fraction <40%, and those randomized to amiodarone hydrochloride received fixed doses of 200 mg/day. Both studies had weeks-long loading dose schedules. Intent-to-treat all-cause mortality results were as follows:

These data are consistent with the results of a pooled analysis of 13 smaller, controlled studies involving patients with structural heart disease (including myocardial infarction) where total mortality was reduced by only 13% (odds ratio 0.87, [95% confidence interval 0.75 to 0.99] p=0.03) based on classic fixed effects meta-analysis.

Patients with life-threatening arrhythmias may experience serious adverse events during their treatment and therefore should be properly monitored. Amiodarone hydrochloride should be administered only by healthcare professionals who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone hydrochloride therapy, and who have access to facilities adequate for monitoring the effectiveness and adverse events of treatment (see 1 Indications ).

Loading Phase

The higher doses of oral amiodarone hydrochloride used in the loading phase may sometimes be associated with adverse effects such as nausea or tremor. The nausea may respond to dividing the total dose into two or three fractions taken with meals, or by decreasing the total daily dose. The tremor may respond to dose reduction as well.

Carcinogenesis and Mutagenesis

Oral amiodarone hydrochloride caused a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors in rats was greater than the incidence in controls 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 conducted with amiodarone hydrochloride (Ames, micronucleus, and lysogenic induction tests) were negative.

In a study which amiodarone hydrochloride was orally 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*).

Cardiovascular

Proarrhythmia/QT Interval Prolongation

Amiodarone hydrochloride may cause a worsening of the existing arrhythmias or precipitate a new arrhythmia. Amiodarone hydrochloride causes prolongation of the QT interval. Proarrhythmia, primarily torsades de pointes, has been associated with prolongation of the QTc interval to 500 ms or greater. Proarrhythmic effects generally occur in the context of QT prolongation factors such as drug interactions and/or electrolytic disorders. Despite QT interval prolongation, amiodarone hydrochloride exhibits a low torsadogenic activity. Proarrhythmia has been reported (2% to 5%) with oral amiodarone hydrochloride, especially in the presence of concomitant antiarrhythmic therapy and has included new-onset VF, incessant VT, increased resistance to cardioversion, and paroxysmal polymorphic VT associated with QT prolongation “torsades de pointes”. Although QTc prolongation occurred frequently in patients receiving IV amiodarone hydrochloride, torsades de pointes or new-onset VF occurred infrequently (less than 2% of all patients treated with IV amiodarone hydrochloride in controlled clinical trials). Patients should be

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

monitored carefully for QTc prolongation during amiodarone hydrochloride therapy. Combination of amiodarone hydrochloride with other antiarrhythmic therapy that prolongs the QTc should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent.

The need to co-administer amiodarone hydrochloride with any other drug known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient.

Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without torsades de pointes, in patients taking amiodarone hydrochloride when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly.

A careful assessment of the potential risks and benefits of administering oral amiodarone hydrochloride must be made in patients with thyroid dysfunction due to the possibility of arrhythmia breakthrough or exacerbation of arrhythmia in these patients. For patients receiving IV amiodarone hydrochloride, death may result.

Even in patients at high risk of arrhythmic death, in whom the toxicity of amiodarone hydrochloride is an acceptable risk, amiodarone hydrochloride 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 hydrochloride effectively and safely poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of amiodarone hydrochloride 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 hydrochloride must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone hydrochloride 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.

Bradycardia and AV Block

In patients treated with oral amiodarone hydrochloride, symptomatic bradycardia or sinus arrest with suppression of escape foci occurs in approximately 2% to 4% of patients. Bradycardia was reported as an adverse drug reaction in 4.9% of patients receiving IV amiodarone hydrochloride for life-threatening VT/VF in clinical trials. AV block was reported as an adverse drug reaction in 1.4% of patients receiving IV amiodarone hydrochloride. There was no dose-related increase in bradycardia or AV block in these studies.

In patients who develop symptomatic bradycardia while taking oral amiodarone hydrochloride, dose reduction or discontinuation, and possibly pacing, may be considered. Due to the large body load of amiodarone hydrochloride that accumulates with chronic dose administration, and the long half-life of the drug, serum concentrations decline slowly after dose reduction or discontinuation.

Severe Bradycardia

Cases of severe, potentially life-threatening bradycardia and heart block have been observed when amiodarone hydrochloride is used in combination with sofosbuvir alone or in combination with another hepatitis C virus (HCV) direct acting antiviral (DAA), such as daclatasvir, simeprevir, or ledipasvir. Therefore, coadministration of these agents with amiodarone hydrochloride is not recommended.

If concomitant use with amiodarone hydrochloride cannot be avoided, it is recommended that patients are closely monitored when initiating sofosbuvir alone or in combination with other DAAs. Patients who are identified as being at high risk of bradyarrhythmia should be continuously monitored for at least 48 hours in an appropriate clinical setting after initiation of the concomitant treatment with sofosbuvir.

Due to the long half-life of amiodarone hydrochloride, appropriate monitoring should also be carried out for patients who have discontinued amiodarone hydrochloride within the past few months and are to be initiated on sofosbuvir alone or in combination with other direct DAAs.

Patients receiving these hepatitis C medicines with amiodarone hydrochloride, with or without other medicines that lower heart rate, should be warned of the symptoms of bradycardia and heart block and should be advised to seek urgent medical advice if they experience them.

Intravenous Amiodarone

Hypotension

Hypotension is the most common adverse event seen with IV amiodarone hydrochloride therapy: it is uncommon (<1%) during oral amiodarone hydrochloride therapy. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse effect in 288 (16%) of 1836 patients treated with IV amiodarone hydrochloride. 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 temporary discontinuation of IV amiodarone hydrochloride therapy was reported in 3% of the 814 patients, with permanent discontinuation required in an additional 2% of the 814 patients. In some cases, hypotension may be refractory resulting in fatal outcome.

Oral Amiodarone

Cardiac Disorders

SANDOZ AMIODARONE should be used with caution in patients with latent or manifest heart failure because this condition may be worsened by its administration. In these cases, Sandoz Amiodarone should be given with appropriate concurrent therapy.

SANDOZ AMIODARONE therapy may be considered in the treatment of patients with Wolff-Parkinson-White (WPW) syndrome, atrial flutter, or atrial fibrillation, when these conditions are complicated by life-threatening ventricular tachyarrhythmias. In such cases, care is required since the effect of oral amiodarone hydrochloride in these conditions does not appear to be uniform. Electrophysiologic studies may be of value in the selection of these patients who may respond to oral amiodarone hydrochloride, particularly in WPW syndrome.

Implantable Cardiac Devices

In patients with implanted defibrillators or pacemakers, chronic administration of anti-arrhythmic drugs affects pacing or defibrillating thresholds. Therefore, at the inception of and during amiodarone hydrochloride treatment, pacing and defibrillation thresholds should be assessed.

Endocrine and Metabolism

Thyrotoxicosis

Amiodarone hydrochloride -induced hyperthyroidism may result in thyrotoxicosis and/or the possibility of arrhythmia breakthrough or aggravation. 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 (also see 7 Warnings and Precautions, Thyroid Dysfunction below).

Thyroid Abnormalities and Dysfunction

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. Both hyper- and hypothyroidism may occur during, or soon after treatment with SANDOZ AMIODARONE. Because of its release of inorganic iodine, or perhaps for other reasons, SANDOZ AMIODARONE 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 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 hydrochloride -treated patients, free thyroxine index values may be normal. Hypothyroidism is best managed by amiodarone hydrochloride dose reduction and/or thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue SANDOZ AMIODARONE tablets 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 arrhythmia breakthrough or aggravation, which may result in death. There have been reports of death associated with amiodarone hydrochloride -induced thyrotoxicosis. In fact, 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 amiodarone hydrochloride.

The institution of anti-thyroid drugs, beta-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of anti-thyroid drugs may be especially delayed in amiodarone hydrochloride -induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. There have been reports of death associated with amiodarone hydrochloride -induced thyrotoxicosis. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone hydrochloride -induced hyperthyroidism. Experience with thyroid surgery in this setting is extremely limited, and this form of therapy could induce thyroid storm. Amiodarone hydrochloride -induced hyperthyroidism may be followed by a transient period of hypothyroidism.

There have been post-marketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone. In some instances hyperthyroidism was also present.

In a rat carcinogenicity study, at doses of 5, 16 and 50 mg/kg/day, amiodarone hydrochloride produced statistically significant dose-related changes in the thyroid gland, including follicular adenomas and carcinomas. The significance of these changes for the long-term use of amiodarone hydrochloride in humans is unknown.

Neonatal Hypo- or Hyperthyroidism

SANDOZ 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 its oral administration. If SANDOZ AMIODARONE is used during pregnancy, or if the patient becomes pregnant while taking SANDOZ AMIODARONE, the patient should be apprised of the potential hazard to the fetus.

In general, amiodarone hydrochloride should be used during pregnancy only if the potential benefit to the mother justifies the unknown risk to the fetus.

In pregnant rats and rabbits, amiodarone hydrochloride in dose of 25 mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose∗). had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose*) caused abortions in greater than 90% of the animals. In the rat, doses of 50 mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose.*) Adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose*).

Gastrointestinal

Certain gastrointestinal reactions (e.g., nausea, vomiting, constipation, and bad taste) occur frequently at the initiation of therapy when high doses are used. These may disappear on reduction of the dose.

Hepatic/Biliary/Pancreatic

Liver Enzyme Elevations

In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of amiodarone hydrochloride therapy. However, patients receiving oral amiodarone hydrochloride should be monitored carefully for evidence of progressive hepatic injury.

Elevations of blood hepatic enzyme values-alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) - are seen commonly in patients with immediately life-threatening VT/VF. Interpreting elevated AST activity can be difficult because the values may be elevated in patients with recent myocardial infarction, congestive heart failure, and in those who have received multiple electrical defibrillations.

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

If the increase in hepatic enzyme levels exceeds three times normal or double in a patient with elevated baseline, discontinuation of SANDOZ AMIODARONE should be considered.

Asymptomatic elevations of liver enzymes (AST/SGOT and ALT/SGPT) are frequently associated with the use of oral amiodarone hydrochloride. The mechanism whereby this hepatic effect occurs has not been defined. Phospholipidosis and fibrosis of the liver resembling alcoholic hepatitis or cirrhosis, accompanied by only a mild elevation of hepatic enzymes, have been reported in association with the use of oral amiodarone hydrochloride. Rises in hepatic enzymes, especially when associated with clinical signs and symptoms of hepatitis, or with asymptomatic hepatomegaly, may indicate a liver scan and, if needed, a liver biopsy with ultrastructural study. If serum enzyme levels increase significantly, or persist over time, consideration should be given to discontinuation or reducing the dose of amiodarone hydrochloride. Hepatic failure has been a rare cause of death in patients treated with oral amiodarone hydrochloride.

Approximately 54% of patients receiving IV amiodarone in clinical studies had baseline elevations in liver enzyme values, and 13% had clinically significant elevations. In 81% of patients with 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.

Rare cases of fatal hepatocellular necrosis after treatment with IV amiodarone hydrochloride have been reported. Two patients, one 28 and the other 60 years of age, received an initial infusion of 1500 mg over 5 hours, a rate much higher than recommended. Both patients developed hepatic and renal failure within 24 hours after the start of IV amiodarone hydrochloride treatment and died on day 14 and day 4, respectively. Because these episodes of hepatic necrosis may have been due to the rapid rate of infusion and hypotension is related to the rate of infusion, the initial rate of infusion should be monitored closely and should not exceed that recommended.

Monitoring and Laboratory Tests

SANDOZ AMIODARONE should be used only by healthcare professionals familiar with and with access to (directly or 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 technique.

In addition, the following should be considered and/or monitored for patient on amiodarone hydrochloride:

Electrolyte Disturbances

Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in any patient with potassium or magnesium deficiency, patients with hypokalemia or hypomagnesemia should have the condition corrected before instituting SANDOZ AMIODARONE tablets therapy, since these disorders can exaggerate the degree of QTc prolongation and increase the potential for torsades de pointes. Special attention should be given to electrolyte and acid-base in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics. Use caution when co-administering SANDOZ AMIODARONE with drugs which may induce hypokalemia and/or hypomagnesemia.

Thyroid Function

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 amiodarone hydrochloride withdrawal.

Liver Enzyme Elevations

In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of SANDOZ AMIODARONE therapy. However, patients receiving SANDOZ AMIODARONE should be monitored carefully for evidence of progressive hepatic injury.

QTc Prolongation

Patients should be monitored carefully for QTc prolongation during amiodarone hydrochloride therapy.

Surgery

It is recommended that FiO₂ and the determinants of oxygen delivery to the tissues (e.g., SaO₂, PaO₂) be closely monitored in patients on SANDOZ AMIODARONE.

Geriatrics

During chronic treatment with oral amiodarone hydrochloride, close monitoring may be prudent for elderly patients.

Ventricular Dysfunction

During chronic treatment with oral amiodarone hydrochloride, close monitoring may be prudent for patients with severe left ventricular dysfunction.

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. 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. 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 amiodarone hydrochloride. 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
3. 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/1000 normal beats).

While these issues remain unsettled for amiodarone hydrochloride, as for other agents, the prescriber of SANDOZ AMIODARONE 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 amiodarone hydrochloride, 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 amiodarone hydrochloride, 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.

Neurologic

Nervous System Disorders

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

Ophthalmologic

Loss of Vision

Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with amiodarone hydrochloride. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and/or neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt ophthalmic examination is recommended. Appearance of optic neuropathy and/or neuritis calls for re-evaluation of amiodarone hydrochloride therapy. The risks and complications of antiarrhythmic therapy with amiodarone hydrochloride must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmic examination, including fundoscopy and slit-lamp examination, is recommended during administration of SANDOZ AMIODARONE (see 8.2 Adverse Reactions, Ophthalmological Abnormalities).

Ocular Abnormalities (Corneal Microdeposits)

Corneal micro-deposits 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 8.2 Adverse Reactions, Ophthalmological Abnormalities).

Peri-Operative Considerations

Surgery

Occurrences of adult respiratory syndrome (ARDS) and low cardiac output syndrome have been reported postoperatively in patients receiving oral amiodarone hydrochloride therapy who have undergone either cardiac or noncardiac surgery. An intra-aortic balloon pump augmentation has been required in some patients with the low cardiac output syndrome at discontinuation of cardiopulmonary bypass. In the case of ARDS, although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. A number of patients who developed ARDS were subjected to a high concentration of oxygen in the inspired air; this could have been a factor in the respiratory complications. 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 Sandoz Amiodarone. Caution should also be exercised in considering SANDOZ AMIODARONE patients for surgery in the presence of preoperative pulmonary dysfunction. However, as amiodarone hydrochloride has a very long half-life, withdrawal before surgery implies delaying operations by several weeks and putting patients at increased risk of malignant dysrhythmias. The ARDS in these cases has rarely been fatal.

Hypotension independent of, or associated with, discontinuation of cardiopulmonary bypass following open-heart surgery has been reported. Blood vessels may respond poorly to adrenoreceptor agonists. Atropine-resistant bradycardia and complete heart block have also been reported in patients being weaned from cardiopulmonary bypass.

Corneal Refractive Surgery

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

Volatile anaesthetic agents: close peri-operative monitoring is recommended in patients undergoing general anaesthesia who are on amiodarone hydrochloride therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalation anaesthetics.

Primary graft dysfunction (PGD) post cardiac transplant

There is supportive evidence based on observational studies linking recipient use of amiodarone pre-heart transplant with increased risk of primary graft dysfunction. The certainty of the evidence is low due to the lack of randomization and retrospective nature of these observational studies, that are susceptible to confounding and bias.

PGD is a life-threatening complication of heart transplantation that presents as a left, right or biventricular dysfunction occurring within the first 24 hours of transplant surgery for which there is no identifiable secondary cause. Severe PGD may be irreversible.

For patients who are on a heart transplant waiting list, consideration should be given to use of an alternative antiarrhythmic drug as early as possible before transplant.

Reproductive Health: Female and Male Potential

Urogenital System Disorders

Oral amiodarone hydrochloride -induced epididymitis has been observed in some patients. This form of epididymitis is rare, benign, self-limited, and requires no treatment. Healthcare professionals should be aware of it to protect their patients from unnecessary invasive urologic examinations and antibiotic therapy.

Respiratory

Intravenous and Oral amiodarone hydrochloride

Pulmonary Toxicity

There have been post-marketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with oral amiodarone hydrochloride with or without initial IV therapy. Findings have included pulmonary infiltrates and/or mass on X-ray, pulmonary alveolar hemorrhage, pleural effusion, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure and/or death.

One of the most serious complications resulting from oral amiodarone hydrochloride therapy is pulmonary toxicity, characterized by pneumonitis. Clinical symptoms include cough, progressive dyspnea, accompanied by functional, radiographic, gallium-scan, weight loss, weakness and pathological data consistent with pulmonary toxicity. On chest x-ray, there is a diffuse interstitial pattern lung involvement frequently with patchy alveolar infiltrates, particularly in the upper lobe. Predicting which patient will develop pulmonary toxicity has been difficult (see 2 Contraindications). Pulmonary toxicity can appear abruptly either early or late during therapy and it commonly mimics viral or bacterial infection or worsening congestive heart failure. The relationship of pulmonary toxicity to duration of therapy, maintenance dose, and total dose is unclear. The majority of patients have recovered with this management, although some fatalities have occurred. Therefore, when SANDOZ AMIODARONE therapy is initiated, a baseline chest x-ray and pulmonary-function tests, including diffusion capacity, should be performed. The patient should return for a history, physical exam, and chest x-ray every 3 to 6 months.

Pulmonary toxicity secondary to amiodarone hydrochloride seems to result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis (including eosinophilic pneumonia) or interstitial/alveolar pneumonitis, respectively at rates as high as 10-17% in patients with ventricular arrhythmias given doses around 400 mg/day. Pulmonary toxicity has been fatal about 10% of the time.

Recent reports suggest that the use of lower loading and maintenance doses of amiodarone hydrochloride are associated with a decreased incidence of amiodarone hydrochloride -induced pulmonary toxicity.

Hypersensitivity pneumonitis usually appears earlier in the course of therapy, and rechallenging these patients with amiodarone hydrochloride results in a more rapid recurrence of greater severity. Bronchoalveolar lavage is the procedure of choice to confirm this diagnosis, which can be made when a T suppressor/cytotoxic (CD8-positive) lymphocytosis is noted. Steroid therapy should be instituted and amiodarone hydrochloride therapy discontinued in these patients.

Interstitial/alveolar pneumonitis may result from the release of oxygen radicals and/or phospholipidosis and is characterized by findings of diffuse alveolar damage, interstitial pneumonitis or fibrosis in lung biopsy specimens. Phospholipidosis (foamy cells, foamy macrophages), due to inhibition of phospholipase, will be present in most cases of amiodarone hydrochloride -induced pulmonary toxicity; however, these changes also are present in approximately 50% of all patients on amiodarone hydrochloride therapy. These cells should be used as markers of therapy, but not as evidence of toxicity. A diagnosis of amiodarone-induced interstitial/alveolar pneumonitis should lead, at a minimum, to dose reduction or, preferably to withdrawal of the amiodarone hydrochloride to establish reversibility, especially if other acceptable antiarrhythmic therapies are available. Where these measures have been instituted, a reduction in symptoms of amiodarone hydrochloride -induced pulmonary toxicity was usually noted within the first week, and a clinical improvement was greatest in the first two to three weeks. Chest x-ray changes usually resolve within two to four months. According to some experts steroids may prove beneficial. Prednisone in doses of 40 to 60 mg/day or equivalent doses of other steroids have been given and tapered over the course of several weeks depending upon the condition of the patient. In some cases rechallenge with amiodarone hydrochloride at a lower dose has not resulted in return of toxicity.

In a patient receiving SANDOZ AMIODARONE, any new respiratory symptoms should suggest the possibility of pulmonary toxicity, and the history, physical exam, chest x-ray, and pulmonary-function tests (with diffusion capacity) should be repeated and evaluated. A 15% decrease in diffusion capacity has a high sensitivity but only a moderate specificity for pulmonary toxicity; as the decrease in diffusion capacity approaches 30%, the sensitivity decreases but the specificity increases. A gallium-scan also may be performed as part of the diagnostic workup.

Fatalities, secondary to pulmonary toxicity, have occurred in approximately 10% of cases. However, in patients with life-threatening arrhythmias, discontinuation of SANDOZ AMIODARONE therapy due to suspected drug-induced pulmonary toxicity should be undertaken with caution, as the most common cause of death in these patients is sudden cardiac death. Therefore, every effort should be made to rule out other causes of respiratory impairment (i.e. congestive heart failure with Swan-Ganz catheterization if necessary, respiratory infection, pulmonary embolism, malignancy, etc.) before discontinuing SANDOZ AMIODARONE in these patients. In addition, bronchoalveolar lavage, transbronchial lung biopsy and/or open lung biopsy may be necessary to confirm the diagnosis, especially in those cases where no acceptable alternative therapy is available.

If a diagnosis of amiodarone hydrochloride -induced hypersensitivity pneumonitis is made, amiodarone hydrochloride should be discontinued, and treatment with steroids should be instituted. If a diagnosis of amiodarone-induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, SANDOZ AMIODARONE discontinued or, at a minimum, reduced in dosage.

Some cases of amiodarone hydrochloride -induced interstitial/alveolar pneumonitis may resolve following a reduction in amiodarone hydrochloride dosage in conjunction with the administration of steroids. In some patients, rechallenge at a lower dose has not resulted in return of interstitial/alveolar pneumonitis; however, in some patients (perhaps because of severe alveolar damage) the pulmonary lesions have not been reversible.

Only 1 of more than 1000 patients treated with IV amiodarone hydrochloride in clinical studies developed pulmonary fibrosis. For that patient, the condition was diagnosed 3 months after treatment with IV amiodarone hydrochloride, during which time she had received oral amiodarone hydrochloride. IV amiodarone hydrochloride therapy should be discontinued if a diagnosis of pulmonary fibrosis is made.

During clinical studies of IV amiodarone hydrochloride, 2% of patients were reported to have adult respiratory distress syndrome (ARDS). ARDS is a disorder characterized by bilateral, diffuse pulmonary infiltrates with pulmonary edema and varying degrees of respiratory insufficiency. The clinical and radiographic picture can arise after a variety of lung injuries, such as those resulting from trauma, shock, prolonged cardiopulmonary resuscitation, and aspiration pneumonia, conditions present in many of the patients enrolled in the clinical studies. It is not possible to determine what role, if any, IV amiodarone hydrochloride played in causing or exacerbating the pulmonary disorder in those patients.

Skin

Dermatologic Disorders/Photosensitivity

Oral amiodarone hydrochloride induces photosensitization in about 10% of patients. Sunscreen preparations or protective clothing may afford some protection to individual patients experiencing photosensitization. Blue-grey discolouration of exposed skin has been reported during long-term treatment. With discontinuation of therapy, the pigmentation regresses slowly over a period of up to several years. 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.

Intravenous and Oral amiodarone hydrochloride

Severe Bullous reactions

Life-threatening or even fatal cutaneous reactions: Steven-Johnson syndrome (SJS), Toxic

Epidermal Necrolysis (TEN) have been reported (see 8 Adverse Reactions). If symptoms or signs of SJS, TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present amiodarone hydrochloride treatment should be discontinued immediately.

7.1 Special Populations

7.1.1 Pregnancy

Amiodarone hydrochloride has been shown to be embryotoxic in some animal species. In three different human case reports, both the parent drug and its DEA metabolite have been shown to pass through the placenta, quantitatively ranging between 10% and 50% of human maternal serum concentrations. Although amiodarone hydrochloride use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. Therefore, amiodarone hydrochloride should be used during pregnancy only if the potential benefit to the mother justifies the risk to the fetus.

In addition to causing infrequent congenital goiter/hypothyroidism and hyperthyroidism (see 7 Warnings and Precautions, Neonatal Hypo- or Hyperthyroidism), amiodarone hydrochloride has caused a variety of adverse effects in animals.

In a reproductive study in which amiodarone hydrochloride was given intravenously to rabbits at dosages of 5, 10, or 25 mg/kg per day (about 0.1, 0.3, and 0.7 times the maximum recommended human dose [MRHD] on a body surface area basis), maternal deaths occurred in all groups, including controls. Embryotoxicity (as manifested by fewer full-term fetuses and increased resorptions with concomitantly lower litter weights) occurred at dosages of 10 mg/kg and above. No evidence of embryotoxicity was observed at 5 mg/kg and no teratogenicity was observed at any dosages.

In a teratology study in which amiodarone hydrochloride was administered by continuous IV infusion to rats at dosages of 25, 50, or 100 mg/kg per day (about 0.4, 0.7, and 1.4 times the MRHD when compared on a body surface area basis), maternal toxicity (as evidenced by reduced weight gain and food consumption) and embryotoxicity (as evidenced by increased resorptions, decreased live litter size, reduced body weights, and retarded sternum and metacarpal ossification) were observed in the 100 mg/kg group. Intravenous amiodarone hydrochloride should be used during pregnancy only if the potential benefit to the mother justifies the risk to the fetus.

Use During Labour and Delivery: It is not known whether the use of amiodarone hydrochloride during labour or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect on the duration of gestation or on parturition.

7.1.2 Breastfeeding

Amiodarone hydrochloride and its DEA metabolite 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 hydrochloride have demonstrated reduced viability and reduced body weight gains. The risk of exposing the infant to amiodarone hydrochloride should be weighed against the potential benefit of arrhythmia suppression in the mother. The mother should be advised to discontinue nursing.

7.1.3 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Clinical studies of amiodarone hydrochloride tablets did not include sufficient number of subjects aged 65 years 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.

8 Adverse Reactions

8.1 Adverse Reaction Overview

Because of the extensive distribution of amiodarone hydrochloride in body tissues, and the prolonged time required for its elimination from the body following discontinuation of long-term therapy, the relationship between adverse reactions and dosage and duration of therapy, has not been fully established. For some adverse reactions - for example, corneal microdeposits - a relationship to dosage and duration of therapy has been established, so that corneal deposits are reversible with dose-reduction or with discontinuation of therapy. However, for other adverse reactions - for example, fibrosing alveolitis or peripheral neuropathy - the dose relationship and the reversibility of the adverse reaction have not been established. Certain gastrointestinal reactions (e.g. nausea, vomiting, constipation, and bad taste) and central nervous system reactions (e.g. fatigue, headaches, vertigo, nightmares, and sleeplessness) occur frequently at the initiation of therapy when high doses are used. These may disappear on reduction of the dose. The time and dose relationship of adverse events are under continued study.

The most serious and potentially life-threatening adverse effects associated with the use of amiodarone hydrochloride are pulmonary fibrosis, the aggravation of arrhythmias, and cirrhotic hepatitis. Published data reflecting the North American experience with chronic oral amiodarone hydrochloride therapy suggest that amiodarone hydrochloride -associated adverse drug reactions are very common, having occurred in approximately 75% of patients taking 400 mg or more per day; these adverse events have led to the discontinuation of amiodarone treatment in 7% to 18% of patients. The adverse reactions most frequently requiring discontinuation of amiodarone hydrochloride have included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. Other symptoms causing discontinuations less often have included visual disturbances, solar dermatitis, blue skin discolouration, hyperthyroidism, and hypothyroidism.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Please see Tables 3 (oral amiodarone hydrochloride) and 4 (intravenous amiodarone hydrochloride), below.

Commonly Observed Adverse Reactions

Intravenous amiodarone hydrochloride

In a total of 1836 patients in controlled and uncontrolled clinical trials, 14% of patients received IV amiodarone hydrochloride for up to 1 week, 5% received it for up to 2 weeks, 2% received it for up to 3 weeks, and 1% received it for more than 3 weeks, without an increased incidence of serious adverse events. The mean duration of therapy in these studies was 5.6 days.

Overall, treatment was discontinued in 9% of the patients because of adverse events. The most common serious adverse events leading to discontinuation of IV amiodarone hydrochloride therapy were ventricular tachycardia (2%), hypotension (2%), cardiac arrest (asystole/cardiac arrest/electromechanical dissociation) (1%), and cardiogenic shock (1%).

The following adverse events are based upon retrospective multicentre analysis of 241 patients treated at various doses of amiodarone for 2 to 1515 days (mean duration: 441.3 days).

Table 3 – Incidence of Adverse Events in patients receiving oral amiodarone hydrochloride

* Based on one retrospective study from 1981 to June 1986 at the Mayo Clinic, up to 2% optic neuropath with visual impairment/decreased acuity.

Table 4 lists the most common (incidence ≥ 1%) adverse drug reactions during IV amiodarone hydrochloride therapy that were collected from controlled and open-label clinical trials involving 1836 patients with hemodynamically unstable VT or VF.

Table 4 – Summary tabulation of Adverse Drug Reactions in patients receiving IV amiodarone hydrochloride in controlled and open-label studies (≥ 1% incidence)

Ophthalmological Abnormalities: Corneal microdeposits are apparent upon slit-lamp examination in virtually all adult patients who have taken amiodarone for longer than 6 months. These deposits may give rise to symptoms such as visual halos or blurred vision (see 7 Warnings and Precautions). Other reported amiodarone hydrochloride -associated abnormalities have included photophobia corneal degeneration, papilledema, photosensitivity, eye discomfort, dry eyes, scotoma, lens opacities, and macular degeneration, optic neuropathy and/or optic neuritis, in some cases progressing to permanent blindness (see 7 Warnings and Precautions, Ophthalmologic).

Neurological Abnormalities: Occurring in 20% to 40% of patients, these common problems have included ataxia, tremor, fatigue, dizziness, weakness, sleep disorders, headaches, cognitive disorders, disturbances of alertness, peripheral motor and sensory neuropathies, proximal muscle weakness, impotence (see 7 Warnings and Precautions, Neurologic) and pseudotumour cerebri. There have been spontaneous reports of demyelinating polyneuropathy.

Pulmonary Abnormalities: In some studies symptomatic pulmonary disease has been detected at rates as high as 10% to 15%, whereas asymptomatic abnormalities of pulmonary diffusion capacity have been demonstrated at greater than twice that incidence. Pulmonary toxicity has been fatal about 10% of the time (see 7 Warnings and Precautions, Respiratory).

Cardiovascular Abnormalities: Exacerbation of arrhythmia has had a reported incidence of about 2% to 5% in most series (new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and paroxysmal polymorphic ventricular tachycardia (torsades de pointes). In addition, symptomatic bradycardia or sinus arrest with suppression of escape foci has occurred in 2% to 4% of patients. Congestive heart failure has occurred in approximately 3% of patients. Second degree AV block and left bundle branch block (LBBB) have occurred in less than 1% of patients, vasculitis and angioedema have also been reported. Hypotension independent of - as well as associated with - discontinuation of cardiopulmonary bypass following open heart surgery has also been reported (see 7 Warnings and Precautions, Cardiovascular).

Gastrointestinal Abnormalities: Complaints of this nature have occurred in about 25% of patients and have included nausea, vomiting, constipation, anorexia, abnormal taste and smell, abnormal salivation, dyspepsia, abdominal pain, and diarrhea (see 7 Warnings and Precautions, Gastrointestinal).

Hepatic Abnormalities: Abnormal elevations of serum levels of enzymes associated with hepatic dysfunction have occurred in approximately 15% of patients. Symptomatic hepatitis has occurred in less than 1% of patients and cholestatic hepatitis and cirrhosis have been reported (see 7 Warnings and Precautions, Hepatic/Biliary/Pancreatic). The frequency of rare serious liver injury, abnormal liver-function tests, hepatitis, cholestatic hepatitis and cirrhosis is undetermined. Overt liver disease can occur however, and has been fatal in a few cases.

Dermatologic Abnormalities: These have occurred in approximately 15% of patients, with photosensitivity (10% of patients) being the most common. Blue-grey skin pigmentation has been reported in 2% to 3% of patients. Hair loss (alopecia) has been observed in up to 4% of patients. Other amiodarone hydrochloride -associated phenomena reported with less than 1% incidence have included non-specific skin eruptions, pruritus, acquired keratoderma, hyperhidrosis, onycholysis, generalized pustular psoriasis, vasculitis and polyserositis, and toxic epidermal necrolysis (sometimes fatal) (see 7 Warnings and Precautions, Dermatologic Disorders/Photosensitivity).

Thyroid Abnormalities: Amiodarone hydrochloride -associated hypothyroidism has been reported in 2% to 4% of patients in most series but in 8% to 10% of patients with other series: hyperthyroidism has been reported in 1% to 3% of patients (see 7 Warnings and Precautions, Thyroid Dysfunction).

8.3 Less Common Clinical Trial Adverse Reactions

Cardiovascular: Hypotension, cardiac conduction abnormalities.

Dermatologic: Alopecia, onycholysis.

Neurological: Tinnitus.

Thyroid: Goiter.

Other: Spontaneous ecchymosis, epididymitis.

8.5 Post-Market Adverse Reactions

In post-marketing surveillance, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, eosinophilic pneumonia, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis/acute pancreatitis, dry mouth, constipation, renal impairment, renal insufficiency, acute renal failure, 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, eczema, urticaria, erythema multiforme, exfoliative dermatitis, severe skin reactions sometimes fatal including toxic epidermal necrolysis/ Stevens-Johnson syndrome, bullous dermatitis and drug reactions with eosinophilia and systemic symptoms (DRESS), skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma including bone marrow granuloma, myopathy, muscle weakness, rhabdomyolysis, demyelinating polyneuropathy, hallucination, confusional state, disorientation, delirium, epididymitis, decreased appetite, parosmia, libido decreased and impotence, also have been reported in patients receiving amiodarone hydrochloride.

Women receiving amiodarone hydrochloride have been reported to be at greater risk of experiencing torsade de pointes.

Also, in patients receiving recommended dosages, there have been postmarketing reports of the following injection site reactions: pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing (see 4 Dosage and Administration).

Injury, poisoning and procedural complications: primary graft dysfunction post cardiac transplant

9 Drug Interactions

9.2 Drug Interactions Overview

Volatile Anesthetic Agents

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

Beta-Blockers

Amiodarone hydrochloride should be used with caution in patients receiving ß-receptor blocking agents (e.g., propranolol, a CYP3A4 inhibitor) because of the possible potentiation of bradycardia, sinus arrest, and AV block. If necessary, amiodarone hydrochloride can continue to be used after insertion of a pacemaker in patients with severe bradycardia or sinus arrest.

Calcium Channel Antagonists

Amiodarone hydrochloride should be used with caution in patients receiving 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 hydrochloride 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 hydrochloride and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone hydrochloride increases the prothrombin time by 100% after 3 to 4 days, the dose of warfarin should be reduced by one-third to one-half, and prothombin 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.

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 hydrochloride.

Drugs Affecting Cardiac Conduction

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

Drugs prolonging QT

Co-administration of amiodarone hydrochloride with drugs known to prolong the QT interval must be based on a careful assessment of the potential risks and benefits for each patient since the risk of torsade de pointes may increase and patients should be monitored for QT prolongation.

Antiarrhythmics

In general, combination of amiodarone hydrochloride 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 hydrochloride. During transfer to amiodarone hydrochloride the dose levels of previously administered agents should be reduced by 30 to 50% several days after the addition of amiodarone hydrochloride, when arrhythmia suppression should be beginning.

The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone hydrochloride 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 hydrochloride -treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose.

Interactions via Cytochrome P450 System

Amiodarone hydrochloride 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 10 Clinical Pharmacology, Pharmacokinetics). Amiodarone hydrochloride is a substrate and an inhibitor of CYP3A4 and a substrate of p-glycoprotein. Therefore, amiodarone hydrochloride 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 hydrochloride have been reported, chiefly with the oral formulation, 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 hydrochloride, potential for drug interactions exists not only with concomitant medication but also with drugs administered after discontinuation of amiodarone hydrochloride.

Examples of drugs that may have serum concentrations increased by amiodarone

Amiodarone hydrochloride inhibits p-glycoprotein and certain CYP450 enzymes (enzyme inhibition: CYP3A4,CYP2C9, CYP2D6). This can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates of p-glycoprotein and may lead to toxic effects. Due to the long half-life of amiodarone hydrochloride, interactions may be observed for several months after discontinuation of amiodarone hydrochloride. Reported examples of this interaction include the following:

HMG-CoA Reductase Inhibitors

HMG-CoA reductase inhibitors that are CYP3A4 substrates (including simvastatin and atorvastatin) in combination with amiodarone hydrochloride have been associated with reports of myopathy/rhabdomyolysis.

Immunosuppressives

Oral amiodarone hydrochloride administered in combination with cyclosporine (CYP3A4 substrate) has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine. Combination of amiodarone hydrochloride 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 hydrochloride. During transfer to amiodarone hydrochloride the dose levels of previously administered agents should be reduced by 30 % to 50% several days after the addition of amiodarone hydrochloride, when arrhythmia suppression should be beginning. The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone hydrochloride 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 hydrochloride is continued. In amiodarone hydrochloride -treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose.

Antihypertensives

Amiodarone hydrochloride should be used with caution in patients receiving ß-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 hydrochloride 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 hydrochloride and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone hydrochloride 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.

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

Protease Inhibitors

Protease inhibitors are known to inhibit CYP3A4 to varying degrees. Inhibition of CYP3A4 by indinavir has been reported to result in increased serum concentrations of amiodarone hydrochloride. Monitoring for amiodarone hydrochloride toxicity and serial measurement of amiodarone hydrochloride serum concentration during concomitant protein 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 hydrochloride.

Antiviral drugs

Coadministration of amiodarone hydrochloride with sofosbuvir alone or in combination with another HCV direct acting antiviral (such as daclatasvir, simeprevir, or ledipasvir) is not recommended as it may lead to serious symptomatic bradycardia. The mechanism for this bradycardia effect is unknown. If coadministration cannot be avoided, cardiac monitoring is recommended.

Other Drugs

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

P-glucoprotein substrates: amiodarone is a P-gp inhibitor. Co-administration with P-gp substrates is expected to result in an increase of their exposure.

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 hydrochloride 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 hydrochloride has been shown to result in decreases in serum concentrations of amiodarone hydrochloride and desethylamiodarone.

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

Agents which may induce hypokalaemia

Combined therapy with stimulating laxative agents which may cause hypokalaemia thus increasing the risk of torsade de pointes is not recommended. Other types of laxatives should be used.

9.3 Drug-Behaviour Interactions

The interaction of SANDOZ AMIODARONE with individual behavioural risks (e.g. cigarette smoking, cannabis use, and/or alcohol consumption) has not been studied.

9.4 Drug-Drug Interactions

Table 5 – Summary of drug interactions with amiodarone hydrochloride, drugs whose effects may be increased by amiodarone hydrochloride

Table 6 – Summary of drug interactions with amiodarone, drugs that may interfere with the actions of amiodarone

9.5 Drug-Food Interactions

Grapefruit Juice

Grapefruit juice inhibits CYP3A4-mediated metabolism of oral amiodarone hydrochloride in the intestinal mucosa, resulting in significant increased plasma levels of amiodarone hydrochloride (Cmax and AUC increased by 84% and 50%, respectively); therefore, grapefruit juice should not be taken during treatment with oral amiodarone hydrochloride. Therefore, this information should be considered when changing from intravenous amiodarone to oral amiodarone hydrochloride.

9.6 Drug-Herb Interactions

St. John’s Wort

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

9.7 Drug-Laboratory Test interactions

Interactions with laboratory tests have not been established.

10 Clinical Pharmacology

10.1 Mechanism of Action

Amiodarone hydrochloride is generally considered a class III antiarrhythmic drug, but it possesses electrophysiologic characteristics of all four Vaughan Williams classes. Like Class I drugs, amiodarone hydrochloride blocks sodium channels at rapid pacing frequencies, and like Class II drugs, it exerts antisympathetic activity. One of its main effects, with prolonged administration, is to lengthen the cardiac action potential, a Class III effect. The negative chronotropic effect of amiodarone hydrochloride in nodal tissues is similar to the effect of Class IV drugs. In addition to blocking sodium channels, amiodarone hydrochloride blocks myocardial potassium channels, which contributes to slowing of conduction and prolongation of refractoriness (Class III effect). The antisympathetic action and block of calcium and potassium channels are responsible for the negative dromotropic effects on the sinus node and for the slowing of conduction and prolongation of refractoriness in the atrioventricular (AV) node.

Additionally, amiodarone hydrochloride has vasodilatory action that can decrease cardiac workload and consequently myocardial oxygen consumption.

A comparison of the electrophysiologic effects of oral and intravenous (IV) amiodarone hydrochloride is shown in Table 7 below.

Table 7 – Effects of oral and intravenous Amiodarone on electrophysiologic parameters

↔ No change

Abbreviations: SCL=sinus cycle length; QRS=a measure of intraventricular conduction;

QTc=corrected QT, a measure of repolarization; AH=atrial His, a measure of intranodal conduction;

HV=His ventricular, a measure of infranodal conduction; ERP=effective refractory period; RA=right atrium; RV=right ventricle; AVN=atrioventricular node.

At higher doses (>10 mg/kg) of IV amiodarone, prolongation of the ERP RV and modest prolongation of the QRS have been seen. These differences between oral and intravenous focused on the AV node, causing an intranodal conduction delay and increased nodal refractoriness due to calcium channel blockade (Class IV activity) and β-adrenoreceptor antagonism (Class II activity).

10.2 Pharmacodynamics

Amiodarone hydrochloride has been reported to produce negative inotropic and vasodilating effects in animals and humans. After long-term treatment with oral amiodarone hydrochloride in a dose range of 200 to 600 mg/day, patients with decreased left ventricular ejection fraction (LVEF) show no significant change in mean LVEF. Hypotension is uncommon (<1%) during chronic oral amiodarone hydrochloride therapy. In clinical studies of patients with (VF) or (VT), drug-related hypotension occurred in 15.6% of 1 836 patients treated with IV amiodarone hydrochloride. No correlations were seen between the baseline ejection fraction and the occurrence of clinically significant hypotension during infusion of IV amiodarone hydrochloride.

10.3 Pharmacokinetics

Absorption

The absorption of oral amiodarone hydrochloride is slow and variable, with peak serum amiodarone hydrochloride concentrations being attained at 3 to 12 hours after administration. Absorption may continue for up to 15 hours after oral ingestion. There is extensive intersubject variation: mean oral bioavailability is approximately 50% (mean range, 33% to 65%). First-pass metabolism in the gut wall and liver appears to be an important factor in determining the systemic availability of the drug. The mean terminal half-life after steady-state administration is approximately 53 days and has been found in one study (n=8) to range from 26 to 107 days. Since at least 3 to 4 half-lives are needed to approach steady-state concentrations, loading doses must be administered at the onset of oral amiodarone hydrochloride therapy. 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.

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 thirty healthy subjects who received a single 600 mg dose both immediately after consuming a meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (C_max) of amiodarone hydrochloride increase by as much as 2.4 and 3.8 times, respectively, in the presence of food. Food also increased the rate of absorption, decreasing the time to peak plasma concentration (T_max) by 37%.

Distribution

Amiodarone hydrochloride has a very high apparent volume of distribution (approximately 5000 L) with an extensive accumulation in tissues, especially adipose tissues, and in highly perfused organs such as liver, lung, spleen, heart and kidney. One major metabolite of amiodarone hydrochloride, desethylamiodarone, has been identified, but the pharmacological activity of this metabolite is not known in humans. During chronic treatment, the plasma ratio of metabolite to parent compound approximates 1.

Amiodarone hydrochloride exhibits complex disposition characteristics after intravenous administration. Peak serum concentrations after single 5 mg/kg 15-minute intravenous infusions in healthy subjects range between 5 and 41 mg/L. Peak concentrations after 150 mg supplemental infusions in patients with VF or VT range between 7 and 26 mg/L. Due to rapid disposition, serum concentrations decline to 10% of peak values within 30 to 45 minutes after the end of the infusion. In clinical trials, after 48 hours of continued infusions (125, 500, or 1000 mg/day) plus supplemental (150 mg) infusions (for recurrent arrhythmias), amiodarone hydrochloride mean serum concentrations between 0.7 to 1.4 mg/L were observed (n = 260).

Metabolism

Amiodarone hydrochloride is eliminated primarily by hepatic metabolism and biliary excretion. Desethylamiodarone (DEA) is the major active metabolite of amiodarone hydrochloride. At the usual amiodarone hydrochloride daily maintenance dose of 400 mg, mean steady-state DEA/amiodarone hydrochloride ratios ranged from 0.61 to 0.93. High-dose oral amiodarone hydrochloride loading in patients yielded 24-hour DEA/amiodarone hydrochloride ratios of 0.083 to 0.19. High-dose intravenous loading yielded a mean 24-hour DEA/amiodarone hydrochloride ratio of 0.041. No data are presently available on the activity of DEA in humans, but animal studies have shown that it has significant electrophysiologic and antiarrhythmic properties. The major enzyme responsible for the N-deethylation to DEA is believed to be cytochrome P-450 3A4. Large interindividual variability in CYP-450 3A4 activity may explain the variable systemic availability of amiodarone hydrochloride. DEA is highly lipophilic and has a very large apparent volume of distribution, showing a higher concentration than amiodarone hydrochloride in all tissue except fat at steady state. Myocardial concentrations of DEA are approximately 3- to 4.5-fold greater than those of amiodarone hydrochloride during long-term oral amiodarone hydrochloride therapy. However, after either acute oral or acute intravenous administration, both mean serum and mean myocardial DEA concentrations are quite low compared to those of amiodarone hydrochloride.

Elimination

Amiodarone hydrochloride is eliminated primarily by hepatic metabolism and biliary excretion. There is negligible excretion of amiodarone or DEA in urine. Neither amiodarone hydrochloride nor DEA is dialyzable. Amiodarone hydrochloride and DEA cross the placenta and both appear in breast milk.

Table 8 summarizes the mean ranges of pharmacokinetic parameters of amiodarone hydrochloride reported in single dose IV (5 mg/kg over 15 min) and oral (400 or 600 mg) studies of healthy subjects and in in vitro (protein binding) studies. Pharmacokinetics were similar in males and females.

Table 8 – Amiodarone hydrochloride pharmacokinetic profile

Notes: V_C and V_SS denote the central and steady-state volumes of distribution from I.V. studies; F_oral is systemic availability of amiodarone. "—" denotes not available. AMI is Amiodarone. t½ = terminal phase elimination half-life. Desethylamiodarone clearance and volume involve an unknown biotransformation factor.

There is no well-established relationship between drug concentration and therapeutic response for long-term oral use. Steady-state amiodarone hydrochloride concentrations of 1 to 2.5 mg/L, however, have been effective with minimal toxicity following chronic oral amiodarone hydrochloride.

Special Populations and Conditions

• Pediatrics: No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
• Geriatrics: Clinical studies of amiodarone hydrochloride tablets did not include sufficient number of subjects aged 65 years 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.

• Sex: No data on dosage adjustment is available for the oral formulation. Based on a single-dose clinical trial with the intravenous formulation, no gender-based dosage adjustment is required. Recommendations regarding gender-based dosage adjustment are based on intravenous data, and may not be representative of the oral formulation.
• Hepatic Insufficiency: No data on dosage adjustment is available for the oral formulation. Based on a single-dose clinical trial with the intravenous formulation, no dosage adjustment is required for patients with hepatic impairment, although these patients should be monitored closely. Recommendations regarding dosage adjustment for patients with hepatic impairment are based on intravenous data, and may not be representative of the oral formulation (see 7 Warnings and Precautions, Hepatic/Biliary/Pancreatic).
• Renal Insufficiency: No data on dosage adjustment is available for the oral formulation. Based on a single-dose clinical trial with the intravenous formulation, no dosage adjustment is required for patients with renal dysfunction, end-stage renal disease or dialysis. Recommendations regarding dosage adjustment for patients with renal dysfunction, end-stage renal disease or dialysis are based on intravenous data, and may not be representative of the oral formulation.

11 Storage, Stability, and Disposal

SANDOZ AMIODARONE tablets should be stored between 15 and 30°C. Protect from light.

Part 2: Scientific Information

13 Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance: Amiodarone hydrochloride

Chemical name: (2-butyl-3-benzofuranyl)[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]methanone hydrochloride

Molecular formula and molecular mass: C₂₅H₂₉I₂NO₃, 681.78 g/mol

Structural formula:

Physicochemical properties: White to slightly yellow crystalline powder

Pharmaceutical standard: BP

14 Clinical Trials

14.1 Clinical Trials

Intravenous amiodarone hydrochloride

Table 9 – Clinical trials summary

A placebo-controlled study of IV amiodarone hydrochloride in patients with supraventricular arrhythmias and 2- to 3-consecutive-beat ventricular arrhythmias, and a pharmacokinetic/ pharmacodynamic study evaluating rapid IV loading in patients with recurrent, refractory VT/VF have shown rapid onset of antiarrhythmic activity well before significant blood levels of desethylamiodarone (DEA) were present; approximately 1500 mg/day of IV amiodarone hydrochloride were administered using 2- and 3-stage infusion regimens. In the patients with complex ventricular arrhythmias, including sustained and nonsustained VT, amiodarone hydrochloride therapy reduced episodes of VT by 85%.

The acute effectiveness of IV amiodarone hydrochloride in suppressing recurrent VF or hemodynamically unstable VT is supported by two randomized, parallel, dose-response studies of approximately 300 patients each. In these studies, patients with at least two episodes of VF or hemodynamically unstable VT in the preceding 24 hours were randomly assigned to receive doses of approximately 125 or 1000 mg over the first 24 hours, an 8-fold difference. In one study, a middle dose of approximately 500 mg was evaluated. The dose regimen consisted of an initial rapid loading infusion, followed by a slower 6-hour loading infusion, and then an 18-hour maintenance infusion. The maintenance infusion was continued up to hour 48. Additional supplemental infusions of 150 mg were given for “breakthrough” VT/VF more frequently to the 125-mg dose group, thereby considerably reducing the planned 8-fold differences in total dose to 1.8- and 2.6-fold, respectively, in the two studies.

The prospectively defined primary efficacy end point was the rate of VT/VF episodes per hour. For both studies, the median rate was 0.02 episodes per hour in patients receiving the high dose and 0.07 episodes per hour in patients receiving the low dose, or approximately 0.5 versus 1.7 episodes per day (p = 0.07, 2-sided, in both studies). In one study, the time to first episode of VT/VF was significantly prolonged (approximately 10 hours in patients receiving the low dose and 14 hours in patients receiving the high dose). In both studies, significantly fewer supplemental infusions were given to patients in the high-dose group. Mortality was not affected in these studies; at the end of double-blind therapy or after 48 hours, all patients were given open access to whatever treatment (including IV amiodarone hydrochloride) was deemed necessary.

14.2 Comparative Bioavailability Studies

A biostudy conducted in healthy volunteers under fed conditions with SANDOZ AMIODARONE 200 mg tablets vs the Canadian reference drug has shown that the products are bioequivalent (see following table).

Table 10 - Summary table of the comparative bioavailability data

¹ SANDOZ AMIODARONE (amiodarone hydrochloride) 200 mg Tablets (manufactured for Sandoz Canada Inc.)

² Cordarone(amiodarone hydrochloride) 200 mg Tablets ( (Pfizer Canada Inc formerly Wyeth-Ayerst) purchased in Canada.

³ and ⁴ for T_max and T_½el, the arithmetic mean only is presented.

Another study was conducted in healthy volunteers under fasting conditions with SANDOZ AMIODARONE 200 mg tablets vs the Canadian reference drug and has also shown that the products were bioequivalent (see following table).

Table 11 - Summary table of the comparative bioavailability data

¹ SANDOZ AMIODARONE (amiodarone hydrochloride) 200 mg Tablets (manufactured for Sandoz Canada Inc.)

² Cordarone (amiodarone hydrochloride) 200 mg Tablets (Pfizer Canada Inc formerly Wyeth-Ayerst) purchased in Canada.

³ and ⁴ for T_max and T½_el, the arithmetic mean only is presented.

15 Microbiology

No microbiological information is required for this drug product.

16 Non-Clinical Toxicology

Acute Toxicity

Amiodarone hydrochloride was evaluated in acute oral studies in mice, rats, and dogs, and in acute intravenous studies in rats and dogs. Multiple-dose toxicity studies were performed by oral administration to mice (20 months), rats (3 to 104 weeks), dogs (4 weeks to 9 months), and pigs (3 or 10 months). Amiodarone hydrochloride was administered intravenously in multiple-dose toxicity studies to rabbits (6 weeks), dogs (4 weeks), and baboons (4 weeks).

Table 12 – Oral Amiodarone hydrochloride: Acute Toxicity Studies

* Report does not identify strain

Table 13 – Intravenous Amiodarone hydrochloride : Acute Toxicity Studies

* Report does not identify sex or strain of dogs.

Long Term Toxicity/Carcinogenicity

Table 14 – Intravenous Amiodarone hydrochloride : Subchronic Toxicity Studies

IV = Intravenous administration

Table 15: Oral amiodarone hydrochloride : Chronic Toxicity Studies

^* Treatment was followed by a sequential sacrifice of 7 animals on days 11, 18, 25, 39, 67 and 121 of study

^** Animals were dosed 5 days/week

*** Report does not identify strain.

Table 16 - Oral amiodarone hydrochloride: Chronic Toxicity Studies/Carcinogenicity Studies

Table 17 - Oral Amiodarone hydrochloride : Chronic Toxicity Studies

Reproductive Toxicity

Reproductive toxicology studies were performed by both oral and intravenous administration. Amiodarone was administered by oral gavage to mice, rats, and rabbits, and intravenously to rats (continuous infusion) and rabbits (bolus injection). In addition, the mutagenic potential was assessed in studies supporting the oral formulation.

Table 18 - Oral amiodarone hydrochloride : Reproductive Studies

Table 19 - Mutagenicity Studies

Table 20 - Oral amiodarone hydrochloride: Reproductive Studies

IV = Intravenous administration

17 Supporting Product Monographs

1. 1. Pfizer Canada Inc, Cordarone^®, Product Monograph, Control no. 189723, Date of Revision: February 18, 2016.