Amiodarone Hydrochloride (Page 2 of 6)

5.7 Bradycardia

Amiodarone hydrochloride tablet causes symptomatic bradycardia or sinus arrest with suppression of escape foci in 2 to 4% of patients. The risk is increased by electrolytic disorders or use of concomitant antiarrhythmics or negative chronotropes [see Drug Interactions (7)]. Bradycardia may require a pacemaker for rate control.

Postmarketing cases of symptomatic bradycardia, some requiring pacemaker insertion and at least one fatal, have been reported when ledipasvir/sofosbuvir or sofosbuvir with simeprevir were initiated in patients on amiodarone. Bradycardia generally occurred within hours to days, but in some cases presented up to 2 weeks after initiating antiviral treatment. Bradycardia generally resolved after discontinuation of antiviral treatment. The mechanism for this effect is unknown. Monitor heart rate in patients taking or recently discontinuing amiodarone when starting antiviral treatment [see Drug Interactions (7)].

5.8 Implantable Cardiac Devices

In patients with implanted defibrillators or pacemakers, chronic administration of antiarrhythmic drugs may affect pacing or defibrillation thresholds. Therefore, at the inception of and during amiodarone treatment, pacing and defibrillation thresholds should be assessed.

5.9 Fetal Toxicity

Amiodarone hydrochloride tablets may cause fetal harm when administered to a pregnant woman. Fetal exposure may increase the potential for cardiac, thyroid, neurodevelopmental, neurological, and growth effects in neonate [see Use in Specific Populations (8.1)].

5.10 Peripheral Neuropathy

Chronic administration of amiodarone hydrochloride tablets may lead to peripheral neuropathy, which may not resolve when amiodarone hydrochloride tablet is discontinued.

5.11 Photosensitivity and Skin Discoloration

Amiodarone hydrochloride tablets induces photosensitization in about 10% of patients; some protection may be afforded sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or those with excessive sun exposure. Some reversal of discoloration may occur upon drug discontinuation.

5.12 Surgery

Volatile Anesthetic Agents

Patients on amiodarone hydrochloride tablet therapy may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics.

6 ADVERSE REACTIONS

The following serious adverse reactions are described in more detail in other sections of the prescribing information:

Pulmonary Toxicity [see Warnings and Precautions (5.2)]
Hepatic Injury [see Warnings and Precautions (5.3)]
Worsened Arrhythmia [see Warnings and Precautions (5.4)]
Visual Impairment and Loss of Vision [see Warnings and Precautions (5.5)]
Thyroid Abnormalities [see Warnings and Precautions (5.6)]
Bradycardia [see Warnings and Precautions (5.7)]
Peripheral Neuropathy [see Warnings and Precautions (5.10)]
Photosensitivity and Skin Discoloration [see Warnings and Precautions (5.11)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

At the usual maintenance dose (400 mg/day) and above, amiodarone hydrochloride tablets causes adverse reactions in about three-fourths of all patients, resulting in discontinuation in 7 to 18%.

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

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

Thyroid

Common: Hypothyroidism, hyperthyroidism.

Cardiovascular

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

Gastrointestinal

Very common: Nausea, vomiting.

Common: Constipation, anorexia, abdominal pain.

Dermatologic

Common: Solar dermatitis/photosensitivity.

Neurologic

Common: Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias, decreased libido, insomnia, headache, sleep disturbances.

Ophthalmic

Common: Visual disturbances.

Hepatic

Common: Abnormal liver-function tests, nonspecific hepatic disorders.

Respiratory

Common: Pulmonary inflammation or fibrosis.

Other

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

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

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of amiodarone hydrochloride tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hematologic: hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma.

Immune: anaphylactic/anaphylactoid reaction (including shock), angioedema.

Neurologic: pseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), demyelinating polyneuropathy.

Psychiatric: hallucination, confusional state, disorientation, delirium.

Cardiac: hypotension (sometimes fatal), sinus arrest.

Respiratory: eosinophilic pneumonia, acute respiratory distress syndrome in the post-operative setting, bronchospasm, bronchiolitis obliterans organizing pneumonia, pulmonary alveolar hemorrhage, pleural effusion, pleuritis.

Gastrointestinal: pancreatitis, acute pancreatitis.

Hepatic: hepatitis, cholestatic hepatitis, cirrhosis.

Skin and Subcutaneous Tissue Disorders: urticaria, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, bullous dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, pruritus, skin cancer, lupus-like syndrome.

Musculoskeletal: myopathy, muscle weakness, rhabdomyolysis.

Renal: renal impairment, renal insufficiency, acute renal failure.

Reproductive: epididymitis, impotence.

Body as a whole: fever, dry mouth.

Endocrine and metabolic: thyroid nodules/ thyroid cancer, syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Vascular: vasculitis.

7 DRUG INTERACTIONS

Because of amiodarone’s long half-life, expect drug interactions to persist for weeks to months after discontinuation of amiodarone. Drug interactions with amiodarone are described in Table 1 below.

Table 1 Amiodarone Drug Interactions

Concomitant Drug Class/Name

Examples

Clinical Comment

Pharmacodynamic Interactions

QT Prolonging Drugs

class I and III antiarrhythmics, lithium, certain phenothiazines, tricyclic antidepressants, certain fluoroquinolone and macrolide antibiotics, azole antifungals, halogenated inhalation anesthetic agents

Increased risk of Torsade de Pointes. Avoid concomitant use.

Negative Chronotropes

digoxin, beta blockers, verapamil, diltiazem, clonidine, ivabradine

Potentiates the electrophysiologic and hemodynamic effects of amiodarone, resulting in bradycardia, sinus arrest, and AV block. Monitor heart rate.

Pharmacokinetic Interactions

CYP450 Inhibitors

grapefruit juice, certain fluoroquinolone and macrolide antibiotics, azole antifungals, cimetidine, certain protease inhibitors

Increased exposure of amiodarone. Avoid concomitant use.

CYP450 Inducers

St. John’s Wort

Reduced amiodarone serum levels.

Cyclosporine

Increased plasma levels of cyclosporine have been reported resulting in elevated creatinine, despite reduction of cyclosporine dose. Monitor cyclosporine drug levels and renal function with concomitant use.

Cholestyramine

Reduced amiodarone serum levels.

Antiarrhythmics

quinidine, procainamide, flecainide

Reserve concomitant use for patients who are unresponsive to a single agent. Antiarrhythmic metabolism inhibited by amiodarone. Initiate antiarrhythmic at a lower than usual dose and monitor patient carefully. Reduce dose levels of previously administered antiarrhythmic by 30 to 50% for several days after transitioning to oral amiodarone. Evaluate continued need for antiarrhythmic.

Digoxin

Increased digoxin concentration. Reduce digoxin by half or discontinue. If continued, monitor for evidence of toxicity.

HMG-CoA Reductase Inhibitors

simvastatin, lovastatin, atorvastatin

Increased plasma concentration of HMG- CoA reductase inhibitor. Limit the dose of lovastatin to 40 mg. Limit the coadministered dose of simvastatin to 20 mg. Lower starting dose of other CYP3A4 substrates may be required.

Warfarin

Potentiates anticoagulant response and can result in serious or fatal bleeding. Coadministration increases prothrombin time by 100% after 3 to 4 days. Reduce warfarin dose by one-third to one-half and monitor prothrombin times.

Phenytoin

Increased steady-state levels of phenytoin. Monitor phenytoin levels.

Hepatitis C Direct Acting Antiviral

sofosbuvir

Cases of symptomatic bradyarrhythmia requiring pacemaker insertion have been reported in patients on oral maintenance amiodarone who initiated therapy with sofosbuvir.

CYP3A Substrate

lidocaine

Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine given for local anesthesia. Monitor heart rate. A lower starting dose of lidocaine may be required.

CYP3A Substrate

fentanyl

Fentanyl in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.

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