Amiodarone Hydrochloride (Page 3 of 7)

Hyperthyroidism and Thyrotoxicosis

Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. Consider the possibility of hyperthyroidism if any new signs of arrhythmia appear.

Identify hyperthyroidism by relevant clinical signs and symptoms, subnormal serum levels of thyroid stimulating hormone (TSH), abnormally elevated serum free T4, and elevated or normal serum T3. Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone. Amiodarone hyperthyroidism may be followed by a transient period of hypothyroidism.

The institution of antithyroid drugs, β-adrenergic blockers or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism.

When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning.

Neonatal Hypo- or Hyperthyroidism

Amiodarone can cause fetal harm when administered to a pregnant woman. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism associated with oral administration. Inform the patient of the potential hazard to the fetus if amiodarone is administered during pregnancy or if the patient becomes pregnant while taking amiodarone.

Hypothyroidism

Hypothyroidism has been reported in 2 to 4% of patients in most series, but in 8 to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the amiodarone dose and considering the need for thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue amiodarone in some patients.

5.9 Surgery

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

5.10 Corneal Refractive Laser Surgery

Advise patients that most manufacturers of corneal refractive laser surgery devices contraindicate corneal refractive laser surgery in patients taking amiodarone.

5.11 Electrolyte Disturbances

Correct hypokalemia or hypomagnesemia whenever possible before initiating treatment with amiodarone, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics.

6 ADVERSE REACTIONS

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.

In a total of 1836 patients in controlled and uncontrolled clinical trials, 14% of patients received intravenous amiodarone for at least one week, 5% received it for at least 2 weeks, 2% received it for at least 3 weeks, and 1% received it for more than 3 weeks, without an increased incidence of severe adverse reactions. The mean duration of therapy in these studies was 5.6 days; median exposure was 3.7 days.

The most important adverse reactions were hypotension, asystole/cardiac arrest/pulseless electrical activity (PEA), cardiogenic shock, congestive heart failure, bradycardia, liver function test abnormalities, VT, and AV block. Overall, treatment was discontinued for about 9% of the patients because of adverse reactions. The most common adverse reactions leading to discontinuation of intravenous amiodarone therapy were hypotension (1.6%), asystole/cardiac arrest/PEA (1.2%), VT (1.1%), and cardiogenic shock (1%).

Table 5 lists the most common (incidence 2%) adverse reactions during intravenous amiodarone therapy considered at least possibly drug-related. These data were collected in clinical trials involving 1836 patients with life-threatening VT/VF. Data from all assigned treatment groups are pooled because none of the adverse reactions appeared to be dose-related.

Table 5: ADVERSE REACTIONS IN PATIENTS RECEIVING INTRAVENOUS AMIODARONE IN CONTROLLED AND OPEN-LABEL STUDIES (≥ 2% INCIDENCE)
Study Event Controlled Studies(n = 814) Open-Label Studies(n = 1022) Total(n = 1836)
Body as a whole
Fever 24 (2.9%) 13 (1.2%) 37 (2.0%)
Cardiovascular System
Bradycardia 49 (6.0%) 41 (4.0%) 90 (4.9%)
Congestive heart failure 18 (2.2%) 21 (2.0%) 39 (2.1%)
Heart arrest 29 (3.5%) 26 (2.5%) 55 (2.9%)
Hypotension 165 (20.2%) 123 (12.0%) 288 (15.6%)
Ventricular tachycardia 15 (1.8%) 30 (2.9%) 45 (2.4%)
Digestive System
Liver function tests abnormal 35 (4.2%) 29 (2.8%) 64 (3.4%)
Nausea 29 (3.5%) 43 (4.2%) 72 (3.9%)

Other adverse reactions reported in less than 2% of patients receiving intravenous amiodarone in controlled and uncontrolled studies included the following: abnormal kidney function, atrial fibrillation, diarrhea, increased ALT, increased AST, lung edema, nodal arrhythmia, prolonged QT interval, respiratory disorder, shock, sinus bradycardia, Stevens-Johnson syndrome, thrombocytopenia, VF, and vomiting.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of amiodarone. 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.

Body as a Whole: anaphylactic/anaphylactoid reaction (including shock), fever

Cardiovascular: hypotension (sometimes fatal), sinus arrest

Dermatologic: toxic epidermal necrolysis (sometimes fatal), exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, skin cancer, pruritus, angioedema

Endocrine: syndrome of inappropriate antidiuretic hormone secretion (SIADH)

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

Hepatic: hepatitis, cholestatic hepatitis, cirrhosis

Injection Site Reactions: pain, erythema, edema, pigment changes, venous thombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing

Musculoskeletal: myopathy, muscle weakness, rhabdomyolysis

Nervous System: hallucination, confusional state, disorientation, and delirium, pseudotumor cerebri

Pancreatic: pancreatitis

Renal: renal impairment, renal insufficiency, acute renal failure

Respiratory: bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates, and /or mass, pleuritis

Thyroid: thyroid nodules/thyroid cancer

Vascular: vasculitis

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