Amiodarone

Additional information

Pharmacokinetics and dosing

Age and patient’s sex do not have any marked effects on the pharmacokinetics of amiodarone or the major metabolite desethylamiodarone [1, 2]. A pharmacokinetic study in Japanese patients (13 men, 5 women) showed that renal clearance for women was significantly increased by 37% compared with those of men. It was suggested that this sex difference was caused by the distribution to fatty tissue, since amiodarone has an extreme affinity for lipids, and men had higher body fat than women in this study [3].

Women are more susceptible than men to amiodarone-associated bradycardia requiring pacemaker insertion (see Adverse effects). Because the dose related bradycardic effect of amiodarone, it has been suggested to use lower loading and maintenance doses, particularly in elderly women, as age is also associated with an increased need for pacemaker insertion [4].

Effects

No studies with a clinically relevant sex analysis regarding the effects of amiodarone have been found.

Adverse effects

Sex differences in the proarrhythmic potential of QT-prolonging drugs are well documented. Women have a greater risk than men of developing dangerous ventricular tachycardias, Torsade de Pointes (TdP), when given drugs prolonging repolarization [5]. It is suggested that this could be explained by a female predisposition to prolonged cardiac repolarization. Even in the normal population, women have a longer average QT-interval than men [6]. However, it has been argued that the increased risk of TdP might be due to women having higher amiodarone concentrations as standard doses are usually used and women in general have a lower body weight than men [7].

Amiodarone markedly prolongs repolarization and may aggravate ventricular tachycardias. However, TdP and other drug-induced tachyarrhythmias associated with chronic amiodarone treatment are unusual. It appears that the beta-adrenergic receptor- and calcium channel-blocking activities of amiodarone lower the otherwise high propensity of causing TdP expected with this drug. The risk may be enhanced with co-administration of other antiarrhythmics. Female sex has been identified as a risk factor for amiodarone-associated TdP [8, 9]. The prevalence of TdP have shown to be less than 1% in amiodarone-treated patients [10].

An American prospective study (583 men, 390 women) in patients with new-onset atrial fibrillation found that women were more susceptible than men to amiodarone-associated bradycardia requiring pacemaker insertion. After adjusting for amiodarone dose, the effect of amiodarone use remained significantly greater in women. It is suggested that additional caution should be taken when amiodarone is being prescribed to women [4].

Risk of fracture in elderly patients treated with antiarrhythmic drugs was investigated in a Danish population-based nation-wide pharmacoepidemiological case-control study (240 428 men, 258 189 women). Treatment with amiodarone was associated with a similarly increased fracture risk in men and women [11].

In a Swiss retrospective study (72 men, 192 women), side effects of amiodarone were reported more in women than men (56% vs. 36%). The most frequent side effects with a significant sex difference were dysthyroidism (29% in women vs. 17% in men) and phototoxicity (21% in women vs. 8% in men) [12]. A Dutch nested case-control analysis (2809 men, 2713 women) found an increased risk for thyroid disorders in users of amiodarone compared with users of other antiarrhythmics with similar odd ratios in men and women. A dose-response relationship was found only in men, with a tendency to develop thyroid disorder at higher doses [13].

Amiodarone is associated with pulmonary toxicity, and a Canadian retrospective observational cohort study (26 410 men, 30 983 women) reported a higher incidence rate in men than in women [14].

In a Taiwanese retrospective population-based cohort study on amiodarone use and risk of optic neuropathy (17084 men, 13791 women), male sex was associated with a risk of developing optic neuropathy (HR 3.05; 95% CI 1.42-6.55; p=0.004). The authors suggest this may be due to sex- differences in physiology, enzymatic activity, and hormones [15].

Another Taiwanese retrospective cohort study on cancer risk after amiodarone therapy (3674 men, 2744 women), found an increased risk of incident cancer in men but not in women (HR 1.90; 95 % CO 1.38-2.62; p<0.001). The authors suggest that this may be explained by the higher clearance rate of amiodarone in women, as well as differences in body fat and hormonal stimuli [16].

An association between amiodarone use and risk of acute pancreatitis has been reported in a Taiwanese case-control study (15570 men, 9360 women), with similar risk in men and women (crude OR 1.00; 95% CI 0.94-1.07) [17].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

The effect of sex on referral for atrial fibrillation and subsequent management was examined in a Swiss retrospective study (72 men, 192 women). Women were referred three times less often than men. There was no sex-related difference in the subsequent treatment decisions [12]. Similar findings, a lower referral rate but similar utilization of antiarrhythmic drugs, were found in a Swedish prospective questionnaire study (105 men, 109 women) [18].