Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Aventis Pharma Limited, One Onslow Street, Guildford, Surrey, GU1 4YS, UK or trading as: Sanofi-aventis or Sanofi, One Onslow Street, Guildford, Surrey, GU1 4YS, UK
Cordarone is a product for the treatment of tachyarrhythmias and has complex pharmacological actions. Its effects are anti-adrenergic (partial alpha and beta blocker). It has haemodynamic effects (increased blood flow and systemic/coronary vasodilation). The drug reduces myocardial oxygen consumption and has been shown to have a sparing effect of rat myocardial ATP utilisation, with decreased oxidative processes. Amiodarone inhibits the metabolic and biochemical effects of catecholamines on the heart and inhibits Na+ and K+ activated ATP-ase.
No controlled paediatric studies have been undertaken.
In published studies the safety of amiodarone was evaluated in 1118 paediatric patients with various arrhythmias. The following doses were used in paediatric clinical trials.
Loading dose: 10 to 20 mg/kg/day for 7 to 10 days (or 500mg/m²/day if expressed per square meter).
Maintenance dose: the minimum effective dosage should be used; according to individual response, it may range between 5 to 10 mg/kg/day (or 250 mg/m²/day if expressed per square meter).
Loading dose: 5 mg/kg body weight over 20 minutes to 2 hours.
Maintenance dose: 10 to 15 mg/kg/day from few hours to several days.
If needed, oral therapy may be initiated concomitantly at the usual loading dose.
Amiodarone is metabolised mainly by CYP3A4, and also by CYP2C8, however the pharmacokinetics of amiodarone are unusual and complex, and have not been completely elucidated.
Absorption following oral administration is variable and may be prolonged, with enterohepatic cycling. The major metabolite is desethylamiodarone. Amiodarone is highly protein bound (>95%). Renal excretion is minimal and faecal excretion is the major route. A study in both healthy volunteers and patients after intravenous administration of amiodarone reported that the calculated volumes of distribution and total blood clearance using a two-compartment open model were similar for both groups. Elimination of amiodarone after intravenous injection appeared to be biexponential with a distribution phase lasting about 4 hours. The very high volume of distribution combined with a relatively low apparent volume for the central compartment suggests extensive tissue distribution. A bolus IV injection of 400mg gave a terminal T½ of approximately 11 hours.
Amiodarone and its metabolite, desethylamiodarone, exhibit a potential in vitro to inhibit CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2A6, CYP2B6 and CYP 2C8. Amiodarone and desethylamiodarone have also a potential to inhibit some transporters such as P-gp and organic cation transporter (OCT2) (One study shows a 1.1% increase in concentration of creatinine (an OCT 2 substrate). In vivo data describe amiodarone interactions on CYP3A4, CYP2C9, CYP2D6 and P-gp substrates.
No controlled paediatric studies have been undertaken. In the limited published data available in paediatric patients, there were no differences noted compared to adults.
In a 2-years carcinogenicity study in rats, amiodarone caused an increase in thyroid follicular tumours (adenomas and/or carcinomas) in both sexes at clinical relevant exposures. Since mutagenicity findings were negative, an epigenic rather than genotoxic mechanism is proposed for this type of tumour induction. In the mouse, carcinomas were not observed, but a dose-dependent thyroid follicular hyperplasia was seen. These effects on the thyroid in rats and mice are most likely due to effects of amiodarone on the synthesis and/or release of thyroid gland hormones. The relevance of these findings to man is low.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
