Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Zentiva Pharma UK Limited, One Onslow Street, Guildford, Surrey, GU1 4YS, United Kingdom Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK
Amiodarone hydrochloride is an antiarrhythmic.
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 500 mg/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 a few hours to several days
If needed, oral therapy may be initiated concomitantly at the usual loading dose.
Amiodarone is strongly protein bound and the plasma half-life is usually of the order of 50 days. However there may be considerable inter-patient variation; in individual patients a half-life of less than 20 days and a half-life of more than 100 days has been reported. High doses of Cordarone X, for example 600 mg/day, should be given initially to achieve effective tissue levels as rapidly as possible. Owing to the long half-life of the drug, a maintenance dose of only 200 mg/day, or less is usually necessary. Sufficient time must be allowed for a new distribution equilibrium to be achieved between adjustments of dose.
The long half-life is a valuable safeguard for patients with potentially lethal arrhythmias as omission of occasional doses does not significantly influence the protection afforded by Cordarone X.
No controlled paediatric studies have been undertaken. In the limited published data available in paediatric patients, there were no differences noted compared to adults.
Amiodarone is metabolised mainly by CYP3A4, and also by CYP2C8. Amiodarone and its metabolite, desethylamiodarone, exhibit a potential in vitro to inhibit CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2A6, CYP2B6 and 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 creatine (a OCT 2 substrate). In vivo data describe amiodarone interactions on CYP3A4, CYP2C9, CYP2D6 and P-gp substrates.
In a 2-year 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.
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