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Eur J Clin Pharmacol. 2005 Aug;61(7):531-6. Epub 2005 Jul 23.

Comparison of information on the pharmacokinetic interactions of Ca antagonists in the package inserts from three countries (Japan, USA and UK).

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  • 1Division of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.



Ca antagonists are one of the most popular classes of drugs used to treat hypertension and angina. These drugs may interact with either CYP3A4 or MDR-1 substrates, with the degree of interaction differing with each drug. We carried out a literature search to examine and compare the extent to which crucial pharmacokinetic (PK) information is included in package inserts (PIs) in Japan, USA and the UK.


A MEDLINE search from 1966 to November 2004 was undertaken with the aim of identifying studies on clinical PK drug interactions between seven Ca antagonists that are available in three countries and three CYP3A4 inhibitors (erythromycin, itraconazole and cimetidine), a CYP3A4 inhibitory food, grapefruit juice (GFJ) and the MDR-1 substrate, digoxin. The current PIs for Ca antagonists were obtained from the website of the regulatory authorities or the electronic Medicines Compendium.


Of all possible combinations of seven Ca antagonists with three CYP3A4 inhibitor drugs, drug interaction information was available in the literature on nine combinations: Seven of these were listed in the USA PIs, two in the UK PIs, and none in the Japanese PIs. Interaction studies with GFJ were reported for every Ca antagonist; PIs in the USA provided quantitative data for four of these interactions, whereas UK PIs provided quantitative data for only one of the interactions and Japanese PIs provided no quantitative information. The PK data of co-medication of digoxin with Ca antagonists have been reported for every Ca antagonists. The USA PIs provided quantitative data for five Ca antagonists, whereas the UK PIs provided quantitative data for three Ca antagonists and Japanese PIs provided no quantitative data.


The literature search revealed that PIs in the USA provided a great deal of quantitative information on PK interactions between Ca antagonists and other drugs or GFJ. In contrast, PIs in the UK and Japan did not provide sufficient information. We conclude that crucial quantitative information on these drug interactions should be incorporated in PIs, especially in Japan and the UK, as a means of assisting healthcare providers.

[PubMed - indexed for MEDLINE]
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