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The macrolide antibiotics are metabolized by cytochrome P-450 enzymes in the liver and interactions with similarly metabolized compounds have been described. Simultaneous treatment with erythromycin and warfarin is known to decrease warfarin clearance and prolong prothrombin time. Roxithromycin (RU 28965), a new erythromycin derivative with improved pharmacokinetic properties, might then, because of structure similarity, be expected to interact with warfarin. In 21 healthy volunteers, the effect of orally administered roxithromycin (150 mg b.i.d.) on warfarin steady-state kinetics, and the effects of warfarin on roxithromycin kinetics, were investigated in a double-blind, randomized study versus placebo. Since the warfarin enantiomers, R- and S-warfarin have both different potency and different metabolism, the ratio between the enantiomers with and without roxithromycin, was also determined. In this study, mean AUC for warfarin increased slightly from day 14 of warfarin treatment to day 28, but no difference was found between the roxithromycin group and the placebo group, and no change appeared in the ratio between the warfarin enantiomers. A moderate increase in dosage was needed to maintain hypocoagulability during warfarin medication, but there was no difference between the roxithromycin group and the placebo groups, respectively. In addition, roxithromycin kinetics appeared to be unaffected by warfarin treatment.
There have been reports of an interaction when theophylline and macrolides are given together, and also when carbamazepine is given with macrolides. We compared the kinetics of theophylline and carbamazepine, given alone and then in combination with roxithromycin. Roxithromycin had little effect on the pharmacokinetics of theophylline and none on carbamazepine, and roxithromycin can be given with either of the drugs without any need to alter the dose.
The pharmacokinetic interactions of ofloxacin (2 X 200 mg) and theophylline (3 X 200 mg) were investigated in 12 healthy volunteers over a period of two weeks. In the first week, theophylline was given over five days to reach a steady state. In the second week, the combination of theophylline and ofloxacin was applied. Cmax, tmax, AUC0-8, the serum elimination constant and serum half-life of theophylline were not changed when theophylline was given alone or in combination with ofloxacin. The kinetic parameters of ofloxacin were in accordance with data from the literature.
The risk assessment of drugs in pregnancy can be improved through better knowledge and interpretation of significant experimental findings. Embryo-fetal effects can be considered as the endpoint of importance, after excluding that their occurrence is related to maternal toxicity. If embryo-fetal toxic effects occur in the presence of maternal toxicity, the dam influence should be clearly assessed, and can be taken into account in the determination of a safety margin. A determination of the lowest developmental toxic dose, if any, apart from any maternal toxicity, should be made. With positive animal developmental findings, interpretation should take into account various parameters including the incidence and the severity of the embryo-fetal insult, interspecies reproducibility, the level of exposure, metabolic pathways, and the results of possible mechanistic investigations. Hierarchization of the experimental findings should take into account all these parameters together to provide support for the risk assessment in humans.
The task of the Drug Interactions working party of the French Medicines Agency is to select the clinically relevant interactions. This selection is carried out on the basis of an analysis of published and unpublished observed cases (pharmacovigilance), a follow-up of interactions which could be subsequently selected in view of new data, and an update of the labelling of interactions which have been already selected. The conclusions of the working group are subjected to approval by the French Medicines Registration Committee. This leads mainly to: a harmonization of the Drug Interactions heading, in the Summary of Products Characteristics, for drugs of the same pharmacological class; the yearly publishing of an addendum to the Vidal relative to 'Drug Interactions', which reflects precisely the working group's conclusions; the acknowledgement, at Community level, of the above mentioned drug interactions labelling, i.e. clinically relevant adverse drug reactions, pharmacokinetic or pharmacodynamic mechanism of action (if known), recommendations (four levels), and corresponding co-prescription management, if necessary.