dose 3 mg) on average six-fold. When ketoconazole was administered 12 hours after budesonide the concentration was on average increased only three-fold showing that separation of the administration times can reduce the increase in plasma levels. Limited data about this interaction for high-dose inhaled budesonide indicates that marked increases in plasma levels (on average four fold) may occur if itraconazole, 200 mg once daily, is administered concomitantly with inhaled budesonide (single dose of 1000 micrograms).
Pharmacodynamic interactions
β adrenergic blockers can weaken or inhibit the effect of formoterol. A fixed-dose combination therapy of budesonide and formoterol fumarate dihydrate should therefore not be given together with β adrenergic blockers (including eye drops) unless there are compelling resons.
Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), monoamine oxidase inhibitors and tricyclic antidepressants can prolong the QTc-interval and increase the risk of ventricular arrhythmias.
In addition L-Dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards β2 sympathomimetics.
Concomitant treatment with monoamine oxidase inhibitors including medicinal products with similar properties such as furazolidone and procarbazine may precipitate hypertensive reactions.
There is an elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons.
Concomitant use of other β adrenergic medicinal products and anticholinergic medicinal products can have a potentially additive bronchodilating effect.
Hypokalaemia may increase the disposition towards arrhythmias in patients who are treated with digitalis glycosides.
Budesonide and formoterol have not been observed to interact with any other medicinal products used in the treatment of asthma.
Paediatric population
Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Pregnancy
For a fixed-dose combination therapy of budesonide and formoterol fumarate dihydrate or the concomitant treatment with formoterol and budesonide, no clinical data on exposed pregnancies are available. Data from an embryo-fetal development study in the rat, showed no evidence of any additional effect from the combination.
There are no adequate data from use of formoterol in pregnant women. In animal studies formoterol has caused adverse reactions in reproduction studies at very high systemic exposure levels (see section 5.3).
Data on approximately 2000 exposed pregnancies indicate no increased teratogenic risk associated with the use of inhaled budesonide. In animal studies glucocorticosteroids have been shown to induce malformations (see section 5.3). This is not likely to be relevant for humans given recommended doses.
Animal studies have also identified an involvement of excess prenatal glucocorticoids in increased risks for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range.
During pregnancy, a fixed-dose combination therapy of budesonide and formoterol fumarate dihydrate should only be used when the benefits outweigh the potential risks. The lowest effective dose of budesonide needed |
