Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction
Pharmacokinetic interactions

Medicinal products eliminated through metabolism or active secretion
There are no data on the effects of amifampridine on the metabolism or active secretion of other medicinal products. Thus, special care should be taken in patients undergoing concomitant treatment with medicinal products eliminated through metabolism or active secretion. Monitoring is advised when possible. The dose of the concomitantly given medicinal product should be adjusted if necessary. Concomitant use of medicinal products with a narrow therapeutic window is contraindicated (see section 4.3).

Substances which are potent inhibitors of enzymes that metabolise medicinal products (see section 5.2)
Potent cytochrome P450 (CYP450) enzyme inhibitors e.g. cimetidine, ketoconazole are not likely to inhibit the metabolism of amifampridine by human N-acetyl-transferase enzymes (NATs) giving rise to increased amifampridine exposure. The results from the in vitro CYP450 inhibition study indicate amifampridine is unlikely to play a role in metabolic-based clinical drug-drug interactions related to inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 metabolism of co-administered medicinal products. Regardless, patients should be closely monitored for adverse reactions when initiating treatment with a potent enzyme or renal transporter inhibitor. If treatment with a potent inhibitor is discontinued, patients should be monitored for efficacy as an increase of amifampridine dose may be necessary.

Substances which are potent inducers of enzymes that metabolise medicinal products (see section 5.2) The results from in vitro studies suggest there is low potential for drug-drug interactions due to enzyme induction of CYP1A2, CYP2B6, and CYP3A4 enzymes by amifampridine.

Pharmacodynamic interactions

Based on the pharmacodynamic properties of amifampridine, the concomitant use with sultopride or other medicinal products known to cause QT prolongation (e.g., disopyramide, cisapride, domperidone, rifampicin and ketoconazole) is contraindicated as this combination may lead to an enhanced risk of ventricular tachycardia, notably torsade de pointes (see sections 4.3 and 5.1).


Combinations requiring precautions for use
Medicinal products known to lower the epileptic threshold
The concomitant use of amifampridine and substances known to lower the epileptic threshold may lead to an increased risk of seizures. The decision to administer proconvulsant or epileptic-threshold lowering substances concomitantly should be carefully considered in the light of the severity of the associated risks. These substances include most anti-depressants (tricyclic antidepressants, selective serotonin uptake inhibitors), neuroleptics (phenothiazines and butyrophenones), mefloquine, bupropion and tramadol (see sections 4.4 and 5.1).

Combinations to be taken into consideration

Medicinal products with atropinic effects
The concomitant use of amifampridine and medicinal products with atropinic effects may reduce the effect of both active substances and should be taken into consideration. Medicinal products with atropinic effects include tricyclic anti-depressants, most H1 atropinic anti-histamines, anticholinergic, anti-Parkinson medicinal products, atropinic antispasmodics, disopyramide, phenothiazine neuroleptics and clozapine.

Medicinal products with cholinergic effects
The concomitant use of amifampridine and medicinal products with cholinergic effects (e.g. direct or indirect cholinesterase inhibitors) may lead to an increased effect of both products and should be taken into consideration.

Non depolarising muscle relaxant acting medicinal products
The concomitant use of amifampridine and medicinal products with non-depolarising muscle relaxant effects (e.g. mivacurium, pipercurium) may lead to a decreased effect of both products and should be taken into consideration.

Depolarising muscle relaxant acting medicinal products
The concomitant use of amifampridine and medicinal products with depolarising muscle relaxant effects (e.g. suxamethonium) may lead to a decreased effect of both products and should be taken into consideration.