In vivo and in vitro pharmacodynamic drug interactions
MAO inhibitors and pethidine
Xadago must not be administered along with other MAO inhibitors (including moclobemide) as there may be a risk of non-selective MAO inhibition that may lead to a hypertensive crisis (see section 4.3).
Serious adverse reactions have been reported with the concomitant use of pethidine and MAO inhibitors. As this may be a class-effect, the concomitant administration of Xadago and pethidine is contraindicated (see section 4.3).
There have been reports of medicinal product interactions with the concomitant use of MAO inhibitors and sympathomimetic medicinal products. In view of the MAO inhibitory activity of safinamide, concomitant administration of Xadago and sympathomimetics, such as those present in nasal and oral decongestants or cold medicinal products containing ephedrine or pseudoephedrine, requires caution (see section 4.4).
Dextromethorphan
There have been reports of medicinal product interactions with the concomitant use of dextromethorphan and non-selective MAO inhibitors. In view of the MAO inhibitory activity of safinamide, the concomitant administration of Xadago and dextromethorphan is not recommended, or if concomitant treatment is necessary, it should be used with caution (see section 4.4).
Antidepressants
The concomitant use of Xadago and fluoxetine or fluvoxamine should be avoided (see section 4.4), this precaution is based on the occurrence of serious adverse reactions (e.g. serotonin syndrome), although rare, that have occurred when SSRIs and dextromethorphan have been used with MAO inhibitors. If necessary, the concomitant use of these medicinal products should be at the lowest effective dose. A washout period corresponding to 5 half-lives of the SSRI used previously should be considered prior to initiating treatment with Xadago.
Serious adverse reactions have been reported with the concomitant use of selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic/tetracyclic antidepressants and MAO inhibitors (see section 4.4). In view of the selective and reversible MAO-B inhibitory activity of safinamide, antidepressants may be administered but used at the lowest doses necessary.
Tyramine/safinamide interaction
Results of one intravenous and two short term oral tyramine challenge studies, as well as results of home monitoring of blood pressure after meals during chronic dosing in two therapeutic trials in PD patients, did not detect any clinically important increase in blood pressure. Three therapeutic studies performed in PD patients without any tyramine restriction, also did not detect any evidence of tyramine potentiation. Xadago can, therefore, be used safely without any dietary tyramine restrictions.
In vivo and in vitro pharmacokinetic drug interactions
There was no effect on the clearance of safinamide in patients with PD receiving safinamide as adjunct to chronic L-dopa and/or DA-agonists and safinamide treatment did not change the pharmacokinetic profile of co-administered L-dopa.
In an in vivo drug-drug interaction study performed with ketoconazole, there was no clinically relevant effect on the levels of safinamide. Human studies eva luating the interaction of safinamide with CYP1A2 and CYP3A4 substrates (caffeine and midazolam), did not demonstrate any clinically significant effects on the pharmacokinetic profile of safinamide. This is in line with the results of the in vitro tests in which no meaningful CYP induction or inhibition by safinamide was observed and it was shown that CYP enzymes play a minor role in the biotransformation of safinamide (see section 5.2)
Safinamide may transiently inhibit BCRP in vitro. However, in a drug-drug-interaction study with diclofenac in humans no significant interactions were observed. Therefore, no precautions are necessary when safinamide is taken with medicinal products that are BCRP substrates (e.g., pitavastatin, pravastatin, ciprofloxacin, methotrexate, topotecan, diclofenac or glyburide).
Safinamide is almost exclusively eliminated via metabolism, largely by high capacity amidases that have not yet been characterized. Safinamide is eliminated mainly in the urine. In human liver microsomes (HLM), the N-dealkylation step appears to be catalysed by CYP3A4, as safinamide clearance in HLM was inhibited by ketoconazole by 90%. There are currently no marketed medicinal products known to cause clinically significant drug-drug interactions through inhibition or induction of amidase enzymes.
Safinamide inhibits OCT1 in vitro at clinically relevant portal vein concentrations. Therefore, caution is necessary when safinamide is taken concomitantly with medicinal products that are OCT1 substrates and have a tmax similar to safinamide (2 hours) (e.g. metformin, aciclovir, ganciclovir) as exposure to these substrates might be increased as a consequence.
The metabolite NW-1153 is a substrate for OAT3 at clinically relevant concentrations.
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