4.5 Interaction with other medicinal products and other forms of interaction

 Anti-neoplastic, immunosuppressive or immune-modulating therapies

Anti-neoplastic, immunosuppressive or immune-modulating therapies should not be co-administered due to the risk of additive immune system effects (see sections 4.3 and 4.4). Caution is also indicated when switching patients from long-acting therapies with immune effects, such as natalizumab or mitoxantrone (see section 4.4). In multiple sclerosis clinical studies the concomitant treatment of relapses with a short course of corticosteroids was not associated with an increased rate of infection.

Vaccination

During and for up to two months after treatment with Gilenya vaccination may be less effective. The use of live attenuated vaccines may carry a risk of infections and should therefore be avoided.

Bradycardia-inducing substances

Fingolimod has been studied in combination with atenolol and diltiazem. When fingolimod was used with atenolol in an interaction study in healthy volunteers, there was an additional 15% reduction of heart rate at fingolimod treatment initiation, an effect not seen with diltiazem. At treatment initiation in patients receiving beta blockers, or other substances which may decrease heart rate, such as class Ia and III antiarrhythmics, calcium channel blockers like verapamil or diltiazem, digoxin, anticholinesteratic agents or pilocarpine, caution should be exercised because of the additive effects on heart rate (see section 4.4). The potential risks and benefits of initiating fingolimod treatment in patients already on a substance which lowers the heart rate should be considered.

Pharmacokinetic interactions of other substances on fingolimod

Fingolimod is metabolised mainly by CYP4F2. Other enzymes like CYP3A4 may also contribute to its metabolism. Co-administration of fingolimod with ketoconazole resulted in a 1.7-fold increase in fingolimod and fingolimod phosphate exposure (AUC). Caution should be exercised with substances that may inhibit CYP3A4 (protease inhibitors, azole antifungals, some macrolides such as clarithromycin or telithromycin).

Pharmacokinetic interactions of fingolimod on other substances

Fingolimod is unlikely to interact with substances mainly cleared by the CYP450 enzymes or by substrates of the main transporter proteins.

Co-administration of fingolimod with ciclosporin did not elicit any change in the ciclosporin or fingolimod exposure. Therefore, fingolimod is not expected to alter the pharmacokinetics of medicinal products that are CYP3A4 substrates. Potent inhibitors of transporter proteins are not expected to influence fingolimod disposition.

Co-administration of fingolimod with oral contraceptives (ethinylestradiol and levonorgestrel) did not elicit any change in oral contraceptive exposure. No interaction studies have been performed with oral contraceptives containing other progestagens, however an effect of fingolimod on their exposure is not expected.

It is not known whether the concomitant administration of strong CYP450 inducers may decrease the exposure to fingolimod and fing