oducts. class Ia and class III antiarrhythmic medicinal products have been associated with cases of torsades de pointes in patients with bradycardia. Since initiation of Gilenya treatment results in decreased heart rate, Gilenya should not be co-administered with these medicinal products.
At treatment initiation in patients receiving beta blockers, or other substances which may decrease heart rate (e.g. verapamil, digoxin, anticholinesteratic agents or pilocarpine), caution should be exercised because of the additive effects on heart rate (see also section 4.5).
If therapy is discontinued for more than 2 weeks, the effects on heart rate and atrioventricular conduction may recur on re-introduction of Gilenya treatment and the same precautions as for treatment initiation should apply.
QT interval
In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at steady-state, when a negative chronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of QTcI, with the upper limit of the 90% CI 13.0 ms. There is no dose- or exposure-response relationship of fingolimod and QTcI prolongation. There is no consistent signal of increased incidence of QTcI outliers, either absolute or change from baseline, associated with fingolimod treatment.
The clinical relevance of this finding is unknown. In the multiple sclerosis studies, clinically relevant effects on prolongation of the QTc-interval have not been observed but patients at risk for QT prolongation were not included in clinical studies. Medicinal products that may prolong QTc interval are best avoided in patients with relevant risk factors, for example, hypokalaemia, congenital QT prolongation, congestive heart failure, concomitant administration of antiarrhythmic medicinal products in class Ia (e.g. quinidine, disopyramide), or class III (e.g. amiodarone, sotalol).
Infections
A core pharmacodynamic effect of Gilenya is a dose-dependent reduction of the peripheral lymphocyte count to 20-30% of baseline values. This is due to the reversible sequestration of lymphocytes in lymphoid tissues (see section 5.1).
Before initiating treatment with Gilenya, a recent complete blood count (CBC) (i.e. within 6 months) should be available. Assessments of CBC are also recommended periodically during treatment, and in case of signs of infection. Absolute lymphocyte count <0.2x109/l, if confirmed, should lead to treatment interruption until recovery, because in clinical studies, fingolimod treatment was interrupted in patients with absolute lymphocyte count <0.2x109/l.
Initiation of treatment with Gilenya should be delayed in patients with severe active infection until resolution.
Before initiating Gilenya therapy, patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV. VZV vaccination of antibody negative patients should be considered prior to commencing treatment with Gilenya, following which initiation of treatment with Gilenya should be postponed for 1 month to allow full effect of vaccination to occur.
The immune system effects of Gilenya may increase the risk of infections (see section 4.8). Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. During treatment, patients receiving Gilenya should be instructed to report symptoms of infecti
