REGULATORY DILEMMA OF ONGOING SAFETY REVIEW OF DRUG GILENYA® (FINGOLIMOD)-EXPIERENCE FROM MEDICINES AND MEDICAL DEVICES AGENCY OF SERBIA-ALIMS-

V Stanimirovic1, D Nikolic2, A Nikolic3, B Stanimirovic4, B Stanimirovic5. 1Medicines and Medical Devices Agency of Serbia-ALIMS, Beograd, 11000, Serbia, 2Clinical Center Bezanijska kosa, Beograd, Serbia, 11000, Serbia, 3Institute for Cardiovascular disease DEDINJE, Beograd Serbia, 11000, Serbia, 4Univ G/O Clinic Narodni front, Beograd, Serbia, 11000, Serbia, 5Medical Faculty Beograd, Serbia, 11000, Serbia

Gilenya® (fingolimod hydrochloride), Novartis, is sphingosine 1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction.It has reduced the rate of relapses in relapsing-remitting multiple sclerosis (MS) by over half, but has serious adverse effects. Fingolimod has been evaluated in a series of in vitro and in vivo pharmacological tests .Non clinical results related to CVS: Fingolimod provoked an increased sinus frequency and a slight QT shortening in isolated pig hearts. H ERG tail inhibition detected current from 200 ng/mL by 25.2 % in HEK293 cells which is well above the human Cmax,ss at the therapeutic dose of 0.5 mg/day. In wistar rats decreased heart rate and sinus arrhythmia were observed at 10 mg/kg. In guinea pigs, an intravenous dose from 0.01 mg/kg caused sinus arrhythmia and 0.1 and 1 mg/kg decreased heart rate and blood pressure. In conscious dogs, p.o. doses from 5 mg/kg showed a decrease in heart rate and an increase in blood pressure from 2.5 mg/kg. In monkeys p.o. doses at 10 mg/kg caused an increased systolic and diastolic blood pressure 4-72 hours after administration with maximum increase after 6 hr and a decreased heart rate 8-12 hr after administration by approximately 22%, compared to baseline.

Developmental toxicity, including teratogenicity and embryolethality has been reported in rats and rabbits following oral administration of fingolimod during organogenesis. In rats, the most frequently reported fetal visceral malformations were persistent truncus arteriosus and ventricular septal defect. Fingolimod affects the receptor (sphingosine 1-phosphate) which is involved in vascular formation during embryogenesis.During pregnancy and lactation,p.o. fingolimod in rats influenced reduction of pup survival and a neurobehavioral in the offspring. The effects of fingolimod during labor and delivery are unknown. Although as the risk of bradycardia after the first dose of Gilenya® was known when it was authorised, EMA issued MAA for this bio-drug, on 17/03/2011. According to EU legislation, it is: “ prescription only drug” (Rp). But on 20/01/2012 EMA CHMP has begun a review of the benefits and risks of the MS medicine Gilenya®. This follows concerns over the effects of the medicine on the heart after the first dose. The review was started following reports of heart problems in patients taking Gilenya®, as well as 11 the deaths of patients in the United States less than 24 hours after the first dose. The exact cause of this patients’ death is still unexplained.

Novartis submitted to ALIMS the request for getting Gilenya® MAA in Serbia on 1/06/2011.

CONCLUSION

After reviewing all available non-clinical and clinical data and according to National Law on Medicines and Medical devices, ALIMS' s assessor suggested to the Commission for registration new medicines to put this drug on the stronger regime of issuing, than it is in EU: In Serbia it could be issued only inside the stacionary health institution (“SZR”).

Key words: fingolimod, bradicardia, proscription, ALIMS