INTRODUCTION
Fingolimod (Gilenya) is an oral immunosuppressant used as a disease-modifying drug in the treatment of relapsing-remitting multiple sclerosis. The guideline of the Croatian Health Insurance Institute for the use of fingolimod (N457) is: "As monotherapy in highly active relapsing-remitting multiple sclerosis with phases of relapse and remission with EDSS <= 6 and absence of pregnancy- I. in patients with active disease and who have not responded to a complete and appropriate treatment regimen with at least one course-modifying therapy (interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate), or when the criteria for discontinuation of the therapy according to current guidelines in the drug list are met. The disease is considered active despite previous therapy when following criteria are met a) >= 4 new T2 hyperintensive lesions on MR, or b) >= 2 relapses. Treatment is approved by the Hospital Drug Committee for the next 6 months at the expense of the hospital budget, and afterwards at the expense of the Croatian Health Insurance- Fund for very expensive drugs. Treatment for patients with severe rapidly progressive relapsing-remitting multiple sclerosis is approved at the expense of the hospital budget. "(1).
FINGOLIMOD AND LIVER DAMAGE
One of the most common reasons for discontinuation of fingolimod therapy is an increase in transaminases, indicative of inflammation or damage to liver cells. During clinical trials with fingolimod, an increase in transaminase levels of at least 3-fold the upper limit of normal (ULN) was observed in 8% of adults and up to 5-fold the ULN in 1.8% of subjects. In addition, reintroduction of fingolimod into therapy was observed to result in liver damage in some patients, suggesting causality. In clinical trials, elevations in transaminases were recorded at different times during treatment, although most occurred during the first 12 months of treatment. Transaminase levels returned to normal within approximately 2 months after cessation of treatment (3). In late 2020, the European Medicines Agency (EMA) reported cases of liver failure in patients on fingolimod, including three cases requiring liver transplantation. Other drug agencies around the world have also issued warnings about the link between fingolimod and liver damage. The first signs of liver damage in these patients were elevated liver enzymes and bilirubin. The occurrence of these laboratory abnormalities was noted as early as 10 days after the first dose, but also after prolonged use of the drug (2). Due to the severity of this side effect, the Summary of Product Characteristics was amended; The EMA recommended monitoring of hepatic function, including bilirubin, before and during fingolimod treatment (at 1, 3, 6, 9, and 12 months during treatment) and 2 months after cessation of therapy due to the long half-life of fingolimod of 6 to 9 days ( 2).
Pharmacokinetics of fingolimod
Absorption of fingolimod is slow (12-16 hours) and extensive (bioavailability about 93%), and is not significantly affected by food. The pharmacologically active metabolite responsible for its efficacy is fingolimod phosphate. Fingolimod and fingolimod phosphate are highly bound to plasma proteins (> 99%) and are extensively distributed to tissues. Fingolimod is transformed in humans by reversible stereoselective phosphorylation into the already mentioned pharmacologically active (S) -enantiomer of fingolimod phosphate. Fingolimod is eliminated by oxidative biotransformation catalyzed mainly by CYP4F2 (or CYP3A4) and possibly other isoenzymes, followed by degradation similar to that of fatty acids to inactive metabolites. Following oral administration, approximately 81% of the dose is slowly excreted in the urine in the form of inactive metabolites. The elimination half-life (t1/2) of fingolimod is 6-9 days.
CONCLUSION
Since the introduction of fingolimod on the market, numerous side effects have been reported with its use. The post-marketing data confirm the possibility of serious side effects, especially cardiac and hepatic. Adverse cardiac side effects have already been reported during clinical trials, and in 2017, based on additional safety data collected, the use of fingolimod in patients with severe heart disease was contraindicated (2).
What does this mean for the clinical practice?
Based on a limited number of randomized controlled clinical trials, indirect comparisons of therapeutic lines, observational studies, and clinical experience, the clinical utility of fingolimod compared to other disease-modifying drugs (eg interferon beta-1a, the only drug fingolimod was compared to in a randomized placebo-controlled trial ) is relatively modest (4, 5). Due to potentially serious side effects, the benefit-risk balance should be carefully weighed when deciding to initiate fingolimod or change the treatment line to fingolimod. In persons on fingolimod who have elevated transaminases 3x the ULN, more frequent monitoring of transaminase levels is recommended. Fingolimod therapy should be discontinued in subjects with a transaminase level greater than 5 times the ULN or a transaminase level greater than 3 times the ULN, with a concomitant increase in bilirubin to a value greater than 2x the ULN. Furthermore, fingolimod should be discontinued in case of liver damage without a known cause.
References:
1. HZZO. Tražilica za lijekove. Gilenya (fingolimod). https://hzzo.hr/trazilica-za-lijekove?query=gilenya Pristup 11.7.2021.
2. Sažetak opisa svojstava lijeka Gilenya (fingolimod), Novartis Europharm Limited, 16.11.2020.
3. Direct Healthcare Professional Communication Gilenya (fingolimod) – Updated recommendations to minimise the risk of drug-i nduced liver injury (DILI). https://www.ema.europa.eu/en/documents/dhpc/direct-healthcare-professional-communication-dhpc-gilenya-fingolimod-updated-recommendations_en.pdf Pristup 11.7.2021.
4. Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults. Comparative efficacy. UpToDate, 2021.
5. NICE. Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis. https://www.nice.org.uk/guidance/ta254 Pristup 7.11.2021.