Fingolimod

307.478

307.47

3QN8BYN5QF

DTXSID40167363

C74202

L04AA27|L - Antineoplastic and immunomodulating agents

66.5

4.2

1.0±0.1 g/cm3

121-124 °C

479.498

243.8±28.7 °C

1.531

H2O: soluble

8None

The LD50 of fingolimod in rats ranges from 300-600 mg/kg. Prescribing information for fingolimod does not mention symptoms or management of an overdose, however, a case report of an intentional overdose with 14mg of fingolimod and 2g phenoxymethylpenicillin resulted in hypotension in bradycardia, resolved by administering atropine. Since fingolimod has been associated with cardiotoxicity, it would be reasonable to expect cardiac effects such as bradycardia and heart block in the case of an overdose.

In large randomized controlled trials of fingolimod in patients with multiple sclerosis, serum ALT elevations above 3 times ULN were reported in 8% to 14% of fingolimod compared to 2% to 3% of placebo recipients. The enzyme elevations were usually transient and not associated with symptoms or jaundice and required drug discontinuation in less than 1% of cases. No instances of acute hepatitis or clinically apparent liver injury were reported in the preregistration trials of fingolimod. Subsequent to its approval and more wide scale use, however, instances of clinically apparent liver injury attributed to fingolimod were reported including cases of acute liver failure requiring emergency liver transplantation. The onset of liver injury was often within days or weeks of starting treatment and the pattern of liver enzyme elevations was usually hepatocellular. In addition, at least one instance of reactivation of hepatitis B in an inactive HBsAg carrier has been reported. Thus, mild-to-moderate and transient serum enzyme elevations during therapy are not uncommon, and clinically apparent liver injury with jaundice due to fingolimod can occur.

The protein binding of fingolimod and its active metabolite exceeds 99.7%.

Fingolimod is indicated for the treatment of patients aged 10 and above with relapsing forms of multiple sclerosis, which may include clinically isolated syndrome, relapsing-remitting disease, as well as active secondary progressive disease. This drug is being studied for administration in patients infected with COVID-19 with a high risk for acute respiratory distress syndrome, or ARDS. As of April 3 2020, this is currently not an approved indication and clinical trials are underway.|Gilenya is indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis for the following groups of adult patients and paediatric patients aged 10 years and older:Patients with highly active disease despite a full and adequate course of treatment with at least one disease modifying therapy (for exceptions and information about washout periods see sections 4.4 and 5.1).orPatients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.|Indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis for the following groups of adult patients and paediatric patients aged 10 years and older:Patients with highly active disease despite a full and adequate course of treatment with at least one disease modifying therapyorPatients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.|Indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis for the following groups of adult and paediatric patients aged 10 years and older:Patients with highly active disease despite a full and adequate course of treatment with at least one disease modifying therapy (for exceptions and information about washout periods see sections 4.4 and 5.1)orPatients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.

Fingolimod is an orally available immunomodulatory drug used to treat relapsing multiple sclerosis. Fingolimod is associated with transient serum enzyme elevations during therapy and with rare instances of clinically apparent, acute liver injury that can be severe and even fatal.

Multiple Sclerosis Agents

In multiple sclerosis, fingolimod binds to sphingosine receptors, reducing its associated neuroinflammation.In COVID-19, it may reduce lung inflammation and improve the clinical outcomes of patients with this disease. Cardiovascular effects Fingolimod causes a transient reduction in heart rate and AV conduction during treatment initiation. It has the potential to prolong the QT interval.

Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging. (See all compounds classified as Immunosuppressive Agents.)|Agents that affect the function of G-protein coupled SPHINGOSINE 1-PHOSPHATE RECEPTORS. Their binding to the receptors blocks lymphocyte migration and are often used as IMMUNOSUPPRESSANTS. (See all compounds classified as Sphingosine 1 Phosphate Receptor Modulators.)

Fingolimod is slowly but efficiently absorbed in the gastrointestinal tract. AUC varies greatly, depending on the patient, and pharmacokinetic studies demonstrate a range of AUC values for fingolimod. The Tmax of fingolimod ranges between 12-16 hours and its bioavailability is 90-93%. Steady-state concentrations of fingolimod are achieved within 1-2 months after initiation when it is administered in a single daily dose.|About 81% of an oral dose of fingolimod is excreted in the urine in the form of inactive metabolites. Intact fingolimod and its active metabolite account for less than 2.5% of the dose, and can be found excreted in the feces.|The volume of distribution of fingolimod is about 1200±260 L. It is approximately 86% distributed in the red blood cells (RBC).|Fingolimod blood clearance is 6.3±2.3 L/h, according to prescribing information. Another resource mentions it ranges from 6-8 L/h.

Sphingosine kinase metabolizes fingolimod to an active metabolite, fingolimod phosphate. Fingolimod metabolism occurs via 3 major metabolic pathways: firstly, phosphorylation of the (S)-enantiomer of fingolimod-phosphate (pharmacologically active), secondly, oxidation by cytochrome P450 4F2 (CYP4F2), and thirdly, fatty acid-like metabolism to various inactive metabolites. The formation of inactive non-polar ceramide analogs of fingolimod also occurs during its metabolism.

The half-life of fingolimod and its active metabolite ranges from 6-9 days.

Sphingosine‐1‐phosphate (S1P) is an important phospholipid that binds to various G‐protein‐coupled receptor subtypes, which can be identified as S1P1–5R. S1P and the receptors it binds to perform regular functions in the immune, cardiovascular, pulmonary, and nervous system. S1P can be expressed ubiquitously, playing an important role in regulating inflammation. S1P1R, S1P2R, and S1P3R receptors can be found in the cardiovascular, immune, and central nervous systems. S1P4R is found on lymphocytic and hematopoietic cells, while S1P5R expression is found only on the spleen (on natural killer cells) or in the central nervous system. The active form of the drug, fingolimod phosphate, is a sphingosine 1-phosphate receptor modulator that exerts its mechanism of action in MS by binding to various sphingosine 1-phosphate receptors (1, 3, 4, and 5). It suppresses the exit of lymphocytes from lymph nodes, leading to a lower level of lymphocytes circulating in peripheral circulation. This reduces the inflammation that is associated with MS. The mechanism of action of fingolimod is not fully understood, but may be related to reduced lymphocyte circulation into the central nervous system. Immune modulating treatment such as fingolimod is not typically employed for SARS-CoV-2 pneumonia. Despite this, with the tissue findings of pulmonary edema and hyaline membrane formation, the timely use of immune modulators such as fingolimod can be considered to prevent acute respiratory distress syndrome (ARDS) associated with COVID-19.

2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol hydrochloride

Human drugs -> Gilenya -> EMA Drug Category|Immunosuppressants -> Human pharmacotherapeutic group|Human drugs -> Rare disease (orphan)|Human drugs -> Fingolimod Accord -> EMA Drug Category|Immunosuppressants, Selective immunosuppressants -> Human pharmacotherapeutic group|Human drugs -> Fingolimod Mylan -> EMA Drug Category