Products and approval
Fingolimod is commercially available in capsule form (Gilenya) and has been approved in many countries since 2011. First generic products were registered in 2020 and entered the market in 2021. Fingolimod was the first specific multiple sclerosis drug to be administered orally, rather than being injected subcutaneously or as an infusion. In 2019, its successor drug, siponimod, was registered in the United States (Mayzent).
Structure and properties
Fingolimod (C19H34ClNO2, Mr = 343.9 g/mol) is present in the drug as fingolimod hydrochloride, a white powder that is soluble in water. It is a prodrug and, analogous to sphingosine, is stereoselectively phosphorylated primarily in the liver by sphingosine kinase-2 (SphK-2) to the active metabolite ()-fingolimod phosphate. Fingolimod is a structural analog of sphingosine and sphingosine-1-phosphate, respectively. It was derived from myriocin, which is found in the tubular fungus.
Effects
Fingolimod (ATC L04AA27) is selectively immunosuppressive and centrally neuroprotective. It reduced the frequency of relapses by up to 52% in studies, decreasing disability progression by 30%. Fingolimod further reduces heart rate and conduction velocity at the AV node, especially early in treatment.
Mechanism of action
The active metabolite ()-fingolimod phosphate is an analog of sphingosine-1-phosphate (S1P), which is a mediator involved in numerous biological processes in the organism. Among other things, S1P represents a signal for immune cell migration. Fingolimod phosphate is a high-affinity agonist and a functional antagonist at sphingosine-1-phosphate receptors on lymphocytes. Receptor modulation results in downregulation of cell surface receptors and reduces sensitivity to endogenous ligand. It thus blocks the exit of lymphocytes from the lymph nodes into the peripheral circulation and reduces the number of lymphocytes in the blood to 20-30% of the initial value. This process is fully reversible. The effects are based on the inhibition of the passage of lymphocytes into the central nervous system. This prevents inflammation and tissue damage by the autoaggressive immune cells. Furthermore, there is evidence that fingolimod crosses the blood–brain barrier and directly exerts neuroprotective properties; other pleiotropic effects are discussed (see literature). The transient reduction in heart rate is also a consequence of the interaction of fingolimod phosphate with S1P receptors. View large
Indications
For the treatment of relapsing-remitting multiple sclerosis (RRMS).
Dosage
According to the SmPC. Fingolimod may be administered once daily due to its long half-life of 6-9 days. The intake is independent of meals.
Contraindications
Fingolimod is contraindicated in patients with certain cardiovascular diseases, severe hepatic insufficiency or cirrhosis, hepatitis B, macular edema, in children and adolescents, and during pregnancy and lactation. For complete precautions, see the drug label.
Interactions
Fingolimod is phosphorylated (see above), biotransformed to inactive ceramide analogs, and metabolized by CYP4F2. CYP2D6*1, 2E1, 3A4, and 4F12 are involved to a lesser extent. Pharmacokinetic Interactions:
- CYP inhibition (e.g., ketoconazole) or induction.
Pharmacodynamic interactions:
- Antiarrhythmics, beta-blockers.
- Vaccinations
- Cytostatics, antineoplastics, immunosuppressants, immunomodulators.
Adverse effects
Because fingolimod suppresses the immune system, it may increase the risk of infectious diseases and may promote, for example, influenza, acute bronchitis, sinusitis, herpes infections, gastrointestinal flu, and fungal skin infections as adverse effects. Fingolimod lowers the heart rate at the beginning of treatment and very rarely can cause AV block. Other possible common adverse effects include headache, dizziness, high blood pressure, weakness, diarrhea, cough, difficulty breathing, visual disturbances, back pain, depression, elevated liver enzymes, lymphopenia, leukopenia (reduction in white blood cells), and macular edema.
