GLOMATIN

Indications

• Relapsing forms of multiple sclerosis (RRMS)

Dosage

Children: Refer to the BNF for Children for appropriate dosing information.

Adults: 500 micrograms once daily.

Mechanism of action

Fingolimod is a sphingosine-1-phosphate receptor modulator. It binds to S1P receptors (specifically S1P1, S1P3, S1P4, and S1P5), preventing lymphocytes from exiting lymph nodes. This results in a reduced number of circulating lymphocytes, which decreases neuroinflammation and may help mitigate the effects of multiple sclerosis.

Pharmacodynamics

In the context of multiple sclerosis, fingolimod reduces neuroinflammation by binding to sphingosine receptors. It also causes transient bradycardia and may prolong the QT interval when treatment is initiated. There is some evidence suggesting fingolimod may also reduce lung inflammation in conditions like COVID-19, although its primary use is in MS.

Pharmacokinetics

Fingolimod is well absorbed after oral administration, with peak plasma concentrations typically occurring within 12-16 hours. It undergoes extensive first-pass metabolism to its active form, fingolimod phosphate. The half-life is approximately 6-9 hours for fingolimod and about 30 hours for its active metabolite. The drug is primarily excreted via urine and feces. The pharmacokinetics may be influenced by liver function and concurrent medications.

Contra-indications

• Known risk of cardiovascular events
• Pregnancy
• Women of childbearing potential not using effective contraception

Adverse effects

• Skin cancers
• Lymphoma
• Progressive multifocal leukoencephalopathy (PML)
• Bradycardia
• Transient reduction in heart rate
• Liver injury
• Herpes meningitis

Interactions

• Monoclonal antibodies (increases risk of generalized infection, possibly life-threatening)
• St. John's Wort (decreases exposure)
• Alemtuzumab (increases risk of generalized infection, possibly life-threatening)
• Live vaccines (increases risk of generalized infection, possibly life-threatening)

Precautions

• Perform baseline MRI and repeat as necessary during treatment
• Monitor for skin lesions before starting and every 6 to 12 months
• Assess benefit-risk balance on a case-by-case basis
• Pregnancy should be excluded before treatment initiation and monitored throughout
• Use effective contraception during treatment and for 2 months post-treatment
• Monitor for signs of infection and seek immediate medical attention if symptoms develop

Pregnancy

Fingolimod is contraindicated in pregnancy due to an increased risk of congenital malformations. Treatment should be stopped immediately if pregnancy occurs, and the patient referred for close monitoring.

Breast-feeding

Data on the excretion of fingolimod in human milk is not available, and caution is advised.

Storage

Store at room temperature, below 25°C, in a dry place. Keep out of reach of children.

Formulations

• Gastro-resistant capsule, 500 micrograms

Mechanism of action

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 systems. 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 the 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.

Pharmacodynamics

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. Fingolimod causes a transient reduction in heart rate and AV conduction during treatment initiation. It has the potential to prolong the QT interval.