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Summary: Fingolimod was the first-oral tablet to be licensed in MS. It is a highly effective drug reducing the relapse rate by over 50%, reducing worsening disability and the development of new lesions on MRI, and slowing the loss of brain volume loss. Fingolimod works by trapping lymphocytes in lymph nodes and causes a low lymphocyte count in virtually all MSers on the drug. It is a maintenance therapy that is taken continuously and hence causes systemic immunosuppression. As a result of this fingolimod is associated with rare opportunistic infections and secondary malignancies, for example lymphomas and skin cancers. As it is anti-trafficking drug, i.e. it blocks lymphocytes migrating into the CNS of MSers, when it is stopped it is associated with rebound disease activity. Rebound typically occurs at around 6-8 weeks after stopping the drug. Fingolimod has off target effects, for example it slows the heart rate down and hence has to be started in hospital.
Trade Names: Gilenya
Mode of action: Fingolimod is a sphingosine 1-phosphate receptor modulator. Fingolimod is converted to an active drug fingolimod phosphate in the body. Fingolimod phosphate binds to its receptor called the sphingosine 1-phosphate (S1P) receptor 1 located on lymphocytes, which causes the receptors to be internalised and removed from the surface of the cells. By preventing S1P receptors to recirculate onto the surface of lymphocytes, fingolimod blocks the capacity of lymphocytes to egress from lymph nodes, causing a redistribution, rather than depletion, of lymphocytes.
Efficacy: High, it is licensed in the UK as a second-line therapy for MSers with highly-active MS
Class: Maintenance, immunosuppressive
Immunosuppression: Yes, systemic
Posology: In adults, the recommended dose of fingolimod is one 0.5 mg capsule taken orally once daily. In children with MS (10 years of age and above), the recommended dose is dependent on body weight:
- Body weight ≤40 kg: one 0.25 mg capsule taken orally once daily.
- Body weight >40 kg: one 0.5 mg capsule taken orally once daily.
When MSers are start on 0.25 mg capsules and subsequently reach a stable body weight above 40 kg they should be switched to 0.5 mg capsules. Please note that when switching from a 0.25 mg to a 0.5 mg daily dose, it is recommended to repeat the same first dose monitoring as for treatment initiation. Fingolimod can be taken with or without food. Fingolimod capsules should always be swallowed intact, without opening them. The same first dose monitoring as for treatment initiation is recommended when treatment is interrupted for:
- 1 day or more during the first 2 weeks of treatment.
- more than 7 days during weeks 3 and 4 of treatment.
- more than 2 weeks after one month of treatment.
If the treatment interruption is of shorter duration than the above, the treatment should be continued with the next dose as planned.
Main adverse events:
Adverse events of special interest:
- Cardiac: The main adverse event is a transient slowing of the heart rate that can rarely be associated with a heart block. This is why fingolimod is started in hospital with cardiac monitoring. The cardiac conduction abnormalities are usually transient and asymptomatic. Due to the cardiac side effects concurrent therapy with beta blockers, heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem), or other substances which may decrease heart rate (e.g. ivabradine, digoxin, anticholinesterase inhibitors or pilocarpine) is not recommended. The effects on heart rate and cardiac conduction may recur on re-introduction of fingolimod treatment depending on duration of the interruption and time since start of treatment. As fingolimod may prolong the so called QT interval on your ECG fingolimod is best avoided in MSers with relevant risk factors, for example,low potassium or congenital QT prolongation.
- Immunosuppressive effects: Fingolimod predisposes MSers to an infection risk, including opportunistic infections, and increases the risk of developing lymphomas and other malignancies, particularly those of the skin. Before initiating treatment with fingolimod it is important to do a baseline infection screen and to check the full blood count. It is important to have antibodies or immunity to varicella (chickenpox) prior to starting treatment. If you are varicella negative it is recommended that you receive a full course of one of the varicella vaccines. Opportunistic infections include fungal infections, for example cryptococcal meningitis and progressive multifocal leukoencephalopathy (PML). Human papilloma virus (HPV) infection, including papilloma, dysplasia, warts and HPV-related cancers, has been reported in MSers on fingolimod, which is why we recommend cervical smears or HPV testing at baseline.
- Macular oedema: Swelling of the macular, the central part of the retina, occurs in ~ 1 in 200 MSers treated with fingolimod. This can cause symptoms and can be detected using the so called Amsler grid (see below). It is important you are assessed at an eye clinic 3-4 months after initiating fingolimod to screen for this complication. Please note that if you have a history of uveitis (inflammation in the eye) or have diabetes mellitus you are at increased risk of developing macular oedema. I tend to avoid prescribing fingolimod to MSers with diabetes.
- Liver: Increased liver enzymes have been reported in MSers on fingolimod. This is why your LFTs (liver function tests are monitored after starting fingolimod and if the go above 5x the upper limit of normal Fingolimod needs to be stopped. LFTs are recommended at 1, 3, 6, 9 and 12 months after therapy and then 6 monthly after that. You need to be aware that if you develop any symptoms suggestive of liver problems, such as unexplained nausea, vomiting, abdominal pain, fatigue, loss of appetite, or jaundice and/or dark urine, should have liver enzymes checked. If you have pre-existing liver disease most neurologists would avoid using fingolimod.
- High blood pressure: Fingolimod increases your blood pressure by a small amount. If you do develop hypertension you may need to start antihypertensive medications; this occurs in ~ 1 in 20 MSers treated with fingolimod.
- Respiratory effects: Fingolimod causes a minor reduction in lung function, which is why neurologists tend to avoid using fingolimod in MSers with pre-existing lung disease.
- Vascular side effects: Rare cases of a condition called posterior reversible encephalopathy syndrome (PRES) have been reported on fingolimod. Symptoms can include sudden onset of severe headache, nausea, vomiting, altered mental status, visual disturbances and seizures. If you suspect you have PRES you should contact your doctor urgently.
- Cutaneous neoplasms: Basal cell carcinoma (BCC) and other cutaneous neoplasms, including malignant melanoma, squamous cell carcinoma, Kaposi's sarcoma and Merkel cell carcinoma, have all been reported in MSers on fingolimod. Please be vigilant for any new skin lesions and bring it to the attention of your doctor, who may need to refer you to see a dermatologist. In our centre we encourage our patients to take pictures of lesions with their smartphone camera and email them to us. We often get back a dermatology opinion very quickly this way. In high risk MSers, i.e. those who have a dysplastic naevus syndrome, severe sun damage and/or prior history of skin cancer, we refer to dermatology for regular (annual) skin cancer screening. At present annual skin screening is not justified in low-risk patients. Since there is a potential risk of malignant skin lesions you need to be careful with excessive sunlight exposure or phototherapy with UV-B-radiation or PUVA-photochemotherapy.
- Rebound disease activity: Severe exacerbation of disease have been observed in MSers stopping fingolimod treatment. The possibility of recurrence of exceptionally high disease activity needs to be carefully considered when sequencing treatments. Rebound typically occurs after 6-8 weeks after stopping fingolimod.
Neutralizing Antibodies (NAbs): Not a problem as fingolimod is a small molecule and not a biological (protein) therapy
Pharmacovigilance monitoring requirements:
- Baseline: FBC, U&E, LFTs, TFTs, serum immunoglobulin levels, serology (VZV, HIV-1&2, hepatitis B&C, syphilis, EBV and CMV), TB elispot, up-to-date cervical smear and/or HPV testing, a pregnancy test, BP and an ECG. Lung function tests are recommended in anyone with a history of asthma or lung disease.
- Follow-up: FBC, LFTs and blood pressure should be monitored at months 1, 3, 6, 9 and 12 on therapy and 6-monthly thereafter.
- Visual function: Macular oedema screening should be done at month 3-4 in an eye clinic.
- Self-monitoring: All MSers should be warned about opportunistic infections and informed to look-out for symptoms suggestive of infections, suspicious skin lesions and symptoms of liver dysfunction. Women should be reminded to self-examine their breasts monthly and should have cervical smears and/or HPV testing done 3 yearly. MSers need to be aware of visual symptoms and can sell assess their macular function with an Amsler grid. There are several Amsler grid apps available for smartphones. Routine blood pressures need to be done to
Rebaselining: A rebaseline MRI needs to be done after fingolimod has had sufficient time to work. As fingolimod works quite rapidly I would recommend that an MRI is done 3-6 months after starting treatment and to include Gd-enhancement as part of the rebaselining MRI.
Women of childbearing potential and pregnancy: If you are a women of childbearing age before starting fingolimod treatment I would recommend a negative pregnancy test result. Fingolimod is potentially teratogenic, i.e. can cause birth defects, therefore it is essential for you to have effective contraception whilst on fingolimod treatment. Since it takes ~2 months to eliminate fingolimod from the body on stopping treatment the potential risk to the foetus may persist and contraception should be continued during that period. If you do fall pregnant whilst on fingolimod we would not automatically recommend termination of pregnancy, but refer you to a high-risk antenatal clinic for counselling and foetal screening. There have been many babies, who have been exposed to fingolimod in the uterus, who have been born without any overt problems.
Breast-feeding: As fingolimod is excreted in breast milk of lactating women and its potential for serious adverse reactions in nursing infants, women on fingolimod should not breastfeed.
Fertility: I am not aware of any data to suggest that fingolimod is be associated with reduced female fertility.
Male Fertility: Fingolimod has not been shown to affect sperm counts or sperm motility. There is no need for male MSers to stop fingolimod if they want to father a child.
Travel: MSers need to be aware that travel may be affected by being on fingolimod, for example some countries require you to be vaccinated against yellow fever, which is a live attenuated vaccine and hence contraindicated. If you travel to places associated with exotic infections, for example dengue fever, you may be at risk of complications from these infections because fingolimod is an immunosuppressive agent.
Summary of Product Characteristics (SmPC): Gilenya
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