Teriflunomide
Summary: Teriflunomide (Teri) is a moderately effective platform therapy for treating active MS; it reduces the relapse rate by ~30% and slows the acquisition of disability to a similar degree. It reduces MRI activity by ~70% and slows down brain volume loss, but not to the same degree as highly effective DMTs. Teri is licensed as a first-line therapy in the UK. It is taken as a daily 14 mg tablet. Although Teri inhibits cell proliferation it is not an immunosuppressive agent and is classified as an 'immunomodulatory therapy'. Teriflunomide has not been associated with opportunistic infections, secondary malignancies, a blunted antibody response to vaccines or lymphopaenia (low lymphocyte counts). Low lymphocyte counts only occurs is a small minority of MSers. In general Teri is well tolerated with only a small number of MSers (<5%) developing abnormal liver function tests or gastrointestinal symptoms (mainly diarrhoea) that results in them stopping the therapy. Teri can cause mild hair thinning that is transient; please note this is not alopecia or baldness and in my experience is not a problem for the drug. Teri is considered to be teratogenic, i.e. has the potential to cause foetal abnormalities when women fall pregnant on the drug, which makes it unsuitable for women of childbearing age who are planning to start, or extend, their families. Teri has a long half life and hence stays in the body for months. There is a rapid elimination procedure that is able to remove Teri from the body within days. When Teri is started the EMA requires blood monitoring to be done every 2 weeks for 6 months and then 2 monthly after that. I think these requirements are excessive and a lot of neurologists use the American guidelines, i.e. monthly tests for 6 months and the 3-6 monthly after that. It is the monitoring requirements and who pays for them that has made it difficult to use Teri on the NHS. In clinical practice Teri seems to be much more effective than the results of the clinical trial suggest, which may explain its popularity in other countries. Interestingly, people who start Teri as a second- or third-line DMT seem to do better than those using it 1st-line. I have no idea why Teri is more effective after MSers have failed other DMTs, but it may have something to do with its alternative modes of action, for example its antiviral effects.
Trade Names: Aubagio
Mode of action: Teriflunomide probably has several modes of action but mainly works by inhibiting an enzyme called dihydroorotate dehydrogenase (DHO-OH) which affects pyrimidine metabolism in cells. This results in inhibiting the division of cells, i..e. it is called and antiproliferative agent. It is this action on lymphocytes is how it is thought work in MS. Teriflunomide also broad-spectrum activity against many viruses.
Efficacy: Moderate, it is licensed in the UK as a platform or 1st-line therapy for MSers with active MS
Class: Maintenance, immunomodulator
Immunosuppression: No
Posology: The recommended dose of teriflunomide is 14 mg once daily, but 7mg has also shown to be effective. A 7-mg tablet is available in the US. Teri can be taken with or without food.
Main adverse events:
Liver: Elevations of liver enzymes have been observed on Teri. These are seen within the first 6 months of treatment. MSers with pre-existing liver disease or those who consume excessive quantities of alcohol may be at increased risk of developing elevated liver enzymes on teriflunomide.
Blood pressure: High blood pressure may occur during treatment with teriflunomide.
Infections: No increase in serious infections have been observed with teriflunomide. The safety of teriflunomide in MSers with latent tuberculosis is unknown, which is why I recommend screening for TB infection prior to starting Teri.
Lung: Interstitial lung disease (ILD) has been rarely reported in MSers on teriflunomide. Therefore any new onset or worsening breathing or chest problems, such as persistent cough and shortness of breath need to be investigated.
Blood: Teri causes a small drop in the circulating number of white blood cells. This drop is in the order of ~15% and not sufficient to cause any problems. In a small number of MSers (<5%) the drop may be more profound an require them to stop taking the medication.
Skin: A few cases of a severe hypersensitivity skin reactions have been reported on Teri, including Stevens-Johnson syndrome, toxic epidermal necrolysis and a condition called DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms). Please look out for any skin rash.
Neuropathy: Rare cases of peripheral neuropathy have been reported in MSers on Teri. Please watch out for tingling sensations andor loss of feeling in the toes and fingers; these symptoms tend to be symmetrical, which helps differentiate it from MS symptoms.
Neutralizing Antibodies (NAbs): NAbs are not a problem on Teri as Teri 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 and syphilis), TB elispot, up-to-date cervical smear and/or HPV testing, a pregnancy test and baseline blood pressure are done.
- Follow-up: Liver enzymes should be assessed every two weeks during the first 6 months of treatment, and every 8 weeks thereafter or as indicated by clinical signs and symptoms such as unexplained nausea, vomiting, abdominal pain, fatigue, loss of appetite, or jaundice and/or dark urine. Full blood cell counts need only be performed every 6 months or when MSers on Teri develop an infection on treatment.
Rebaselining: A rebaseline MRI needs to be done after teriflunomide has had sufficient time to work. I would recommend that an MRI is done 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 teriflunomide treatment I would recommend having a negative pregnancy test. As teriflunomide is potentially teratogenic, i.e. can cause birth defects, it is essential for you to have effective contraception whilst on teriflunomide treatment. Since it takes many to eliminate teriflunomide from the body on stopping treatment the potential risk to the foetus may persist and contraception should be continued during this period or you should undergo the rapid elimination procedure.
If there is any delay in onset of your period (menses) or any other reason for you to suspect pregnancy, you must notify your nurse of doctor immediately and undergo pregnancy testing. If pregnant, it is possible that rapidly lowering the blood level of teriflunomide, by instituting the accelerated elimination procedure. Please note that if you do fall pregnant whilst on teriflunomide 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 teriflunomide in the womb, who have been born without any overt problems.
Breast-feeding: As teriflunomide is excreted into breast milk of lactating women and its potential for adverse reactions in nursing infants, women on fingolimod should not breastfeed.
Fertility: There is no evidence that teriflunomide affects either male or female fertility.
Male Fertility: The risk of toxicity to the embryo through teriflunomide affecting the sperm is low. Animal studies have shown no evidence that teriflunomide adversely affects male fertility or damages sperm. Despite this some regulatory authorities have recommended that men wishing to father a child should also discontinue teriflunomide treatment and undergo the accelerated elimination procedure. However, this is not recommended by the EMA. Based on the data I don't recommend that males MSers wanting to start or extend a family stop teriflunomide or take any specific precautions.
Vaccination: Two clinical studies have shown that vaccinations to component or inactivated vaccines were safe and effective whilst on teriflunomide. However, the use of live attenuated vaccines may carry a risk of infections and the current recommendation is that these should therefore be avoided.
Travel: MSers need to be aware that travel may be affected by being on teriflunomide, for example some countries require you to be vaccinated against yellow fever, which is a live attenuated vaccine and hence contraindicated.
Summary of Product Characteristics (SmPC): Aubagio