Starting oral MS medications – how safe are they?
When starting a treatment for multiple sclerosis, many people now opt for an oral medication as an easier, less painful alternative to the older injectable medications. Two therapies – Aubagio and Tecfidera – are the most common first-choice agents. (In Canada, Gilenya [fingolimod] is kept in reserve as a second-line therapy although it is used as an initial therapy in some countries.)
The chief advantage of the injectables was their safety record. The interferons (Betaseron/Extavia, Avonex and Rebif) and Copaxone have been used for twenty years and have been associated with few serious side effects over the long term.
Aubagio and Tecfidera are newer MS treatments, so it’s fair to ask if their safety will match the injectables’ track record.
Aubagio (teriflunomide): This medication is derived from Arava (leflunomide), a drug approved by the U.S. Food and Drug Administration in 1998 for the treatment of rheumatoid arthritis. Clinical development of Aubagio began a few years after, so there is safety information for people in the extension of the initial phase II study who have taken the drug for the past 12 years (Kremenchutzky and colleagues. AAN 2015; abstract P7.223). During this observation period, no new or unexpected side effects emerged. The most common side effects were stuffy nose, numbness in the hands and feet, fatigue, muscle weakness, and upper respiratory tract infections. About 18% of people stopped treatment over the 12-year period because of side effects.
Safety was also examined by looking at the pooled data from four trials and extensions (Leist and colleagues. AAN 2015; abstract P7.268). Again, no unexpected safety issues emerged. The most common side effects were hair thinning, diarrhea, increases in liver enzymes, nausea and headache. There was no increased risk of infections with Aubagio, which is unlike what is seen with many other MS drugs. There was also no indication that Aubagio is associated with a risk of cancer.
A potential safety issue with Aubagio is its effects on the liver. This is because of liver toxicities that occurred with Arava in people with rheumatoid arthritis. Liver safety has been examined in an analysis of all subjects in the clinical development program (Marziniak and colleagues. EAN 2015; abstract P1254). Liver function was assessed with blood tests, which measure the level of liver enzymes (if they are elevated there’s a risk of liver damage). Overall, 2.2% of people taking Aubagio developed serious elevations in liver enzymes (compared to 2.7% of people taking a placebo). After six years on treatment, about 6% of people needed to stop treatment because of this issue. While liver problems are generally mild and resolve on their own, it’s important to have periodic blood tests to ensure that no damage is occurring to the liver. (Periodic blood tests are also required for people taking an interferon for the same reason.)
Tecfidera (dimethyl fumarate, or DMF): Various fumarate formulations have been used to treat psoriasis in Europe for the past fifty years, although they were never approved in North America. It isn’t clear how applicable the fumarate data are to Tecfidera. The longer term safety of Tecfidera has been examined in an analysis of people in the two phase III trials who continued treatment in the ENDORSE extension study (Pozzilli and colleagues. ECTRIMS 2014; abstract P066). Overall, the most common side effects with Tecfidera were stuffy nose, urinary tract infection, headache, respiratory tract infection, flushing, nausea/vomiting and diarrhea. The cancer incidence was low and similar to what was seen with placebo, so this doesn’t appear to be an issue.
About 6% stopped treatment due to side effects in the first 40 months on treatment. A majority of these occurred in the first six months and were mostly due to flushing or stomach-related problems. So tolerating the drug may be difficult, but there appears to be a low risk of serious adverse effects.
A bigger safety issue that has recently emerged with Tecfidera is PML (progressive multifocal leukoencephalopathy), a potentially fatal brain infection. Two cases of PML (one fatal) have been reported thus far with Tecfidera, and several additional cases have been seen in people taking fumarates for psoriasis. The estimated risk of PML is very low, but a warning about PML was added to the U.S. product label in December 2014. (PML risk was also added to the Gilenya product label in the U.S. in August 2015.)
The current thinking is that PML may be due to a persistently low blood cell count (called lymphopenia), which indicates that the immune system is compromised and unable to fight off the virus that causes PML. However, this may not be the whole story. There has been at least one case of PML in a person taking non-branded DMF who didn’t have lymphopenia (Nieuwkamp and colleagues. N Engl J Med 2015;372:1474-1476), as well as reactivation of other viral infections (such as herpes) (van Kester and colleagues. N Engl J Med 2015;373:583-584). Periodic blood tests may provide some indication that a problem is developing but may not give the full picture. In clinical trials, about 6% of people had persistently low blood cell counts, although higher rates (28% in one study) have been reported by MS centres (Longbrake & Cross. AAN 2015; abstract P3.240).
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