Assessing risks of multiple sclerosis therapies

Journal of the Neurological Sciences 332 (2013) 59–65

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Assessing risks of multiple sclerosis therapies Valeriy Parfenov, Myriam Schluep, Renaud Du Pasquier ⁎ Service of Neurology, Department of Clinical Neurosciences, University Hospital of Lausanne, CHUV BH-10, 46 rue du Bugnon, 1011 Lausanne, Switzerland

a r t i c l e

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Article history: Received 19 April 2012 Received in revised form 21 May 2013 Accepted 12 June 2013 Available online 5 July 2013 Keywords: Multiple sclerosis Treatment Safety Complications Monitoring Drug approval

a b s t r a c t Over the last two decades, thanks to the discovery of several pharmaceutical agents, multiple sclerosis (MS) has been transformed into a treatable disorder although the degree of therapeutic response may vary considerably. As more medications find their entry into the MS market, a clinician faces a mounting challenge of comparing risk and benefit profiles of various agents in an attempt to find the best treatment approach for each individual patient. In this review, we aim to summarize the available data on safety profiles of available MS therapies while focusing mostly on serious medication specific potential adverse events without discussing the teratogenic potential of each agent (unless there is a black box warning) or hypersensitivity reactions. Our goal is to provide a clinician with guidance on assuring the appropriate safety monitoring for patients treated with one of the agents discussed. We also comment on the future of risk management in MS and discuss possible enhancements to the current model of drug approval process and general strategies to improve the patient safety. © 2013 Elsevier B.V. All rights reserved.

1. Introduction Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder affecting the central nervous system that commonly results in progressive accumulation of disability. Over the last two decades, thanks to the discovery of several pharmaceutical agents, this disease has been transformed into a treatable disorder although the degree of therapeutic response may vary considerably. As more medications find their entry into the MS market, a clinician faces a mounting challenge of comparing risk and benefit profiles of various agents in an attempt to find the best treatment approach for each patient. Since MS is a chronic disorder that most of the time requires prolonged exposure to a therapeutic agent, knowledge of safety profiles of available therapies becomes of utmost importance since the risk of developing an adverse event can be augmented with the duration of treatment. Unfortunately, phase III trials are generally designed to evaluate efficacy and not necessarily occurrence of rare side effects. This can make the assessment of treatment safety profiles challenging at times. In addition, on the contrary to other diseases with grimmer prognosis, such as cancer, MS is not a fatal disorder and, hence, risk tolerance tends to be lower for MS patients and their treating physicians alike, although some available therapies are used in both conditions (mitoxantrone). As a result of a flurry of recent highly publicized reports of medication withdrawals from the market secondary to safety concerns, there is an increased awareness and fear of medication adverse events among patients and health care professionals. These events also gave rise to a widely held impression that the pharmaceutical industry could downplay safety risks. Thus, drug-regulatory agencies frequently call for increased ⁎ Corresponding author. Tel.: +41 21 314 1228; fax: +41 21 314 1256. E-mail address: [email protected] (R. Du Pasquier). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.06.013

regulation to assure the patient safety [1]. These elements contribute to the increased government regulation of the industry that may result in decreased availability of new therapies leading to increased frustration of patients and physicians. In the end, the burden lies on shoulders of doctors to critically evaluate the available information with the goal of coming up with an optimal treatment strategy that satisfies the risk– benefit ratio requirements of the individual patient and the physician. In this review, we aim to summarize the available data on safety profiles of available MS therapies while focusing mostly on serious medication specific potential adverse events without discussing the teratogenic potential of each agent or hypersensitivity reactions. Our goal is to provide a clinician with guidance on assuring the appropriate safety monitoring for patients treated with one of the agents discussed. Finally, we comment on the future of risk management in MS and discuss possible enhancements to the current model of drug approval process and general strategies to improve the patient safety.

2. Interferon beta Interferon beta (IFNb) is one of the most commonly prescribed therapies for relapsing remitting MS (RRMS). Although considered to be generally safe, certain adverse events are possible and, thus, regular monitoring is recommended. Up to 75% of patients experience flu-like symptoms such as fever, headache, muscle pain, fatigue, and chills [2]. Non-steroidal antiinflammatory drugs (NSAIDs) are generally effective. The most common observed laboratory abnormalities are elevation of liver enzymes and leukopenia [3–9]. These changes are seldom serious, generally reversible, and most of the time do not require the discontinuation of therapy [8,9]. However, reports of fulminant liver

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failure as well as reports of unmasking of preexisting autoimmune hepatitis or psoriasis do exist [10–13]. Hence, the recommendation for regular monitoring of liver enzymes is maintained. Complete blood count with differential and complete metabolic panel that includes liver function tests should be obtained monthly in the first 3 months with quarterly checks for the rest of the first year of treatment [2]. Thereafter, provided no laboratory abnormalities have been observed, the blood work can be performed on a semi-annual to annual basis. If significant laboratory abnormalities are found while under treatment, lowering the medication dose or even temporary discontinuation of therapy would have to be considered. A syndrome resembling thrombotic thrombocytopenic purpura (TTP) with fever, thrombocytopenia, and renal failure has been reported in two women treated with IFNb-1a for MS [2]. One of the authors (VP) has also taken care of a male patient that has developed a TTP-like syndrome that was thought to be possibly related to IFNb-1a 3 × 44 μg/week therapy since it was the only medication that patient was taking at the time. The hospital course was very complicated, but the patient did eventually have a good recovery with plasma exchange treatment. Therefore, patients should be counseled on the importance of talking to their doctors if they experience excessive fatigue and fever that are out of proportion to the usual interferon treatment associated flu-like symptoms, especially if accompanied by a decrease in urine output. Reports of depression associated with interferon therapy are well known, however controversy still exists, since depression is quite common in MS patients in general, whether they are treated with IFNb or not. A recent review has described eleven cases of severe depression with suicide attempts among MS patients treated with interferon beta who had no prior psychiatric history [14]. On the other hand, other studies found no evidence to support the claim that IFNb can cause or exacerbate depression [15]. Regardless, all MS patients need to be screened for signs of depression and if those are present, appropriate treatment should be instituted (antidepressant, psychiatry evaluation, etc). Inquiring about patient's mood should be an integral part of any follow-up visit, especially if patient is treated with IFNb. 3. Glatiramer acetate (GA) Glatiramer acetate is a random polymer of glutamic acid, lysine, alanine, and tyrosine. The most common side effect, aside from local injection site reactions, is a post-injection reaction that may happen to 10–15% of patients that is manifested by chest tightness, shortness of breath, palpitations, anxiety and flushing lasting 15–30 min [16]. These events have not been associated with any cardiovascular or other systemic consequences. Educating the patient on this possible side effect is important in order to relieve the potential anxiety should this event take place. GA has not been associated with liver function abnormalities, leukopenia, or depression [16,17].

ejection fraction (LVEF) to congestive heart failure (CHF). This applies to both cancer and MS patients treated with this agent. Initial safety data from the original study were fairly reassuring, however a number of Class III studies documented generally higher cardiotoxicity in mitoxantrone-treated MS patients although the reported frequency, severity, and time course of cardiac complications varied significantly [20–32]. Consolidating the data from these studies gives an estimated 12% rate of decreased LVEF and 0.4% risk of CHF, although the differences in mitoxantrone regimens and cardiac monitoring between different centers make this figure more of an approximation [20]. RENEW, an ongoing phase IV study of mitoxantrone is aimed at assessing the long-term safety and tolerability of treatment. As of January 2008, CHF was noted in 2% of the observed patients while 13% of patients, for whom serial cardiac function results were available, had LVEF b 50%. A general recommendation is to obtain a baseline assessment of LVEF prior to the initial treatment and if it is found to be less than 50% or if a patient has any history of cardiovascular disease, treatment should be withheld. In terms of subsequent monitoring, an assessment of LVEF should be performed before each dose and treatment needs to be stopped if decrease in systolic function is found. Since the total cumulated dose of mitoxantrone is thought to influence the cardiotoxic effect, the upper dose limit should be strictly defined for each patient. In 2008, the U.S. Food and Drug Administration (FDA) made the further recommendation that patients undergo annual cardiac function assessment after completing mitoxantrone treatment due to the potential for delayed cardiotoxicity [20]. Another potential dreaded complication of mitoxantrone therapy is treatment related acute leukemia (TRAL). The majority of TRAL cases in the MS population occur within a few years of mitoxantrone use. Initially, the risk of TRAL in MS patients was estimated to be 0.07% after a mean follow-up of 36 months in 1378 patients [33]. However, a more recent number of Class III and IV case series and case reports have suggested a higher risk of TRAL than previously thought [34–48]. Combining the data from the series above will give an estimated TRAL risk of 0.81%, although the fact that this number is merely an approximation has to be once again emphasized since the length of follow-up was quite variable among the studies [20]. A recent Italian multicenter retrospective study reported the risk of TRAL of 0.93% with an additional observation that patients who developed TRAL had received a higher mean cumulative dose of mitoxantrone than patients who did not [43]. In terms of routine monitoring, complete blood counts are recommended prior to each infusion and if patient develops an infection since leukopenia is quite common and patients are considered to be immunosuppressed when treated with mitoxantrone. Because this agent is eliminated primarily via biliary excretion, complete metabolic panel with liver function tests should be performed as well prior to each treatment. Pregnancy test is also recommended prior to each treatment due to teratogenicity of this medication. 5. Natalizumab

4. Mitoxantrone Mitoxantrone is an anthracenedione that is used to treat several types of cancer [18]. It has also shown efficacy in the treatment of worsening relapsing–remitting or secondary progressive MS [19]. Mitoxantrone is usually given intravenously at a dose of 12 mg/m2 every 3 months until a maximum cumulative lifetime dose of 140 mg/m2 is reached, although lower cumulative doses are commonly used [20]. Mitoxantrone is a good example that emphasizes the importance of continued postmarketing safety evaluation since figures from initial studies may often misrepresent the actual occurrence of adverse events. Significant potential safety concerns have been found with this agent and were discussed in detail in a recent review [20]. Cardiotoxicity is a well known potential complication of mitoxantrone therapy with patients developing varying degrees of cardiac dysfunction ranging from an asymptomatic decrease in left ventricular

Natalizumab is a monoclonal antibody directed against alpha-4integrin that is approved as a second-line treatment of RRMS in patients who either fail first-line treatment or who have highly active disease. In MS clinical trials, infectious complications other than progressive multifocal leukoencephalopathy (PML) were infrequent, however, frequency of herpes infections, pneumonia, and urinary tract infections was slightly higher in patients treated with natalizumab [49,50]. Therefore, patients need to be advised on reporting signs/symptoms of serious infections to their physicians. A potential complication of treatment with this agent that received most attention is PML, which is an opportunistic viral infection of the central nervous system caused by the human polyoma JC virus (JCV) [51,52]. With the advent and more wide-spread use of new immunosuppressive therapies to treat various autoimmune disorders, this disease that was previously seen mostly in AIDS and cancer patients, has become more common and better

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recognized [53]. According to Biogen Idec, as of February 29, 2012 there have been 212 natalizumab associated PML cases of which 46 (22%) have died [54]. The general risk of PML has been quoted as 1/1000, however, most recently, based on the 212 cases, the overall risk of PML is estimated to be 2.13 per 1000 patients [54]. Fig. 1 demonstrates the incidence of PML depending on the duration of treatment [54]. The strategy of risk stratification is often employed, when possible, in order to improve patient safety [55]. There is an obvious need to find a way to screen patients treated with natalizumab with the goal of detecting persons at higher risk for developing PML. One potential approach would be trying to detect the reactivation of the virus in the blood or urine of treated patients. In our institution, we have performed a study evaluating this approach [56]. We were unable to detect JCV reactivation neither in blood nor in urine of natalizumab treated patients up to 18 months of treatment. Similar findings have been reported by most authors [57,59–61], but not all [58]. Recently, StratifyJCV™ a two-step ELISA assay was developed to evaluate the JCV serological status to help risk-stratify the patients that are considered for treatment with natalizumab [62]. In the study, all 17 of the pre-PML samples that were available tested seropositive for JCV antibodies. As a result of further investigations, a following model has been proposed to stratify the risk of PML in different patient populations depending on their JCV antibody status, duration of natalizumab therapy, and prior immunosuppressant use [55] (Table 1). Hence, a reasonable approach to monitoring would be obtaining JCV serology before initiating the treatment to initially risk-stratify the patient. If the test is negative, the patient has very low risk to develop PML since he/she is not infected. If therapy with natalizumab is started, checking serology for JCV on an annual basis is thought to be reasonable since patients may seroconvert that could increase their risk of PML. A baseline brain MRI with gadolinium is recommended within 3 months prior to initiation of therapy with Tysabri. If patient were to develop any new sign or symptom suggestive of PML, a repeat MRI of the brain is recommended and treatment with natalizumab should be withheld. If imaging is suggestive of PML, lumbar puncture is crucial to send JCV PCR in the cerebrospinal fluid (CSF), although a false negative result is possible, in particular early in the disease process [63,64]. A yearly MRI of the brain is often requested for patients treated with natalizumab regardless of presence or absence of new symptoms, although this approach has yet to be validated. Another potential side effect of natalizumab therapy is hepatotoxicity. Spontaneous cases of serious liver injury have been reported, but tend to be fairly infrequent [65]. Recently, a case of autoimmune hepatitis in the setting of natalizumab therapy in an MS patient has

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Table 1 Estimated incidence of progressive multifocal leukoencephalopathy (PML) stratified by known risk factors of anti-JCV antibody status, prior immunosuppressant use, and natalizumab treatment duration. Adapted from Fox et al. Risk stratification and patient counseling for natalizumab in multiple sclerosis Neurology. 2012 Feb 7;78(6):436–7. JCV antibody status

Prior immunosuppression?

Overall risk of PML

Risk of PML up to 24 months of therapy

Risk of PML after 24 months of therapy

Negative

No Yes No Yes

1 in 17693 1 in 6239 1 in 442 1 in 177

1 in 1 in 1 in 1 in

1 1 1 1

Positive

51526 18171 1288 454

in 9629 in 3396 in 241 in 85

been reported [66]. It is recommended that liver function tests be monitored on a regular basis and patients need to be counseled on signs and symptoms of liver insufficiency. Complete metabolic panel (CMP) including liver function tests has to be obtained prior to initiation of therapy. Frequency of subsequent monitoring varies between centers. One approach would be monthly CMP for six months after initiation of therapy followed by quarterly draws for the rest of the first year. Subsequent monitoring can be performed on a quarterly to a semiannual basis. There are no specific recommendations on complete blood count (CBC) monitoring, but CBC is routinely obtained along with CMP in most centers, since natalizumab is known to induce increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells along with transient decreases in hemoglobin [67]. 6. Fingolimod Fingolimod is an oral sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes [68,69]. This was the first available oral therapy for RRMS. Several safety issues have been found with fingolimod during trials that makes patient selection and monitoring of paramount importance. The overall incidence of infections in the phase 3 FREEDOMS study was similar in patients receiving fingolimod 0.5 mg or placebo [70]. Fingolimod is known to cause a dose-dependent reduction in peripheral lymphocyte count to 20–30% of baseline values [71]. However, no clear relationship was found between nadir lymphocyte counts and infection with lymphocyte counts recovering to baseline values within 45 days of stopping the treatment [72]. Nevertheless, two fatal herpetic infections (disseminated primary varicella zoster and herpes simplex

Fig. 1. Tysabri PML incidence by treatment duration (as of February 29, 2012). Source: Biogen IDEC Medical info. http://www.biogenidec.ch/medizinische_fachkreise.aspx?ID=10389 (accessed 27 March 2012).

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encephalitis) were reported in the fingolimod 1.25 mg group of the TRANSFORMS study [73]. More recently, a case of primary varicella zoster virus (VZV) infection when treated with fingolimod was reported with favorable outcome after treatment with intravenous acyclovir [74]. The patient had negative serologies for VZV at initial presentation and had subsequently seroconverted. In view of these cases, it appears prudent to check serologies for varicella prior to treatment initiation and, if found to be negative, vaccinating the patient is recommended with the treatment to be started no sooner than one month after the vaccination [71]. Some centers advocate for equally checking serologies for measles, rubella, and mumps depending on the age and sex of the patient, although this is not universally recommended. One has also to keep in mind that once the treatment with fingolimod is started, one should avoid administering live vaccines to the patient. CBC with differential is recommended prior to initiation of treatment. However, the value of repeated CBC monitoring is unclear. Fingolimod seems to cause significant reduction of number of CD4+ cells in the blood and a slight reduction of CD8+ cells [75]. However, it is unclear what role would routine T cell subset monitoring play in the management of patients treated with fingolimod. To clarify answers to these questions, fingolimod will also be assessed in a 5-year post-authorization safety study, with observation for serious infections and other potential adverse events in a clinical practice setting [76]. Elevations of liver enzymes have been reported with fingolimod. During clinical trials, 3-fold the upper limit of normal or greater elevation in liver transaminases occurred in 8% of patients treated with fingolimod 0.5 mg, as compared to 2% of patients treated with placebo [71]. Transaminase levels returned to normal within 2 months after discontinuation of treatment (therapy was stopped when transaminase levels were over five times of upper limit of normal). It is important to obtain a CMP that includes liver panel prior to initiation of therapy. If any evidence of liver dysfunction is found or there is a history of preexisting liver disease, risks and benefits of therapy have to be carefully considered before initiating the treatment with fingolimod. Routine CMP monitoring is reasonable although frequency varies between centers. One approach would be monthly CMP for three months with quarterly checks thereafter. With emergence of more safety data, the monitoring recommendations might have to be adjusted. Another potential complication of fingolimod therapy is macular edema that has been reported in 0.4% of patients and usually occurred within 3–4 months of treatment initiation [70,71]. The risk is higher in patients with diabetes and with history of uveitis. Therefore, a recommendation is to perform an adequate ophthalmologic evaluation (in most cases by an ophthalmologist) prior to and 3–4 months after treatment initiation. If any visual complaints arise during treatment, an additional ophthalmologic evaluation should be undertaken. Since at least some degree of permanent visual acuity loss has been reported with fingolimod associated macular edema, should a patient develop this complication, switching to a different MS therapy should be considered, unless benefits of fingolimod therapy are thought to significantly outweigh risks. Potential cardiovascular complications of fingolimod therapy include episodes of bradycardia with infrequent occurrences of first- or second-degree atrioventricular block, especially after the initial dose. Heart-rate decreases generally start 2 h after the administration of the first dose, reaching the nadir after 4 to 5 h, with attenuation beginning at 6 h. With continued dosing, however, the heart rate generally returns to baseline within one month of chronic treatment [70,71]. Recently, new concerns have emerged about cardiovascular safety of fingolimod with reports of 11 patient deaths out of which four involved serious heart-related events (three were myocardial infarctions and another an arrhythmia) [77,78]. The seven other deaths are of unknown cause [77]. The recommendation is to obtain a baseline electrocardiogram (ECG) prior to initiation of therapy, especially if patients are taking anti-arrhythmic medications such as beta- or calcium-channel blockers. Based on recent reports of patient deaths, European Medicines Agency

issued a new recommendation of continuous ECG monitoring for the first 6 h after the first dose with additional measurement of blood pressure and heart rate every hour. Extending the monitoring is recommended if patient develops any signs or symptoms of cardiac dysfunction during the initial monitoring [77]. Overall, caution has to be exercised when using fingolimod in patients with known cardiac problems. An alternative therapy should probably be sought in patients with known cardiac conduction abnormalities or severe cardiac disease. Mild blood pressure elevations have been reported in patients taking fingolimod, hence, regular blood pressure checks should be performed, especially in patients with cardiovascular risk factors. Dose-dependent reductions in forced expiratory volume over one second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) were observed in patients treated with fingolimod. At month 24 of treatment, the reduction from baseline for FEV1 was 3.1% and for DLCO was 3.8% in fingolimod 0.5 mg group and 2% and 2.7% in placebo group respectively. Even though routine pre-treatment spirometric evaluation is not recommended, it might be of benefit in patients at risk for respiratory insufficiency. In addition, if clinically indicated, spirometric evaluation with evaluation of DLCO should be performed during treatment [70,71]. Some concerns of increased skin cancer risks with fingolimod therapy have been raised but not validated. Three cases of skin cancer (basal-cell carcinoma, malignant melanoma, Bowen's disease) were documented with 1.25 mg of fingolimod, four cases (all basal cell carcinomas) with 0.5 mg of fingolimod, and four cases (three basal cell carcinomas and one melanoma) with placebo [70]. Recently, another case of melanoma has been reported in a patient treated with 1.25 mg of fingolimod for 57 months [79]. More longitudinal safety data is needed to make any definite conclusions about the carcinogenic potential of fingolimod. Meanwhile, it is reasonable to instruct patients to perform skin self-examination every three to six months. In addition, requesting a baseline and subsequent annual dermatological skin exam seems to be reasonable until more safety data becomes available. 7. Teriflunomide Teriflunomide is one of the two new oral MS therapies that have become available more recently. It blocks de novo pyrimidine synthesis by inhibiting dihydroorotate dehydrogenase that results in decreased proliferation of rapidly dividing cells such as T cells [80]. It does carry black box warnings of hepatotoxicity and teratogenicity. Since the cousin drug leflunomide, which is used to treat rheumatoid arthritis, has been associated with hepatotoxicity, including fatal liver failure, and therapeutic doses of both drugs result in similar plasma teriflunomide concentrations, close liver function monitoring is recommended and this medication is contraindicated for patients with significant hepatic impairment [81]. In placebo controlled trials, 3% of patients on 7 mg dose and 5% of patients on 14 mg have developed elevations of ALT exceeding three times upper level of normal as compared to 4% of patients in placebo group. Most of these elevations occurred during the first year of treatment and half of the cases returned to normal without drug discontinuation. One patient was reported to have developed jaundice and ALT elevation of 32 times upper level of normal, but has recovered after plasmapheresis and accelerated elimination procedure [81]. It is generally recommended that liver function testing, including transaminase and bilirubin levels be performed within 6 months prior to initiation of therapy. Subsequently, liver function needs to be monitored on a monthly basis for the first six months. Afterwards, monitoring liver function every 6 months seems reasonable. Testing should be performed sooner if signs of liver dysfunction develop. If ALT elevation exceeding three times of upper level of normal is detected, discontinuation of therapy will need to be considered. If significant liver injury is suspected,

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teriflunomide should be stopped and accelerated elimination procedure must be initiated since it may take more than 8 months for plasma teriflunomide levels to drop to levels below 0.02 mg/L. Administration of either cholestyramine at a dose of 8 g every 8 h or activated charcoal at a dose of 50 g every 12 h for an 11 day duration will decrease plasma teriflunomide concentration by more than 98% [81]. Another black box warning is potential teratogenicity that has been shown in animal studies of teriflunomide. Every woman of childbearing potential should have pregnancy excluded prior to initiation of therapy. Counseling on teratogenicity of the drug as well as on importance of reliable contraception while on the medication needs to be provided. The drug must be immediately discontinued if pregnancy is confirmed and accelerated elimination procedure needs to be started. Teriflunomide plasma level of less than 0.02 mg/L has to be confirmed after the completion of the elimination protocol. In addition, it is also recommended that accelerated elimination procedure is completed for every woman of childbearing age after the discontinuation of teriflunomide, regardless of her pregnancy status [81]. Leukopenia is common in patients treated with teriflunomide with mean decrease of 15% in white blood cell counts. Hence, a recommendation of a complete blood count is to be obtained within 6 months prior to initiation of therapy. The frequency of subsequent testing is not strictly defined, but checking the complete blood count every three months, at least during the first year of treatment seems reasonable. Even though no increase in serious infections has been observed among patients treated with teriflunomide as compared to placebo, screening for tuberculosis prior to initiating the therapy and avoiding live vaccines while on treatment have both been recommended [81]. Less common adverse effects also include peripheral neuropathy and acute renal failure. A good clinical follow-up is probably sufficient to monitor for appearance of peripheral neuropathy. Since elevations of creatinine were mostly found between 12 weeks and two years of treatment, one might consider checking renal function after three months of therapy. Subsequent monitoring needs to be defined on an individual basis.

8. Dimethyl fumarate Dimethyl fumarate is the latest MS treatment to arrive to the market. It is thought to mediate its effects via activation of the nuclear 1 factor (erythroid-derived 2)–like 2 (Nrf2) antioxidant response pathway that is the primary cellular defense against the oxidative stress [82]. Lymphopenia is quite common among patients treated with dimethyl fumarate with mean lymphocyte counts decreasing by 30% during first year of treatment and remaining stable thereafter [83]. Therefore, it is recommended that a complete blood count (CBC) with differential be obtained within 6 months of initiation of treatment and on a yearly basis thereafter. However, one might consider being more cautious during the first year of treatment and obtaining a CBC every 3 to 6 months. Despite the decrease in lymphocyte count, there was no increase in infections as compared to the placebo group [84]. The most common side effects are flushing, abdominal pain, diarrhea and nausea [83]. Recently, two cases of PML have been reported in patients with psoriasis who were treated with fumaric acid. One patient had received dimethyl fumarate/monoethyl fumarate combination as monotherapy for three years before developing PML [85] The other patient was undergoing monotherapy with the preparation of dimethyl fumarate, in which copper gluconate was used as an additive, for five years [86]. In an accompanying editorial, Biogen Idec collaborators (Biogen being the company that markets dimethyl funarate for MS) point out that the preparations containing not only dimethyl fumarate, but also other compounds, may have precipitated the severe lymphocytopenia that was present in both patients for years [87]. It must also be emphasized that, thus far, there are no reports of PML in MS patients receiving dimethyl fumarate. Nevertheless, close clinical observation of MS patients

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treated with this medication is warranted and screening for lymphopenia every 3 months at least during the first year of treatment should be considered. 9. Emerging MS therapies Several other agents including alemtuzumab, ocrelizumab, and daclizumab are being actively studied as potential MS therapies with promising preliminary results and may enter the market soon [88]. Increased risk of infections and certain autoimmune conditions are sited as potential safety issues. As our goal is to review safety profiles of already approved MS treatments, we will not go into a more detailed discussion of these still investigational medications. 10. Discussion The importance of medication safety review cannot be overemphasized as more pharmaceutical agents get approved and as we reach new milestones in terms of duration of treatment with already approved agents. In addition to some monitoring and risk stratification strategies described above that should be employed by physicians when treating patients with certain drugs, several steps can and should also be taken by regulatory agencies and pharmaceutical industry alike to enhance the safety profiles of approved medications. European Medicine Agency (EMEA) and the U.S. Food and Drug Administration (FDA) should require submission of an adverse event management plan along with application for marketing authorization. In addition, recent introduction by EMEA of “conditional marketing authorization” that is valid for a limited period of time and requires further studies for continued marketing, effectively addresses the issue of inadequate follow-through on post-marketing studies [89–91]. The value of well designed observational studies should not be underestimated, since they only rarely overestimate the effects of treatment when compared to randomized controlled trials [92]. Populationlevel observational data can provide valuable safety information at all stages of a drug's life cycle by offering insights into the appropriate populations for enrolment in clinical trials (including from a safety standpoint), as well as into the development of risk management strategies prior to drug launch and during the marketing stage [93]. The concept of “phased launch” has gained some publicity for it could be a valuable tool in assuring an adequate safety prior to full launch of the drug. The phased launch is a middle ground between the looseness of spontaneous reporting of adverse events and the constraints and expense of clinical trials [89]. During the phased launch there is an earlier but limited real-patient access to the drug («real-life under scrutiny»). Active surveillance would help to address what some have called “the evidence-free zone at the time of launch of new drugs” and would enhance understanding of a medication's safety profile at every stage of research and market life [89]. Assuring medication safety is an important task that requires close collaboration of regulatory agencies, pharmaceutical industry, treating physicians, and patients alike. Conflicts of interest VP: has received travel stipend for scientific meetings from Novartis. RDP: has received travel grants and/or honoraria for talks from Bayer, Biogen idec, Merck Serono, Novartis, and Teva. MS: has received travel grants and/or honoraria for talks from Bayer, Biogen idec, Merck Serono, Novartis, and Teva. References [1] Eichler HG, Abadie E, Raine JM, Salmonson T. Safe drugs and the cost of good intentions. NEJM 2009;360(14):1378–80.

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