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1 CURRENT MEDICAL RESEARCH AND OPINIONÕ VOL. 24, NO. 9, 2008, doi: / ß 2008 Informa UK Ltd. All rights reserved: reproduction in whole or part not permitted REVIEW Managing adverse effects of disease-modifying agents used for treatment of multiple sclerosis Harold Moses Jr a and David W. Brandes b a Vanderbilt Stallworth Rehabilitation Hospital, Vanderbilt University Medical Center, Nashville, TN, USA b Northridge MS Center, Northridge, CA, USA Address for correspondence: Harold Moses Jr, MD, Vanderbilt Stallworth Rehabilitation Hospital, 2201 Childrens Way, Nashville, TN 37212, USA. Tel.: þ ; Fax: þ ; Key words: Adverse events Disease-modifying therapy Multiple sclerosis Treatment ABSTRACT Background: First-line agents approved in the United States for treatment of relapsing multiple sclerosis (MS) include intramuscular interferon beta (IFNb)-1a, subcutaneous (SC) IFNb-1a, SC IFNb-1b, and SC glatiramer acetate. Intravenous mitoxantrone is the only agent approved for secondary progressive MS, progressive relapsing MS, and worsening relapsing MS. Intravenous natalizumab is approved for relapsing forms of MS generally in patients Copyright Informa UK Limited 2008 Not for Sale or Comercial Distribution Unauthorized use prohibited. Authorised users can download, display, view and print a single copy for personal use who have an inadequate response to, or are unable to tolerate, first-line therapies. Corticosteroids are commonly used to treat relapses. This paper reviews the incidence and management of common adverse events (AEs) associated with these treatments. Methods: MEDLINE and EMBASE were searched for clinical trials and other publications between 1985 and 2007 reporting AEs associated with MS therapies, using these search terms: multiple sclerosis, interferon, Avonex, Betaseron, Rebif, glatiramer, copolymer 1, Copaxone, mitoxantrone, natalizumab, adverse events. Results: A class-specific flu-like syndrome associated with IFNb can be managed through initial dose escalation and administration of analgesics and antipyretics, prophylactically or symptomatically. Injection-site reactions can occur in patients receiving injectable therapies, particularly SC IFNb or glatiramer acetate. The greatest risk to patients receiving mitoxantrone is cardiotoxicity; thus, the cumulative dose is limited. Allergic reactions occur rarely with natalizumab, and there is a potential risk of progressive multifocal leukoencephalopathy. AEs associated with short-term pulse corticosteroid therapy are usually transient and largely resolve after treatment is completed. Conclusions: To improve adherence to therapy, it is important to educate patients regarding AEs and to manage AEs proactively. Introduction Disease-modifying agents have become the mainstay of relapsing-remitting multiple sclerosis (RRMS) treatment. At this time, six agents are US Food and Drug Administration (FDA)-approved for use in RRMS. Four of the agents are considered first-line (platform) therapy and include intramuscular (IM) interferon beta (IFNb)-1a (Avonex a ) 30mg once weekly, subcutaneous (SC) IFNb-1a (Rebif b )22mg or44mg three times weekly, SC IFNb-1b (Betaseron c ) 250 mg every other day, and SC glatiramer acetate (Copaxone d ) 20 mg daily 1 4. a Avonex is a registered trademark of Biogen Idec, Inc., Cambridge, MA, USA b Rebif is a registered trademark of EMD Serono, Inc., Rockland, MA, USA c Betaseron is a registered trademark of Berlex Laboratories, Montvale, NJ, USA d Copaxone is a registered trademark of Teva Pharmaceutical Industries, Inc., Kansas City, MO, USA Article 4163/

2 Natalizumab (Tysabri a ) 300 mg intravenously (IV) every 4weeks 5 is generally indicated forpatientswithrelapsing MS who have an inadequate response to first-line therapies. Mitoxantrone (Novantrone b ) 12mg/m 2 every 3 months is approved for worsening RRMS and progressive forms of MS, excluding primary progressive MS. Corticosteroids such as IV methylprednisolone (Solu-Medrol c ) may be used to treat exacerbations of MS symptoms 6. Use of these disease-modifying agents is associated with both class-specific and agent-specific adverse events (AEs) that can reduce adherence to therapy. Adherence to therapy is defined as (1) compliance with the dosing regimen and (2) persistence with the therapy over time. Nonadherence to therapy is a common problem in the treatment of most chronic diseases, including MS. Proactive management of AEs will likely increase adherence to therapy. Treatment discontinuations often occur when patients have unrealistic expectations of treatment effects or when patients are uninformed about the potential AEs of treatment 7. Realistic expectations of disease-modifying therapy include a reduction in clinical exacerbations, decreased progression of disability early in the disease course, and diminished MRI activity. Although most patients are told initially that the current MS treatments are not expected to improve their pre-existing symptoms, they need reinforcement of this concept during subsequent visits. Many patients discontinue therapy due to lack of perceived efficacy when their condition does not improve. Most AEs can be managed with appropriate injection technique, dose titration, and pharmacotherapies, including prophylactic and relief-producing agents. The objective of this article is to review the common AEs of MS treatments and effective management options. Interferon beta Flu-like symptoms and injection-site reactions are the most common AEs reported with IFNb products (Table 1) 1 3. Flu-like symptoms are class-specific effects, whereas injection-site reactions are agentspecific effects that occur more often following SC injection than IM injection 8. Although the positive effects of IFNb may not be apparent for several months, the AEs of this treatment are especially marked during the early months of treatment 9. Therefore, to improve adherence to therapy, it is important to educate patients regarding the early AEs that may occur and to manage these events actively. Flu-like symptoms Flu-like symptoms, including fever, chills, myalgia, headache, and malaise 10, are reported in up to 75% of patients receiving IFNb 11. The symptoms usually begin 3 6 h after an injection and subside within 24 h. The incidence of flu-like symptoms typically declines during the first 3 months of treatment, although these symptoms may continue or recur in some patients 12,13. Patients at greatest risk for experiencing flu-like symptoms include females and those with low body weight 10. To manage flu-like symptoms, patients may be advised to inject their IFNb in the evening just before bedtime so that the majority of the potential flu-like events occur during sleep 9. Alternatively, if sleep is disrupted by symptoms of IFNb, patients may benefit from taking their medication earlier in the day. When once-weekly doses of IM IFNb-1a are used, it is helpful to suggest that patients administer treatment on weekends or on a day when symptoms will be less disruptive 8. Methods The MEDLINE and EMBASE databases were searched for studies published between 1985 and 2007, using the following search terms: multiple sclerosis, interferon, Avonex, Betaseron, Rebif, glatiramer, copolymer 1, Copaxone, mitoxantrone, natalizumab, and adverse events. The pivotal clinical trials were identified for each of the target therapies. In addition, smaller clinical trials, case studies, and reviews that provided insight into the management of specific AEs were selected for this review. Nonsteroidal anti-inflammatory drugs Prophylactic use of analgesics/antipyretic agents can prevent or decrease flu-like symptoms (Table 2) 14. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen/paracetamol can be taken during the initial treatment period by patients who do not have contraindications to the use of these agents 9,10. Patients need to be advised to take ibuprofen or acetaminophen at the time of an injection and 4 h after an injection. After this initial treatment period, NSAIDs or acetaminophen may be used as needed up to the recommended daily dosages of the selected agent. a Tysabri is a registered trademark of Biogen Idec, Inc., Cambridge, MA, USA b Novantrone is a registered trademark of EMD Serono, Inc., Rockland, MA, USA c Solu-Medrol is a registered trademark of Pharmacia & Upjohn Company, New York, NY, USA 2680 Managing adverse effects of DMTs in MS ß 2008 Informa UK Ltd - Curr Med Res Opin 2008; 24(09)

3 Table 1. Incidence of selected adverse effects associated with interferon beta (IFNb) therapies in MS 1 3 IM IFNb-1a 30 mg SC IFNb-1b 250 mg SC IFNb-1a 44 mg Flu-like symptoms, % Flu-like symptoms 49 (29) 60 (41) 59 (51) Myalgia 29 (22) 27 (16) 25 (20) Fever 20 (9) 36 (22) 28 (16) Chills 19 (5) 25 (11) Malaise 8 (4) 5 (1) Injection-site complications, % Injection-site reaction 3 (1) 85 (29) 92 (39) Injection-site necrosis 5 (0) 3 (0) Other effects, % Asthenia 24 (18) 61 (54) Depression 18 (14) 25 (25) Headache 58 (55) 57 (48) 70 (63) Hypertonia 50 (40) 6 (5) Rash 24 (18) 5 (3) Abnormal vision/eye disorder 4 (2) 13 (7) MS ¼ multiple sclerosis; IM ¼ intramuscular; SC ¼ subcutaneous Numbers in parentheses represent the incidence in the placebo groups Table 2. Treatment of adverse effects associated with interferon beta (IFNb) 9,11,14 Adverse effect Flu-like symptoms Injection-site inflammation Injection-site necrosis Menstrual disorders Depression Laboratory abnormalities Intervention NSAIDs, acetaminophen (paracetamol), low-dose corticosteroids, or pentoxifylline Decrease IFNb dose by 25 50% for 4 6 weeks Corticosteroids Topical corticosteroids, topical anesthetics, systemic NSAIDs Topical antibiotics, surgery if needed Oral contraceptives to regulate cycle Antidepressants Discontinue treatment or reduce dose until values are within the following limits: Hemoglobin: > 10 g/dl White blood cells: > 3000/mm 3 Granulocytes: > 1500/mm 3 Lymphocytes: > 1000/mm 3 Thrombocytes: > 75,000/mm 3 Bilirubin: < 2.5 baseline value Transaminases (AST, ALT): < 5 baseline value Alkaline phosphatase: < 5 baseline value NSAIDs ¼ nonsteroidal anti-inflammatory drugs; AST ¼ aspirate aminotransferase; ALT ¼ alanine aminotransferase Walther and Hohlfeld report that, in their experience, the effects of ibuprofen appear to be more beneficial than those of aspirin or acetaminophen 11. However, the results of a recent study suggest that acetaminophen and ibuprofen are equally effective in managing flu-like symptoms in MS patients who are receiving treatment with IFNb 12. This open-label study included 106 patients who were to begin treatment with IFNb and had not received recent treatment with corticosteroids. Patients took either acetaminophen 1 g or ibuprofen 400 mg immediately before and 6 h after each dose of IFNb-1a. If needed, patients took additional medication within 48 h of their injections (up to 8 g of acetaminophen and up to 3.2 g of ibuprofen, administered in doses of 1 g and 400 mg, respectively). At baseline, 92% of the acetaminophen group and 90% of the ibuprofen group reported flu-like symptoms. After 12 weeks of treatment, 60% of the acetaminophen group and 57% of the ibuprofen group experienced flu-like symptoms. Neither treatment was found superior; each reduced flu-like symptoms to some degree during the 12-week study. ß 2008 Informa UK - Curr Med Res Opin 2008; 24(09) Managing adverse effects of DMTs in MS Moses & Brandes 2681

4 Oral corticosteroids Oral corticosteroids also may be used in patients with flu-like symptoms. In one study, patients who were receiving IFNb-1b were treated with acetaminophen or acetaminophen plus prednisone. Acetaminophen 500 mg was administered 4 h before injection, at the time of injection, and 4 h after injection; prednisone 30 mg was administered daily for the first 2 weeks and then tapered for the following 2 weeks. During the first 2 weeks, the percentage of patients with flu-like symptoms was significantly lower in the group that received corticosteroids (43%) than in the group that did not (80%); however, this effect was not evident at month 3 of treatment 14. It is well-known that long-term courses of corticosteroids are associated with AEs; therefore, corticosteroids should be considered second-line treatment after treatment failure with NSAIDs. If needed, prednisone 30 mg/day may be initiated for 2 weeks, followed by a 2-week taper 9. Alternatively, prednisone 10 mg may be administered with or without acetaminophen at the time of the injection and every 4 6 h for the following 12-h period 8. Although this dosing regimen is acceptable for patients who are receiving IFNb-1a weekly, it is not as suitable for those who are receiving SC IFNb-1a three times weekly or IFNb-1b every other day, due to potential long-term AEs of corticosteroids. Pentoxifylline Pentoxifylline also has been used to treat the flu-like symptoms of IFNb 15. When administered twice daily, pentoxifylline 800 mg was associated with significantly fewer reports of fever, chills, and myalgias in patients receiving treatment with IFNb-1b compared with patients receiving IFNb-1b alone. However, other symptomatic treatments should be exhausted before considering pentoxifylline because high doses may cause tachycardia and hypotension 9. Dose titration Dose titration should be considered for all patients beginning therapy with IFNb. As shown in a recent pilot study, dose titration in combination with analgesics reduced the frequency of flu-like symptoms among patients initiating treatment with intramuscular IFNb-1a 13. In this open-label study, 47 patients were randomized to receive analgesics (either acetaminophen or ibuprofen) and IM IFNb-1a initiated at either a full dose (30 mg once-weekly), one-quarter dose titrated over 6 weeks to the full dose at the seventh week, or one-half dose for 6 weeks followed by the full dose at the seventh week. The combination of analgesics and one-quarter dose titration significantly reduced the frequency of flu-like symptoms among patients in the first 2 weeks of therapy compared with those initiating treatment at the full dose ( p ¼ 0.015), with similar trends over subsequent weeks 13. To reduce flu-like symptoms, treatment may commence at one-quarter to one-half the recommended dose, followed by increasing doses every 2 4 weeks 10. With this approach, few patients fail drug initiation, and most gradually become comfortable with their treatment 7. Injection-site reactions Pain associated with injections is similar for IM and SC administration 8. However, injection-site reactions, which can vary from mild erythema to severe necrosis, are seen more frequently in patients who receive SC IFNb 7. These events are reported in 86 92% of patients during the early phase of treatment with SC IFNb 2,3,9, with some evidence suggesting greater susceptibility among women and smokers 7,16. Skin necrosis is reported in 4% of patients treated with SC IFNb-1b and in 3% of patients treated with SC IFNb-1a 2,3. There are no known reports of skin lesions or necrosis associated with the use of IM IFNb. Although the pathogenic mechanisms for skin necrosis are unclear, a number of factors are reported to provoke the development of skin necrosis, including nonsterile injection technique, use of cold injection solutions, failure to rotate injection sites, and exposure of recent injection sites to ultraviolet light 9. A number of techniques may be used to treat or prevent skin reactions. Patient education is essential. Proper injection technique may reduce the incidence of some skin reactions 17. Thus, the first self-injection of IFNb should be performed in the presence of an experienced nurse or in the physician s office 10. The availability of autoinjectors for SC IFNb also may reduce problems associated with improper injection technique as well as needle phobia 18. NSAIDs and the application of ice to the injection site before and after treatment can help to alleviate injection-site pain. Antihistamine or hydrocortisone (1%) creams may be used to treat areas of red patchy skin that sometimes develop at the site of injection 11. However, topical corticosteroids should not be applied to skin necrosis because wound healing is prolonged and the risk of infection is increased 9. Suggestions to reduce the occurrence of injection-site reactions include the proper use of sterile technique, rotation of injection sites, use of topical anesthetics, and allowing medications to warm to room temperature before injection 9,11. There is a gradual reduction in the frequency and severity of skin reactions over the first 6 months of treatment. However, if severe reactions to SC IFNb are observed, IM IFNb may be an alternative Managing adverse effects of DMTs in MS ß 2008 Informa UK Ltd - Curr Med Res Opin 2008; 24(09)

5 Depression An early study of IFNb-1b reported one suicide and four attempted suicides 19 ; however, data from several trials that followed did not replicate those findings A recent study that analyzed depressive symptom ratings in an MS clinic population reported that the IFNb drug class is not associated substantially with the development of depression 25. University of Calgary Multiple Sclerosis Clinic data from 163 patients treated with either IM or SC IFNb-1a, IFNb-1b, or glatiramer acetate were analyzed. At baseline, there were a substantial number of depressed patients in both the IFNb group (28.8%) and the glatiramer acetate group (22.7%) 25. After 3 months of treatment, the prevalence of depression was somewhat higher in the IFNb group (40.0% and 21.3%, respectively). These data suggest that depression is common in patients with MS and should be monitored while patients are on any therapy. The prevalence of depression is higher in patients with MS than in those without MS and in those with other chronic conditions 26. Depression in MS may be attributable to several factors, including the stress of having such an illness, effects of the disease process on areas of the central nervous system that affect mood, disappointment with treatment, or a true drug-induced effect 11. All patients with MS should be monitored for the development of depression and treated accordingly with antidepressants and/or psychotherapy. According to one study, the treatment of depression is associated with increased adherence to MS therapies 27. The development or worsening of depression in patients with MS generally should not preclude patients from receiving treatment with IFNb, but treatment of the depression should be undertaken. Abnormal laboratory values Abnormal laboratory values, such as leukopenia, neutropenia, lymphopenia, and elevated levels of liver transaminases, are more commonly associated with SC IFNb (Table 3) 1 3. In the pivotal clinical trial of SC IFNb-1b, 80% of patients receiving 8 MIU and 65% of patients receiving placebo had lymphopenia, and 17% of patients receiving 8 MIU and 4% of patients receiving placebo had mild neutropenia, while elevated transaminases were reported in 14 patients receiving 8 MIU compared with five patients receiving placebo, over 3 years 28. In the pivotal clinical trial of SC IFNb-1a, in the first 3 months of therapy lymphopenia was reported in 9.3% of patients receiving 44 mg SC IFNb-1a versus 3.7% of patients receiving placebo, leukopenia in 6.5% of patients receiving 44 mg SC IFNb-1a versus 1.6% of patients receiving placebo, and elevated alanine aminotransferase in 5.4% of patients receiving 44 mg SC IFNb-1a versus 1.1% of patients receiving placebo 21. In contrast, the pivotal clinical trial of IM IFNb-1a reported that no evidence of liver enzyme elevation or leukopenia was observed over the 2-year course of the study, although anemia was observed in 3% of patients receiving IM IFNb-1a and in 1% of patients receiving placebo 20. Postmarketing studies showed a higher incidence of abnormal laboratory values overall. For example, in a retrospective study, 13 of 52 (25%) patients treated with IM IFNb-1a were reported to experience World Health Organization grade 1 hepatic enzyme elevations from baseline 29. In contrast, 138 of 350 (39.4%) patients treated with SC IFNb-1b experienced grade 1 and grade 2 elevations from baseline in hepatic enzymes, and 97 of 258 (37.6%) patients treated with SC IFNb-1a experienced elevations of grades 1, 2, and The alterations in hepatic enzymes were significantly associated with the frequency of injections. Therefore, complete and differential blood cell counts and blood chemistry, including liver function tests, should be performed at 1, 3, and 6 months following introduction of SC IFNb-1b or SC IFNb-1a and every 6 12 months thereafter if values are stable 7. Complete and differential blood cell counts and blood chemistry, including liver function tests, also are recommended during therapy with IM IFNb-1a 20. The management of liver Table 3. Laboratory abnormalities reported during treatment with interferon beta (IFNb) therapies in MS 1 3 IM IFNb-1a 30 mg, % SC IFNb-1b 250 mg, % SC IFNb-1a 44 mg, % Anemia 4 (1) Lymphocytes < 1500/mm 3 88 (70) Leukopenia 36 (14) ANC < 1500/mm 3 14 (5) ALT increased 27 (4) WBC < 3000/mm 3 14 (4) AST increased 17 (4) ALT > 5 baseline 10 (4) Lymphadenopathy 12 (8) Lymphadenopathy 8 (4) Abnormal hepatic function 9 (2) AST > 5 baseline 3 (1) Thrombocytopenia 8 (2) Anemia 5 (3) Numbers in parentheses represent the percentage in the placebo groups MS ¼ multiple sclerosis; IM ¼ intramuscular; SC ¼ subcutaneous; ANC ¼ absolute neutrophil count; WBC ¼ white blood cells; ALT ¼ alanine aminotransferase; AST ¼ aspirate aminotransferase ß 2008 Informa UK - Curr Med Res Opin 2008; 24(09) Managing adverse effects of DMTs in MS Moses & Brandes 2683

6 dysfunction depends on its severity (Figure 1). Limits of acceptable laboratory values are shown in Table 3. Most patients with grade 1 aminotransferase elevations return to normal with continued IFNb treatment 30 ; thus, re-evaluation of liver function tests are recommended 1 month later 31. If aminotransferase elevations persist or progress to grade 2, the IFN dose should be decreased, and the standard dose may be resumed when liver function tests return to baseline levels. IFN treatment should be discontinued at grade 3 levels or higher. Management of abnormalities in complete blood count also depends on their severity. If patients experience declines in total white blood cell count < 3000 ml, they should be re-evaluated 1 month later. Thyroid abnormalities Thyroid abnormalities, including hypo- and hyperthyroidism and thyroid autoimmunity, may occur in patients with MS receiving IFNb 1 3,7, Although thyroid abnormalities were not reported in the pivotal clinical trials, some later studies have reported new cases and cases of worsening thyroid function in patients with pre-existing thyroid abnormalities at baseline. In some instances, thyroid abnormalities were transient, subclinical, and resolved without dose adjustment 36, while treatment discontinuation was necessary in some patients 37. In a long-term study in 103 patients with MS treated with IM IFNb-1a or IFNb-1b for up to 7 years 38, thyroid abnormalities including hypothyroidism, hyperthyroidism, or thyroid autoimmunity were observed in 24% of patients, a prevalence comparable with the general population. These abnormalities were transient in 56% of cases and subclinical in 92% of cases. Based on the outcomes of this study, the authors recommended assessing serum thyroid-stimulating hormone and anti-thyroid antibody levels every 3 months in the first year of IFN treatment. In patients with thyroid dysfunction or autoimmunity, thyroid-stimulating hormone should be monitored every 6 12 months. Treatment with levothyroxine was recommended only for patients with symptomatic hypothyroidism, with periodic withdrawal of thyroid treatment and re-evaluation of thyroid function 38. Menstrual abnormalities Menstrual irregularities have been reported in patients treated with IFNb-1b 3, and postmarketing data reveal that similar abnormalities have occurred in patients treated with IM IFNb-1a. Irregular menses, secondary amenorrhea, spotting, and increased bleeding are the most common irregularities reported 7. If a patient experiences menstrual irregularities while receiving IFNb, it is helpful to rule out other possible causes. The use of oral contraceptives may be helpful in managing irregularities. A temporary dose reduction or treatment discontinuation should be considered if warranted 9. Pregnancy No prospective studies have been conducted on the effects of IFNb on pregnancy outcomes in humans, and IFNb products are in pregnancy category C. In a study that compiled pregnancy outcomes among women participating in clinical trials of SC IFNb-1a, women who received SC IFNb-1a mg three Grade 1 ( >ULN 2.5 ULN) Grade 2 ( >2.5 ULN 5 ULN) Grade 3 (>5 ULN 20 ULN) Continue therapy Recheck LFTs in 1 month Decrease interferon beta dose Stop other hepatotoxic drugs Discontinue interferon beta Discontinue other hepatotoxic drugs Check hepatitis panel Recheck LFTs in 1 month Recheck LFTs in 2 weeks Refer patient for GI consultation When LFTs return to baseline, resume standard dose Figure 1. Management of liver function test abnormalities. ULN, upper limit of normal; LFTs, liver function tests; GI, gastrointestinal. Adapted with permission from: Langer-Gould A, Moses HH, Murray TJ, et al. Strategies for managing the side-effects of treatments for multiple sclerosis. Neurology 2004;63(Suppl 5):S Managing adverse effects of DMTs in MS ß 2008 Informa UK Ltd - Curr Med Res Opin 2008; 24(09)

7 times weekly or IM IFNb-1a 30 mg once weekly at conception, or who had discontinued in the 2 weeks prior to conception, had a 16% rate of spontaneous pregnancy loss, a rate not significantly higher than that estimated for the general population 39. A longitudinal cohort study evaluated pregnancy outcomes among women who became pregnant while receiving SC IFNb-1a mg three times weekly, IM IFNb-1a 30 mg once weekly, or SC IFNb-1b 2 6 MIU every other day (n ¼ 16; 23 gestations) versus healthy women (n ¼ 12; 21 gestations) 40. Women who received IFNb had a higher rate of miscarriages and stillbirths (39.1%) than healthy controls (5%; p ¼ 0.032). In addition, the mean birth weight in the IFNb-exposed babies was significantly lower than that of the healthy control group ( g vs g, respectively; p ¼ 0.002). Women who become pregnant while receiving IFNb should consider discontinuing treatment and enrolling in a pregnancy registry maintained by the drug manufacturers 1 3. Additional adverse effects Some adverse effects, while not serious, may affect quality of life and thus merit discussion. Alopecia has been reported in approximately 4% of patients receiving IFNb 1,41. Treatments generally include vitamin E supplements, zinc, or minoxidil 7,41. Headache also is a common AE among patients receiving IFNb, often occurring in combination with other flu-like symptoms, and has been reported in up to 67% of patients receiving IFNb 3,20,21. Headache can be managed with the same medications used for flu-like symptoms, either as prophylactic treatment or as needed. Migraine headache unresponsive to other treatments can be treated with oral triptan therapy 7,41. Rare adverse effects A number of rare AEs have been reported in patients undergoing treatment with IFNb,including autoimmune hypothyroidism and hyperthyroidism 32 35, autoimmune hepatitis 33,35, myasthenia gravis 42, granulomatous dermatitis with sarcoid-like features 43, and hemolytic uremic syndrome 44. Other rare effects include capillary leak syndrome 45, thrombotic thrombocytopenic purpura 46, anaphylactic shock 47, psoriasis exacerbation 48, insomnia 3, and hearing loss 49. Glatiramer acetate Glatiramer acetate is not associated with flu-like symptoms. The most common AE associated with the use of glatiramer acetate is injection-site reactions (up to 73% of patients) (Table 4) 4. Injection-site reactions associated with glatiramer acetate are similar to those associated with IFNb, and include pain, erythema, pruritus, inflammation, bruising, and induration 18. Injection-site reactions should be managed as described previously. Based on a chart review, Edgar and colleagues identified 76 patients with MS at their outpatient clinic who were receiving glatiramer acetate or had a history of glatiramer acetate use 50. Examination of glatiramer acetate injection sites over a 6-month period revealed a significant percentage of patients (45%, all women) with evidence of mild (20 patients), moderate (nine patients), or severe (five patients) lipoatrophy. These changes may represent an allergic reaction or mechanical injury. Given the frequency of lipoatrophy, patients receiving glatiramer acetate should conduct regular examinations of their injection sites, including visual inspection and manual palpation. Patients should be advised to discontinue injections at sites where lipoatrophy is identified, and for some patients, switching treatment may be warranted. Less common reactions include immediate postinjection reactions (10%), chest pain (21%), dyspnea (19%), anxiety (23%), and lymphadenopathy (12%) 4,7. When these types of reactions occur, subsequent doses should be administered at 25% of the recommended dose Table 4. Incidence of selected adverse effects in patients treated with glatiramer acetate* 49 Glatiramer acetate, % n ¼ 201 Placebo, % n ¼ 206 Injection-site reactions Injection-site pain Injection-site erythema Injection-site inflammation Injection-site pruritus 40 6 Injection-site mass Injection-site induration 13 0 Injection-site welt 11 2 Other effects Vasodilation Arthralgia Anxiety Hypertonia Nausea Chest pain Dyspnea 19 7 Flu-like syndrome Pruritus Rash Palpitations 17 8 Sweating Lymphadenopathy 12 6 Diarrhea *Incidence of 10% ß 2008 Informa UK - Curr Med Res Opin 2008; 24(09) Managing adverse effects of DMTs in MS Moses & Brandes 2685

8 followed by dose increases of 25% until the full dose is reached 7. Immediate postinjection reactions are generally transient and self-limiting and include flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria 4. To avert anxiety and panic that can result from fear associated with breathing difficulty and chest pain, patients should be advised about the possibility of these AEs prior to starting therapy. Patients can be reassured that these symptoms subside and cause no permanent damage. If these systemic reactions persist despite dose titration, therapy with glatiramer acetate should be discontinued 4. Routine laboratory monitoring is not necessary in patients receiving glatiramer acetate 18. Lymphadenopathy, a painless, drug-induced lymph node hypertrophy, occurred in approximately 12% of patients in premarketing studies 4. Patients should have axillary and inguinal lymph nodes palpated at follow-up visits to monitor for lymphadenopathy. Patients with lymphadenopathy should discontinue treatment until hematologic malignancy can be ruled out, and should be evaluated via manual blood smear. Lymph node biopsy should be carried out in the case of an abnormal blood smear, if there are constitutional symptoms suspicious for hematologic malignancy, or if there are findings consistent with a suppurative lymphadenitis 41. Mitoxantrone The use of mitoxantrone typically is limited to patients with rapidly advancing disease who have failed other therapies 51. Patients with left ventricular ejection fraction (LVEF) < 50% or baseline neutrophil counts < 1500 cells/mm 3 should not be treated with mitoxantrone 31. The most serious potential side effect of mitoxantrone is cardiotoxicity, which may include reduced LVEF, irreversible heart failure, and cardiomyopathy 31,52. Cardiotoxicity may occur during treatment or months to years after treatment has been discontinued 31. Patients who received prior treatment with anthracyclines or mediastinal radiotherapy and those with pre-existing cardiac disease may be at higher risk for developing cardiac toxicity. An optimal approach to monitoring for signs of cardiotoxicity is not established 51 ; however, the manufacturer recommends an evaluation of LVEF (by echocardiogram or multiplegated acquisition scan) in all patients before the start of therapy, before each dose, and in patients who display signs or symptoms of heart failure during treatment. Because of the importance of accurate LVEF measurements in patients receiving mitoxantrone, serial LVEF evaluations should be done in a consistent manner. Patients should not receive mitoxantrone if their LVEF drops below 50% or if they experience a clinically significant drop in LVEF 31. Routine laboratory testing should include complete blood counts (including platelets). Because the liver is the primary metabolic site for mitoxantrone, liver function tests should be conducted just before each dose. Mitoxantrone is not recommended for patients with abnormal liver function. It should be noted that women with childbearing potential need a pregnancy test before each dose 52. A retrospective analysis evaluated incidence of cardiotoxicity in three large studies of mitoxantrone in MS patients, including the pivotal clinical trial, an open-label study, and a retrospective study of mitoxantrone 53,54. Among patients who received mitoxantrone in the pivotal clinical trial, two out of 65 patients in the 5 mg/m 2 group and two out of 62 patients in the 12 mg/m 2 group had asymptomatic reduction of LVEF to < 50% with cumulative doses ranging from mg/m 254. In an open-label study of 802 patients, 655 of whom had LVEF tested at baseline and followup, 13 had asymptomatic reduction of LVEF to < 50% of baseline 53. In the retrospective study of 452 patients who received mitoxantrone, two patients had congestive heart failure and died from cardiac dysfunction 53. The retrospective analysis concluded that an asymptomatic reduction in LVEF of < 50% was about three times less likely at doses < 100 mg/mm 3 compared with higher doses 53, similar to an earlier analysis that suggested that doses of up to 96 mg/m 2 are safe 55. The manufacturer recommends that the cumulative lifetime dose of mitoxantrone not exceed 140 mg/m 2 in patients with MS (i.e., 3 years of treatment when administered every 3 months) 18. Another rare but potentially life-threatening complication of mitoxantrone use is therapy-related acute leukemia. The precise frequency of this complication is unknown but is estimated to occur in % of treated patients 56,57. The therapy-related acute leukemias that have been reported are acute myeloblastic leukemias. In three case reports, the patients did not develop clinical evidence of leukemia until months after their last dose of mitoxantrone Other common AEs from treatment with mitoxantrone in patients with MS include nausea, alopecia, menstrual disorders, urinary tract infection, stomatitis, and arrhythmia. The most common laboratory abnormalities include leukopenia and increases in gamma glutamyl transferase 31. Before treatment initiation, patients should be advised of the potentially serious AEs of mitoxantrone, especially the risk of cardiotoxicity. Patients also should be warned that there may be a temporary blue-green discoloration of their urine for 24 h after treatment as well as possible discoloration of the sclera Managing adverse effects of DMTs in MS ß 2008 Informa UK Ltd - Curr Med Res Opin 2008; 24(09)

9 Because permanent amenorrhea can occur with mitoxantrone therapy (as with most high-dose chemotherapeutic agents), women with childbearing potential should be advised about this side effect and, further, should be counseled to avoid becoming pregnant because of the risk of fetal harm 31. Referral to an obstetrician before treatment initiation should be considered for those women who may still want to become pregnant. Natalizumab Natalizumab is the most recently FDA-approved disease-modifying agent for the treatment of relapsing forms of MS. In the phase 3 study of natalizumab monotherapy, the most common AEs observed were headache, fatigue, and arthralgia. Serious AEs among patients treated with natalizumab included cholelithiasis (< 1%) and hypersensitivity reactions (4%) 61. Natalizumab treatment must be discontinued if a patient experiences a hypersensitivity reaction 5. Approximately 24% of patients receiving natalizumab and 18% of patients receiving placebo in the phase 3 study of natalizumab monotherapy experienced infusion reactions, defined as an event occurring within 2 h after the start of the infusion. The most common infusion reaction was headache (5% of patients receiving natalizumab, 3% of patients receiving placebo) 61. Prophylactic treatment of headache with aspirin, NSAIDs, or acetaminophen is usually beneficial. Progressive multifocal leukoencephalopathy After initial approval in the United States, three patients who received natalizumab developed progressive multifocal leukoencephalopathy (PML), prompting a voluntary withdrawal of natalizumab from the marketplace PML was seen only in patients receiving natalizumab plus another immunomodulatory/ immunosuppressive combination therapy, either IM IFNb-1a or azathioprine and infliximab. An extensive safety review of all patients who had received at least one dose of natalizumab uncovered no additional cases of PML, and estimated that the risk of PML among patients taking natalizumab was approximately one patient out of 1000, based on a population who had received a mean of 17.9 monthly doses of natalizumab 66. The risk of PML among patients receiving natalizumab for longer periods of time has not been determined. An expert panel of neurologists, neuroradiologists, and neurovirologists recently published recommendations for a diagnostic and management algorithm for the use of natalizumab 67. They recommend that natalizumab not be used in patients with HIV/AIDS or other history of immunodeficiency or hematological malignancy. In addition, patients who received prior treatment with immunosuppressant or antineoplastic medications should be carefully evaluated for signs and symptoms of ongoing immunocompromise before beginning natalizumab therapy. Recommended assessments include a pretreatment cranial MRI within 3 months of initiation of treatment with natalizumab. A washout period of 3 months or longer before initiating treatment with natalizumab was recommended for immunosuppressant drugs, including azathioprine, methotrexate, mycophenolate mofetil, mitoxantrone, and cyclophosphamide; however, because the data are unclear, no recommendations were made with regard to a washout for IFNb or glatiramer acetate. Procedures have been instituted to control distribution and to closely monitor all patients who receive natalizumab (in the United States, this includes the Tysabri Outreach Unified Commitment to Health [TOUCH TM ] Prescribing Program) 5. Corticosteroids Exacerbations of MS symptoms are typically treated with pulse doses of oral or IV corticosteroids, which are reported to decrease the severity and duration of these symptoms IV methylprednisolone is useful for patients with severe relapses and for those who are no longer responsive to oral corticosteroids. Chronic treatment using daily or alternate-day doses of corticosteroids is not proven to affect the natural history of MS 68. However, several studies have shown benefit with IV methylprednisolone administered every 1 6 months. For example, a 2-year study in 108 patients with secondary progressive MS found a significant delay in time to sustained progression among patients receiving high-dose (500 mg) compared with low-dose (10 mg) IV methylprednisolone every 8 weeks 71. Another study among 88 patients with RRMS demonstrated that pulsed IV methylprednisolone (1g/day for 5 days with an oral prednisone taper) given every 4 months for 3 years and then every 6 months for the following 2 years provided significant benefits on T1 black hole volume, brain parenchymal volume, and disability compared with IV methylprednisolone (same dose schedule) provided only at relapses 72. Similarly, eight of nine patients with RRMS who received IV methylprednisolone 500 mg every month for 6 months had significantly fewer gadolinium-enhancing lesions and significantly reduced T2 lesion volume compared with the previous 6 months 73. A number of long-term complications are associated with the more frequent dosing pattern and chronic use ß 2008 Informa UK - Curr Med Res Opin 2008; 24(09) Managing adverse effects of DMTs in MS Moses & Brandes 2687

10 of corticosteroids. These complications may include osteoporosis, aseptic necrosis of the hip and shoulder, adrenal suppression, hyperlipidemia, cataracts, hyperglycemia, hypertension, and increased risk of glaucoma by increasing intraocular pressure 74. However, a study of MS patients who received IV methylprednisolone every 4 months found no significant correlation between bone mineral density and lifetime average methylprednisolone dosage 75. In contrast, short-term treatment complications of corticosteroids are usually transient and resolve quickly after completion of the course of treatment. Short-term treatment complications may include truncal obesity, acne, hyperpigmentation, hypokalemia, myopathy, glucose intolerance, pancreatitis, hypertension, and increased leukocyte counts 76. Allergic reactions or more severe anaphylactic reactions including bronchospasm, hypotension, or anaphylactic shock have been reported rarely with IV corticosteroids 6,77. Both bradycardia 78 and tachycardia 79 have been reported following administration of high doses of IV methylprednisolone. Although cardiac AEs are rare, it has been suggested that IV methylprednisolone be administered at a slow rate under close supervision, particularly in patients with pre-existing cardiovascular disease 79. As with other treatments, patients should be counseled about anticipated AEs associated with corticosteroids. Standard testing in the physician s office can be used to monitor blood glucose levels for diabetes and blood pressure for hypertension. Recent studies have shown a higher risk of osteoporosis in patients with MS, independent of steroid exposure 75,80,81. Nonetheless, patients who receive chronic or recurring treatment with corticosteroids should be monitored carefully for osteoporosis. Among patients receiving long-term glucocorticoid therapy, bone mineral density measurement of the lumbar spine or hip should be done at baseline and every 6 12 months in patients receiving therapy to prevent bone loss 82. Weight-bearing exercise may help in the prevention of osteoporosis, and vitamin D ( IU) may facilitate the absorption of calcium 76,82,83. Bisphosphonate treatment also has been shown to be effective in preventing and treating glucocorticoid-induced osteoporosis; it is recommended in conjunction with vitamin D and calcium both to prevent glucocorticoid-induced osteoporosis and to treat patients with osteoporosis or fractures resulting from glucocorticoid-induced osteoporosis 82,84. The importance of a proper diet that includes increased amounts of vegetable protein and limited amounts of fats and sugars or simple carbohydrates should be stressed. Abdominal pain or bone pain should be evaluated promptly. Discussion This review identified the most common or serious AEs associated with disease-modifying therapy for MS via reports of clinical trials, case studies, package inserts, and other published sources. The recommendations of this review for management of AEs are based on those of the drug manufacturers when available, and on published recommendations from clinical experience. Because of their limitations of size and inclusion/exclusion criteria, clinical trials are likely to identify most common AEs, whereas rarer AEs may only become apparent during the postmarketing period after greater numbers of patients have received treatments for a longer period of time, and under conditions that are less controlled than in clinical trials. This review did not attempt to identify every postmarketing case study report of AEs, but instead used those that were the most illustrative of common or serious AEs to provide insight into recognition and management of these AEs. Conclusion All treatments for MS are associated with potential AEs. Most of these AEs can be treated prophylactically and symptomatically. Treatment plans for patients with MS that incorporate guidelines for recognition and management of AEs will help to minimize the discomfort and inconvenience that patients may experience with common AEs, thereby enhancing patients adherence to therapy. In addition, such treatment plans will help to minimize the risk of more serious AEs. It is recommended that healthcare providers invest the time required to teach patients what they need to know to manage their disease successfully. A proactive approach, discussing treatment expectations with patients before treatment begins and re-assessing each patient s level of understanding within the first few weeks of treatment, can make a significant difference for both the patient and the healthcare provider. Acknowledgments Declaration of interest: This manuscript was supported by Biogen Idec, Inc. The authors acknowledge Sabrina Maurer and Matthew Hasson of Scientific Connexions, Newtown, PA, USA, for a preliminary draft and editorial assistance in preparing the manuscript. The authors provided final manuscript preparation, review, and approval. HM has received research support from Biogen Idec, Genentech, Novartis, Serono, and Teva Neurosciences, as well as honoraria and speaking fees from Bayer, Biogen Idec, Pfizer, EMD Serono, 2688 Managing adverse effects of DMTs in MS ß 2008 Informa UK Ltd - Curr Med Res Opin 2008; 24(09)

11 Questcor, and Teva Neurosciences. DWB has received research support from Biogen Idec and Teva Neurosciences and has served on advisory boards and speakers bureaus for Biogen Idec, Berlex (now Bayer), Elan Pharmaceuticals, Serono, and Teva Neurosciences. References 1. Avonex (interferon beta-1a) [package insert]. Cambridge, MA: Biogen Idec, Inc.; Betaseron (interferon beta-1b) [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals 3. Rebif (interferon beta-1a) [package insert]. Rockland, MA: Serono, Inc.; Copaxone (glatiramer acetate injection) [package insert]. Kansas City, MO: Teva Pharmaceutical Industries, Inc.; Tysabri (natalizumab) [package insert]. Cambridge, MA: Biogen Idec Inc.; Solu-Medrol (methylprednisolone sodium succinate) [package insert]. New York, NY: Pharmacia & Upjohn Company; Frohman E, Phillips T, Kokel K, et al. Disease-modifying therapy in multiple sclerosis: strategies for optimizing management. Neurologist 2002;8: Munschauer FE 3rd, Kinkel RP. 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