Although clinical descriptions of multiple

Transcription

1 CURRENT STATE OF THERAPY: THE PHARMACISTS PERSPECTIVE * Melody Ryan, PharmD, MPH, BCPS, CGP ABSTRACT Having demonstrated significant benefits in relapsing forms of multiple sclerosis, immunosuppression and immunomodulation are the mainstays of therapeutic strategies in this disease. This article focuses on comparative efficacy and adverse-effect profiles of currently available disease-modifying therapies, which include 3 interferon products, glatiramer acetate, mitoxantrone, and natalizumab. Also included are ways to mitigate common adverse effects such as injection site reactions and flu-like symptoms, as well as a discussion on acute exacerbations and treatment adherence. The latter is an issue, because 17% to 40% of patients stop taking disease-modifying drugs within 1 year of treatment initiation as a result of numerous reasons, such as perceived lack of efficacy and adverse effects. (Adv Stud Pharm. 2009;6(3):63-67) Although clinical descriptions of multiple sclerosis (MS) date back to the 14th century, it was not until the late 20th century when effective treatment was introduced. Earlier unsuccessful trials using questionable therapies such as oral myelin and tumor necrosis factor *Based on a presentation by Dr Ryan from a Webcast series held May June Associate Professor, Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Associate Professor, Department of Neurology, University of Kentucky College of Medicine, Lexington, Kentucky. Address correspondence to: Melody Ryan, PharmD, MPH, BCPS, CGP, Associate Professor, Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, 725 Rose Street, Lexington, KY maryan1@ .uky.edu. inhibitors paved the way to the 1990s, when interferons (IFNs) were first proven to alter the natural history of relapsing-remitting MS (RRMS). 1 Today, immunosuppression and immunomodulation remain the mainstay of therapeutic strategies, having demonstrated significant benefits in RRMS and in delaying conversion from a single clinical attack (otherwise known as clinically isolated syndrome) to clinically definite MS. 1 Currently available disease-modifying therapies include 3 IFN products (including intramuscular [IM] and subcutaneous [SC] formulations), glatiramer acetate, a chemotherapeutic agent (mitoxantrone), and a monoclonal antibody (natalizumab). COMPARATIVE EFFICACY OF CURRENT TREATMENTS In comparing effectiveness of IFNs, the route of administration does not appear to be particularly important, but it may impact the dose-response effect. As summarized in Table 1, the weekly dose of the medication ranges from the lowest (with the IM onceweekly formulation) to the highest (with the IFNβ-1a SC formulation), and although the IFNβ-1b regimen appears to equal the highest dose, it actually equates to an intermediate dose after being converted to the equivalent IFNβ-1a dose. 2-6 Three randomized trials have compared efficacy of the different IFN formulations in relapsing MS. In the 2-year study comparing IFNβ-1a 30 µg IM weekly to IFNβ-1b 250 µg SC every other day, more patients taking IFNβ-1b remained relapse free (51% vs 39%; P =.03) and free from new T2 lesions (55% vs 26%; P <.0003). 7 In the 24-week trial comparing IFNβ-1a 44 µg SC 3 times weekly to IFNβ-1a 30 µg IM every week, the higher dose was, again, more effective in keeping patients relapse-free (P =.005). 5 A 36-month study that compared IFNβ-1a at the usual dose of 30 µg IM every week to IFNβ-1a at twice the usual dose (60 µg IM every week) found no differences between University of Tennessee Advanced Studies in Pharmacy 63

2 Table 1. IFN Dosing IFN Weekly Formulation Dose Route Frequency Dose IFNβ-1a 30 µg IM Weekly 30 µg (1 ml) IFNβ-1a 44 µg SC 3 times 132 µg (0.5 ml) weekly IFNβ-1b 0.25 mg SC Every other 875 µg (1 ml) day (Equivalent to µg IFNβ-1a) IFN = interferon; IM = intramuscular; SC = subcutaneous. dose groups in disability progression or effects on magnetic resonance imaging measures. 8 Two studies compared efficacy of interferons (ie, IFNβ-1a SC, IFNβ-1b 500 µg, and IFNβ-1b 250 µg) to that of glatiramer acetate and found no differences between the agents in time to first relapse or in relapse rate. 9,10 Natalizumab has been shown to be quite effective in delaying the time to disability in MS (starting from week 24), but the agent is associated with significant adverse effects, as discussed in the next section. 11 IDENTIFYING AND MANAGING ADVERSE EFFECTS Adverse-effect profiles of the various MS therapies are outlined in Table 2. 2,5,12-15 IFNs differ in their dosing schedules and routes of administration (Table 1), but share a common adverse-effect profile, which often includes flu-like symptoms (in 28% 76% of patients), injection site reactions (more common with SC dosing), laboratory abnormalities (increases in liver function tests, decreased white blood cell counts), menstrual abnormalities, depression, palpitations, and dyspnea. 5,12,13 Flu-like symptoms often begin within a few hours of administration and usually last no more than 24 hours, which may be quite significant for injections that are given every other day or 3 times weekly. 12 Injection site reactions may include unusual effects such as lipoatrophy (atrophy of fatty tissue under the skin) or common events such as erythema, sensitivity, or swelling at the site of injection. Being able to minimize some of the more common adverse reactions is very important, particularly for pharmacists trying to encourage patients to adhere to therapy. In reducing injection site reactions, it is helpful to rotate between all available injection sites on both sides of the body and also within each site. Other strategies include using clean injection technique, warming medication to room temperature, avoiding partial intradermic injection by ensuring complete skin penetration, using auto-injectors (which may aid in skin penetration), injecting into buttocks, applying hydrocortisone cream (15 30 minutes prior to injection), and icing injection sites. 12,16,17 Pharmacists may help patients master proper injection technique by reviewing important points with the patient and then asking the patient to demonstrate an injection to make certain of correct administration. For patients suffering from flu-like symptoms, it is important to encourage perseverance because symptoms significantly decrease or disappear after 2 to 3 months of therapy. 12 Preventive techniques include administering the injection at bedtime in hopes of sleeping through the majority of symptoms, increasing the dose gradually (eg, starting with onefourth of full dose and increasing by one-fourth of dose every week to 2 weeks, until full dose is reached), treating with acetaminophen or a nonsteroidal antiinflammatory drug (30 minutes prior to injection and then every 4 6 hours afterward as needed), and using a short course of low-dose prednisone. 12 Because IFNs are also associated with more serious, albeit rare, adverse effects (Table 2), monitoring of liver function tests and white blood cell count at 1 month, 3 months, 6 months, and then periodically thereafter, is recommended. 12 Another serious concern is development of neutralizing antibodies (NAbs) to IFNβ, which may reduce clinical effects of the medication, increasing the risk of clinical relapse. Development of NAbs can occur a few months to 2 years after treatment begins and appears to be dependant on medication frequency and route of administration. The incidence of NAbs to SC IFNβ-1b, SC IFNβ-1a, and IM IFNβ-1a is 28% to 47%, 12% to 28%, and 2% to 6%, respectively Different from other types of antibodies, NAbs may disappear with continued treatment, resulting in return of therapeutic efficacy. However, NAbs usually do not disappear when titers are very high and they exhibit cross-reactivity with other IFNβ products. The European Federation of Neurological Societies has recommend- 64 Vol. 6, No. 3 September 2009

3 Table 2. Adverse Effects of MS Therapies INFβ-1 Glatiramer Acetate Natalizumab Mitoxantrone Flu-like symptoms Injection site reactions Headache Nausea/vomiting Injection site reactions Post-injection systemic reaction Fatigue Alopecia Laboratory abnormalities Depression Hypersensitivity Amenorrhea Menstrual abnormalities Infections Myelosuppression Depression Melanoma* Acute leukemia* Palpitations Hepatotoxicity* Cardiotoxicity* Dyspnea Progressive multifocal Hepatic failure* leukoencephalopathy* Persistent leukopenia/neutropenia* Skin necrosis* *Rare. IFN = interferon; MS = multiple sclerosis. ed that patients have antibody testing at 1 and 2 years of therapy, and in those who are positive for NAbs, repeat testing every 3 to 6 months, with discontinuation of therapy in those with high titers Glatiramer acetate is very commonly associated with injection site reactions, which are known to occur in up to 90% of patients and are typically raised areas at the injection site that are accompanied by considerable erythema in surrounding areas. 12 Compared to injection site reactions associated with IFN, those related to glatiramer acetate are much more sensitive, painful, and longer lasting, but they have similar preventive techniques. 12,25 Glatiramer acetate is less commonly associated with post-injection systemic reactions, which may present as chest tightness and panic-type symptoms. Reducing subsequent injections to 25% of the usual dose and then increasing by 25% of dose/week may minimize occurrence of these reactions. 12 Natalizumab is most commonly associated with headache and fatigue, and is less commonly associated with development of antibodies. Hypersensitivity may occur, usually within 2 hours of infusion, requiring patients to remain at the infusion site for post-treatment monitoring. Other potential risks associated with natalizumab include infections, malignancy, hepatotoxicity (may occur as early as 6 days after treatment initiation), and progressive multifocal leukoencephalopathy (PML). 13,14 A devastating complication, PML is rapidly fatal and usually occurs in patients who are immunocompromised. Although patients generally do not recover from PML, plasma exchange may accelerate drug clearance and restore leukocyte function. 15 As a result of at least 3 reported cases of PML, natalizumab was previously withdrawn from the market, but has since been re-introduced with restrictions for use as monotherapy in patients with relapsing disease who have not responded well to other treatments. Mitoxantrone, which is dosed every 3 months and has a lifetime dose limit of 140 mg/m 2 (ie, 3 years of uninterrupted therapy), is commonly associated with nausea, vomiting, alopecia, and amenorrhea. Amenorrhea may not resolve after treatment discontinuation, and is thus, a concern in young women who may wish to have children. More serious adverse effects include myelosuppression, acute leukemia, and cardiotoxicity. Patients treated with mitoxantrone should undergo monitoring, at baseline and after each infusion of 100 mg/m 2 or more, for ejection fraction (contraindicated if <50%), complete blood count (hold if neutrophils <1500/mm 3 ), liver function tests (hold if abnormal), and pregnancy (contraindicated). 12 TREATMENT ADHERENCE Between 17% and 40% of patients stop taking disease-modifying drugs within 1 year of treatment initiation. Numerous studies have examined potential reasons for this high discontinuation rate, and thus far, research has suggested a multifactorial rationale for decreased adherence. 26,27 Perceived lack of efficacy, one of the identified factors, can originate from either the patient or the prescriber, essentially because it can be difficult to ascertain whether the drug is actually pre- University of Tennessee Advanced Studies in Pharmacy 65

4 venting relapses, which tend to occur unpredictably (eg, every 6 months or every few years) in a particular patient. For example, if patients do not experience any relapses while on therapy, they may question whether they would have had relapses without therapy. Alternatively, if patients do experience a relapse while on treatment, which is likely in the first 2 years, they may doubt the drug s efficacy. As discussed earlier, adverse effects are a significant factor with all of these agents, and many patients may choose to discontinue treatment after experiencing a complication. Depression, which occurs in approximately 40% of patients during the first 6 months of treatment with either IFNs or glatiramer acetate, may be a more significant contributor to decreased adherence than previously thought and perhaps should be treated to improve adherence. 28 In examining predictors of adherence, patients who are considered adherent usually have a higher level of education and tend to score higher on tests of self-efficacy (belief in positive impact from therapy), whereas those who are considered nonadherent have higher levels of disability, spasticity, and fatigue. 29 In improving adherence, patient education is paramount and should be used to equip patients with realistic expectations from therapy. For example, patients should be informed that they may continue to have relapses while on therapy, but the number of relapses is expected to be substantially reduced. Proactively managing adverse effects and ensuring correct injection technique by calling and troubleshooting with patients 1 to 2 weeks after therapy initiation may encourage them to continue treatment. ACUTE EXACERBATIONS In patients with acute exacerbations, corticosteroids are known to speed functional recovery via several immune-related effects, including prevention of inflammatory cytokine activation, inhibition of T-cell activation, prevention of central nervous system entry of activated immune cells, and increased death of activated immune cells. 30 Studies examining combination therapy, involving either methylprednisolone/methotrexate, INFβ-1a IM/methotrexate, or methylprednisolone/ methotrexate/infβ-1a, found no significant benefits, compared to monotherapy, in patients with RRMS. 31 CONCLUSIONS Disease-modifying therapy with immunomodulating agents remains the most effective strategy for altering the course of MS, but significant adverse effects may have a negative impact on patient adherence. Being aware of the unique safety profile of current treatments and being able to educate patients on ways to minimize adverse effects, as well as on proper injection techniques, is vital for pharmacists working with patients with MS. REFERENCES 1. Lublin F. History of modern multiple sclerosis therapy. J Neurol. 2005;252(suppl 3):iii3-iii9. 2. Goodin DS, Frohman EM, Garmany GP Jr, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. 2002;58: Sturzebecher S, Maibauer R, Heuner A, et al. Pharmacodynamic comparison of single doses of INF-beta 1a and INF-beta 1b in healthy volunteers. J Interferon Cytokine Res. 1999;19: Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet. 2002;359: Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology. 2002;59: Clanet M, Radue EW, Kappos L, et al. A randomized, double-blind, dose-comparison study of weekly interferon beta- 1a in relapsing MS. Neurology. 2002;59: Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet. 2002;359: Clanet M, Radue EW, Kappos L, et al. A randomized, double-blind, dose-comparison study of weekly interferon beta- 1a in relapsing MS. Neurology. 2002;59: Mikol DD, Barkhof F, Chang P, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008;7: O'Connor P, Arnason B, Comi G, et al. Interferon beta-1b 500 mcg, interferon beta-1b 250 mcg and glatiramer acetate: primary outcomes of the Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose study. Presented at: American Academy of Neurology 60th Annual Meeting; April 12-19, 2008; Chicago, IL. 11. Polman CH, O'Connor PW, Havrdova E. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354: Galetta SL, Markowitz C. US FDA-approved disease-modifying treatments for multiple sclerosis: review of adverse effect profiles. CNS Drugs. 2009;19: Goodin DS, Cohen BA, O'Connor P, et al. Assessment: the use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;71: Vol. 6, No. 3 September 2009

5 14. Goodman AD, Rossman H, Bar-Or A, et al. GLANCE: results of a phase 2, randomized, double-blind, placebocontrolled study. Neurology. 2009;72: Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology. 2009;72: Rio J, Nos C, Bonaventura I, et al. Corticosteroids, ibuprofen, and acetaminophen for IFNbeta-1a flu symptoms in MS: a randomized trial. Neurology. 2004;63: Bayas A, Reickmann P. Managing the adverse effects of interferon-beta therapy in multiple sclerosis. Drug Saf. 2000;22: Vartanian T, Solberg SP, Rice G. Impact of neutralizing antibodies on the clinical efficacy of interferon beta in multiple sclerosis. J Neurol. 2004;251(suppl 2): Hartung HP, Munschauer F 3rd, Schellekens H. Significance of neutralizing antibodies to interferon beta during treatment of multiple sclerosis: expert opinions based on the Proceedings of an International Consensus Conference. Eur J Neurol. 2005;12: Koch-Henriksen N, Sorensen P, Bendtzen K, Flachs E. The clinical effect of neutralizing antibodies against interferonbeta is independent of the type of interferon-beta used for patients with relapsing-remitting multiple sclerosis. Mult Scler. 2009;15: Sorensen PS, Koch-Henriksen N, Flachs EM, Bendtzen K. Is the treatment effect of IFN-beta restored after the disappearance of neutralizing antibodies? Mult Scler. 2008;14: Sorensen PS, Deisenhammer F, Duda P, et al. Guidelines on use of anti-inf-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on INF-beta antibodies in multiple sclerosis. Eur J Neurol. 2005;12: Goodin DS, Frohman EM, Hurwitz B, et al. Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2007;68: Bellomi F, Bramanti P, Trojano M, et al. Neutralizing and binding antibodies to interferon beta in patients with multiple sclerosis: a comparison of assay results from three Italian centers. J Immunoassay Immunochem. 2009;30: Jolly H, Simpson K, Bishop B, et al. Impact of warm compresses on local injection-site reactions with self-administered glatiramer acetate. J Neurosci Nurs. 2008;40: Río J, Porcel J, Téllez N, et al. Factors related with treatment adherence to interferon beta and glatiramer acetate therapy in multiple sclerosis. Mult Scler. 2005;11: Daugherty KK, Butler JS, Mattingly M, Ryan M. Factors leading patients to discontinue multiple sclerosis therapies. J Am Pharm Assoc. 2005;45: Mohr DC, Goodkin DE, Likosky W, et al. Treatment of depression improves adherence to interferon beta-1b therapy for multiple sclerosis. Arch Neurol. 1997;54: Fraser C, Morgante L, Hadjimichael O, Vollmer T. A prospective study of adherence to glatiramer acetate in individuals with multiple sclerosis. J Neurosci Nurs. 2004;36: Sloka JS, Stefanelli M. The mechanism of action of methylprednisolone in the treatment of multiple sclerosis. Mult Scler. 2005;11: Cohen JA, Imrey PB, Calabresi PA, et al. Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS. Neurology. 2009;72: University of Tennessee Advanced Studies in Pharmacy 67