continuing education for pharmacists

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1 continuing education for pharmacists Multiple Sclerosis: Medical Management with Disease-Modifying Therapy Thomas A. Gossel, R.Ph., Ph.D., Professor Emeritus, Ohio Northern University, Ada, Ohio and J. Richard Wuest, R.Ph., PharmD, Professor Emeritus, University of Cincinnati, Cincinnati, Ohio Volume XXIX, No. 5 Dr. Thomas A. Gossel and Dr. J. Richard Wuest have no relevant financial relationships to disclose. Goal. The goal of this lesson is to discuss disease-modifying therapy for treatment of multiple sclerosis. Objectives. At the conclusion of this lesson, successful participants should be able to: 1. recognize the pharmacologic classification and duration of action for drugs used in treatment of multiple sclerosis; 2. demonstrate an understanding of the mechanism of action, major adverse events and therapeutic applications associated with the drugs; 3. identify the route and means of administering the drugs; and 4. exhibit knowledge of information relative to multiple sclerosis pharmacotherapy to convey to patients and their caregivers. Multiple Sclerosis Past, Present and Future Multiple sclerosis (MS) was mentioned briefly in the medical literature early in the 19 th century. It achieved full clinic-pathological characterization during the late decades of that century and began to reveal many of its mysteries concerning etiology and pathogenesis throughout the 20 th century. As the millennium ended, the affliction yielded somewhat to parenterallyadministered disease-modifying Gossel Wuest therapy (DMT). In 2010 approval was granted for marketing the first drug in a new category of therapies to follow an orally-administered DMT. Future studies will no doubt continue to resolve issues of heterogeneity and complexity of MS, and we can expect a mechanismbased classification that defines successful strategies that will limit and repair the damage to central neurons. Disease Overview MS is a chronic, neurodegenerative and debilitating inflammatory disease of the central nervous system (CNS) that affects an estimated 400,000 persons in the United States, and 2.5 million worldwide. It may be progressive or episodic. The disease course varies among patients and is categorized into four subtypes by clinical course: relapsing-remitting MS, secondaryprogressive MS, primary-progressive MS, and progressive-relapsing MS. At onset, approximately 85 percent of all MS patients present with relapsing-remitting MS, of whom almost half will experience a gradual progression of disability within 10 years of their initial attack, and 90 percent will develop intensification of their disease process within 25 years. MS afflicts females more often than males, but males experience a later average age of onset of disease along with a faster progression to disability than females. Pathogenesis. MS onsets when the immune system cannot prevent peripheral autoreactive T-cells (i.e., those outside the CNS) from becoming activated against myelin-associated antigens. These T-cells then cross a compromised blood-brain-barrier to enter into the CNS where they initiate inflammation followed by demyelination of neurons within the CNS, while sparing peripheral nerves and muscles. Myelin, the white lipid-protein complex (i.e., the white matter of the CNS) consists of parallel layers of lipids including cerebroside (a general description of an acid amide of a fatty acid), phospholipids and cholesterol, which constitute 75 percent of myelin s dry weight. This inhibits sodium and potassium movement across the neuronal membrane almost completely, thus preventing generation of neuronal action potentials. Damage to the myelin sheath can lead to disruption of electrical impulses to regions beyond the axons. Normal neuronal transmission is, therefore, delayed or terminated, thereby disrupting functions such

2 as vision, sensation and coordination of movement. MS symptoms appear when the immune system can no longer prevent interaction between autoreactive T-lymphocytes and myelinassociated antigens. Demyelination is noted as well-demarcated, focal, scattered and hardened lesions (i.e., plaques, or scleroses) upon the central neurons. The presence of these plaques, which may vary in size from 1 to 2 millimeters to several centimeters, is the hallmark of MS, and source of the descriptive terminology multiple sclerosis that defines the disease. Demyelination is followed by scar tissue formation. Once neuronal injury occurs, the damage is usually irreversible; however, if remyelination should occur, it tends to be abnormal and incomplete. Management of MS Altering the natural course of MS and diminishing the risk for progressive disability over time are pivotal aims in the clinical management of MS. The past three decades, especially, have shown significant progress in understanding the pathogenesis of MS, which has led to development of effective DMTs (Table 1), with many more currently in development. Despite this progress, huge challenges remain. The precise cause(s) of MS remains unknown, its pathophysiologic mechanisms are diverse, currently available therapies are only partially effective and efficacy is achieved only when treatment begins early in its relapsing forms. As a chronic and so far incurable disease, therapy is required for an indefinite, if not lifelong, period of time. MS management may be categorized into two objectives: (1) modification of the primary disease process and (2) treatment of specific symptoms. The most important therapeutic goal for controlling the disease is to postpone or prevent long-term disability. Anti-inflammatory Agents in Acute Relapses. It was noted in 1951 that MS patients treated with adrenocorticotropic hormone (ACTH), an agent that stimulates synthesis and release of adrenocortical hormones, appeared to recover more quickly from acute exacerbations (relapses). The undesirable adverse effects associated with ACTH stimulated development and use of many synthetic glucocorticoids. At this time, methylprednisolone (Medrol, and others) is the treatment of choice when corticosteroid therapy is chosen for treatment during periods of acute relapses. Current therapeutic management of severe acute relapses of MS involves use of the drug administered in a daily dose of 500 mg or 1 gm given IV. Treatment should be initiated promptly after symptom onset and continued three to five days. There is no evidence that tapered doses of prednisone are useful or even desirable. Although corticosteroids hasten recovery from acute attacks, they do not prevent relapses. It is speculated that these agents inhibit secretion of at least two cytokines (any of a number of regulatory proteins released by the immune system that act as intracellular mediators in the generation of an immune response): tumor necrosis factor (TNF) and interleukin (IL)-6. Corticosteroids may also interfere with the synthesis and/or secretion of interferon (IFN)-gamma and IL-2 by activated T-cells. Consequently, DMTs result in faster recovery from relapses, but exhibit no demonstrable effect on the degree of disability, or timing or severity of future relapses. Corticosteroids provide short-term benefit for accelerating functional recovery in patients with acute MS attacks. There does not appear to be long-term benefit following their brief use. Disease-Modifying Therapy The Multiple Sclerosis Council for Clinical Practice Guidelines and the National Multiple Sclerosis Society recommend the early use of DMTs in patients who have relapsing forms of MS. The interferons, glatiramer and fingolimod are recommended for first-line treatment in patients with relapsingremitting MS. Mitoxantrone is used in relapsing disease that is intensifying, but is also given to patients with worsening secondaryprogressive MS with or without relapses. Natalizumab is recommended primarily for patients who are unable to tolerate or have not responded adequately to other DMTs. Although clinical trials of some DMTs in patients with progressive forms of MS have failed to provide conclusive evidence of disease modification, these drugs are still used in these patients. There is strong evidence that early treatment may significantly alter the course of the disease. Individual decision for one or the other therapies is currently based on the preferred route of administration and individual tolerability of the agent used. Neuronal injury due to demyelination, which is responsible for the permanent disability in MS, is known to occur early in the disease process. Studies suggest a causal link between acute inflammation and loss of neuronal function along with the accepted role of chronic demyelination. Moreover, highly active disease early on correlates positively with increased disability at a later stage, along with increased likelihood of secondary progression. Thus, early treatment could potentially delay or prevent onset of permanent disability. Therapy should also be continued in the absence of overt symptoms during periods of remission, to prevent or slow the development of new plaques or worsen existing plaques. Despite the recommendation for initiating treatment early after confirmed diagnosis, only about one-half of all MS patients are believed to currently use a DMT. Interferons. These drugs are successful DMTs for treating MS. They alter the immune system in an attempt to control the immunologic events that lead to demyelination of central neurons. They include the four IFN-beta products,

3 Table 1 Approved disease-modifying therapy for treatment of multiple sclerosis First-line Trade names Dosage form Recommended dose Interferonβ-1b Betaseron SC injection 0.25 mg every other day Interferonβ-1b Extavia SC injection 0.25 mg every other day Interferonβ-1a Avonex IM injection 30 µg once weekly Interferonβ-1a Rebif SC injection µg 3 times weekly Glatiramer Copaxone SC injection 20 mg daily Fingolimod Gilenya Oral capsule 0.5 mg once daily Second-line Mitoxantrone Novantrone, IV injection 12 mg/m 2 given as a short & others (5-15 min) infusion every 3 months Natalizumab Tysabri IV injection 300 mg infused over 1 hour every 4 weeks SC, subcutaneous; IM, intramuscular; IV, intravenous which differ only slightly in their pharmacodynamics and pharmacokinetics, and glatiramer acetate. (see Table 1). The three known forms of native IFN are tagged alpha (α), beta (β) and gamma (γ), and are produced by different cells in the body. Each IFN possesses antiviral activity, but they have different actions on the immune system. In MS, the immune system is deregulated, which permits damage to the myelin sheath that normally insulates central neurons. Of the three, only IFNβ, a carbohydratebearing protein produced by cells in the skin and connective tissues (fibroblasts), has been shown conclusively to be effective in treating relapsing forms of MS. The IFNβ compounds modify the immune system by interrupting proliferation of T-lymphocytes. This down-regulation is not specific for the factors involved in the pathogenesis of MS. Moreover, the IFNs may also modify non-autoimmune functions. IFNβ reduces the number of relapses, retards disease progression, and reduces the number of MS lesions within the CNS. The exact mechanism of action is unknown. Its immune-modulating propensity may include the ability to inhibit synthesis of IFNγ, augment activity of T-suppressor cells, and inhibit antigen expression induced by IFNγ on the surfaces of antigenpresenting cells. IFNβ-1b. This biosynthetic form of type 1 IFN is a product of recombinant DNA technology utilizing genetically modified cultures of Escherichia coli. It is not glycosylated like naturally occurring IFNβ-1b, and its amino acid sequence differs slightly from the native form in that cysteine has been substituted in the drug for serine in the natural form. The drug (Betaseron, Extavia) is self-administered by subcutaneous injection every other day. The most frequent adverse event reported in clinical trials was an influenza-like syndrome, with symptoms of fever, chills, headache, myalgia, arthralgia, nausea, vomiting and diarrhea. This usually resolved within 12 hours and tolerance developed gradually in most patients. Acetaminophen, ibuprofen, or aspirin can generally control symptoms although the syndrome may be particularly troublesome for some patients. Depression, anxiety, confusion, and other mental changes are also reported. Patients to be treated with Betaseron should be informed that depression with suicidal tendency may be an adverse effect. It is suggested that patients be evaluated carefully if they show tendencies toward these effects. Significant decreases in white blood cell counts and elevation of liver enzymes have been reported for type 1 IFNs. Baseline, along with periodic laboratory tests are, therefore, recommended to monitor for possible leukopenia (reduced leukocytes), thrombocytopenia (decreased platelets), and abnormal liver function. IFNβ-1a. The second IFN in the nonspecific immunomodulator category is IFNβ-1a (Avonex and Rebif). Originally extracted from human fibroblasts, the process was arduous, produced only limited amounts of IFN and required a labor-intensive purification procedure. Today, these products are manufactured via recombinant DNA technology using Chinese hamster ovary cells. Mammalian cells are an ideal medium because they are able to facilitate addition of sugar molecules to the structure, a process known as glycosylation, which produces a carbohydrate structure similar to that found in native IFNβ. The most common adverse effects in clinical trials were influenza-like symptoms, abdominal pain, depression, liver enzyme elevations and hematologic abnormalities. Patients should be aware of signs of jaundice such as yellowing of the skin or whites of the eyes, easy bruising and loss of appetite. Therapy should be stopped if jaundice or other adverse symptoms suggestive of liver dysfunction appear. Avonex is administered by once-weekly IM injection; Rebif is given SC, three times weekly. Glatiramer Acetate. The first in a unique class of MS drugs, glatiramer acetate (Copaxone) is a synthetic non-ifn, nonsteroidal agent that is a member of the glatiramoid class of compounds. It is described as the acetate salt of a standardized, random-sequence polypeptide consisting of four naturally occurring amino acids, L-glutamic acid, L-lysine, L-alanine, and L-tyrosine, that results in a copolymer structurally similar to myelin basic protein, a major component of myelin.

4 Although its mechanism of action is unknown, it is proposed that glatiramer acts by modifying immune processes responsible for the pathogenesis of MS. It works through a unique mechanism. Each of the two processes that appear to be triggered by the drug, induction of antigen-specific suppressor T-cells in the periphery and the inhibition of effector T-cells, has the capacity to interrupt the autoimmune inflammatory process that results in demyelination of central neurons. Controlled clinical trials have shown that glatiramer is at least as effective as the IFNs. Efficacy is noted early after therapy is begun, and appears to increase with time. Glatiramer has the most favorable adverse effects profile of all approved parenterally-administered drugs for MS. It may be the drug of choice for individuals who cannot tolerate IFN therapy or, who after taking the drugs awhile, must reduce their dosage due to laboratory abnormalities or onset of other problems. Following administration of glatiramer, patients may experience a transient, systemic, immediate post-injection reaction consisting of flushing, chest pain, palpitations, anxiety, dyspnea, throat constriction and urticaria. There are no known drug-drug interactions with glatiramer. It does not increase the risk of hepatotoxicity or depression, as is the case with IFN therapy. Glatiramer is administered as a SC injection each day. Mitoxantrone. Mitoxantrone (Novantrone, and others) is an analog of doxorubicin (Adriamycin). Before approval for use in MS, it was used to treat prostate cancer and nonlymphocytic leukemia. It is the only drug indicated for treatment of secondary-progressive MS, and is also approved for patients with progressive-relapsing MS. It is used in patients refractory to other immunomodulators and in worsening disease. At this point, mitoxantrone is the only DMT available generically. Mitoxantrone acts via several mechanisms. It is taken into DNA strands where it inhibits proliferation of T-cells, B-cells and macrophages. Moreover, it decreases the secretion of pro-inflammatory cytokines and increases an antiinflammatory response via promotion of the T-cell suppressor function. In addition, mitoxantrone inhibits macrophage-mediated myelin degradation. In patients receiving mitoxantrone, adverse reactions that can usually be managed include transient leukopenia and neutropenia peaking around 10 to 14 days post-infusion, liver enzyme elevation, nausea, alopecia, urinary tract infections and bluish urine discoloration. Like its counterpart doxorubicin, more serious effects include functional cardiac changes. There are reports of a significant decrease in left ventricular ejection fraction among patients receiving mitoxantrone. Reports of irreversible congestive heart failure, sometimes appearing years after drug discontinuation, are also recorded. Therefore, mitoxantrone use should be limited to persons with normal cardiac function, at a dose and frequency of 12 mg/m 2 once every three months. Periodic cardiac monitoring is required throughout treatment. The lifetime cumulative dose is limited to 140 mg/m 2 (approximately eight to 12 doses over two to three years). Because mitoxantrone can increase the risk for infection by decreasing the number of white blood cells, blood counts should be obtained and liver function evaluated prior to each dose. Natalizumab. Natalizumab (Tysabri) is a humanized monoclonal antibody approved as monotherapy for treatment of relapsingremitting MS in patients who have experienced an inadequate response to or cannot tolerate alternative DMT. Safety and efficacy in patients with chronic progressive MS have not been fully established. Natalizumab is an integrin receptor (a family of cell-surface receptors that mediate interactions among cells and components of the extracellular matrix) antagonist that binds to the α 4 subunit of α 4 β 1 and α 4 β 7 integrins expressed on the surface of all leukocytes except neutrophils. This action inhibits adhesion of leukocytes to their counter-receptor(s). Natalizumab is believed to inhibit the interaction of the α 4 β 1 integrin with vascular cell adhesion molecule 1, and the α 4 β 7 integrin with mucosal adhesion cell adhesion molecule 1, respectively. By inhibiting these interactions, natalizumab may prevent an inflammatory cascade responsible for CNS lesions. Natalizumab was originally approved in 2004 for treatment of relapsing-remitting MS. It was withdrawn in 2005 after three patients developed progressive multifocal leukoencephalopathy (PML), a rare but serious opportunistic viral infection of the brain. Marketing resumed in 2006 with a boxed warning cautioning about the risk of PML. Subsequently, more than 50 additional confirmed PML cases have been reported in association with natalizumab therapy. In 2008 FDA issued another warning advising of a risk of hepatic injury with natalizumab. At present, the drug is available only through a special restricted distribution program called the TOUCH Prescribing Program. Adherence to Therapy Protocol MS has a progressive course that may be slowed significantly by strict adherence to DMT protocol. Adherence is the extent to which a patient s behavior coincides with a treatment plan. Patients with good adherence can expect a 30 percent decrease in relapse rates; missed dosages or increased frequency of parenteral therapy, however, are associated with continued disease progression. Relapses may signify poor adherence, underscoring the need for monitoring therapy closely. This is particularly hard to sustain because these drugs require parenteral administration throughout life, with a modest reduction in the rate of disease pro-

5 gression such that the patient may not easily perceive improvement. For many patients, especially those with newly diagnosed MS, the thought of self-injection is unpleasant and may add undue stress to a situation that is already difficult to accept. Convincing patients to use a drug that requires parenteral administration every other day or even weekly can be difficult if they only suffer from symptoms they may consider to be mild. A number of studies have estimated the proportion of MS patients who discontinue treatment with DMTs. One post-marketing trial of IFN therapy revealed that the proportion discontinuing treatment within three years ranged between 15 percent (for IM IFNβ-1a) and 41 percent (for SC IFNβ-1b). Similar results were obtained by other studies, including 39 percent of relapsing-remitting MS patients over a five-year period who were started on either IFNβ-1b or IFNβ-1a, and 32 percent of patients over a two-year period following initiation with IFNβ-1b, IFNβ- 1a or glatiramer. Patients in all three studies had clinically defined relapsing-remitting MS. The factors that affect adherence with treatment in MS patients are well known. In the literature, among patients treated with IFNβ or glatiramer, most of them discontinued therapy within the first two years of treatment with 30 to 50 percent reportedly due to a perceived lack of efficacy, while 22 to 70 percent were due to adverse effects, the primary ones included injection site reactions, influenzalike symptoms and depression. Fingolimod. The long awaited arrival of a first-line oral formulation (Gilenya) for treating relapsing forms of MS is welcome news for patients. The potential advantages of oral therapy for modifying the course of relapsing-remitting MS are significant. Since publication of the first pivotal trial of IFNβ-1b in 1993, patients and practitioners have been eagerly anticipating approval of a therapy that avoids the use of needles. Fingolimod (Table 2) is a synthetic structural analog of sphingosine 1-phosphate (S1P), which is a naturally occurring lysophospholipid, a potent signaling lipid. S1P interacts with five known subtypes of S1P receptors (S1P 1-5 ) distributed throughout the body, which lead to a variety of physiologic processes. S1P 1-3 are found throughout the immune, cardiovascular and central nervous systems. Their activation on smooth muscle and endothelial cells regulates vascular homeostasis and permeability. Activation of S1P 1 receptors on atrial muscle regulates heart rate. S1P 4 response is generally confined to the hematopoietic (pertaining to or affecting the formation of blood cells) and lymphoid tissues, and S1P 5 is expressed in the white matter of the CNS. Fingolimod is a prodrug that undergoes rapid phosphorylation in vivo by sphingosine kinase into fingolimod-phosphate, the biologically active compound. The drug has a novel mechanism of action. Fingolimod-phosphate is a nonselective S1P receptor agonist that binds with four of the five S1P receptor subtypes to modify their signaling pathways. Because of its lipophilic nature, the drug readily crosses the blood-brain-barrier to interact with S1P receptors widely expressed throughout the CNS. Binding to S1P 1 receptors is of particular importance to the drug s proposed mechanism of action in MS. S1P 1, highly expressed on T- and B-lymphocytes, is responsible for regulating their egress from lymphoid tissue. Binding of fingolimod-phosphate to S1P 1 acts to down-regulate the receptor with subsequent sequestration (isolation) of lymphocytes in the lymph tissue, to prevent their recirculation, and reducing peripheral lymphocyte counts. Fingolimod is not believed to destroy lymphocytes; therefore, many immune functions including activation, proliferation and effector functions of T- and B- lymphocytes remain undisturbed during treatment. However, immune function that relies on naïve Table 2 Highlights of prescribing information for fingolimod Trade name: Gilenya Manufacturer: Novartis Pharmaceutical Corp, East Hanover, New Jersey Approval date: September 2010 Indications & use: Treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. Dosage & administration: 0.5 mg orally once daily, with or without food Dosage form & strength: 0.5 mg hard capsules Contraindications: None Warnings & precautions: Bradycardia and/or atrioventricular block after first dose of Gilenya: Observe patients. Infections: Gilenya may increase risk of infection. Macular edema: Macular edema may occur with or without visual symptoms. Decreased pulmonary tests with Gilenya: Obtain spirometry & diffusion lung capacity for CO when clinically indicated. Hepatic effects: Drug may increase liver transaminases. Fetal risk: Women of childbearing age should use effective contraception during & for two months after discontinuing use of the drug. Adverse effects: Reported at incidence of >10 percent were headache, influenza, diarrhea, back pain, liver transaminase elevations and cough. Drug interactions: Class 1a or Class III antiarrhythmic drugs, beta-adrenergic blockers, ketoconazole and vaccines should be used cautiously. Medication Guide: An FDAapproved Medication Guide must be dispensed with each new and refilled prescription for Gilenya. T-cells and central memory cells may be reduced or delayed. Given the theory that aggressive lymphocyte penetration into the CNS contributes to the inflammation and

6 neural degeneration via demyelination found in MS, the drug s major benefit may be due to its ability to sequester lymphocytes within the lymphoid tissues. Moreover, S1P 1 receptors expressed in the CNS are known to modulate neurogenesis (development of neurons) and neural function. Fingolimod may, therefore, have the ability to facilitate restoration of nerve cell function and supplement endogenous CNS repair. Fingolimod has been shown to improve myelination in animal models of experimental allergic encephalitis and is beneficial in a wide variety of graft-rejection and autoimmune models. In these situations, fingolimod reduces infiltration of macrophages to the CNS, conserves expression of myelin genes, and is active in prophylactic and therapeutic regimens. It has even been shown to reverse demyelination in experimental models. The most common adverse events reported in 10 to 20 percent of fingolimod-treated patients included fatigue, melanocytic nevus (also known as a banal nevus or nevocytic nevus, or a mole), influenza virus infection, lower respiratory tract or lung infection, back pain, diarrhea, cough and abnormal liver function tests. Effects occurring in more than 20 percent of fingolimodtreated patients in premarketing clinical trials were nasopharyngitis and headache. Serious adverse events occurred in 7 to 11 percent and included three deaths, the causes listed as disseminated primary varicella zoster infection, herpes simplex encephalitis and suicide. Serious adverse events noted in more than 1 percent of patients included MS relapse, basal cell carcinoma and sinus bradycardia. The cardiovascular events were consistent with the known presence of S1P receptors in myocytes. Bradycardia appears to be transient and dose-related in response to the first dose of fingolimod. In one study, maximal reduction in heart rate of eight beats per minute in the 0.5- mg group and 10 beats per minute in the 1.25-mg group occurred four to five hours after the first dose and began restoring at six hours. Most cases of bradycardia were asymptomatic and resolved within 24 hours. The long-term implications of this are unclear. Other clinical adverse events observed during these trials are notable. Edema was reported in a small percentage of patients. Six of seven cases resolved within six months upon drug discontinuation. Skin cancer was reported in phase 2 testing. In two trials, 15 fingolimod-treated patients were found to have skin cancer, all successfully excised. Laboratory abnormalities included decreased lymphocyte count, mild decrease in mean forced expiratory volume in one second (FEV 1 ), and a reversible increase of alanine transferase to greater than three times the upper limit of normal. Overview and Summary DMT can be considered in all MS patients with definite relapsing disease. The drugs currently available offer partial benefit; however, they appear to delay the progression of MS. Fingolimod represents the first wave of active therapies and will be followed by other, possibly more potent and less toxic, oral drugs. Fingolimod s novel mechanism of action and convenient route of administration distinguish it from all other FDA-approved DMTs for treating relapsing forms of MS. The future should bring improved understanding of how the immune system, environmental influences, and genetics interact in MS. Reversing disability is a goal for therapy. At this point, the future for patients with MS looks much brighter than it did at the onset of the 21 st century. The authors, the Ohio Pharmacists Foundation and the Ohio Pharmacists Association disclaim any liability to you or your patients resulting from reliance solely upon the information contained herein. Bibliography for additional reading and inquiry is available upon request. This lesson is a knowledge-based CE activity and is targeted to pharmacists in all practice settings. Program H01-P Release date: Expiration date: CE Hours: 1.5 (0.15 CEU) The Ohio Pharmacists Foundation Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

7 continuing education quiz Multiple Sclerosis: Medical Management with Disease-Modifying Therapy 1. At onset, the highest percentage of patients with MS present with which of the following forms? a. Primary-progressive c. Relapsing-remitting b. Progressive-relapsing d. Secondary-progressive 2. Myelin is the CNS : a. grey matter. b. white matter. 3. Once neuronal injury occurs in patients with MS, it is usually: a. irreversible. b. reversible. 4. Therapy with corticosteroids in patients with MS: a. prevents relapses, but does not hasten recovery from acute attacks. b. hastens recovery from acute attacks and prevents relapses. c. does not prevent relapses nor hasten recovery from acute attacks. d. hastens recovery from acute attacks, but does not prevent relapses. 5. Despite the recommendation for initiating treatment early after a confirmed diagnosis, the portion of MS patients believed to use disease-modifying therapy is: a. one-fourth. c. one-half. b. one-third. d. two thirds. 6. Which of the following forms of interferon has been shown to be effective in treating relapsing forms of MS? a. Alpha (IFNα) c. Gamma (IFNγ) b. Beta (IFNβ) Completely fill in the lettered box corresponding to your answer. 1. [a] [b] [c] [d] 6. [a] [b] [c] 11. [a] [b] [c] [d] 2. [a] [b] 7. [a] [b] [c] [d] 12. [a] [b] [c] 3. [a] [b] 8. [a] [b] [c] [d] 13. [a] [b] 4. [a] [b] [c] [d] 9. [a] [b] [c] 14. [a] [b] [c] [d] 5. [a] [b] [c] [d] 10. [a] [b] [c] [d] 15. [a] [b] [c] [d] I am enclosing $10 (member); $15 (nonmember) for this month s quiz made payable to: Ohio Pharmacists Association. 1. Rate this lesson: (Excellent) (Poor) 2. Did it meet each of its objectives? yes no If no, list any unmet 3. Was the content balanced and without commercial bias? yes no 4. Did the program meet your educational/practice needs? yes no 5. How long did it take you to read this lesson and complete the quiz? 6. Comments/future topics welcome. Please print. Program H01-P 0.15 CEU Name Address City, State, Zip Return to Correspondence Course, OPA, 2674 Federated Blvd, Columbus, OH or fax to When Interferonβ-1b is prescribed, which of the following trade name products should be dispensed? a. Betaseron c. Copaxone b. Rebif d. Gilenya 8. Which of the following is the only currently available oral form of MS therapy? a. Betaseron c. Copaxone b. Rebif d. Gilenya 9. Controlled clinical trials have shown that glatiramer is: a. less effective than the interferons. b. at least as effective as the interferons. c. more effective than the interferons. 10. Mitoxantrone was used to treat which of the following types of cancer? a. Breast c. Lung b. Colon d. Prostate 11. Natalizumab antagonizes which of the following types of receptors? a. Integrin c. Hyalin b. Insulin d. Hemoglobin 12. The response to S1P 4 is generally confined to lymphoid and which of the following types of tissues? a. Hematophagic c. Hematopoietic b. Hematoplegic 13. Fingolimod is: a. believed to destroy lymphocytes. b. not believed to destroy lymphocytes. 14. The correct dosage for Gilenya is 0.5 mg: a. once daily. c. three times a day. b. twice daily. d. four times a day. 15. Only three deaths occurred in patients in clinical trials with fingolimod, the cause of which was attributed to each of the following EXCEPT: a. disseminated primary varicella zoster infection. b. herpes simplex encephalitis. c. myocardial infarction. d. suicide. To receive CE credit, your quiz must be postmarked no later than May 15, A passing grade of 80% must be attained. CE statements of credit are mailed February, April, June, August, October, and December. Send inquiries to opa@ohiopharmacists.org. may 2011