- Introduction to drugs for the treatment of multiple sclerosis
- What are steroids, and which ones are available?
- What are disease modifying drugs, and which ones are available?
- Avonex (interferon beta-1a)
- Rebif (interferon beta-1a)
- Betaseron and Extavia (interferon beta-1b)
- Copaxone (glatiramer acetate)
- Novantrone (mitoxantrone)
- Tysabri (natalizumab)
- Aubagio (teriflunomide)
- Gilenya (fingolimod)
- Lemtrada (alemtuzumab)
- Plegridy (peginterferon beta-1a)
- Tecfidera (dimethyl fumarate or DMF)
- Ampyra (dalfampridine)
Introduction to drugs for the treatment of multiple sclerosis
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that leads to the degeneration of nerves in the brain and spinal cord. The immune or infection-fighting system in MS patients attacks the body's own cells, causing progressive damage in the brain and spinal cord. Symptoms of MS include vision problems, muscle weakness, trouble walking or speaking, numbness and tingling, problems related to bowel or bladder control, and others. Although MS was first identified over a century ago, a cure still remains to be found. Available therapies help improve patients overall quality of life and minimize long term disability (by reducing inflammation, delaying the progression of the disease, reducing the frequency and severity of acute attacks, and improving walking speed). Physical, occupational, speech, and cognitive therapy also are used for improving function.
What are steroids, and which ones are available?
Steroids available for the treatment of MS include:
Steroids are mainly used for treating acute episodes of MS. Steroids help to reduce the body's autoimmune response. In doing so, steroids help to shorten the length of an attack, and rapidly reduce inflammation. Since their use is associated with significant long-term side effects, steroids are used only for short periods of time. Side effects of steroids include psychosis, bloating, insomnia (sleeping problems), headache, bone loss, suppression of the immune system, moon (rounded) face, stomach ulcers, and increases in blood sugar.
What are disease modifying drugs, and which ones are available?
Disease modifying drugs (DMDs) can decrease the frequency and severity of acute attacks, delay the progression of MS, and slow down the progression of disease related disability and cognitive decline. DMDs are most effective when started early in the course of the disease.
Interferon beta-1a, the active chemical in Avonex and Rebif, is a naturally occurring protein found in the body. Avonex and Rebif are synthesized using recombinant DNA technology, and the synthetic chemicals are identical to the natural protein. Although the mechanism of action of interferon beta-1a in MS is unknown, interferon beta-1a is thought to inhibit the expression of chemicals that trigger the autoimmune response which causes inflammation and neurodegeneration associated with MS. Avonex and Rebif are used for the treatment of patients with relapsing forms of MS to slow the progression of physical disability and decrease the frequency of flare ups. Interferons, type beta-1a and 1b, are associated with significant side effects. The most common side effects are injection site reactions. Flu-like symptoms are also common but can be managed with acetaminophen (Tylenol), ibuprofen (Motrin), and glucocorticoids. Additionally, interferons may cause liver damage and depression. Depression and flu-like symptoms are transient and usually decrease or go away with time.
Avonex (interferon beta-1a)
Avonex is administered by intramuscular injection once a week. Once weekly Avonex is preferred over Rebif (administered 3 times weekly) by some patients because of fewer injections and injection-site reactions. In clinical studies disease progression was slower in Avonex treated patients. Compared to patients treated with placebo, the risk of progressive physical disability was reduced by 37% in patients treated with Avonex. Side effects associated with Avonex include flu-like symptoms, depression, abnormal liver tests, and a drop in red and white blood cells and platelets. Allergic reactions, seizures, and heart failure also have been associated with Avonex. Due to the risk of miscarriage or harm to fetus, Avonex should only be used during pregnancy if the potential benefit justifies the potential harm to the fetus. Females of reproductive potential should be made aware of the risk and use appropriate birth control while receiving treatment. Avonex is classified FDA pregnancy risk category C.
Rebif (interferon beta-1a)
Rebif is the second formulation of interferon beta-1a which was approved by the FDA for relapsing-remitting MS in March 2002. Rebif was approved after the EVIDENCE study showed that Rebif was more effective than Avonex. Study findings show that approximately 75% of patients treated with Rebif did not relapse at 24 weeks of treatment versus 63% for Avonex. Additionally, at the end of 48 weeks, 62% of Rebif treated patients were relapse free compared to 52% for Avonex.
Rebif is administered by subcutaneous injection three times weekly. Common side effects associated with Rebif are injection site reactions, flu-like symptoms, abdominal pain, depression, abnormal liver tests and abnormalities of the cells in the blood. Less common and transient side effects include thyroid dysfunction, shortness of breath, tachycardia, and neutralizing antibodies. Due to the risk of miscarriage or harm to fetus, Rebif should only be used during pregnancy if the potential benefit justifies the potential harm to the fetus. Rebif is classified FDA pregnancy risk category C.
Betaseron and Extavia (interferon beta-1b)
Interferon beta-1b, the active chemical in Betaseron, is a naturally occurring protein found in the body. Betaseron is synthesized using recombinant DNA technology and is identical to the natural protein. Although the exact mechanism of action of interferon beta in MS is unknown, it is thought that interferon beta-1b inhibits the expression of chemicals such as interleukin-1 beta, tumor necrosis factor, interleukin 6, and others which cause the inflammation and neurodegeneration associated with MS. Betaseron is used for the treatment of patients with relapsing forms of MS to decrease the frequency of acute flare ups. Betaseron was approved by the FDA on July 23th 1993 for the treatment of relapsing-remitting MS. Betaseron is injected subcutaneously every other day. In clinical trials patients treated with Betaseron experienced fewer flare ups. Side effects associated with Betaseron include flu-like symptoms, depression, abnormal liver tests, skin reactions, thyroid dysfunction, and a drop in red and white blood cells and platelets. Allergic reactions and necrosis (cell death) of the skin have also been associated with Betaseron. Betaseron is classified FDA pregnancy risk category C and should only be used during pregnancy if clearly needed. Four women participating in the Betaseron RRMS clinical trial experienced spontaneous abortions. Although it is not clear if the abortions were related to Betaseron therapy, the manufacturer recommended limiting its use to patients who clearly need it. Patients exposed to Betaseron during pregnancy are encouraged to enroll in the Betaseron Pregnancy Registry by either calling 1-800-478-7049 or visiting the Betaseron Pregnancy Registry website.
Extavia (interferon beta-1b)
Extavia, a second formulation of interferon beta-1b, was approved by the FDA for the treatment of relapsing-remitting MS in August 2009. Importantly, Extavia is identical to Betaseron and therefore shares the same pharmacological benefits and risks for side effects. As with Betaseron, Extavia is administered via subcutaneous injection every other day.
Copaxone (glatiramer acetate)
Copaxone is used for reducing the frequency of acute flare ups in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). Glatiramer acetate is a synthetic protein that modifies the immune reactions which may be responsible for MS, but its exact mechanism of action is unknown. Glatiramer acetate can now be administered via subcutaneous injection either once daily or 3 times per week. The new formulation (40 mg/ml) approved in January 2014 has allowed greater patient convenience with administration three times per week compared to daily dosing with the original 20 mg/ml product. Glatiramer acetate comes in prefilled syringes which should be stored in the refrigerator but can be kept at room temperature for up to a week. In clinical trials glatiramer acetate reduced the frequency of relapses and damages to nerves in patients with RRMS. In one such trial, glatiramer acetate was compared to placebo for a period of 2 years using a randomized double blind study design. At 2 years, the relapse rate was significantly lower in the glatiramer treated group at 1.19 versus 1.68 for the placebo group. Furthermore, patients in the placebo group experienced increased disability at 41% versus 22% for the glatiramer group.
Also in a separate study, use of glatiramer acetate was associated with a significant reduction in the formation of new disease-related lesions in the brain on imaging. The most common side effects associated with glatiramer acetate are vasodilation, rash, shortness of breath, chest pain, and injection site reactions including pain, redness, itching, or lump. Some patients report flushing, chest tightness or pain, heart palpitations, anxiety, and trouble breathing after an injection of glatiramer acetate. These symptoms generally appear within minutes after an injection, last a few minutes, and then subside. One advantage of glatiramer acetate treatment is that it has somewhat of a milder side effect profile and does not produce flu-like symptoms, fatigue, or depression which is a significant concern with many of the currently available MS therapies including interferons and steroids. Due to risk of potential harm to the fetus, glatiramer acetate should be used in pregnancy only if clearly needed.
Mitoxantrone or brand name Novantrone is used for reducing neurologic disability and the frequency of acute flare ups in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting MS. Due to risk for cardiac toxicity (heart problems) and limited evidence demonstrating clear benefits, the American Academy of Neurology recommends that use of mitoxantrone be reserved for patient who have rapidly progressing disease and who have failed to respond to other treatment options. Mitoxantrone is a synthetic (man-made) injectable drug that interacts with deoxyribonucleic acid (DNA). It interferes with immune reactions by inhibiting the proliferation or growth of B cells, T cells, and macrophages, all of which are important cells of the immune system. It also impairs the presentation of antigens to cells of the immune system and the secretion of interferon gamma, TNFα and IL-2, chemicals that promote inflammation. The mechanism of action of mitoxantrone in MS is not known but may be related to the modification of the immune system as discussed. In clinical trials, mitoxantrone improved disability, ambulation, frequency of relapse, and neurologic status better than placebo. Mitoxantrone is administered as an intravenous infusion dosed at 12 mg/m2 every 3 months. As mitoxantrone may have toxic effects on the heart, it is not recommended for use in patients with left ventricular ejection fraction (LVEF) <50%, patients with clinically significant reduction in LVEF, or in those who have received a cumulative lifetime dose of mitoxantrone of 140 mg/m2. Furthermore, mitoxantrone should not be administered to patients with white blood cell counts less than 1500 cells/mm3, abnormal liver tests, or who are pregnant.
Side effects of treatment include nausea, hair thinning, loss of menstrual periods, bladder infections, and mouth sores. Heart failure and drops in white blood cell or platelet counts may also occur. Low white blood cell counts may lead to infections while low platelets may cause bleeding. Mitoxantrone is dark blue in color and may turn the urine or the sclera of the eyes a blue-green color. Mitoxantrone was approved by the FDA to treat RRMS or secondary progressive MS in October 2000. Mitoxantrone is also approved to treat various types of cancers or tumors, and has been used medically since 1987. Mitoxantrone is classified as FDA pregnancy category D and should not be used during pregnancy as it may cause harm to the unborn fetus. Females who may become pregnant must be made aware of the risk and use appropriate forms of birth control (contraception). Females who are of childbearing potential should have a pregnancy test prior to each dose of mitoxantrone.
Tysabri is used to delay the progression of physical disability and reduce the frequency of clinically important flare-ups in patients with relapsing MS. Because natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal viral infection of the brain, it is reserved for patients with active RRMS who have failed to adequately respond or are intolerant to the beta interferons or glatiramer acetate. Due to the risk of PML, natalizumab is available only through a restricted distribution program called the TOUCH Prescribing Program. Also, due to the risk for PML, natalizumab should not be co-administrated with immunosuppressants. The mechanism of action of natalizumab in MS is not well understood. Natalizumab is a humanized monoclonal antibody and is an alpha-4 integrin antagonist or blocker. It binds to integrins expressed on the surface of white blood cells (except neutrophils) and inhibits adhesion of the white blood cells to their receptors. Natalizumab is thought to exert its benefits in MS by preventing migration of white blood cells into the brain and spinal cord. As white blood cells play an important role in promoting the inflammation of MS and the degeneration of nerves, natalizumab reduces relapse and appearance of brain lesions by reducing their numbers in the brain and spinal cord. In clinical studies natalizumab delayed the onset of sustained increase in disability. In a phase II clinical study that compared natalizumab to placebo, natalizumab showed to significantly decrease the number of new gadolinium-enhancing lesions by more than 90%. Additionally, in the AFFIRM trial (A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis), natalizumab reduced the annual relapse rate by more than 60%, reduced gadolinium-enhancing lesions by more than 90%, and significantly delayed the progression of disability.
Natalizumab is infused intravenously every 4 weeks. The most common side effects in MS include headache, stomach pain, joint pain, fatigue, depression, urinary tract infection, lower respiratory tract infection, pain in the extremities, diarrhea, and rash. Rare but serious side effects include progressive multifocal leukoencephalopathy (PML), liver dysfunction, and potentially life-threatening infections such as meningitis and encephalitis. Natalizumab is classified as FDA pregnancy risk category C and should only be used in pregnancy if clearly needed. Natalizumab was approved by the FDA for the treatment of MS in November 2004. Besides being effective in treating MS, natalizumab is also used to treat moderate to severe Crohn's disease.
Aubagio is an oral immunomodulator. It works by altering the immune signals without causing significant cell toxicity or bone marrow suppression. More specifically, teriflunomide inhibits dihydroorotate dehydrogenase, an enzyme used to make pyrimidine -- which is required to make DNA. Teriflunomide is used for the treatment of relapsing forms of MS. It was approved by the FDA in September 2013. Although the exact mechanism of teriflunomide in the treatment of MS is unknown, it is thought to play an important role in reducing the over activation of the immune system by decreasing the number of white blood cells in the brain and spinal cord. In the clinical study which demonstrated the effectiveness of teriflunomide, patients treated with teriflunomide were reported to experience a 31% relative risk reduction in their annual MS relapse rate. Furthermore, the percent of patients who remained relapse-free at week 108 for the 14 mg teriflunomide, 7 mg teriflunomide, and placebo was 56.5%, 53.7%, and 45.6% respectively. The usual recommended dose of teriflunomide is 7 mg or 14 mg orally once a day without regard to food. The most common side effects associated with teriflunomide treatment are alopecia (hair loss or thinning), diarrhea, influenza (flu), paresthesia (tingling, burning, prickling, or pricking sensations of the skin), and decrease in liver enzymes. Less common but potentially serious side effects include serious liver injury, kidney failure, increased risk of serious infections such as tuberculosis, increase in blood potassium levels, high blood pressure, breathing problems, serious skin problems, and a drop in white blood cell count. Teriflunomide may impair the development of the fetus or cause fetal death, and therefore should not be used during pregnancy. Pregnant women, women who wish to get pregnant, or men who wish to father a child should discontinue the use of teriflunomide.
Gilenya is the first oral medication approved for the treatment of relapsing-remitting MS. Fingolimod helps to decrease the frequency of acute attacks and delays the accumulation of physical disability. Fingolimod is a sphingosine 1-phosphate receptor modulator and is thought to help reduce the number of lymphocytes (white blood cells) in the peripheral blood. Although the exact mechanism by which fingolimod helps to treat MS is unknown, it may be related to its involvement in reducing the migration of white blood cells into the brain and spinal cord. The effectiveness of treatment with fingolimod was demonstrated in the TRANSFORMS trial that compared oral fingolimod (0.5 mg orally once a day) to intramuscular interferon beta-1a (30 mcg once weekly) for a period of 12 months. The annualized relapse rate was significantly lower in the fingolimod recipients at 0.16 versus 0.33 for the interferon beta-1a recipients. The usual recommended dose of fingolimod is 0.5 mg orally once a day without regard to food. Initiation of treatment with fingolimod may cause a decrease in the heart rate. Therefore, the first dose of fingolimod must be administered in a clinical setting where the patient is observed by healthcare providers for at least 6 hours. The most common side effects of treatment include headache, influenza, diarrhea, back pain, an increase in liver enzymes and cough. Other significant side effects which have been reported in clinical trials and require monitoring Include, a drop in white blood cell counts, macular retinal edema (eye problems), AV block (abnormal conduction in the heart), and the risk for infections. Also, when given with oral ketoconazole (an azole antifungal), there is a concern for increased blood levels of fingolimod and the consequent risk for side effects. Because fingolimod may reduce the immune response to vaccines, administration of live attenuated vaccines should be avoided during and for 2 months after stopping treatment with fingolimod. Use of fingolimod during pregnancy should be avoided if possible due to concerns for causing harm to the fetus. Additionally, women of child bearing potential are advised to use effective contraceptive methods during and for at least 2 months after stopping fingolimod. Fingolimod was approved by the FDA in September 2010.
Lemtrada is a humanized monoclonal antibody directed against the CD52 antigen. The CD52 antigen is found on the surface of numerous cells in the body including white blood cells, NK cells, monocytes, macrophages, platelets, and others. Alemtuzumab is used to treat relapsing forms of MS and is generally reserved for patients who have failed to adequately respond to two or more MS treatments. In the CARE-MS clinical trial, alemtuzumab proved to be more effective than interferon beta-1a in reducing the relapse rate in patients with relapsing-remitting MS (RRMS). The annualized relapse rate was 0.18 for the alemtuzumab group versus 0.39 for the interferon beta-1a group. Similar findings were also demonstrated in the CARE-MS II study which evaluated adult patients with RRMS who had experienced at least one relapse while being treated with interferon beta-1a or glatiramer. At 2 years, alemtuzumab was superior in reducing relapse and the progression of disability.
Alemtuzumab is administered by intravenous infusion at 12 mg/day over 4 hours for two treatment courses. The first treatment course is given once daily for 5 consecutive days (60 mg total dose), followed by the second treatment course 12 months later for 3 consecutive days (36 mg total dose). Due to the significant risk of infusion reactions (infusion reactions occurred in approximately 90% of patients), patients are premedicated with high dose corticosteroids (1000 mg of methylprednisolone or equivalent) immediately prior to infusion and for the first 3 days of each treatment course. Additionally, patients must also receive prophylaxis for herpes and pneumocystis jirovecii pneumonia (PCP) during treatment and for several weeks after. HIV-infected patients should not use alemtuzumab. The most common side effects of alemtuzumab treatment are rash, headache, fever, nausea, nasopharyngitis (common cold), urinary tract infection, fatigue, insomnia (difficulty sleeping), upper respiratory tract infection, herpes viral infection, urticaria (hives), pruritus (itching), thyroid gland disorders, fungal infection, arthralgia (joint pain), pain in the extremity, back pain, diarrhea, sinusitis, oropharyngeal pain (mouth pain or sore throat), paresthesia (tingling, pricking, burning sensations in the skin), dizziness, stomach pain, flushing and vomiting. Due to the potential risk of causing harm to the fetus, alemtuzumab should be avoided in pregnancy if possible. Alemtuzumab was approved by the FDA in November 2014 for the treatment of RRMS. In addition to treating MS, alemtuzumab is also used to treat chronic lymphocytic leukemia (CLL), a type of blood cancer.
Plegridy (peginterferon beta-1a)
Plegridgy is the newest formulation of interferon beta-1a which is designed to have a longer half-life, and therefore requires less frequent dosing. As peginterferon beta-1a requires fewer injections, it may be better tolerated than the nonpeglyated interferon formulations. The exact mechanism by which peginterferon beta-1a exerts its therapeutic benefits in MS is unknown but is thought to be similar to that of the other interferons. As such, peginterferon is thought to decrease inflammation and have neuroprotective effects. Approval of peginterferon beta-1a was based on the results of the ADVANCE clinical trial which compared peginterferon (125 mcg every 2 weeks or every 4 weeks) to placebo. The annualized relapse rate at 48 weeks was 0.256 for the peginterferon every 2 week group, 0.288 for the every 4 week group, and 0.397 for the placebo group. Additionally, peginterferon treatment was associated with statistically significant improvements in reducing disability progression and brain lesions. Peginterferon beta-1a is administered subcutaneously every 14 days. The recommended dose is 125 mcg every 14 days, with most patients titrated as follows; 63 mcg on day 1, then 94 mcg on day 15, and finally 125 mcg (full dose) on day 29. The most common side effects of treatment are injection site reactions (pain, redness, or itching), flu-like symptoms, fever, headache, muscle pain, chills, joint pain, and weakness. Other reported side effects include liver disease, depression, seizures, allergic or anaphylactic reactions, decrease in blood counts, and worsening of heart disease. Peginterferon beta-1a is not recommended for use during pregnancy due to the potential risk of causing harm to the fetus. Peginterferon beta-1a was approved by the FDA in August 2014.
Tecfidera (dimethyl fumarate or DMF)
Tecfidera is an oral medication used to treat relapsing forms of MS. The exact mechanism by which dimethyl fumarate provides therapeutic benefits in MS is not known but is appears to have neuroprotective and anti-inflammatory properties. Evidence of clinical effectiveness of dimethyl fumarate treatment was provided in the “Efficacy and Safety Study of Oral Dimethyl Fumarate (BG-12) with Active Reference in Relapsing Remitting Multiple Sclerosis (CONFIRM)” study that showed that dimethyl fumarate decreased the annualized relapse rate by 44% at twice daily dosing and 51% at three times daily dosing. Similarly, in the “Determination of the Efficacy and Safety of Oral BG-12 in Relapsing-Remitting MS” study, dimethyl fumarate decreased the annualized relapse rate by 47% with 240 mg twice daily dosing and 52% with 240 mg three times daily dosing. Treatment with dimethyl fumarate is usually started with 120 mg orally twice a day for 7 days followed by 240 mg twice daily thereafter. Dimethyl fumarate is available in 120 mg and 240 mg delayed release capsules which should not be crushed, chewed, or broken. Capsules may be taken with or without food; however taking with food may decrease the incidence of flushing. The most common side effects of treatment are flushing, stomach pain, diarrhea, and nausea. These side effects usually decrease over the first month of treatment. Other reported side effects include itching, a drop in white blood cell counts, increase in liver enzymes, and loss of protein in the urine. Due to the potential risk of causing harm to the fetus, dimethyl fumarate should be avoided in pregnancy if possible. Dimethyl fumarate was approved by the FDA in March 2013.
Ampyra is used for improving walking in patients with MS. Benefits of dalfampridine in MS is demonstrated by an increase in walking speed. Although its mechanism of action in MS is not fully understood, dalfampridine is a potassium channel blocker. In animal studies, dalfampridine improved conduction of impulses in damaged nerves by blocking potassium channels. In clinical trials dalfampridine improved walking speed more than placebo. In one clinical study, 34.8% of dalfampridine treated patients experienced improved walking as compared with 8.3% of placebo recipients. In a separate study, 42.9% of dalfampridine recipients showed improved walking speed versus 9.3% for the placebo group. Dalfampridine is administered orally twice daily without regard to food. Dalfampridine is available in 10 mg tablets which must be swallowed whole. Patients with a history of seizures, or moderate or severe renal failure should not use dalfampridine. Common side effects of dalfampridine include urinary tract infection, insomnia (difficulty sleeping), dizziness, headache, nausea, constipation, back pain, balance disorder, MS relapse, nasopharyngitis, heartburn, weakness, throat pain and burning, and tingling or itchiness of skin. Dalfampridine has not been adequately evaluated in pregnancy and is classified as FDA pregnancy risk category C. Due to the lack of conclusive safety data, Dalfampridine should only be used during pregnancy if the potential benefit justifies the potential harm to the fetus. Dalfampridine was approved by the FDA for MS treatment in January 2010.
Prescribing Information for Avonex (interferon beta-1a); Betaseron (interferon beta-1b); Copaxone (glatiramer acetate); Rebif (interferon beta-1a); Novantrone (mitoxantrone); Tysabri (natalizumab); AMPYRA (dalfampridine); Aubagio (teriflunomide); Gilenya (fingolimod); Lemtrada (alemtuzumab), Plegridy (peginterferon beta-1a), Tecfidera (dimethyl fumarate); Extavia (interferon beta-1b)Litzinger MH, Litzinger M. Multiple Sclerosis: A therapeutic overview. US Pharmacist 2009;34(1):HS3-HS9
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Drug information for Avonex (interferon beta-1a); Betaseron (interferon beta-1b); Copaxone (glatiramer acetate); Rebif (interferon beta-1a); Novantrone (mitoxantrone); Tysabri (natalizumab); AMPYRA (dalfampridine); Aubagio (teriflunomide); Gilenya (fingolimod); Plegridy (peginterferon beta-1a); Tecfidera (dimethyl fumarate); Lemtrada (alemtuzumab), Ampyra (dalfampridine); Extavia (interferon beta-1b)
Lexicomp: Drug Information [online database]. Drug information for Avonex (interferon beta-1a); Betaseron (interferon beta-1b); Copaxone (glatiramer acetate); Rebif (interferon beta-1a); Novantrone (mitoxantrone); Tysabri (natalizumab); AMPYRA (dalfampridine); Aubagio (teriflunomide); Gilenya (fingolimod); Plegridy (peginterferon beta-1a); Tecfidera (dimethyl fumarate); Lemtrada (alemtuzumab); Extavia (interferon beta-1b)
DiPiro et al. Pharmacotherapy: A Pathophysiologic Approach, 9th edition. Chapter 39: Multiple Sclerosis. Access Pharmacy [online].
Joseph Carcione, DO
American board of Psychiatry and Neurology