The different MS Drugs – a comparison

Drug Name	Interferon beta-1a (Avonex)
Description	Prescribed in USA as Avonex, administered by IM route (Biogen). Avonex is indicated for treatment of patients with relapsing forms of MS to slow the accumulation of physical disability and to decrease the frequency of clinical exacerbations. Patients with MS in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with MS. Safety and efficacy in patients with chronic progressive MS have not been established. Believed to act via ability to counteract cell surface expression of proinflammatory or pro-adhesion molecules on immune cells, among other effects. More studies needed to fully understand mechanisms of action. Differs from interferon beta-1b (Betaseron, see below) only in that it has amino acid sequence identical to that of natural compound and is glycosylated. Presence of glycosylation is claimed to lead to structural stability and presumably to higher biological potency. Interferons act through common receptor that activates Jak/Stat pathway of signal transduction molecules, which, in turn, leads to activation of interferon-responsive genes. Interferon beta may decrease expression of B7-1 (a proinflammatory molecule) on surface of immune cells and increase levels of TGF-beta (anti-inflammatory molecule) in circulation of patients with MS. Interferon beta-1a is the only ABCR drug administered on a weekly schedule. Frequency of development of neutralizing antibodies against interferon is higher with interferon beta-1b than with interferon beta-1a, but clinical significance of neutralizing antibodies still unclear and controversial. May delay progression of disease in patients that have only manifested one clinical attack but have MRI evidence of MS.
Adult Dose	30 mcg IM weekly
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; liver dysfunction; severe leukopenia; thrombocytopenia; lactation
Interactions	None reported
Pregnancy	X – Contraindicated; benefit does not outweigh risk
Precautions	Common adverse effect is flu-like reaction following administration, usually lasting minutes or hours; 88% of patients no longer experience this effect after second month of treatment Flu-like effects can be minimized by taking over-the-counter acetaminophen or anti-inflammatory drugs such as aspirin or ibuprofen a few hours prior to and a few hours after injection; besides flu-like illness, patients may experience injection-site skin reactions which may range from mild (slight erythema) to severe (skin necrosis). Adverse effects may include hepatotoxicity (liver enzyme elevation) and myelosuppression (leukopenia); caution in preexisting seizure disorder; cases of exacerbation of thyroid dysfunction have been described-caution when using in patients with uncontrolled thyroid dysfunction; interferons are abortifacients; data on human teratogenicity are limited; extreme caution in patients with severe depression

Drug Name	Interferon beta-1b (Betaseron in US, Betaferon in Europe)
Description	Indicated for treatment of relapsing forms of MS to reduce the frequency of clinical exacerbations (Europe indications include treatment of secondary progressive MS with active disease). Acts via ability to counteract cell surface expression of proinflammatory or pro-adhesion molecules on immune cells, among other effects. More studies needed to fully understand mechanisms of action. May decrease expression of B7-1 (proinflammatory molecule) on surface of immune cells and increase levels of TGF-beta (anti-inflammatory) in circulation of patients with MS. Acts through common receptor that activates Jak/Stat pathway of signal transduction molecules, which, in turn, leads to activation of interferon-responsive genes. Frequency of development of neutralizing antibodies against interferon is higher with interferon beta-1b than with interferon beta-1a, but interferon beta-1b nAbs disappear faster. The clinical significance of nAbs is still unclear and controversial.
Adult Dose	8 million U SC qod (high-dose, high-frequency interferon)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; liver dysfunction; severe leukopenia; thrombocytopenia; lactation
Interactions	None reported
Pregnancy	X – Contraindicated; benefit does not outweigh risk
Precautions	Has adverse effect profile similar to Avonex (ie, flu-like reaction following administration tends to disappear after 2 mo on drug); flu-like effects can be minimized by taking over-the-counter acetaminophen or anti-inflammatory drugs such as aspirin or ibuprofen a few hours prior to and a few hours after injection; besides flu-like illness, patients may experience injection-site skin reactions Adverse effects may include hepatotoxicity (liver enzyme elevation) and myelosuppression (leukopenia); cases of exacerbation of thyroid dysfunction have been described-caution when using in patients with uncontrolled thyroid dysfunction; interferons are abortifacients; data on human teratogenicity are limited; use with extreme caution in patients with severe depression

Drug Name	Glatiramer acetate (Copaxone)
Description	Mix of amino acids proposed to mimic myelin proteins when presented on surface of antigen-presenting cells. Copaxone is indicated for reduction of the frequency of relapses in patients with RRMS. In theory, lymphocytes reactive against CNS myelin would be diverted to bind to Copaxone in circulation, thus decreasing entry of immune cells across blood-brain barrier. Most mechanisms of action, however, remain unknown, and wider effect on immune system responsiveness may be at play. Has safest side effect profile of ABCRs.
Adult Dose	20 mg SC qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; pregnancy and lactation
Interactions	None reported
Pregnancy	B – Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Common adverse effects are sensation of chest tightness or flushing following administration; no evidence of heart arrhythmias, angina, or pleuritic involvement Other adverse effects include palpitations, shortness of breath, hypertonia, sweating, diarrhea, insomnia, nausea, injection-site skin reactions, and lipoatrophic lesions

Drug Name	Interferon beta-1a (Rebif)
Description	Indicated for treatment of relapsing forms of MS to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability. Believed to act via ability to counteract cell surface expression of proinflammatory or pro-adhesion molecules on immune cells, among other effects. More studies needed to fully understand mechanisms of action. Differs from interferon beta-1b (Betaseron, see above) only in that it has amino acid sequence identical to that of natural compound and is glycosylated. Presence of glycosylation is claimed to lead to structural stability and presumably to higher biological potency. Interferons act through common receptor that activates Jak/Stat pathway of signal transduction molecules, which, in turn, leads to activation of interferon-responsive genes. Interferon beta may decrease expression of B7-1 (a proinflammatory molecule) on surface of immune cells and increase levels of TGF-beta (anti-inflammatory) in circulation of patients with MS. Frequency of development of neutralizing antibodies against interferon is higher with interferon beta-1b than with interferon beta-1a, but clinical significance still unclear and controversial. For instance, neutralizing antibodies in patients taking interferon beta-1b disappear faster than those in patients taking interferon beta-1a. May delay progression of disease in patients that have only manifested one clinical attack but have MRI evidence of MS.
Adult Dose	44 mcg/dose SC 3 times/wk (at least 48 h between each dose) (high-dose, high-frequency interferon)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; liver dysfunction; severe leukopenia; thrombocytopenia; lactation
Interactions	None reported
Pregnancy	C – Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Common adverse effect is flu-like reaction following administration, usually lasting minutes or hours; 88% of patients no longer experience this effect after second mo of treatment Flu-like effects can be minimized by taking over-the-counter acetaminophen or anti-inflammatory drugs such as aspirin or ibuprofen a few hours prior to and a few hours after injection; besides flu-like illness, patients may experience injection-site skin reactions, which may range from mild (slight erythema or stinging sensations) to severe (skin necrosis) Adverse effects may include hepatotoxicity (liver enzyme elevation) and myelosuppression (leukopenia); caution in preexisting seizure disorder; cases of exacerbation of thyroid dysfunction have been described-caution when using in patients with uncontrolled thyroid dysfunction; interferons are abortifacients; data on teratogenicity are limited; extreme caution in patients with severe depression

Drug Name	Natalizumab (Tysabri)
Description	Three cases of progressive multifocal leukoencephalopathy (PML) associated with natalizumab use prompted temporary withdrawal from the market in 2005. Natalizumab was later reapproved in 2006 by the FDA for commercialization under a special restricted distribution program known as TOUCH. The drug now carries a package insert black box warning about potential risks of opportunistic infections. Patients, physicians, and pharmacists must be involved in the TOUCH program in order to receive, prescribe, or dispense (respectively) natalizumab. Indicated as monotherapy for MS, not to be used with other immune system-modifying drugs. Because of risks of PML, natalizumab is now generally recommended for patients who have had an inadequate response to, or are unable to tolerate alternate MS therapies. Recombinant humanized IgG4-1C monoclonal antibody produced in murine myeloma cells. Binds to alpha-4 subunits of alpha-4-beta-1 and alpha-4-beta-7 integrins expressed on leukocyte surface, which inhibits alpha-4-mediated leukocyte adhesion to their receptors. Clinical effect in MS may be secondary to blocking interaction of alpha-4-beta-1 expressed by inflammatory cells with VCAM-1 on vascular endothelial cells and with CS-1 and/or osteopontin expressed by parenchymal brain cells. Indicated for relapsing MS and to reduce symptom exacerbation frequency.
Adult Dose	300 mg IV q4wk; dilute in 100 mL 0.9% NaCl and infuse over 1 h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, current infections, concomitant use of immunosuppressors
Interactions	Interferon beta-1a decreases clearance by 30%
Pregnancy	C – Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Uncommon serious adverse effects include infections (eg, PML, pneumonia), hypersensitivity reactions, severe depression, and gallstones; common adverse effects include mild infections (eg, UTI, lower respiratory tract, GI, vaginal), headache, mild depression, joint pain, and menstrual disorders; excreted in breast milk; infusion-related adverse effects include urticaria, pruritus, and rigors (discontinue infusion and treat accordingly); can only be prescribed under the TOUCH program; clinically significant hepatotoxicity has been reported during postmarketing surveillance, monitor transaminase serum levels and bilirubin (discontinue if elevated or jaundice emerges)

Drug Category: Corticosteroids

These agents reduce acute inflammation and expedite recovery from acute exacerbations of MS. They may be used for “rescue” therapy as monthly boosters in patients who respond poorly to the ABC immunomodulators. Methylprednisolone, a glucocorticoid, has greater anti-inflammatory potency than prednisolone and even less tendency to induce water and sodium retention.

Drug Name	Methylprednisolone (Solu-Medrol, Depo-Medrol)
Description	For treatment of inflammatory and autoimmune reactions. By reversing increased capillary permeability and suppressing PMN activity, may decrease inflammation. Also may alter expression of some proinflammatory cytokines.
Adult Dose	500-1000 mg IV (mix in 150-200 mL isotonic saline or D5 isotonic saline) infused over 1-2 h for 3-5 d without prednisone taper
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; systemic fungal infections; severe bone density loss; hip osteonecrosis; cataracts; psychosis
Interactions	Cyclosporine may induce seizures; phenytoin, phenobarbital, or rifampin may reduce levels because of their hepatic enzyme-inducing effects; ketoconazole may increase levels; may decrease levels of salicylates; may increase or decrease levels of anticoagulants; may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; monitor patients for hypokalemia when taking with diuretics
Pregnancy	C – Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution or discontinue in patients with early evidence of cataracts, bone density loss, hyperglycemia, psychosis, euphoria, emotional irritability, adrenal dysfunction, fluid retention, arrhythmias, or anaphylactoid reactions; monitor for decreased bone density in prolonged treatment; steroid-induced myopathy can occur, especially in underlying neuromuscular transmission disorders

Drug Category: Immunosuppressors

These agents are used for their ability to suppress immune reactions.

Drug Name	Mitoxantrone (Novantrone)
Description	Anthracenedione compound used for SPMS and RPMS. Induces DNA cross-links and strand breaks and leads to apoptosis. Mitoxantrone also interferes with RNA and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. Indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting MS (ie, patients whose neurologic status is significantly abnormal between relapses). Not indicated in the treatment of patients with primary progressive MS.
Adult Dose	5 mg/m2 and 12 mg/m2 IV every 3 mo (clinical trial)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; heart disease; severe infections
Interactions	None reported
Pregnancy	D – Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Because of risk of severe myelosuppression and heart dysfunction, only clinicians experienced in chemotherapy should administer this medication High risk of leading to long-term myocardial dysfunction; perform baseline and follow-up cardiac function tests (2D-echocardiography and ejection fraction measurements); increased risk of cardiotoxicity commonly seen after cumulative dose of 120-160 mg/m2, as observed in oncology studies; hair thinning, alopecia, and nausea usually mild but common; may cause menstrual disorders or infertility; GI bleeding and mucositis/stomatitis may occur; increases chances of infections

Drug Name	Cyclophosphamide (Cytoxan, Neosar)
Description	Metabolized in liver by mixed-function microsomal oxidase system. Mechanism of action believed to involve DNA cross-linking. Has been used off-label for secondary progressive MS, especially for patients with dramatic, rapid progression. Thought to be more effective if given in early stage of progression.
Adult Dose	Induction phase: 600 mg/m2 IV qod for 5 d initial dose, accompanied by Solu-Medrol 1 g IV qd for 8 d Monthly booster doses: adjust dose on basis of WBC counts on days 8, 11, and 14 after previous dose (to establish nadir) and WBC count before treatment; use following recommendations: Total WBC nadir 1500-2000/�L: 1-day booster dose of 800 mg/m2/mo, accompanied by Solu-Medrol 1000 mg IV Total WBC nadir <1500/�L, decrease dose by 100-200 mg/m2 Total WBC nadir >2200/�L, increase dose by 200 mg/m2 Total WBC count before cyclophosphamide dose should be >4000/�L If 3000-4000/�L, 75% of dose If 2000-3000/�L, 50% of dose If <2000/�L, booster not given and WBC count checked in 1 wk (Boosters should be given 1 day per mo for 12 mo, at which time effects of therapy should be reevaluated; if therapy working, give booster q6wk for another year, and then q2mo for a third year; authors do not advise administering cyclophosphamide for more than 3 consecutive years)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; profound myelosuppression; active infections; hair thinning; alopecia; severe leukopenia; liver function abnormalities
Interactions	Long-term phenobarbital may increase metabolism of cyclophosphamide and ability to induce leukopenia; inhibits cholinesterases and thus potentiates effect of succinylcholine chloride
Pregnancy	D – Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Causes infertility; increased risks of bladder hemorrhage or cancer or other secondary malignancies; increased risk of opportunistic infections; patients should be hydrated adequately while receiving cyclophosphamide

Drug Name	Azathioprine (Imuran)
Description	This immunosuppressive antimetabolite drug is an imidazolyl derivative of 6-mercaptopurine. Cleaved in vivo to mercaptopurine and converted to 6-thiouric acid by xanthine oxidase. Generally used in treatment of transplant rejection or severe, active, erosive rheumatoid arthritis. Has been used off-label for MS.
Adult Dose	1 mg/kg (50-100 mg)/d PO given bid or single-dose schedule Dose can be increased gradually (0.5 mg/kg increments); not to exceed 2.5 mg/kg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; pregnancy; previous treatment with alkylating agents such as chlorambucil, melphalan, or cyclophosphamide owing to possible increased risk of neoplasia
Interactions	ACE inhibitors may induce anemia or leukopenia; may inhibit anticoagulant action of warfarin; allopurinol inhibits drug’s detoxification pathway, thus reduce to one third to one quarter usual dose if used with allopurinol
Pregnancy	D – Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Patients with serious hematologic or hepatic disorders should not use this medication; causes leukopenia or thrombocytopenia, nausea, vomiting, or diarrhea; <1% of patients may develop hepatotoxicity; instruct patients to contact their physician if they develop fever or any other evidence of infection

Drug Name	Methotrexate (Rheumatrex)
Description	Immunosuppressive metabolite drug used for some neoplasias (including leukemia), psoriasis, and rheumatoid arthritis. Interferes with DNA synthesis, repair, and cellular replication. Inhibits dihydrofolic acid reductase, which participates in synthesis of thymidylate and purine nucleotides. Has been used off-label for MS.
Adult Dose	7.5-15 mg PO qwk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Chloramphenicol interferes with intestinal absorption; NSAIDs and phenytoin elevate levels; probenecid impairs renal tubular transport of methotrexate
Pregnancy	D – Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Use caution in patients with history of alcohol abuse, liver dysfunction, or renal dysfunction; may cause neurotoxicity (leukoencephalopathy), renal or liver damage, pulmonary fibrosis or pneumonitis (fully reversible), diarrhea, ulcerative stomatitis, hemorrhagic enteritis, seizures, anemia, leukopenia, or thrombocytopenia; may cause alopecia and photosensitivity, but these rarely occur at doses used for treating MS

Drug Category: Antiviral, anti-Parkinson agent

This agent is used for treatment of fatigue in MS.

Drug Name	Amantadine hydrochloride (Symmetrel)
Description	Mechanism of counteracting fatigue unclear. May have antiviral effects by inhibiting replication of some viruses, including influenza A.
Adult Dose	100 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Either triamterene or hydrochlorothiazide (or both) may increase plasma levels; thioridazine may worsen tremor in elderly patients with Parkinson disease
Pregnancy	C – Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Patients with history of seizure should be observed carefully for signs of seizure recurrence; because of its anticholinergic effects, use caution by prescribing limited quantities to patients at risk of overdosing; may induce suicidal ideation in some patients, or may exacerbate existing mental disorders; use with caution in patients taking CNS stimulants; acute withdrawal should be avoided in patients with Parkinson disease, as acute parkinsonian crisis may ensue; because excreted in urine, reduce dose in patients with renal insufficiency or who are aged 65 years or older

Drug Category: Central nervous system stimulants

These agents are used for treatment of fatigue without interfering with normal sleep architecture. They promote wakefulness.

Drug Name	Modafinil (Provigil)
Description	Mechanism of action currently unknown. Listed in Schedule IV of the Controlled Substances Act. Patients should be observed for signs of use or abuse, as drug has psychoactive and euphoric effects similar to those seen with other scheduled CNS stimulants (eg, methylphenidate).
Adult Dose	100-200 mg PO qd; some patients may require as much as 300 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; history of left ventricular hypertrophy, ischemic ECG changes, chest pain, or arrhythmias as response to CNS stimulants
Interactions	Reversible inhibitor of drug-metabolizing enzyme CYP2C19, and therefore must be used with caution with other drugs metabolized by this enzyme, including diazepam, phenytoin, and propranolol; in individuals deficient in CYP2D6 (7-10% of Caucasian population), levels of CYP2D6 substrate drugs such as SSRIs and TCAs may be elevated, as these individuals may use CYP2C19 as ancillary elimination pathway Effectiveness of oral contraceptives may be reduced during treatment and for 1 mo after discontinuing medication; methylphenidate may delay absorption; may increase levels of clomipramine; levels potentially can be altered by drugs such as carbamazepine, phenobarbital, rifampin, ketoconazole, or itraconazole; may decrease levels of cyclosporine; patients receiving CYPC29 substrates phenytoin or warfarin with modafinil should be monitored for signs of toxicity
Pregnancy	C – Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Dose should be reduced in patients with severe hepatic impairment; most common adverse effects are headache and anxiety, but both occur in <17% of patients; less common adverse effects are irritability, restless legs syndrome, epigastric discomfort, dizziness, infection, insomnia, and nausea; patients may be advised not to operate hazardous machinery or drive an automobile until reasonably clear that drug does not place them at risk because, in some patients, drug may affect judgment, motor skills, or thinking; used with caution in patients with recent myocardial infarction, unstable angina, or history of psychosis