Philadelphia Finance

Jan 31 2018

The different MS Drugs – a comparison

#ms #drugs #comparison


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X Contraindicated; benefit does not outweigh risk

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

Interferon beta-1b (Betaseron in US, Betaferon in Europe)

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.

8 million U SC qod (high-dose, high-frequency interferon)

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

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

Interferon beta-1a (Rebif)

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.

44 mcg/dose SC 3 times/wk (at least 48 h between each dose) (high-dose, high-frequency interferon)

C Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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.

Methylprednisolone (Solu-Medrol, Depo-Medrol)

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

C Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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.

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/m 2. 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

Cyclophosphamide (Cytoxan, Neosar)

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.

Induction phase: 600 mg/m 2 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/m 2 /mo, accompanied by Solu-Medrol 1000 mg IV
Total WBC nadir 1500/�L, decrease dose by 100-200 mg/m 2
Total WBC nadir 2200/�L, increase dose by 200 mg/m 2
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)


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