Drugs for inflammatory bowel disease

Extended-and delayed-release mesalamine formulations with pH-sensitive coatings Asacol, Asacol HD, Lialda, Aminosalicylates Mesalamine – delayed- or extended-release maintenance of remi

Treatment Guidelines

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Drugs for Inflammatory Bowel Disease

Tables

Treatment Guidelines

Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication

Volume 10 (Issue 115) March 2012

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Inflammatory bowel disease (IBD) is generally

classi-fied as either Crohn’s disease (CD) or ulcerative

colitis (UC) More detailed guidelines on their

treat-ment are available from the American College of

Gastroenterology.1,2

AMINOSALICYLATES

The active moiety of all the aminosalicylates used to

treat IBD is 5-aminosalicylate (5-ASA), also called

mesalamine

MECHANISM OF ACTION — 5-ASA has

anti-inflammatory, antimicrobial and antioxidant effects

The anti-inflammatory effect is probably due to

inhibition of leukotriene production and reduction in

interleukin-1 (IL-1) and tumor necrosis factor alpha

(TNF-) signaling 5-ASA also activates a colonocyte differentiation factor and has other antiproliferative effects, which may protect against colorectal cancer.3

FORMULATIONS — Oral mesalamine is absorbed

in the small intestine and does not reach the colon

Pentasa is an ethylcellulose-coated formulation that

releases mesalamine gradually throughout the

gas-trointestinal tract Asacol and Asacol HD tablets are

coated with a pH-sensitive film that dissolves at the higher pH of the terminal ileum and proximal colon,

releasing the drug Lialda and Apriso both delay the

release of the drug until it reaches the distal ileum and colon.4,5 Sulfasalazine (Azulfidine, and others), bal-salazide (Colazal, and others) and olsalazine (Dipentum) are prodrugs; mesalamine is azo-bonded

to a second moiety and released in the colon following bacterial cleavage of the bond Mesalamine is also

available as an enema (Rowasa, and others) and as a rectal suppository (Canasa).

EFFICACY — In clinical trials, use of

aminosalicy-lates generally achieved remission in about 35-50% of patients with mild or moderate UC and maintained the remission for 6 months or more in about 55-75% of patients In distal UC and proctitis, mesalamine sup-positories or enemas may be more effective than oral formulations both at inducing and maintaining remis-sion Combination therapy with oral and rectal mesalamine has been reported to be more effective than either alone.6

In CD, aminosalicylates are only modestly more effec-tive than placebo in inducing remission, and those that are released in the colon are ineffective for CD of the small intestine Data are insufficient to support use of these drugs for maintenance of remission in CD.7

ADVERSE EFFECTS — The most common adverse

effects of mesalamine have been nausea, vomiting,

RECOMMENDATIONS

Ulcerative Colitis – An aminosalicylate is generally

used first for treatment and maintenance of

remis-sion Mercaptopurine or azathioprine is often used in

patients with moderate to severe disease Prednisone

can be used to treat severe relapses Patients with

treatment-refractory disease may respond to a TNF

inhibitor, such as infliximab

Crohn’s Disease – Prednisone can be used to

induce remission Azathioprine or mercaptopurine

is often used for maintenance of remission

Moderate to severe Crohn’s disease that has not

responded to other drugs may respond to a TNF

inhibitor, such as infliximab Some clinicians would

use a TNF inhibitor alone or in combination with

azathioprine for initial treatment of moderate to

severe disease Metronidazole or ciprofloxacin may

be helpful in some patients Methotrexate is an

alternative for patients with steroid-resistant or

steroid-dependent disease

For further information call: 800-211-2769

diarrhea, headache and abdominal pain

Nephrotox-icity can occur Pancreatitis, hepatotoxNephrotox-icity and a

lupus-like syndrome have been reported

DRUG INTERACTIONS — Mesalamine inhibits

thiopurine methyltransferase in vitro and may interfere

with the metabolism of azathioprine and mercaptopurine, which might increase their toxicity, but seldom does except in patients with an inherited deficiency of thiopurine methytransferase Extended-and delayed-release mesalamine formulations with

pH-sensitive coatings (Asacol, Asacol HD, Lialda,

Aminosalicylates

Mesalamine –

delayed- or extended-release

maintenance of remission Asacol HD (Warner Chilcott) 800 mg delayed-release tabs Treatment of moderate UC C

maintenance of remission

Mesalamine – prodrugs

Colazal (Salix)

Azulfidine En-tabs (Pfizer)

Mesalamine – rectal

SF Rowasa (Meda)

Antibiotics

Flagyl (GD Searle)

Cipro (Bayer)

Xifaxin (Salix)

Corticosteroids

Budesonide –

colon; maintenance of remission for up to

3 months Hydrocortisone –

left-sided UC

the distal portion of the rectum in patients who cannot retain hydrocortisone or other corticosteroid enemas

IBD = inflammatory bowel disease; UC = ulcerative colitis; CD = Crohn’s disease

1 FDA Pregnancy Categories: A = controlled studies show no risk; B = no evidence of risk; C = risk cannot be ruled out; D = positive evidence of risk;

X = contraindicated in pregnancy

2 Not officially categorized

Table 1 Drugs for Inflammatory Bowel Disease

Apriso) should not be co-administered with antacids,

which might cause premature dissolution of the

coat-ing Theoretically, a similar interaction could occur

with proton-pump inhibitors (PPIs), such as

omepra-zole (Prilosec, and others), or with H2-receptor

antag-onists, such as ranitidine (Zantac, and others).

ANTIBIOTICS

Many experts believe that alterations in the balance of enteric bacteria play a role in the development of IBD and that antibiotic treatment can be helpful,

particular-ly in CD Metronidazole is active against anaerobic

Immunosuppressants

Purinethol (Teva)

ampule

TNF Inhibitors

Adalimumab

have had an inadequate response to con-ventional therapy or have lost response to,

or cannot tolerate, infliximab Certolizumab pegol

CD who have had an inadequate response

to conventional therapy Infliximab

in adults and children with moderate to se-vere CD who have had an inadequate response to conventional therapy; treatment

of fistulas; treatment and maintenance of re-mission in adults and children with moderate

to severe UC who have had an inadequate response to conventional therapy

Integrin Receptor Antagonist

Natalizumab

in adults with moderate to severe CD who have had an inadequate response to,

or are unable to tolerate, conventional therapy and TNF inhibitors.

Probiotics 3

CFU = colony forming units

3 Some available probiotic products.

4 VSL #3 and VSL#3-DS contain lyophilized Bifidobacterium breve, B longum, B infantis, Lactobacillus acidophilus, L plantarum, L paracasei, L bul-garicus and Streptococcus thermophilus.

5 Culturelle contains Lactobacillus GG.

6 Florastor contains Saccharomyces boulardii lyo.

7 Align contains Bifidobacterium infantis 35624.

Table 1 Drugs for Inflammatory Bowel Disease (continued)

bacteria, such as Bacteroides fragilis Ciprofloxacin is

active against both gram-positive and gram-negative

bacteria Rifaximin is a minimally-absorbed antibiotic

(less than 0.4% oral bioavailability) with activity

against enteric gram-positive and gram-negative

organisms These agents are used, sometimes together,

to treat CD colitis and ileocolitis, microperforations

and fistulas, and to treat pouchitis in UC Although

data are limited, they are also used following

resec-tions to prevent recurrence of CD

EFFICACY — A meta-analysis indicated that

antibi-otics are more effective than placebo in inducing

remission in active CD, particularly in fistulizing

disease.8 The evidence that they are effective in

maintaining remission in CD is limited The use of

antibiotics is not recommended in UC, except for

pou-chitis, in which both ciprofloxacin and metronidazole

appear to be effective

ADVERSE EFFECTS — Metronidazole can cause

abdominal discomfort, metallic taste, nausea,

vomit-ing, diarrhea, loss of appetite, ataxia and peripheral

neuropathy Ciprofloxacin can cause nausea,

vomit-ing, diarrhea, abdominal discomfort, headache,

dizziness, QTc prolongation, altered mental status and

lowering of the seizure threshold It has been

associat-ed with an increasassociat-ed risk of developing Clostridium

difficile infection The FDA has issued a black-box

warning regarding the association between

ciprofloxacin and spontaneous tendon rupture

Rifaximin is minimally absorbed, and has an

inci-dence of adverse effects similar to that with placebo

DRUG INTERACTIONS — Taken with alcohol,

metronidazole can cause a disulfiram-like reaction

(flushing, headache, nausea, vomiting, abdominal

cramping) It is a moderate CYP2C9 inhibitor and may

increase serum concentrations of CYP2C9 substrates

such as warfarin (Coumadin, and others).

Ciprofloxacin is a moderate inhibitor of CYP1A2

and may increase serum concentrations of CYP1A2

substrates such as tizanidine (Zanaflex) Antacids and

products containing iron, calcium or magnesium may

prevent full absorption of ciprofloxacin and should

not be taken within 2 hours before or 6 hours after

taking the drug Taking ciprofloxacin with other

drugs that prolong the QT interval may have an

addi-tive effect

In vitro studies show that rifaximin does not inhibit

cytochrome P450 enzymes; it might induce CYP3A4,

but it is minimally absorbed and does not appear to

cause clinically significant interactions with drugs

metabolized by CYP3A4, including oral contraceptives

CORTICOSTEROIDS

Corticosteroids are often effective in both UC and CD

in inducing remission in persistent disease Because of their severe adverse effects, they are used systemically only until acute inflammation is under control, and then are tapered and discontinued

EFFICACY — Not all patients with IBD respond to

systemic corticosteroids In one retrospective study, among 146 patients who required treatment with cor-ticosteroids, 51% of patients with UC and 40% of those with CD had a complete response at 30 days, while 31% and 35% had a partial response.9 Most patients who respond to corticosteroids relapse within

a year if not given maintenance therapy Systemic cor-ticosteroids are ineffective for maintenance treatment

of CD.10

ADVERSE EFFECTS — Corticosteroids can cause

hypertension, fluid retention, increased risk of infec-tion, osteoporosis, cataracts, impaired skin healing, insomnia, mood disorder, glaucoma, Cushing’s syn-drome, hyperglycemia and hypothalamic-pituitary-adrenal (HPA) suppression

RECTAL CORTICOSTEROIDS — Rectally

instilled corticosteroids are effective in the treatment

of distal UC Enemas can reach the splenic flexure, while foam coats only the last 15-20 cm of the colon Hydrocortisone is available in the US as a

100 mg enema or a 10% foam Budesonide enemas are also effective; they are available in Canada, but not in the US

BUDESONIDE — A synthetic corticosteroid with a

strong affinity for glucocorticoid receptors, budes-onide is used orally in a dosage of 9 mg/day to treat mild to moderate active CD of the ileum and/or ascending colon.1,11 Because of extensive first-pass metabolism, budesonide has a high ratio of local anti-inflammatory to systemic effects It is somewhat less effective than conventional oral corticosteroids in inducing remission, and while approved for mainte-nance at 6 mg/day, it does not appear to be effective at preventing relapse beyond 6 months of use.1

Adverse Effects – Budesonide causes less short-term

toxicity than prednisone Whether it is safer in the long term is not clear; its greater affinity for receptors might outweigh its limited systemic availability

Drug Interactions – Budesonide is a CYP3A4

sub-strate and should be used with caution in combination with agents that induce CYP3A4, such as rifamycin derivatives, or inhibit it, such as grapefruit juice or

ketoconazole (Nizoral, and others) Drugs that change

the pH of the gastrointestinal tract (antacids, PPIs,

H2-receptor antagonists) may affect the release and

absorption of budesonide

IMMUNOMODULATORY AGENTS

AZATHIOPRINE AND MERCAPTOPURINE —

Azathioprine (Imuran, and others) and

mercaptop-urine (6-MP; Pmercaptop-urinethol, and others), which is the

active metabolite of azathioprine, are both effective

in maintaining remission in both UC and CD They

are also used to decrease formation of antibodies to

TNF inhibitors, prevent CD recurrence following

sur-gical resection of diseased bowel and to assist with

steroid tapering in corticosteroid-dependent disease

These agents can take 3-6 months to achieve their

maximal effect; they are primarily used for long-term

therapy and not for immediate suppression of active

inflammation

Mechanism of Action – Both azathioprine and

mercaptopurine inhibit purine synthesis; they have

anti-proliferative effects and induce apoptosis in T-cells

Efficacy – In a 30-year review of experience with

aza-thioprine in 622 patients with active IBD, overall remission rates were 45% for CD and 58% for UC Patients treated for more than 6 months had remission rates of 64% and 87%, respectively With continued maintenance treatment, the percentages of IBD patients remaining in remission were 95% after 1 year, 69% after 2 years and 55% after 3 years When the drug was stopped, the percentages of patients remain-ing in remission at 1, 3 and 5 years were 63%, 44% and 35%, respectively.12

In patients with moderate to severe CD not previously exposed to immunosuppressive or biologic therapy,

the combination of azathioprine plus infliximab was

more effective in maintaining steroid-free remission than either drug alone; after 26 weeks of therapy, 56.8% of patients receiving combination therapy were

in steroid-free remission, compared to 44.4% of patients receiving infliximab alone and 30% of those receiving azathioprine alone.13

Adverse Effects – Azathioprine and mercaptopurine

can cause myelosuppression, nausea, vomiting,

Crohn’s Disease

Mild to Moderate:

Rifaximin 800 mg PO bid

Moderate to Severe:

Methotrexate 25 mg IM once/wk Natalizumab 300 mg IV q4 weeks

weeks Methotrexate 15-25 mg IM once/wk Natalizumab 300 mg IV q4 weeks

Perianal and Fistulizing Disease

± Ciprofloxacin 500 mg PO bid Infliximab 5-10 mg/kg IV (weeks 0,

2 and 6)

Mercaptopurine 1.5 mg/kg PO once/d Infliximab 5-10 mg/kg IV q8 weeks

Table 2 Drugs for Crohn’s Disease

diarrhea, hepatotoxicity, rash, Raynaud’s disease,

pul-monary edema, pancreatitis and a hypersensitivity

reaction Long-term use of azathioprine and

mercap-topurine has been associated with a small increase in

the risk of non-melanoma skin cancer and

lym-phoma.14,15 Cases of hepatosplenic T-cell lymphoma

have been reported in patients taking azathioprine or

mercaptoprine either alone or in combination with

TNF inhibitors.16,17

Drug Interactions – Azathioprine and

mercapto-purine may decrease the anticoagulant effect of warfarin; the mechanism is not known Allopurinol

(Zyloprim, and others) and febuxostat (Uloric) inhibit

the metabolism of azathioprine and mercaptopurine

by xanthine oxidase and can cause bone marrow depression with pancytopenia; the dose of azathioprine or mercaptopurine should be reduced if allopurinol is used concurrently, and concomitant use

Ulcerative Colitis

Mild to Moderate:

2 divided doses Mesalamine rectally Canasa 500 mg bid or

1000 mg once/d Rowasa 4 grams once/d Hydrocortisone rectally Colocort 1 enema nightly Cortifoam 1 application once/d or bid

Mesalamine rectally Canasa 500 mg 1-2 x/d Rowasa 2-4 grams once/d

Severe:

Sulfasalazine 1 gram PO qid

Mercaptopurine 1.5 mg/kg PO once/d Infliximab 5 mg/kg IV q8 weeks

Pouchitis

1000 mg once/d Rowasa 4 grams once/d x 3-6 weeks

Infliximab 5mg/kg IV (weeks 0, 2 and 6)

1 More data are needed to determine optimal dosing and duration of treatment.

Table 3 Drugs for Ulcerative Colitis

of febuxostat is contraindicated Mesalamine inhibits

thiopurine methyltransferase and may decrease the

metabolism of azathioprine and mercaptopurine,

which theoretically could also increase their

myelo-toxicity, but seldom does except in patients with an

inherited deficiency of thiopurine methyltransferase

Severe leukopenia has been reported during

concomi-tant therapy with angiotensin-converting enzyme

(ACE) inhibitors or trimethoprim/sulfamethoxazole

(Bactrim, and others).

METHOTREXATE — Methotrexate is used to treat

moderate to severe dependent and

steroid-resistant CD The mechanism of its effectiveness is

unclear, but it blocks the action of dihydrofolate

reduc-tase, inhibits DNA synthesis and causes cell death

When used in combination with a TNF inhibitor, it

decreased formation of antibodies to the inhibitor.18

Methotrexate has not been shown to be effective in UC

Efficacy – In one study in patients with active CD

despite >3 months’ treatment with prednisone, 37 of 94

patients (40%) treated with intramuscular (IM)

methotrexate 25 mg weekly were in clinical remission

after 16 weeks.19Among 40 responders to

methotrex-ate induction who received maintenance treatment

with methotrexate 15 mg IM weekly, 26 (65%) were

still in remission 40 weeks later.20

Adverse Effects – Methotrexate can cause alopecia,

stomatitis, rash, diarrhea, gastrointestinal hemorrhage,

hepatotoxicity, renal failure, interstitial pneumonia,

liver failure, toxic epidermic necrolysis,

Stevens-Johnson syndrome, hypotension, blurred vision,

headache, nephropathy and hyperuricemia

Drug Interactions – Trimethoprim/sulfamethoxazole,

trimethoprim and other drugs that interfere with folate

metabolism may increase bone marrow suppression

caused by methotrexate Drugs that diminish renal

function, particularly NSAIDs, may raise serum

con-centrations of methotrexate and increase its toxicity

CYCLOSPORINE — The calcineurin inhibitor

cyclo-sporine (Sandimmune, and others) is given IV to treat

patients with severe steroid-resistant UC who are

candi-dates for proctocolectomy Its mechanism of action is

thought to be interference with lymphocyte activation

Use of cyclosporine in CD has been limited

Efficacy – In one study, 9 of 11 patients (82%) with

severe refractory UC treated with cyclosporine

improved within a mean of 7 days and avoided

imme-diate surgery.21

Adverse Effects – Cyclosporine can cause diarrhea,

nausea, vomiting, infection, gingival hyperplasia,

prur-itus, headache, seizures, tremors, visual disturbances,

hypertension, hepatotoxicity, nephrotoxicity, paresthe-sias and anaphylaxis

Drug Interactions – Nephrotoxic effects may be

addi-tive when cyclosporine is used in conjunction with nephrotoxic drugs such as aminoglycoside antibiotics Hyperkalemia may develop in the presence of potassium-sparing diuretics such as spironolactone

(Aldactone, and others) Cyclosporine is both a

sub-strate and inhibitor of CYP3A4 and P-glycoprotein; CYP3A4 inhibitors such as ketoconazole may increase its toxicity

TACROLIMUS — Tacrolimus (Prograf, and others),

another calcineurin inhibitor, has been used as an alter-native to cyclosporine to treat patients with refractory

UC.22 Its mechanism of action may involve interfer-ence with lymphocyte activation Data are limited on its use in CD.1

Efficacy – In one study in patients with moderate to

severe refractory UC, improvement occurred within 2 weeks in 68% (13/19) of those treated with oral tacrolimus and in 10% (2/20) of placebo-treated patients.23

Adverse Effects – Tacrolimus can cause tremors, renal

dysfunction, gastrointestinal discomfort, headache, infection, hypomagnesemia, hypertension, insomnia and seizures It has also been associated with an increased risk of lymphoma

Drug Interactions – Additive nephrotoxicity may

occur if tacrolimus is used in combination with other nephrotoxic drugs such as aminoglycosides Tacrolimus is a substrate of CYP3A4 and P-glycopro-tein; CYP3A4 inhibitors such as ketoconazole may increase its toxicity

TNF INHIBITORS

Three tumor necrosis factor (TNF) inhibitors — inflix-imab, adalimumab and certolizumab pegol — are used for treatment of moderate to severe CD Infliximab is also approved by the FDA for treatment of moderate to severe UC not responsive to conventional therapies

MECHANISM OF ACTION – Tumor necrosis factor

alpha (TNF-) is a pro-inflammatory cytokine Infliximab is a human/murine chimeric monoclonal antibody that binds to membrane-bound and soluble TNF- Adalimumab is a genetically engineered human IgG1 monoclonal antibody that binds to

TNF- Certolizumab pegol is a PEGylated Fab’ fragment

of a humanized TNF- antibody.24 Antibodies and antibody fragments that bind TNF- block the inflam-matory cascade.25

EFFICACY — Crohn’s Disease – Infliximab has been

effective in the treatment of moderate to severe CD that

had not responded to other drugs, including systemic

corticosteroids.26In one study, a single 5 mg/kg dose of

the drug produced a clinical response in 22 of 27 patients

(81%) with refractory moderate to severe CD.27In a

ran-domized trial among responders to infliximab who

con-tinued to receive 5 mg/kg of the drug, 44 of 113 (39%)

were in remission at 30 weeks, compared to 23 of 110

(21%) on placebo.28In patients with moderate to severe

CD not previously exposed to immunosuppressive or

biologic therapy, the combination of azathioprine plus

infliximab was more effective in maintaining

steroid-free remission than either drug alone; after 26 weeks of

therapy, 56.8% of patients receiving combination

ther-apy were in steroid-free remission, compared to 44.4%

of patients receiving infliximab alone and 30% of

patients receiving azathioprine alone.13

Infliximab is highly effective in fistulizing CD In one

study, among 94 patients with fistulizing disease, 3

doses of infliximab at weeks 0, 2 and 6 produced

clos-ure of all fistulas in 55% of patients, compared to 13%

with placebo.29In another trial, patients whose fistulas

responded to infliximab were then randomized to

infliximab or placebo given every 8 weeks; after 1

year, 19 of 98 placebo-treated patients (19%) and 33 of

91 infliximab-treated patients (36%) were free of

draining fistulas.30

Infliximab has been shown to reduce CD recurrence

after ileocolonic resection; after 1 year, 1 of 11 patients

(9.1%) treated with infliximab had endoscopic

recur-rence, compared to 11 of 13 patients (84.6%) treated

with placebo.31

The rates of response and remission in CD with other

TNF inhibitors appear to be comparable to those with

infliximab In one study (CHARM), a response to

induc-tion with adalimumab occurred in 499 of 854 patients

(58%) Among responders who received adalimumab

every other week for maintenance, 62 of 172 (36%) of

the patients were still in remission after 12 months.32

In a study with certolizumab pegol (PRECISE 2),

428 of 668 patients (64%) responded to induction, and

after maintenance treatment for 26 weeks, 103 of 215

(48%) of the responders were still in remission.33

Head-to-head comparisons of these agents are

lack-ing.34 Adalimumab has been effective in some patients

who had become refractory to infliximab.35

Certolizumab pegol has also been effective in some

patients who had become refractory or intolerant to

infliximab.36 The TNF inhibitor etanercept (Enbrel),

which is approved for use in rheumatoid arthritis, has

not been effective in Crohn’s disease

Ulcerative Colitis – TNF inhibitors have also been

effective for treatment of UC Among patients with

treatment refractory disease treated with infliximab,

65-70% responded, and about 45% of responders who con-tinued infliximab had a sustained clinical response 54 weeks later.37Induction of remission with adalimumab

occurred in 18.5% of patients with moderate to severe

UC who were anti-TNF naive, compared to 9.2% of placebo-treated patients.38In another study (ULTRA 2)

in 494 patients with moderate to severe UC that had not responded to conventional therapy or immunosuppres-sants, rates of clinical remission after 52 weeks were 17.3% with adalimumab and 8.5% with placebo.39

ADVERSE EFFECTS — Patients treated with TNF

inhibitors are at increased risk for serious infections, including reactivated and disseminated tuberculosis, invasive or disseminated fungal infection, and other opportunistic infections, including those caused by

Legionella and Listeria Tuberculin skin testing and

chest radiography are recommended before starting therapy Inhibition of TNF- has also been associated with reactivation of hepatitis B virus in patients who are chronic carriers, and serologic testing for active hepatitis B infection is recommended before treatment Anti-TNF- therapies have also been associated with injection and infusion reactions and with an increased risk of lymphoma, leukemia, new onset psoriasis, hematologic cytopenias, non-ischemic congestive heart failure and demyelinating disorders Cases of hepatosplenic T-cell lymphoma have been reported in patients taking azathioprine, mercaptopurine and/or a TNF inhibitor.16,17

DRUG INTERACTIONS — Concomitant

adminis-tration of any TNF inhibitor with other biologics may increase the risk of serious infections and neutropenia

INTEGRIN RECEPTOR ANTAGONIST

Natalizumab (Tysabri) is a humanized monoclonal

antibody against alpha-4 integrin, a molecule on leukocytes that mediates adhesion to endothelial receptors and migration into the intestine By blocking leukocyte diapedesis, natalizumab reduces intestinal inflammation It is approved by the FDA for induction and maintenance treatment of moderate to severe CD

EFFICACY — In a controlled trial, natalizumab was

somewhat more effective than placebo in inducing a response in subgroups of CD patients with elevated C-reactive protein (CRP) at baseline, active disease despite immunosuppressants, or prior anti-TNF treatment Among responders maintained on natalizumab, 61% (103/168) had a sustained response at week 36 compared to 28% (48/170) of those maintained on placebo.40 Another trial (ENCORE) that randomized

509 patients with moderate to severe active CD and

ele-vated CRP to natalizumab or placebo at weeks 0, 4 and

8 found that a response at 8 weeks maintained through

week 12 occurred in 48% of patients treated with

natal-izumab and in 32% of those given a placebo.41

ADVERSE EFFECTS — Use of natalizumab in

clin-ical practice has been limited by the rare occurence of

progressive multifocal leukoencephalopathy (PML)

and severe hepatic toxicity Current FDA approval

restricts use of the drug to CD patients who have not

responded to or could not tolerate anti-TNF agents.42

Patients at highest risk for PML are those who have

received natalizumab for >2 years, those who took

other immunosuppressants before receiving

natalizu-mab, and those who have antibodies to JC Virus, which

has been associated with PML A test for JC Virus

anti-bodies has been approved by the FDA.43

DRUG INTERACTIONS — Anti-TNF agents and

immunomodulators such as azathioprine or

mercapto-purine may increase the risk of infectious complications

with natalizumab and should not be used

concomitant-ly Patients taking corticosteroids chronically should be

tapered over 6 months while taking natalizumab

PROBIOTICS

Probiotics are live, nonpathogenic microorganisms

(usu-ally bacteria or yeasts) They are currently marketed for

prevention and treatment of a variety of disorders,

including diarrhea, irritable bowel syndrome and

inflammatory bowel disease.44

MECHANISM OF ACTION — Several mechanisms

of action have been proposed to explain how

probi-otics could have beneficial effects Acetic, lactic and

propionic acid produced by Lactobacillus can lower

intestinal pH and inhibit growth of pathogenic bacteria

such as Escherichia coli and Clostridium spp The

presence of probiotics in the intestinal tract may

physically or chemically prevent adhesion of and

col-onization by pathogenic bacteria They may also

induce or enhance an immune response.45

Saccharomyces boulardii, which is a yeast, has been

shown to inhibit the pathogenicity of bacterial toxins.46

EFFICACY — Probiotics have been used in

inflam-matory bowel disease to maintain remission,

particu-larly in patients with pouchitis after ileoanal

anasto-mosis for severe UC In 3 controlled trials in a total of

more than 600 patients with UC, probiotics

(Escherichia coli Nissle 1917 and Lactobacillus GG)

appeared to be as effective as mesalamine in

main-taining remission.47-49In a 9-month controlled trial in

40 patients with chronic pouchitis, relapses occurred

in 15% of patients treated with probiotics (VSL #3)

and in 100% with placebo.50Probiotics have been less effective in maintenance of CD

ADVERSE EFFECTS — Probiotics can cause

bloat-ing, flatulence, diarrhea and hiccups

DRUG INTERACTIONS — Antibiotics can inactivate

bacteria-derived probiotics Florastor, which contains S.

boulardii, should not be taken with oral systemic

anti-fungal medications, such as fluconazole (Diflucan, and

others).44

1 GR Lichtenstein et al Management of Crohn’s disease in adults Am J Gastroenterol 2009; 104:465.

2 A Kornbluth et al Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee Am J Gastroenterol 2010; 105:501.

3 C Campregher and C Gasche Aminosalicylates Best Pract Res Clin Gastroenterol 2011; 25:535.

4 Once-daily mesalamine (Lialda) for ulcerative colitis Med Lett Drugs Ther 2007; 49:25.

5 Encapsulated mesalamine granules (Apriso) for ulcerative colitis Med Lett Drugs Ther 2009; 51:38.

6 P Marteau et al Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study Gut 2005; 54:960.

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