The medical letter on drugs and therapeutics august 4 2014

The Medical Letter

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Objective Drug Reviews Since 1959

August 4, 2014

Volume 56

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1433
1448 Drugs for Inflammatory Bowel Disease
Volume 56

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The Medical Letter

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on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 56

ISSUE

ISSUE No.

August 4, 2014
Take CME exams
IN THIS ISSUE

1433
1448 Drugs for Inflammatory Bowel Disease
Volume 56

Related article(s) since publication

RECOMMENDATIONS
Ulcerative Colitis: An aminosalicylate is generally
used first for induction and maintenance of remission in mild to moderate disease. Azathioprine or
mercaptopurine is used for maintenance of remission
in patients with moderate to severe disease. Corticosteroids are used to induce remission in patients with
severe disease, or with moderate disease refractory
to other drugs. Patients with corticosteroid-refractory
disease may respond to a TNF inhibitor.
Crohn’s Disease: Corticosteroids are used to induce
remission. Azathioprine or mercaptopurine is used for
maintenance of remission. A TNF inhibitor alone or
in combination with azathioprine or mercaptopurine
can be used for both induction and maintenance of
remission in patients with moderate to severe disease.
AMINOSALICYLATES
Aminosalicylates are effective for induction and maintenance of remission in mild to moderate ulcerative
colitis. They are not recommended for treatment of
Crohn’s disease.
FORMULATIONS — Oral mesalamine is rapidly absorbed
in the small intestine and most of the drug does not
reach the colon. Pentasa releases mesalamine gradually
throughout the gastrointestinal tract. Delzicol, Asacol
HD, Lialda, and Apriso delay the release of the drug
until it reaches the distal ileum and colon. Sulfasalazine
(Azulfidine, and generics), balsalazide (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

generics) and as a rectal suppository (Canasa).
EFFICACY — Aminosalicylates generally induce
remission in about 35-50% of patients with mild to

moderate ulcerative colitis and maintain the remission
for ≥6 months in 55-75%. In distal ulcerative colitis
and proctitis, mesalamine suppositories or enemas
may be more effective than oral formulations at both
inducing and maintaining remission. Combination
therapy with oral and rectal mesalamine may be more
effective for distal ulcerative colitis than either formulation used alone.
ADVERSE EFFECTS — The most common adverse
effects of mesalamine have been nausea, vomiting, diarrhea, headache, and abdominal pain. Nephrotoxicity can
occur. Pancreatitis, hepatotoxicity, pericarditis, pneumonitis, and a lupus-like syndrome have been reported.
PREGNANCY — Most formulations of aminosalicylates are classified as category B (no evidence of harm
in animals; no adequate human studies) for use during
pregnancy. Asacol HD is classified as category C (risk
cannot be ruled out); in animal studies, dibutyl phthalate, an ingredient in its enteric coating, was associated
with fetal malformations and adverse effects on the male
reproductive system. Olsalazine is also classified as
pregnancy category C (embryofetal toxicity in animals;
no adequate human studies).
DRUG INTERACTIONS — Mesalamine inhibits thiopurine methyltransferase in vitro and may interfere with the
metabolism of azathioprine and mercaptopurine, which
could increase their toxicity, but seldom does except in
patients with an inherited deficiency of thiopurine methyltransferase. Extended- and delayed-release mesalamine
formulations with pH-sensitive coatings (Delzicol, Asacol
HD, Lialda, Apriso) should not be coadministered with antacids because premature dissolution of the coating could
occur. Theoretically, a similar interaction could occur
with proton-pump inhibitors (PPIs), such as omeprazole

(Prilosec, and others), or with H2-receptor antagonists,
such as ranitidine (Zantac, and others).
65

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Table 1. Drugs for Ulcerative Colitis
Recommended Drugs

Some Alternatives

Mild to Moderate
Induction of Remission
Mesalamine, oral
Balsalazide
Olsalazine
Mesalamine, rectal
Hydrocortisone, rectal

Maintenance of Remission
Mesalamine, oral
Balsalazide
Olsalazine
Mesalamine, rectal

Moderate to Severe
Induction of Remission
Prednisone
Hydrocortisone
Methylprednisolone

Maintenance of Remission
Azathioprine
Mercaptopurine
Infliximab
Adalimumab

Budesonide
Prednisone
Sulfasalazine
Infliximab
Adalimumab
Golimumab
Vedolizumab
Azathioprine
Mercaptopurine
Sulfasalazine
Infliximab
Adalimumab
Golimumab
Vedolizumab

Infliximab
Adalimumab
Golimumab

Cyclosporine
Tacrolimus
Vedolizumab
Sulfasalazine
Golimumab
Vedolizumab

Pouchitis
Induction of Remission
Ciprofloxacin
Metronidazole
Maintenance of Remission
Probiotics: VSL #3
Metronidazole
Ciprofloxacin
Rifaximin

Rifaximin
Budesonide
Infliximab
Mesalamine, rectal
Infliximab

CORTICOSTEROIDS
Corticosteroids are effective in both ulcerative colitis
and Crohn’s disease for induction of 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 inflammatory bowel
disease respond to systemic corticosteroids. In one

retrospective study in 146 patients who required treatment with corticosteroids, 51% of patients with ulcerative colitis and 40% of those with Crohn’s disease had
a complete response at 30 days; 31% and 35% had a
partial response.1 Most patients who respond to corticosteroids relapse if not given maintenance therapy.
ADVERSE EFFECTS — Corticosteroids can cause
fluid retention, increased risk of infection, osteoporosis, osteonecrosis, cataracts, glaucoma, impaired
66

Vol. 56 (1448)

August 4, 2014

skin healing, acne, insomnia, mood disorders, Cushing’s syndrome, hyperglycemia, and hypothalamicpituitary-adrenal (HPA) axis suppression.
RECTAL CORTICOSTEROIDS — Rectally administered
corticosteroids are effective for treatment of distal ulcerative colitis. Enemas can reach the splenic flexure,
while foam coats only the last 15-20 cm of the colon.
BUDESONIDE — A synthetic corticosteroid with a
strong affinity for glucocorticoid receptors and a high
ratio of local anti-inflammatory to systemic effects,
budesonide has been used orally in an ileal-release
formulation (Entocort EC, and generics) to induce remission in mild to moderate Crohn’s disease of the
ileum and/or ascending colon. While also approved
for maintenance, it does not appear to be effective for
preventing relapse beyond 6 months of use.
Budesonide is also available in an extended-release
formulation (Uceris) that distributes the drug throughout
the colon and is FDA-approved for induction of remission
in mild to moderate ulcerative colitis. In patients with
active mild to moderate ulcerative colitis for at least 6
months, remission occurred more frequently with Uceris
(17.9%) than with Asacol (12.1%) or placebo (7.4%).2

Budesonide enemas are effective for distal ulcerative
colitis; they are available in Canada, but not in the US.
Adverse Effects – Budesonide causes less short-term
corticosteroid toxicity than prednisone. Whether it is
safer in the long term is not clear.
Pregnancy – Budesonide is classified as category C
(evidence of toxicity in animals; no adequate human
studies) for use during pregnancy.
Drug Interactions – Budesonide is a CYP3A4 substrate and should be used with caution or avoided in
combination with drugs that inhibit CYP3A4, which
could increase its toxicity.3 Drugs that change the pH
of the gastrointestinal tract (antacids, PPIs, H2-receptor antagonists) may affect the release and absorption
of oral budesonide.
IMMUNOMODULATORY AGENTS
AZATHIOPRINE AND MERCAPTOPURINE — The
thiopurines azathioprine (Imuran, and generics) and
mercaptopurine (6-MP; Purinethol, and generics),
which is the active metabolite of azathioprine, are
effective for maintaining remission in both ulcerative
colitis and Crohn’s disease. Since they 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.


The Medical Letter

®

Efficacy – In controlled trials, azathioprine and mercaptopurine have been significantly more effective

than placebo in maintaining remission in both ulcerative colitis and Crohn’s disease.4,5
In a study in patients with moderate to severe Crohn’s
disease not previously exposed to immunosuppressive
or biologic therapy, the combination of azathioprine plus
infliximab was more effective than either drug alone;
after 26 weeks of therapy, 56.8% of patients receiving
combination therapy were in steroid-free clinical remission, compared to 44.4% of patients receiving infliximab
alone and 30% of those receiving azathioprine alone.6
The results of another study suggest that the combination of infliximab plus azathioprine is also superior to
either agent alone in the treatment of ulcerative colitis.7
Adverse Effects – Azathioprine and mercaptopurine can
cause myelosuppression, infection, nausea, vomiting,
diarrhea, hepatotoxicity, rash, pulmonary edema, pancreatitis, and a hypersensitivity reaction. Long-term use
has been associated with a small increase in the risk
of non-melanoma skin cancer and lymphoma. Hepatosplenic T-cell lymphoma has been reported in patients
taking azathioprine or mercaptoprine both alone and in
combination with a TNF inhibitor.
Pregnancy – Azathioprine and mercaptopurine are
both classified as category D (positive evidence of
fetal harm) for use during pregnancy.
Drug Interactions – Allopurinol (Zyloprim, and generics)
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 of febuxostat is contraindicated.
Mesalamine inhibits thiopurine methyltransferase and
may decrease the metabolism of azathioprine and mercaptopurine, which theoretically could also increase their
myelotoxicity, but seldom does except in patients with an
inherited deficiency of thiopurine methyltransferase.

Vol. 56 (1448)

August 4, 2014

Table 2. Drugs for Crohn's Disease
Recommended Drugs
Mild to Moderate
Induction of Remission
Budesonide

Maintenance of Remission
Azathioprine
Mercaptopurine
Moderate to Severe
Induction of Remission
Prednisone
Methylprednisolone
Infliximab
Adalimumab
Certolizumab pegol
Maintenance of Remission
Infliximab
Adalimumab
Certolizumab pegol
Azathioprine
Mercaptopurine

Some Alternatives

Prednisone
Metronidazole
Ciprofloxacin
Rifaximin
Budesonide
Methotrexate

Vedolizumab
Natalizumab

Methotrexate
Vedolizumab
Natalizumab

Perianal and Fistulizing Disease
Induction of Remission
Metronidazole ± Ciprofloxacin
Infliximab
Maintenance of Remission
Azathioprine
Mercaptopurine
Infliximab

Methotrexate

Efficacy – Several studies have found methotrexate
effective in maintaining remission in patients with Crohn’s
disease.8 In one study, a combination of methotrexate and
infliximab was no more effective than either drug alone.9
Adverse Effects – Methotrexate can cause myelosuppression, alopecia, rash, stomatitis, vomiting, diarrhea,

gastrointestinal hemorrhage, hepatotoxicity, renal failure,
interstitial pneumonia, liver failure, toxic epidermal necrolysis, Stevens-Johnson syndrome, hypotension, blurred
vision, headache, nephropathy, and hyperuricemia.
Pregnancy – Methotrexate is contraindicated for use
during pregnancy (category X). Pregnancy should be
avoided if either partner is receiving the drug.

Severe leukopenia has been reported during concomitant therapy with angiotensin-converting enzyme (ACE )
inhibitors or trimethoprim/sulfamethoxazole (Bactrim, and
others). Azathioprine and mercaptopurine may decrease
the anticoagulant effect of warfarin (Coumadin, and others).

Drug Interactions – 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
increase serum concentrations of methotrexate and
possibly its toxicity.

METHOTREXATE — In Crohn's disease, methotrexate can be used as an alternative to azathioprine or
mercaptopurine to maintain remission and permit
withdrawal of corticosteroids. It has not been clearly
shown to be effective in ulcerative colitis.

CYCLOSPORINE — The calcineurin inhibitor cyclosporine (Sandimmune, and others) is used as rescue
therapy to avoid colectomy in patients with severe
steroid-resistant ulcerative colitis. Use of cyclosporine
in Crohn’s disease has been limited.
67

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Vol. 56 (1448)

August 4, 2014

Table 3. Drugs for Inflammatory Bowel Disease
Drug
Aminosalicylates2
Mesalamine –
delayed- or extended-release
Apriso (Salix)
Delzicol 3 (Actavis)

Some Formulations

Usual Adult Dosage

Cost1

375 mg ER caps
400 mg DR caps

Maintenance: 1.5 g once/d
Induction: 800 mg tid
Maintenance: 1.6 g daily in divided doses
Induction: 1.6 g tid

Induction: 2.4 or 4.8 g once/d
Maintenance: 2.4 g once/d
Induction: 1 g qid

$348.00
430.20

Induction: 2.25 g tid
Maintenance: 3-6 g daily in divided doses
Induction: 3.3 g bid
Induction: 1.5-3 g daily in 2 divided doses
Maintenance: 500 mg bid
Induction: 1 g qid
Maintenance: 1 g bid
Induction: 3-4 g daily in divided doses
Maintenance: 2 g daily

76.10
127.80
864.00
1087.20

4 g/60 mL enema

Induction: 4 g rectally once/d at bedtime
Maintenance: 2-4 g rectally once/d at bedtime

1000 mg rectal suppository

Induction and maintenance: 1000 mg rectally once/d

370.404
1096.304
997.004
709.20

1, 2.5, 5, 10, 20, 50 mg tabs;
5 mg/5 mL oral solution

Induction: 40-60 mg once/d

15.90

1, 2, 5 mg DR tabs
3 mg caps

Induction: 40-60 mg once/d
Induction: 9 mg once/d
Maintenance: 6 mg once/d6

7464.00
1263.00
2070.90

9 mg ER tabs
100 mg/60 mL enema

Induction: 9 mg once/d
Induction: 1 enema nightly

10% rectal foam

Induction: 1 application once/d or bid

1333.80
182.90
255.80
544.607

Asacol HD (Actavis)
Lialda (Shire)

800 mg DR tabs
1.2 g DR tabs

Pentasa (Shire)

250, 500 mg ER caps

Mesalamine – prodrugs
Balsalazide – generic
Colazal (Salix)
Giazo (Salix)
Olsalazine – Dipentum (Meda)
Sulfasalazine – generic
Azulfidine (Pfizer)
delayed-release – generic
Azulfidine En-tabs (Pfizer)
Mesalamine – rectal
generic

Rowasa (Meda)
SF Rowasa (Meda)
Canasa (Aptalis)
Corticosteroids
Prednisone – generic
delayed-release
Rayos (Horizon)
Budesonide – generic
Entocort EC (AstraZeneca)5
extended-release
Uceris (Santarus)2
Hydrocortisone2 – generic
Colocort (Paddock)
Cortifoam (Meda)

750 mg caps
1.1 g tabs
250 mg caps
500 mg tabs
500 mg enteric-coated DR tabs

445.50
405.00
876.00

49.20
196.80
41.40
192.60

ER = extended-release; DR = delayed-release
1. Approximate wholesale acquisition cost (WAC) for 30 days' treatment at the lowest induction dosage. Prices for Apriso, azathioprine, and mercaptopurine are
based on the lowest maintenance dosage. Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) July 5, 2014. Reprinted with permission by
FDB, Inc. All rights reserved. ©2014. www.fdbhealth.com/policies/drug-pricing-policy. Actual retail prices may be higher.
2. Not FDA-approved for use in Crohn's disease.
3. Delzicol has replaced Asacol due to reproductive safety concerns associated with dibutyl phthalate, a plasticizer in the enteric coating of Asacol. Delzicol does
not contain dibutyl phthalate.
4. Cost for 28 days' treatment.
5. Not FDA-approved for use in ulcerative colitis.
6. FDA-approved for up to 3 months.
7. Cost of two 15-gram aerosol containers (each contains ~14 applications).

Efficacy – One open-label randomized trial comparing cyclosporine to infliximab for treatment of
patients with an acute severe flare of ulcerative
colitis refractory to IV steroids found the two drugs
equally effective.10
Adverse Effects – Cyclosporine can cause diarrhea,
nausea, vomiting, infection, gingival hyperplasia, pruritus, headache, seizures, tremors, visual disturbances,
hypertension, hepatotoxicity, nephrotoxicity, paresthesias, and anaphylaxis.
Pregnancy – Cyclosporine is classified as category C
(embryofetal toxicity in animals; no adequate human
studies) for use during pregnancy.
68

Drug Interactions – Nephrotoxic effects may be additive
when cyclosporine is used in conjunction with other
nephrotoxic drugs such as aminoglycoside antibiotics.
Concurrent use of potassium-sparing diuretics such as
spironolactone (Aldactone, and generics) may increase
the risk of hyperkalemia. Cyclosporine is both a substrate and an inhibitor of CYP3A4 and P-glycoprotein;

CYP3A4 inhibitors may increase its toxicity and CYP3A4
inducers may decrease its effectiveness.3
TACROLIMUS — Tacrolimus (Prograf, and generics),
another calcineurin inhibitor, has been used as an
alternative to cyclosporine to treat patients with
refractory ulcerative colitis. Data are limited on its use
in Crohn’s disease.


The Medical Letter

®

Vol. 56 (1448)

August 4, 2014

Table 3. Drugs for Inflammatory Bowel Disease (continued)
Drug
Immunosuppressants8
Azathioprine – generic
Imuran (Prometheus)
Mercaptopurine – generic
Purinethol (Teva)
Methotrexate10 – generic
Otrexup (Antares)
Rasuvo (Medac)
Cyclosporine – generic
Sandimmune (Novartis)
Tacrolimus – generic

Prograf (Astellas)
TNF Inhibitors
Adalimumab – Humira
(Abbvie)
Certolizumab pegol – Cimzia5
(UCB)
Golimumab – Simponi2
(Janssen)
Infliximab – Remicade
(Janssen)
Integrin Receptor Antagonists
Natalizumab – Tysabri 5
(Elan/Biogen)
Vedolizumab – Entyvio
(Takeda)

Some Formulations

Usual Adult Dosage

Cost1

25, 50, 75, 100 mg tabs
50 mg tabs
50 mg tabs

Maintenance: 2-2.5 mg/kg once/d

$36.709
567.909

170.309
543.309
8.80
548.00

50 mg/2 mL ampule
15 mg/0.4 mL; 25 mg/0.4 mL
autoinjector
15 mg/0.3 mL; 25 mg/0.5 mL
autoinjector
50 mg/mL ampule
50 mg/mL ampule
0.5, 1, 5 mg caps

40 mg/0.8 mL prefilled syringe;
40 mg/0.8 mL single-use pen
200 mg vial (lyophilized powder);
200 mg/mL prefilled syringe
50 mg/0.5 mL, 100 mg/1 mL autoinjector; 50 mg/ 0.5 mL,
100 mg/1 mL prefilled syringe
100 mg vial (lyophilized powder)

Maintenance: 1-1.5 mg/kg once/d
Induction: 25 mg IM/SC11 once/wk
Maintenance: 15-25 mg IM/SC11 once/wk

N.A.12
Induction: 2-4 mg/kg IV daily
Induction: 0.05-0.2 mg/kg/d in 2 divided doses14

Induction: 160 mg SC at wk 0, then 80 mg at wk 2
Maintenance: 40 mg SC every other wk starting at wk 4
Induction: 400 mg SC at wks 0, 2, and 4
Maintenance: 400 mg SC q4 wks
Induction: 200 mg SC at wk 0, then 100 mg SC at wk 2
Maintenance: 100 mg SC q4 wks

91.609,13
173.909,13
398.409
522.009

5400.6015
5538.4015
6234.2015

Induction: 5 mg/kg IV at wks 0, 2, and 6
Maintenance: 5-10 mg/kg IV q8 wks

3539.509,15

300 mg/15 mL vial
(lyophilized powder)
300 mg/20 mL vial
(lyophilized powder)

Induction and maintenance: 300 mg IV q4 wks

9358.0015

Induction: 300 mg IV at wks 0, 2, and 6
Maintenance: 300 mg IV q8 wks

4819.0015

250, 500 mg tabs; 375 mg caps

250 mg tid16

100, 250, 500, 750 mg tabs

500 mg bid

200, 550 mg tabs

600-2000 mg daily in divided doses

Antibiotics8
Metronidazole – generic
Flagyl (Pfizer)
Ciprofloxacin – generic
Cipro (Bayer)
Rifaximin – Xifaxan (Salix)

32.00
422.10
13.90
344.20
1202.40

N.A. = Not available
8. Not FDA-approved for inflammatory bowel disease.
9. Cost based on a 75-kg patient.
10. Use of supplements containing folic acid (1-4 mg daily) or folinic acid (2.5-10 mg weekly 24 hours after the methotrexate dose) may decrease some of methotrexate's adverse effects.
11. Otrexup and Rasuvo are for subcutaneous injection only.
12. Rasuvo has been approved by the FDA, but is not yet available.
13. Cost for 7 days' treatment.
14. Adjust dose to maintain target trough levels of 5-15 ng/mL.
15. Cost for 8 weeks' treatment at the lowest maintenance dosage.
16. 250 mg tid for induction and maintenance of remission in pouchitis; 10-20 mg/kg daily in divided doses for induction of remission in Crohn's disease; 500 mg
tid for induction of remission in perianal and fistulizing disease.

Efficacy – Tacrolimus appears to be effective in
producing clinical improvement in some patients with
corticosteroid-refractory ulcerative colitis. In one doubleblind, randomized trial, clinical response occurred after 2
weeks in 16 of 32 such patients treated with tacrolimus,
compared to 4 of 30 taking a placebo.11 One retrospective
study found that about 60% of patients with steroidrefractory ulcerative colitis treated with tacrolimus had
a clinical remission or showed clinical improvement and
that 33% achieved mucosal healing.12
In one small retrospective study in 24 patients with
severe Crohn’s disease refractory to TNF inhibitors, tacrolimus treatment resulted in clinical response in 16
(67%) patients and steroid-free remission in 5 (21%).13

Adverse Effects – Tacrolimus can cause tremors, renal
dysfunction, gastrointestinal discomfort, headache,
infection, hypomagnesemia, hypertension, insomnia,
and seizures. It has 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-glycoprotein; CYP3A4
inhibitors may increase its toxicity and CYP3A4
inducers may decrease its effectiveness.3 Tacrolimus
can cause QT interval prolongation; it should be used
with caution when other drugs that prolong the QT
interval are taken concurrently.14
69


The Medical Letter

®

TNF INHIBITORS
Three tumor necrosis factor (TNF) inhibitors –
infliximab (Remicade), adalimumab (Humira), and
certolizumab pegol (Cimzia) – are used for treatment
of moderate to severe Crohn’s disease.15 Infliximab is
the only one of the three approved by the FDA for use
in children. Infliximab, adalimumab, and golimumab
(Simponi) are approved by the FDA for treatment of
moderate to severe ulcerative colitis not responsive
to conventional therapies.16 Drug and antibody levels
may sometimes be helpful in the use of these agents.17
EFFICACY — Crohn’s Disease – Infliximab has been
effective for the treatment of moderate to severe Crohn’s
disease that has not responded to other drugs, including systemic corticosteroids. It has been more effective
than placebo in inducing and maintaining remission

and in producing closure of fistulas. Infliximab has also
been shown to reduce Crohn’s disease recurrence after
ileocolonic resection. In an open-label 5-year follow-up
study, 22% of patients treated with infliximab had recurrences, compared to 94% of untreated patients.18
The rates of response and remission in Crohn’s disease treated with other TNF inhibitors appear to be
comparable to those with infliximab. In one study, a
response to induction with adalimumab occurred in
499 of 854 patients (58%). Among responders who
received adalimumab every other week for maintenance, 62 of 172 (36%) were in remission after 12
months.19 In a study with certolizumab pegol, 428 of
668 patients (64%) responded to induction, and after
maintenance treatment for 26 weeks, 103 of 215 (48%)
responders were in remission.20
Head-to-head comparisons of TNF inhibitors are lacking. Adalimumab has been effective in some patients
who had become refractory to infliximab.21 Certolizumab
pegol has also been effective in some patients who had
become refractory or intolerant to infliximab.22 In general,
however, the rate of response to a second TNF inhibitor
has been lower than the rate of response to the first.
Use of a TNF inhibitor in combination with azathioprine
or mercaptopurine may be more effective than either
drug alone (see page 61).
Ulcerative Colitis – TNF inhibitors have also been
effective for treatment of ulcerative colitis. Infliximab,
adalimumab, and golimumab have all been shown to
be significantly more effective than placebo in inducing
and maintaining remission in patients with moderate
to severe ulcerative colitis.23 In a meta-analysis of clinical trials of biologic agents including infliximab, adali70

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August 4, 2014

mumab, golimumab, and the integrin receptor antagonist vedolizumab, there was no conclusive evidence
that any one of these was more effective than any
other in maintaining clinical remission in moderate to
severe ulcerative colitis.24
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, such as those caused
by Legionella and Listeria. Tuberculin skin testing and
chest radiography are recommended before starting
and periodically during therapy. Inhibition of TNF has
also been associated with reactivation of hepatitis B
virus in patients who are chronic carriers; 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 new onset psoriasis, hematologic cytopenias,
non-ischemic congestive heart failure, demyelinating
disorders, and induction of a lupus-like syndrome.
An increased risk of cancer, including lymphoma,
melanoma, and non-melanoma skin cancers, has
been reported with use of TNF inhibitors, but a causeand-effect relationship has not been established.25 A
nationwide study in Denmark found that patients with
inflammatory bowel disease treated with TNF inhibitors and followed for a median of 3.7 years did not
have an increased risk of cancer.26
PREGNANCY — Adalimumab, certolizumab pegol, golimumab, and infliximab are all classified as category B
(no evidence of harm in animals; no adequate human

studies) for use during pregnancy. Placental transfer
of anti-TNF antibodies may be higher during the late
second and third trimesters, especially with infliximab,
adalimumab, and golimumab.
DRUG INTERACTIONS — Concomitant administration of a
TNF inhibitor with another biologic may increase the risk of
serious infections and neutropenia. Patients being treated
with TNF inhibitors should not receive live vaccines.
INTEGRIN RECEPTOR ANTAGONISTS
Two integrin receptor antagonists – natalizumab
(Tysabri) and vedolizumab (Entyvio) – are approved by
the FDA for treatment of inflammatory bowel disease.
Natalizumab is approved for induction and maintenance
treatment of moderate to severe Crohn’s disease.
Vedolizumab is approved for use in both Crohn’s
disease and ulcerative colitis.27 Vedolizumab is a
humanized monoclonal antibody that binds to -4-ß-7


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®

integrin. Specifically blocking the ß-7 integrin is thought
to inhibit leukocyte migration in the intestine, but not in
the central nervous system, thereby decreasing the risk
of progressive multifocal leukoencephalopathy (PML),
which has occurred with natalizumab.
EFFICACY — Natalizumab has been modestly effective in
some studies as an induction agent in patients with moderate to severe Crohn’s disease with active inflammation.

It appears to be more effective at maintaining response
and remission, with significant steroid-sparing effects.28
Vedolizumab has been approved by the FDA for
treatment of Crohn’s disease and ulcerative colitis
in patients who have not responded to or could not
tolerate corticosteroids, immunosuppressants, or TNF
inhibitors. In a randomized, controlled trial in patients
with Crohn’s disease, a clinical remission occurred
after 6 weeks of treatment in 14.5% of vedolizumabtreated patients and in 6.8% of those taking placebo. A
clinical response occurred in 31.4% of patients treated
with vedolizumab and in 25.7% of those randomized
to placebo; this difference was not statistically significant. Responders received maintenance therapy
with vedolizumab every 4 or 8 weeks, or placebo,
for 52 weeks; 36.4% and 39% of patients receiving
vedolizumab every 4 and 8 weeks, respectively, were in
clinical remission at 52 weeks, compared to 21.6% of
those receiving placebo.29
In patients with ulcerative colitis, a clinical response
occurred in 47.1% of vedolizumab-treated patients after
6 weeks of therapy, compared to 25.5% of those taking
placebo. Among responders, continued treatment with
vedolizumab every 4 or 8 weeks resulted in clinical remission at 52 weeks in 44.8% and 41.8%, respectively,
compared to 15.9% with placebo.30
ADVERSE EFFECTS — Use of natalizumab in clinical
practice has been limited by the rare occurence of progressive multifocal leukoencephalopathy (PML) and
severe hepatic toxicity.
No cases of PML have been reported with vedolizumab
to date. In clinical trials of vedolizumab, hypersensitivity reactions have occurred, including one case of
anaphylaxis. Severe infections including tuberculosis, sepsis (sometimes fatal), and meningitis have
occurred. Increased transaminase and bilirubin levels

have been reported.
PREGNANCY — Natalizumab is classified as category C
(toxicity in animals; no adequate human studies) for use
during pregnancy. Vedolizumab is classified as category
B (no evidence of risk in animals; no human studies).

Vol. 56 (1448)

August 4, 2014

DRUG INTERACTIONS — Other biologic agents or immunomodulators may increase the risk of infectious
complications with natalizumab or vedolizumab and
should not be used concomitantly.
ANTIBIOTICS
Many experts believe that alterations in the balance
of enteric bacteria (dysbiosis) play a role in the development of inflammatory bowel disease, but the
evidence that antibiotics are effective in treating
Crohn’s disease or ulcerative colitis is limited, and they
might make dysbiosis worse.31 Metronidazole (Flagyl,
and generics), ciprofloxacin (Cipro, and generics), and
rifaximin (Xifaxan) are used, sometimes together, to
treat Crohn’s disease microperforations and fistulas,
and to treat pouchitis in ulcerative colitis. They have
also been used following resections to prevent recurrence of Crohn’s disease.32,33
EFFICACY — One meta-analysis found antibiotics
more effective than placebo in inducing remission in
active Crohn’s disease, particularly in fistulizing disease.34 A randomized, double-blind trial in more than
400 patients found that 12 weeks of rifaximin 800
mg twice daily induced remission in 62% of patients
with moderately active Crohn’s disease, compared to

43% of those receiving placebo.35 The evidence that
antibiotics are effective in maintaining remission in
Crohn’s disease is limited.
The use of antibiotics is not recommended for ulcerative colitis, except pouchitis, for which ciprofloxacin,
metronidazole, and rifaximin all appear to be effective,
but large controlled trials are lacking.36
ADVERSE EFFECTS — Metronidazole can cause abdominal discomfort, metallic taste, nausea, vomiting,
diarrhea, loss of appetite, ataxia, and peripheral neuropathy. Ciprofloxacin can cause nausea, vomiting,
diarrhea, abdominal discomfort, headache, dizziness,
QT interval prolongation, altered mental status, lowering of the seizure threshold, spontaneous tendon
rupture, and an increased risk of Clostridium difficile
infection. Rifaximin is minimally absorbed and has an
incidence of adverse effects similar to that of 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.6
Ciprofloxacin is a moderate inhibitor of CYP1A2 and may
increase serum concentrations of CYP1A2 substrates
71


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®

such as tizanidine (Zanaflex, and generics). 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 additive effect.14
Rifaximin is minimally absorbed and does not appear
to cause any clinically significant interactions.
PROBIOTICS
Probiotics are live, nonpathogenic microorganisms
(usually bacteria or yeasts). They have been tried for
prevention and treatment of a variety of disorders, including inflammatory bowel disease.37
Probiotics have been used in ulcerative colitis to maintain remission, particularly in patients with pouchitis
after ileoanal anastomosis for severe disease. In small
trials in patients with ulcerative colitis and pouchitis,
VSL #3 was more effective than a placebo for maintenance of remission.38,39 Probiotics have been less effective
for maintenance of remission in Crohn’s disease.
Probiotics can cause bloating, flatulence, diarrhea, and
hiccups. Antibiotics can inactivate bacteria-derived
probiotics. ■
1.

2.
3.
4.

5.

6.
7.

8.
9.

10.

11.

12.

13.

72

GT Ho et al. The efficacy of corticosteroid therapy in inflammatory bowel disease: analysis of a 5-year UK inception cohort.
Aliment Pharmacol Ther 2006; 24:319.
Budesonide (Uceris) for ulcerative colitis. Med Lett Drugs Ther
2013; 55:23.
Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.
A Timmer et al. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database
Syst Rev 2012; 9:CD000478.
E Prefontaine et al. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease. Cochrane Database
Syst Rev 2009; 1:CD000067.
JF Colombel et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010; 362:1383.
R Panaccione et al. Combination therapy with infliximab and
azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology 2014; 146:392.
V Patel et al. Methotrexate for maintenance of remission in
Crohn’s disease. Cochrane Database Syst Rev 2009; 4:CD006884.
BG Feagan et al. Methotrexate in combination with infliximab is
no more effective than infliximab alone in patients with Crohn’s
disease. Gastroenterology 2014; 146:681.
D Laharie et al. Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel,
open-label randomised controlled trial. Lancet 2012; 380:1909.
H Ogata et al. Double-blind, placebo-controlled trial of oral tacrolimus (FK506) in the management of hospitalized patients with steroid-refractory ulcerative colitis. Inflamm Bowel Dis 2012; 18:803.

J Miyoshi et al. Mucosal healing with oral tacrolimus is associated with favorable medium- and long-term prognosis in steroid-refractory/dependent ulcerative colitis patients. J Crohns
Colitis 2013; 7:e609.
ME Gerich et al. Tacrolimus salvage in anti-tumor necrosis factor antibody treatment-refractory Crohn’s disease. Inflamm

Vol. 56 (1448)

August 4, 2014

Bowel Dis 2013; 19:1107.
14. Combined list of all QTdrugs and the list of drugs to avoid for
patients with congenital long QT syndrome. Available at http://
www.crediblemeds.org. Accessed July 23, 2014.
15. TNF inhibitors for Crohn’s disease: when, which, and for how
long? Med Lett Drugs Ther 2013; 55:102.
16. Golimumab (Simponi) for ulcerative colitis. Med Lett Drugs Ther
2014; 56:25.
17. JF Colombel et al. Therapeutic drug monitoring of biologics for
inflammatory bowel disease. Inflamm Bowel Dis 2012; 18:349.
18. M Regueiro et al. Postoperative therapy with infliximab prevents
long-term Crohn’s disease recurrence. Clin Gastroenterol Hepatol 2014 January 16 (epub).
19. JF Colombel et al. Adalimumab for maintenance of clinical
response and remission in patients with Crohn’s disease: the
CHARM trial. Gastroenterology 2007; 132:52.
20. S Schreiber et al. Maintenance therapy with certolizumab pegol
for Crohn’s disease. N Engl J Med 2007; 357:239.
21. WJ Sandborn et al. Adalimumab induction therapy for Crohn
disease previously treated with infliximab: a randomized trial.
Ann Intern Med 2007; 146:829.
22. WJ Sandborn et al. Certolizumab pegol in patients with moderate to severe Crohn's disease and secondary failure to infliximab. Clin Gastroenterol Hepatol 2010; 8:688.
23. WJ Sandborn et al. Subcutaneous golimumab induces clinical

response and remission in patients with moderate-to-severe
ulcerative colitis. Gastroenterology 2014; 146:85.
24. S Danese et al. Biological agents for moderately to severely active ulcerative colitis: a systematic review and network metaanalysis. Ann Intern Med 2014; 160:704.
25. X Mariette et al. Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational
studies: a systematic review and meta-analysis. Ann Rheum
Dis 2011; 70:1895.
26. NN Andersen et al. Association between tumor necrosis factor antagonists and risk of cancer in patients with inflammatory
bowel disease. JAMA 2014; 311:2406.
27. Vedolizumab (Entyvio) for inflammatory bowel disease. Med
Lett Drugs Ther 2014; in press.
28. Natalizumab (Tysabri) for Crohn's disease. Med Lett Drugs Ther
2008; 50:34.
29. WJ Sandborn et al. Vedolizumab as induction and maintenance
therapy for Crohn’s disease. N Engl J Med 2013; 369:711.
30. BG Feagan et al. Vedolizumab as induction and maintenance
therapy for ulcerative colitis. N Engl J Med 2013; 369:699.
31. D Gevers et al. The treatment-naive microbiome in new-onset
Crohn’s disease. Cell Host Microbe 2014; 15:382.
32. HH Herfarth et al. Ciprofloxacin for the prevention of postoperative recurrence in patients with Crohn’s disease: a randomized,
double-blind, placebo-controlled pilot study. Inflamm Bowel Dis
2013; 19:1073.
33. M Mañosa et al. Addition of metronidazole to azathioprine for
the prevention of postoperative recurrence of Crohn’s disease:
a randomized, double-blind, placebo-controlled trial. Inflamm
Bowel Dis 2013; 19:1889.
34. KJ Khan et al. Antibiotic therapy in inflammatory bowel disease:
a systematic review and meta-analysis. Am J Gastroenterol
2011; 106:661.
35. C Prantera et al. Rifaximin-extended intestinal release induces
remission in patients with moderately active Crohn’s disease.

Gastroenterology 2012; 142:473.
36. P Gionchetti et al. The role of antibiotics and probiotics in pouchitis. Ann Gastroenterol 2012; 25:100.
37. Probiotics revisited. Med Lett Drugs Ther 2013; 55:3.
38. M Guslandi. Role of probiotics in the management of pouchitis.
Curr Pharm Des 2014; 20:4561.
39. J Shen et al. Effect of probiotics on inducing remission and
maintaining therapy in ulcerative colitis, Crohn’s disease, and
pouchitis: meta-analysis of randomized controlled trials. Inflamm Bowel Dis 2014; 20:21.


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Issue 1448 Questions

(Correspond to questions #21-30 in Comprehensive Exam #71, available January 2015)
1. Aminosalicylates are:
a. generally used first for induction and maintenance of

remission in mild to moderate ulcerative colitis
b. generally used first for induction and maintenance of
remission in mild to moderate Crohn’s disease
c. available only in oral formulations
d. effective in about 90% of patients with mild to moderate
ulcerative colitis
2. Which of the following is an option for maintenance of remission
in a 26-year-old male patient with moderate Crohn’s disease:
a. golimumab
b. tacrolimus
c. azathioprine
d. cyclosporine
3. Adverse effects associated with azathioprine and
mercaptopurine include:
a. hepatotoxicity
b. myelosuppression
c. rash
d. all of the above
4. Combining azathioprine with infliximab:
a. has been shown to be more effective than either drug alone
in achieving steroid-free remission in Crohn’s disease
b. was not more effective than either drug alone in treatment
of ulcerative colitis
c. can lower serum concentrations of infliximab
d. all of the above
5. A 32-year-old man is hospitalized with severe steroid-resistant
ulcerative colitis. Which of the following drugs could be used to
avoid colectomy?
a. cyclosporine
b. budesonide

c. metronidazole
d. certolizumab

6. A 23-year-old female patient with severe Crohn’s disease
saw an advertisement for adalimumab and asks you for some
information about TNF inhibitors. You could tell her that:
a. TNF inhibitors have been effective for induction and
maintenance of remission in moderate to severe Crohn’s
disease
b. TNF inhibitors can produce closure of fistulas
c. she should not receive live vaccines while taking a TNF
inhibitor
d. all of the above
7. Adverse events that have been associated with TNF inhibitors
include:
a. reactivation of TB
b. injection and infusion reactions
c. new onset psoriasis
d. all of the above
8. Progressive multifocal leukoencephalopathy (PML) has limited
the use of which of the following drugs:
a. vedolizumab
b. natalizumab
c. infliximab
d. all of the above
9. Which of the following drugs is contraindicated for use during
pregnancy?
a. infliximab
b. mesalamine
c. methotrexate

d. vedolizumab
10. A patient asks you about using probiotics for treatment of
ulcerative colitis. You could tell her that:
a. they have been shown to be highly effective for induction
of remission in ulcerative colitis
b. probiotics can cause bloating, flatulence, diarrhea, and
hiccups
c. they are composed of pathogenic organisms
d. all of the above

ACPE UPN: Per Issue Exam: 0379-0000-14-448-H01-P; Release: August 4, 2014, Expire: August 4, 2015
Comprehensive Exam 71: 0379-0000-15-071-H01-P; Release: January 2015, Expire: January 2016

EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
F. Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical
School; Eric J. Epstein, M.D., Albert Einstein College of Medicine; Jane P. Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; Jules Hirsch, M.D., Rockefeller
University; David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital,
Copenhagen; Sandip K. Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M. Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K. Schaefer, M.D., M.P.H.,
Harvard Medical School; F. Estelle R. Simons, M.D., University of Manitoba; Neal H. Steigbigel, M.D., New York University School of Medicine; Arthur M. F. Yee, M.D., Ph.D., F.A.C.R.,
Weill Medical College of Cornell University
MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown
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Arthur Kallet and Harold Aaron, M.D.
Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
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