Evaluation of Oral and Topical Therapies for Mild to Moderate

INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
2
Evaluation of Oral and Topical Therapies for Mild to Moderate Ulcerative Colitis
Author:
Jasmine Ho, PharmD
Columbus Regional Hospital
Clinical Pharmacist
ACPE UAN: 0120-0000-14-011-H01-P
1.5 Contact Hours (1.5 CEU’s)
This is a knowledge based activity
See end article for CE details
Target Audience: Pharmacists
Faculty Disclosure: The faculty have no conflicts
of interest to disclose
Learning Objectives:
At the completion of this activity, the
participant will be able to:
1. Classify disease severity using the ulcerative
colitis disease activity index.
2. List topical and oral therapies for mild to
moderate ulcerative colitis.
3. Identify advantages and disadvantages of
Uceris®, Remicade®, and Humira®.
4. Identify medications for maintenance
remission in mild to moderate ulcerative colitis.
Introduction
Inflammatory bowel disease (IBD)
consists of two conditions known as ulcerative
colitis (UC) and Crohn’s disease (CD). UC
primarily affects the colon and rectum; while
alternatively, CD may affect any location of the
gastrointestinal tract. IBD should not be
confused with Irritable Bowel Syndrome (IBS)
which involves abnormal muscle contractions of
the colon. While the exact cause of UC is
unknown, genetic, environmental, microbial
factors, and autoimmune triggers have been
studied. UC is characterized by continuous
[Type text]
inflammation and ulceration of the intestinal
mucosa and submucosa. The disease affects
approximately 700,000 Americans.1 Disease
severity is highly variable in patients, and is
considered a lifelong disease requiring longterm treatment. Time frames between flare-ups
can vary from months to years. Men and
women are equally affected by UC, with most
diagnoses made during the 30s age range.
However, the disease can occur at any age, and
up to 20% of patients have a first degree
relative with the disease as well.1
Diagnosis
Patients presenting with chronic
diarrhea lasting for weeks may be assessed for
diagnosis. Proctosigmoidoscopy or colonoscopy
procedures are complete to reveal mucosal
changes characteristic of UC. Positive findings
include loss of typical vascular pattern,
granularity, friability, and ulceration. Mucosal
biopsy results suggestive of UC can include
separation, distortion, atrophy of crypts,
inflamed cells, and increased lymphocytes and
plasma cells. A complete history should also be
completed prior to diagnosis for possible causes
of diarrhea such as recent travel or antibiotic
use. Some other helpful tests include stool
studies testing for Escherichia coli, Salmonella,
Shigella, Campylobacter, Giardia and Yersinia.2
Symptoms depend on the severity of
inflammation and the extent of colon affected.
Common symptoms of mild to moderate UC
include rectal bleeding, diarrhea, abdominal
cramping, stool urgency, and tenesmus.1,2 As a
result, other possible symptoms include a loss
of appetite, weight loss, fatigue, fever,
tachycardia, and anemia. A few other
laboratory tests that should be done include a
complete blood count (CBC,) basic metabolic
panel (BMP), erythrocyte sedimentation rate
(ESR), and C-reactive protein. The perinuclear
Page 1
INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
2
antineutrophil cytoplasmic antibody (pANCA)
has been detected in 60-70% of UC patients,
but also in 40% of CD patients. Due to its low
sensitivity, pANCA is not typically used
diagnostically; however, it may be useful in
patients lacking other clinical or pathologic
findings of UC.2
Classification
In general, patients with mild UC
experience four or less stools per day, with or
without blood, and do not present with signs of
systemic toxicity. Patients with moderate UC
experience more frequent bowel movements
and minimal systemic effects. Severe UC is
defined by more than six bloody stools a day
and signs of systemic toxicity.3 Fulminant
disease classification includes more than ten
stools a day with continuous bleeding, signs of
systemic toxicity, and abdominal tenderness
and distension.3 One severity scoring tool
classifies remission, mild, moderate, or severe
disease based on composite scores. The rubric
is often referred to as the Ulcerative Colitis
Disease Activity Index (UCDAI) (Table 1). The
four variables assessed are stool frequency,
extent of rectal bleeding, colonic mucosal
appearance, and the physician’s assessment of
disease. Each variable is graded from 0-3, and
the sum is used for classification.4 However, it is
still imperative to review patient specific
symptomatology concerns such as abdominal
pain, nocturnal bowel patterns, urgency, and
fear of incontinence.
[Type text]
Table 1: Ulcerative Colitis Disease Activity Index4
Stool frequency
Normal
0
1-2 stools/day > normal
1
3-4 stools/day > normal
2
> .4 stools/day > normal
3
Rectal bleeding
None
0
Streaks of blood
1
Signs of systemic toxicity
Heart rate > 90 bpm
Temperature > 37.5°C
Hemoglobin < 10.5 gm/dL
ESR > 30 mm/hr
Obvious blood
Mostly blood
2
3
Mucosal appearance
Normal
0
Mild friability
1
Moderate friability
2
Exudation, spontaneous bleeding
3
Physician’s rating of disease activity
Normal
0
Mild
1
Moderate
2
Severe
3
Total index score ranges:
0-2=Remission
3-6=Mild
7-10=Moderate
> 10=Severe
Location is another important item to
address during classification, particularly for
treatment options. Table 2 describes UC
locations by the extent of inflammation known
as proctitis, proctosigmoiditis, left-sided colitis,
and pancolitis. Also to note are locations distal
or proximal to the descending colon, which may
decide treatment routes. Distal colitis is best
treated with topical agents, whereas proximal
colitis may require oral or combination
therapy.2
Page 2
INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
2
Table 2: Locations of Ulcerative Colitis2
Distal colitis
Proctitis - confined to the last six to seven inches of the rectum
Proctosigmoiditis - extends to the sigmoid colon
Proximal colitis
Left-sided colitis – extends to the descending colon, and may reach the splenic
flexure
Pancolitis – extends through the entire colon and cecum
Treatment Options
Medication management should be
based upon disease distribution, response to
previous treatments, side-effect profile, and
patient preferences. Goals of therapy include
inducing and maintaining remission, improving
quality of life, providing mucosal healing,
avoiding colectomy, minimizing cancer risk, and
reducing the need for long-term
corticosteroids.2 Medication doses and uses are
differentiated by whether induction or
maintenance of remission is goal. Available drug
classes for mild to moderate UC include oral
and topical aminosalicylates, oral or topical
steroids, and oral thiopurines.
In distal colitis, maximum benefit has
been seen with combining oral and topical
aminosalicylate agents versus either treatment
alone.2 Topical mesalamine is also more
effective than topical steroids or oral
aminosalicylates.2 Since proctitis and
proctosigmoiditis are limited to the rectum,
topical treatment with suppositories or enemas
are preferred dosage forms, although
suppositories may be more tolerable for some
patients.2 Proctitis is best treated with
suppositories, which can reach up to ten
centimeters within the rectum.
Proctosigmoiditis is best treated with an enema,
which can reach the proximal sigmoid colon and
splenic flexure in patients able to retain them.
Foam, available as hydrocortisone, has potential
to reach between 15-20 centimeters.2
Advantages of topical versus oral medications
for UC include a faster response, less frequent
[Type text]
dosing, and less systemic absorption.2 If
patients are unable to tolerate topical therapy,
oral therapy is an alternative, however,
response may be delayed.5
For more extensive disease, oral
aminosalicylate therapy should be utilized first.2
Patients failing to achieve remission should
then trial oral and topical aminosalicylate
therapy, followed by oral steroids, and lastly
oral thiopurines.2 If patients are unable to
obtain remission within 4-6 weeks of
aminosalicylates and steroid therapy,
thiopurines have also been shown to benefit
patients.2
Aminosalicylates
Available aminosalicylates for UC are
listed in Table 3. Sulfasalazine was the first
aminosalicylate used for IBD treatment and is
comprised of 5-aminosalicylate (5-ASA) and
sulfapyridine components. Adverse effects of
sulfasalazine are attributed to the sulfapyridine
moiety while therapeutic benefits are
attributed to 5-ASA. Sulfasalazine has
traditionally been the first-line agent for
extensive mild to moderate UC, with an
estimated 80% of patients likely to achieve
remission within 4 weeks on daily doses of 46g.10,11 The best advantage of using
sulfasalazine over newer agents could
potentially be a lower cost.2 Guidelines
recommend titrating to a dose of 4-6 g daily,
however, higher doses increase adverse
effects.2 Contraindications for use include
allergies to sulfonamides and salicylates,
Page 3
INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
2
intestinal or urinary obstruction, and
porphyria.12 Common side effects include
nausea, vomiting, dyspepsia, anorexia,
headache, possible urine discoloration,
abdominal pain, skin rash, and fever.12 Men
may experience oligozoospermia which is
reversible approximately two months after
discontinuing use.11 Severe adverse effects
reported include hematologic abnormalities,
systemic lupus erythematosus, and
hepatotoxicity.12 For patients that experience
gastrointestinal intolerance, a lower starting
dose of 1-2 g daily may be helpful.12
Table 3: Available aminosalicylates for UC treatment2,12,16,22,23,25
Generic
name
Sulfasalazine
Mesalamine
Brand name
Strength supplied
Induction dose
Maintenance dose
Azulfidine®
Sulfazine®
500mg tablet
2g/day orally in evenly divided
doses; not exceeding 8-hour
intervals
Azulfidine
Entabs®
Sulfazine
EC®
500mg EC tablet
Asacol®
400mg DR tablet
Asacol HD®
800mg DR tablet
Delzicol®
400mg DR
capsule
Lialda®
1.2g DR tablet
Pentasa®
250mg CR &
500mg CR
capsule
0.375gm ER
capsule
1g suppository
3-4g/day orally in
evenly divided
doses; not
exceeding 8-hour
intervals
3-4g/day orally in
evenly divided
doses; not
exceeding 8-hour
intervals
800mg orally 3
times daily for 6
weeks
1.6g orally 3 times
daily for 6 weeks
800mg orally 3
times daily (1 hour
before or 2 hours
after a meal) for 6
weeks
2.4 - 4.8 g orally
once daily with
food for up to 8
weeks
1g orally 4 times
daily for up to 8
weeks
-
Apriso®
Canasa®
[Type text]
1 suppository
rectally (retain for
at least 1 to 3
hours) at bedtime
2g/day orally in evenly divided
doses; not exceeding 8-hour
intervals
1.6g/day orally in divided doses
1.6g orally daily in divided doses
2.4g orally once daily with food
1g orally 4 times daily
1.5g orally once daily in the
morning
500 mg – 1g suppository rectally
at bedtime*
Page 4
INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
2
Balsalazide
Olsalazine
Rowasa®
sfRowasa®
4gm/60mL
enema
Colazal®
750mg capsule
Giazo®
1.1g tablet
Dipentum®
250mg capsule
for 3-6 weeks
1 enema rectally
at bedtime (retain
for 8 hours) for 36 weeks
2.25g orally 3
times daily for 8 12 weeks
3.3g orally twice
daily for up to 8
weeks in male
patients
-
2-4g enema rectally at bedtime*
-
-
1g/day orally in 2 divided doses
with food
*Unlabeled FDA indication
Abbreviations: EC=enteric coated, DR=delayed release, ER= extended release
The newer 5-ASA formulations,
mesalamine, balsalazide, and olsalazine, were
developed to provide therapeutic effects of 5ASA and to increase patient tolerability. They
have demonstrated superiority to placebo and
equivalence to sulfasalazine in acute therapy.2
The available therapies can be overwhelming at
first glance, but can be differentiated once
formulations are reviewed. Eighty percent of
patients unable to tolerate sulfasalazine are
able to be treated with a newer agent.2
The pH increases with ascension into
the intestinal tract, requiring pH specific
formulations. Mesalamine only provides
therapeutic use when in direct contact with the
inflamed colon; therefore, pH specific delivery
systems were required for creating mesalamine
as an oral medication. Coatings used to prevent
absorption throughout the gastrointestinal tract
include Eudragit-S, Eudragit-L, ethylcellulose,
and Multi-Matrix System (MMX).13
Asacol®, Asacol HD®, and Delzicol® are
coated with Eudragit-S resin polymer that
disintegrates at a pH greater than 7. The
Eudragit-S coating allows mesalamine to be
delivered to the terminal ileum and proximal
[Type text]
colon.13 Bioequivalence between Delzicol® and
Asacol HD® or Asacol® and Asacol HD® have not
been established and are not interchangeable.16
Mesalamine was first approved with a daily
dose of 2.4g, but the ASCEND I and II trials were
completed to gather safety and efficacy results
of a higher 4.8g dose (Tables 4 and 5). To
summarize the studies, patients with mild UC
may be treated with 2.4g/day, since 4.8 g/day
did not provide additional benefit.14,15 For
patients with moderate UC, the higher dose is
more likely to help achieve overall
improvement, and therefore, can benefit from
starting at the 4.8 g/day dose.14,15 For both
treatment arms, quality of life and
Inflammatory Bowel Disease Questionnaire
(IBDQ) scores improved from baseline to week
6 of therapy.14 The ASCEND II trial, however, did
not find a significant statistical difference
between dose groups for improvement in stool
frequency, rectal bleeding, physician’s global
assessment (PGA), or sigmoidoscopy scores.15
Page 5
INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
2
Table 4: Results from the ASCEND I trial14
Primary outcome results
Mesalamine DR 2.4g Mesalamine DR 4.8g
n=154
n=147
Overall improvement (%)
51
56
p=0.441
Days for clinical assessments to resolve
24
15
(rectal bleeding, stool frequency)
Secondary outcome results with moderate disease
Mesalamine DR 2.4g Mesalamine DR 4.8g
n=96
n=84
Treatment success (%)
57
72
p=0.0719
Median days to symptom relief for stool
frequency and rectal bleeding
p=0.1316
28
20
Table 5: Results from the ASCEND II Trial15
Asacol 2.4g/day
Mesalamine 4.8g/day
n=130
n=124
Primary outcome results
Overall improvement (%)
59.2
71.8
Secondary outcome results
Mesalamine DR 2.4g Mesalamine DR 4.8g
n=130
n=124
Median days for clinical assessments to
32
21
resolve
(rectal bleeding, stool frequency)
p value
p=0.0384
p value
p < 0.05
p=0.1397
Pentasa® is a controlled-release dosage form containing mesalamine microgranules
encapsulated in a moisture-sensitive ethylcellulose coating, which is not pH dependent. This allows slow
release of the medication through a semi-permeable coating.13 In one of the first studies comparing
Asacol® to Pentasa®, Asacol® provided a greater reduction in UCDAI scores, percentage of patients
achieving remission, and experiencing an overall improvement.17 The study, however, did not use the
target dose of 4g/day.
The newest mesalamine formulation is a Multi-Matrix System (MMX) allowing for once daily
dosing, also decreasing pill burden for patients. Lialda® combines the Eudragit-S resin polymer and MMX
to deliver mesalamine to the ileum and cecum.13 In mild to moderate UC, patients taking mesalamine
MMX at a dose of 2.4g or 4.8g/day were able to achieve clinical and endoscopic remission at
comparable rates compared to placebo (Table 6).18,19
[Type text]
Page 6
INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
2
Clinical & endoscopic
remission (%)
Clinical improvement
(%)
Clinical remission (%)
Sigmoidoscopic
Improvement (%)
Treatment failure (%)
Table 6: Results from Lichtenstein GR, Kamm MA, et al19
Placebo
Mesalamine MMX
Mesalamine MMX
n=85
2.4g/day given BID
4.8g/day given once daily
n=88
n=89
Primary outcome results
12.9
34.1***
29.2
p=0.009
Secondary outcome results
25.9
55.7***
59.6***
18.8
35.3
37.5**
61.4
32.6*
69.7**
54.1
28.4***
24.7***
***P<0.001
**P<0.01
*P<0.05
Apriso® contains mesalamine granules
within an Eudragit-L coating triggered to
dissolve at a pH of 6 or greater.13 In one study,
78.9% of patients taking Apriso® remained in
remission at 6 months compared to 58.3% on
placebo (p < 0.001).20 Apriso® is only approved
for remission maintenance, is taken once daily,
and administration should be separated by at
least two hours from antacids.16
In other studies, balsalazide and
olsalazine did not provide statistically significant
results, however they were shown to be more
tolerable than sulfasalazine and are options for
patients with sulfa allergies.21,22 Olsalazine,
however, produced an adverse dose-related
diarrhea effect.23 Colazal® is approved for use in
patients between ages 5-17.24 Giazo®, during
clinical trials, did not provide therapeutic
benefit in females and is recommended for use
only in males.16,24
Topical 5-ASA preparations include
suppositories and enemas. Mesalamine
suppositories are effective in maintaining
remission in proctitis, whereas mesalamine
enemas are effective in patients with
proctosigmoiditis.2 Rowasa® and sfRowasa®
differ in sulfite content, allowing for patients
with sulfite allergies to use sfRowasa®. Topical
[Type text]
application side effects consist of
gastrointestinal symptoms, arthralgia, asthenia,
dizziness, and/or headache. In elderly patients,
blood dyscrasias may occur.16 Patients should
carefully handle Canasa® as staining with
contacted surfaces and clothes can occur.25 For
enema and suppository treatment, patients
should be counseled to empty their bowels
before use, if possible.
Nephrotoxicity with 5-ASAs is rare, but
patients with renal impairment should use
aminosalicylates with caution.2 Appropriate
laboratory monitoring include a baseline serum
creatinine before treatment begins, every 3-6
months during the first year of therapy, and
annually thereafter.26
Glucocorticosteroids
Glucocorticoids were first used in the
1950s for IBD, however due to their adverse
and long-term use effects, they have been
reserved for patients failing to achieve
remission with oral and topical aminosalicylate
therapy.2,27,28 First-line treatment with steroids
should be avoided as one retrospective review
found early corticosteroid use increased the
risk of relapse and steroid-dependence.29
Glucocortocoid adverse effects include
Page 7
INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
2
Cushingoid appearance, emotional and
psychiatric disturbances, increased risk for
infection, metabolic disturbances, ocular
changes, and decreased bone mineral density.2
Patients should have an annual eye exam if they
are continued on steroids, should be considered
for dual energy X-ray scanning, and should be
monitored for endocrine disorders.2
Glucocorticosteroids are effective in
inducing remission and doses are listed in Table
7. In one meta-analysis, steroids reduced
remission failure in 54% of patients compared
to 79% on placebo, with a number needed to
treat (NNT) of 3.27 A prednisone dose range
between 20-60mg daily have been used in
randomized trials.2 Patients can expect to see
improvement within 10 to 14 days of treatment
initiation.2,30 Once clinical improvement has
been reached, the dose should be tapered
down 5-10mg weekly until the dose reaches
20mg daily, followed by another dose decrease
of 2.5mg weekly.2
Hydrocortisone enemas are available as
Colocort® and Cortenema®.31 Generally, they
are used until the patient reaches clinical and
proctological remission. Symptoms may
Brand (generic) drug name
Methylprednisolone*
Prednisone*
Cortifoam®
(hydrocortisone acetate)
Colocort®, Cortenema®
(Hydrocortisone)
Entocort EC®
(budesonide)*
Uceris® (budesonide)
decrease within 3-5 days of therapy, but
proctological improvement may not occur until
2-3 months of therapy.32,33 After completing 21
days of therapy, the dose of hydrocortisone
enemas should be decreased to every other
night for 2-3 weeks, and then finally
discontinued.32,33 If patients fail to achieve
improvement within 2-3 weeks of enema
initiation, therapy should be discontinued.
Important counseling points include shaking the
bottle well before administration, and retaining
the enema for at least an hour, and all night if
possible.32,33
Another option for topical therapy is
foam, available as Cortifoam®, which may be
more tolerable for patients unable to retain
enemas. Hydrocortisone acetate 10% rectal
foam is supplied with an applicator, and when
filled properly, delivers 90mg of hydrocortisone
acetate.34 Patients can expect to have a
minimum of 14 applications with one aerosol
can.34 Administration technique include shaking
the canister well before each use and
positioning the canister upright when
dispensing.30,34
Table 7: Glucocorticosteroids for UC 2,3134,37,38
How supplied
Suggested dosing
Varies
4-48mg PO daily
Varies
40-60mg orally every morning or in two
divided doses
15g aerosol
1 applicatorful rectally 1-2 times daily for 2-3
weeks, then every other day thereafter
100mg/60mL enema
1 enema rectally every night for 21 days or
until remission, then every other night for 2-3
weeks
3mg DR capsule
9mg orally daily in the morning for up to 8
weeks
9mg MMX capsule
9mg orally daily in the morning for up to 8
weeks
*Unlabeled FDA indication
DR= delayed-release
MMX= Multi-Matrix System
[Type text]
Page 8
INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
2
Budesonide, like mesalamine, requires direct contact with inflamed colon to provide therapeutic
use in UC. Delayed release budesonide, currently available as Entocort EC®, does not have an approved
indication for UC, but has been compared to conventional UC treatments. Through the development of
an MMX extended-release dosage form, the role of budesonide has expanded into the oral treatment
options for inducing remission in mild to moderate UC. The oral formulation helps deliver the
glucocorticosteroid throughout the length of the colon. The CORE I Study compared budesonide MMX to
standard oral mesalamine therapy. During the 8 week trial, more patients receiving MMX budesonide
compared to all other treatment arms were able to achieve clinical and endoscopic remission (Table 8).35
Due to its extensive first pass metabolism, budesonide was hypothesized to have fewer systemic effects,
and the study reported similar AEs among all treatment groups.35
Table 8: Results from the CORE I35
Placebo
n=121
Budesonide MMX
9mg
n=123
Budesonide MMX
6mg
n=121
Mesalamine DR
2.4g
n=124
13.2
12.1
0.1393
0.2200
Combined clinical and
endoscopic remission (%)
7.4
Primary endpoint results
17.9
P value
-
0.0143
Clinical improvement (%)
P value
24.8
Secondary endpoint results
33.3
30.6
33.9
0.1420
0.3146
0.1189
Endoscopic improvement (%)
Histological healing (%)
P value
Symptom resolution (%)
P value
33.1
6.6
41.5
4.1
35.5
7.4
33.1
11.3
0.3759
0.8014
0.2003
16.5
28.5
0.0258
¥
28.9
0.0214
¥
25
0.1025
*Statistically significant (p < 0.025)
¥
Statistically significant (p < 0.05)
The CORE II study further evaluated budesonide MMX to Entocort EC®. A larger percentage of
participants receiving budesonide MMX achieved remission, clinical improvement, endoscopic
improvement, histological healing, and symptom resolution (Table 9).36 Overall, increased
glucocorticosteroid-related AEs were similar among treatment arms. Mean cortisol level reductions
occurred in budesonide MMX and DR treatment groups, but remained within normal ranges.36
[Type text]
Page 9
INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
2
Clinical & endoscopic remission
(%)
P value
Table 9: Results from the CORE II36
Placebo
Budesonide
n=89
MMX 9mg
n=109
Primary endpoint results
4.5
17.4
Budesonide
MMX 6mg
n=109
Entocort EC®
n=103
8.3
12.6
0.0481+
0.0047*
Secondary endpoint results
33.7
42.2
25.7
33
Endoscopic improvement (%)
31.5
42.2
25.7
36.9
Histological healing (%)
6.7
16.5*
9.2
13.6
Symptom resolution (%)
11.2
23.9*
13.8
18.4
Clinical improvement (%)
α=0.025
+=0.05
*p < 0.05
Multi-Matrix System budesonide 9mg
was introduced into the US market in January
2013 as Uceris®. Uceris® should be taken once
daily in the morning for up to eight weeks and
has only been studied for remission induction.38
Uceris® should not be chewed, crushed, or
broken due to the MMX formulation. Because
budesonide’s release is pH dependent, patients
should avoid taking acid reducing agents such
as proton pump inhibitors, H2 blockers, and/or
antacids38. Common AEs patients should be
counseled on include diarrhea, nausea,
arthralgia, and headache.38 Postmarketing
reporting has reported anaphylactic reactions,
benign intracranial hypertension, and mood
swings.38
Thiopurines
Thiopurines are a class of
immunomodulators available as azathioprine
(AZA) and mercaptopurine (MP). The
recommended dosing for induction and
maintenance of remission are listed in Table 10.
Thiopurine methyltransferase (TPMT) plays a
[Type text]
critical role in the metabolism of AZA and MP.
Genetic TPMT enzymatic activity varies, possibly
resulting in increased adverse effects or
reduced response to treatment. The active
metabolite 6-thioguanine (6-TGN) has been
associated with myelotoxicity while 6-methylmercaptopurine (6-MMP) has been associated
with hepatotoxicity. Patients with decreased
TPMT activity tend to accumulate more 6-TGN
resulting in increased bone marrow
suppression. Patients with intermediate TPMT
activity are recommended to start at 50% of the
recommended starting dose. Patients with
minimal TPMT activity should not be treated
with thiopurines due to the risk of developing
severe, life-threatening myelotoxicity.39
Thiopurines find their place in therapy
for remission induction in patients refractory to
oral steroids or who continue to have active
disease, but do not require intravenous
therapy.2 In remission maintenance, thiopurines
are used to transition patients from steroiddependence. In a meta-analysis assessing the
efficacy of AZA and MP, they were found to be
Page 10
INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
2
more beneficial in maintaining remission
compared to placebo.40
Patients should be made aware that up
to 3-6 months may be needed before
therapeutic effects are seen.2 Common adverse
effects of MP include drug fever,
hyperpigmentation, and hyperuricemia. Nausea
and vomiting are the most reported adverse
effects with AZA.43 Due to the high risk of
myelosuppression, hepatotoxicity, and infection
from both agents, routine laboratory
Brand (generic) drug name
Imuran® (azathioprine)*
Azasan® (azathioprine)*
Purinethol®
(mercaptopurine)*
*Unlabeled FDA indication
Table 10: Thiopurines for UC treatment2,43,44
Strength
Induction dose
supplied
50mg tablet
1.5-2.5 mg/kg/day orally
75mg tablet
1.5-2.5 mg/kg/day orally
100mg tablet
50 mg tablet
50mg once daily or 11.5mg/kg/day orally
Pharmacist’s role
Pharmacists can take an active role in
counseling patients for possible exacerbating
triggers such as diet, smoking habits, or using
nonsteroidal anti-inflammatory drugs.45 Diets
high in red or processed meat, margarine, and
alcohol have been linked to relapses.46 Evidence
supporting the use of omega-3 fatty acids is
weak.47 Dairy and lactose free diets were not
shown to worsen symptoms or provide a
greater benefit to patients.47
As pharmacists, smoking cessation
should be promoted and encouraged. There is
question, however, if cigarette smoking is
beneficial for patients with UC. Some studies
have demonstrated protection against
developing UC and improving symptoms.
Compared to placebo, transdermal nicotine was
more effective for inducing remission as well.
However, the advantages of smoking or
nicotine use are not superior to conventional
UC treatment options, and the consequences
[Type text]
monitoring is required. CBCs and liver function
tests (LFTs) should be completed at least every
other week for the first 6-8 weeks of therapy,
followed by once every three months
thereafter.41 Pancreatitis has also been
reported within 3 to 4 weeks of therapy and is
dose-independent.42 Signs and symptoms of
malignancy (splenomegaly, hepatomegaly,
abdominal pain, persistent fever, night sweats,
and weight loss) should also be monitored.43,44
Maintenance dose
1.5-2.5mg/kg/day orally
1.5-2.5mg/kg/day orally
1-1.5mg/kg/day orally
outweigh the benefits.2,48 Therefore, nicotine
has a limited role in UC treatment, particularly
in select cases refractory to available treatment
options.2,48
Live vaccines are contraindicated for
patients on glucocorticoid steroids or
thiopurines. If live vaccinations are warranted,
they should be administered 4-12 weeks prior
to initiation of treatment. All patients should
receive influenza and pneumococcal vaccines.26
It’s also imperative pharmacist counsel
patients on medication adherence. A reported
43-72% of patients are nonadherent due to
adverse effects or failing to use maintenance
therapy.49 Barriers to adherence surveyed
include lifestyle, risk of side effects, and
financial factors. An increased risk of relapse,
hospitalizations, and surgery may result from
lack of complicance.13 Providing disease
awareness and emphasizing the importance of
adherence may improve patients’ willingness to
continue their treatment regimens. Along with
Page 11
INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
2
side effect profiles and drug-drug interactions,
other patient specific factors that should be
evaluated prior to and during therapy include
health status, financial resources, willingness to
complete laboratory monitoring, and
perception of pill burden.
In summary, treating mild to moderate
UC should be by the “step-up” approach,
utilizing aminosalicylates, then
glucocorticosteroids, and lastly
immunomodulators. Top-down therapy has
been evaluated for more aggressive treatment
options in hope of altering disease progression;
however its efficacy has not been seen in UC.
The Pharmacists Education Foundation (PEF) is accredited by the Accreditation Council for
Pharmacy Education (ACPE) as a provider of continuing pharmacy education. To receive continuing
pharmacy education (CPE) credit, pharmacists MUST COMPLETE AN ONLINE QUIZ AND EVALUATION
FORM. A score of 70% or above is required to receive CPE credit. The link to the quiz can be accessed
from the MEMBERS page of the IPA website at www.indianapharmacists.org. This is a free service to
IPA members in 2014. Initial release date: 3/24/14. Expiration Date: 3/24/17 Questions: Call IPA at
(317) 634-4968.
References:
1. What is Ulcerative Colitis? Available at: http://www.ccfa.org/what-are-crohns-and-colitis/whatis-ulcerative-colitis/. Accessed 5/14/13.
2. Kornbluth A, Sachar DB, et al. Ulcerative Colitis Practice Guidelines in Adults: American College
of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105:501–523.
3. Satsangi J, Silverberg MS, et al. The Montreal classification of inflammatory bowel disease:
controversies, consensus, and implications. Gut. 2006 June;55(6):749-53.
4. Tursi A, et al. Treatment of Relapsing Mild-to-Moderate Ulcerative Colitis With the Probiotic
VSL#3 as Adjunctive to a Standard Pharmaceutical Treatment: A Double-Blind, Randomized,
Placebo-Controlled Study. Am J Gastroenterol. 2010;105:2218-2227.
5. Safdi M, DeMicco M, et al. A double-blind comparison of oral versus rectal mesalamine versus
combination therapy in the treatment of distal ulcerative colitis. Am J Gastroenterol.
1997;92(10):1867.
6. Chapman NJ, Brown ML, et al. Distribution of mesalamine enemas in patients with active distal
ulcerative colitis. Mayo Clin Proc. 1992;67(3):245.
7. Marteau P, Probert CS, 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(7):960.
[Type text]
Page 12
INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
2
8. Marshall JK, Irvine EJ. Rectal corticosteroids versus alternative treatments in ulcerative colitis: a
meta-analysis. Gut. 1997;40(6):775.
9. Cohen RD, Woseth DM, et al. A meta-analysis and overview of the literature on treatment
options for left-sided ulcerative colitis and ulcerative proctitis. Am J Gastroenterol.
2000;95(5):1263.
10. DIick AP, Grayson MJ, et al. Controlled trial of sulphasalazine in the treatment of ulcerative
colitis. Gut. 1964;5:437-42.
11. O’Morain C, Smethurst P, et al. Reversible male infertility due to sulphasalazine: studies in man
and rat. Gut. 1984;25,1078-1084.
12. Sulfasalazine. In: Lexi-Drugs Online [Internet Database]. Hudson, OH: Lexi-Comp, Inc. Updated
2013 May 20.
13. Ham M, Moss AC. Mesalamine in the treatment and maintenance of remission of ulcerative
colitis. Expert Rev Clin Pharmacol. 2012 March ; 5(2): 113–123.
14. Hanauer SB, Sandborn WJ, et al. Delayed release oral mesalamine 4.8 g/day (800 mg tablets)
compared to 2.4 g/day (400 mg tablets) for the treatment of mildly to moderately active
ulcerative colitis: The ASCEND I trial. Can J Gastroenterol. 2007;21(12):827–834.
15. Hanauer SB, Sandborn WJ, et al. Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet)
for the treatment of moderately active ulcerative colitis: the ASCEND II trial. Am J Gastroenterol.
2005 Nov;100(11):2478-85.
16. Mesalamine. In: Lexi-Drugs Online [Internet Database]. Hudson, OH: Lexi-Comp, Inc. Updated
2013 May 28.
17. Ito H, Lida M, et al. Direct comparison of two different mesalamine formulations for the
induction of remission in patients with ulcerative colitis: a double-blind, randomized study.
Inflamm Bowel Dis. 2010;16:1567-74.
18. Sandborn WJ, Kamm MA, et al. MMX Multi Matrix System mesalazine for the induction of
remission in patients with mild-to-moderate ulcerative colitis: a combined analysis of two
randomized, double-blind, placebo-controlled trials. Aliment Pharmacol Ther. 2007;26(2):205–
215.
19. Lichtenstein GR, Kamm MA, Boddu P, et al. Effect of once- or twice-daily MMX mesalamine
(SPD476) for the induction of remission of mild to moderately active ulcerative colitis. Clin
Gastroenterol Hepatol. 2007;5(1):95–102.
20. Lichtenstein GR, Gordon GL, Zakko S, Murthy U, Sedghi S, Pruitt R, et al. Clinical trial: once-daily
mesalamine granules for maintenance of remission of ulcerative colitis – a six-month placebocontrolled trial. Aliment Pharmacol Ther. 2010;32:990-9.
21. Green JR, Mansfield JC, Gibson JA, Kerrs GD, Thornton. A double-blind comparison of
balsalazide, 6.75 g daily, and sulfasalazine, 3 g daily, in patients with newly diagnosed or
relapsed active ulcerative colitis. Aliment Pharmacol Ther. 2002;16:61-8.
22. Kruis W, Brandes JW, Schreiber S, Theuer D, Krakamp B, Schutz E, et al. Olsalazine vs
mesalamine in the treatment of mild to moderate ulcerative colitis. Aliment Pharmacol Ther.
1998;12:707-15.
23. Olsalazine. In: Lexi-Drugs Online [Internet Database]. Hudson, OH: Lexi-Comp, Inc. Updated 2013
May 20.
[Type text]
Page 13
INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
2
24. Balsalazide. In: Lexi-Drugs Online [Internet Database]. Hudson, OH: Lexi-Comp, Inc. Updated
2013 May 20.
25. Canasa® [package insert]. Axcan Pharma Inc.; Birmingham (AL): 2008 Oct.
26. MacDermott, RP. Management of mild to moderate ulcerative colitis. In: UpToDate, Basow, DS
(Ed), UpToDate, Waltham, MA, 2013.
27. Ford AC, Bernstein CN, et al. Glucocorticosteroid Therapy in Inflammatory Bowel Disease:
Systematic Review and Meta-Analysis. Am J Gastroenterol. 2011;106:590–599.
28. Cohen RD, Woseth DM, et al. A meta-analysis and overview of the literature on treatment
options for left-sided ulcerative colitis and ulcerative proctitis. Am J Gastroenterol.
2000;95(5):1263.
29. Garcia-Planella E, Manosa M, et al. Long-term outcome of ulcerative colitis in patients who
achieve clinical remission with a first course of corticosteroids. Digestive and Liver Disease.
2012;44:206–210.
30. Garud S, Peppercorn MA. Ulcerative colitis: current treatment strategies and future prospects.
Therapeutic Advances in Gastroenterology. (2009) 2(2) 99–108.
31. Hydrocortisone (Topical). In: Lexi-Drugs Online [Internet Database]. Hudson, OH: Lexi-Comp, Inc.
Updated 2013 May 28.
32. Cortenema® [package insert]. ANI Pharmaceuticals, Inc.; Baudette (MN): 2011 Nov.
33. Colocort® [package insert]. Paddock Laboratories, Inc.; Minneapolis (MN): 2008 Aug.
34. Cortifoam® [package insert]. Alaven Pharmaceutical LLC.; Marietta (GA): 2008 Aug.
35. Sandborn WJ, Travis S, et al. Once-Daily Budesonide MMX Extended-Release Tablets Induce
Remission in Patients with Mild to moderate ulcerative colitis: Results from the CORE I study.
Gastroenterology. 2012;143:1218-1226.
36. Travis SPL, Danese S, et al. Once-daily budesonide MMX in active, mild-to-moderate ulcerative
colitis: results from the randomized CORE II study. Gut. 2013;0:1–9.
37. Budesonide (systemic therapy and oral inhalation): Drug information. In: Lexi-Drugs Online
[Internet Database]. Hudson, OH: Lexi-Comp, Inc. Updated 2013 May 28.
38. Uceris® [package insert]. Santaurs Inc.; San Diego (CA): 2013 Jan.
39. Udayakumar N, Shen B. Pros and Cons of Medical Management of Ulcerative Colitis. Clin Colon
Rectal Surg. 2010;23:227–238.
40. Gisbert JP, Linares PM, et al. Meta-analysis: the efficacy of azathioprine and mercaptopurine in
ulcerative colitis. Aliment Pharmacol Ther. 2009; 30(2):126–137.
41. MacDermott, RP. 6-mercaptopurine (6-MP) metabolite monitoring and TPMT testing in the
treatment of inflammatory bowel disease with 6-MP or azathioprine. In: UpToDate, Basow, DS
(Ed), UpToDate, Waltham, MA, 2013.
42. Mardini HE. Azathioprine-induced pancreatitis in Crohn’s disease: a smoking gun or guilt by
association. Aliment Pharmacol Ther. 2005;21(2):195 .
43. Azathioprine. In: Lexi-Drugs Online [Internet Database]. Hudson, OH: Lexi-Comp, Inc. Updated
2013 May 20.
[Type text]
Page 14
INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
2
44. Mercaptopurine. In: Lexi-Drugs Online [Internet Database]. Hudson, OH: Lexi-Comp, Inc.
Updated 2013 May 20.
45. Grimpen F, Pavli P. Advances in the management of inflammatory bowel disease. Internal
Medicine Journal. 2010;40:258–264.
46. Jowett SL, Seal CJ, et al. Influence of dietary factors on the clinical course of ulcerative colitis: a
prospective cohort study. Gut. 2004;53(10):1479-1484.
47. Richman E, Rhodes JM. Review article: evidence-based dietary advice for patients with
inflammatory bowel disease. Aliment Pharmacol Ther. 2013; 38: 1156–1171.
48. Lunney PC, Leong RWL. Review Article: Ulcerative Colitis, Smoking and Nicotine Therapy.
Aliment Pharmacol Ther. 2012;36(11):997-1008.
49. Moradkhani A, Kerwin L, et al. Disease-Specific Knowledge, Coping, and Adherence in Patients
with Inflammatory Bowel Disease. Dig Dis Sci. 2011;56:2972–2977.
[Type text]
Page 15

Download Report