Balsalazide disodium for the treatment of ulcerative colitis Drug Profile

Drug Profile
Balsalazide disodium for the
treatment of ulcerative colitis
Expert Rev. Gastroenterol. Hepatol. 2(2), 177–184 (2008)
Seema A Patil and
Alan C Moss†
†
Author for correspondence
Center for Inflammatory
Bowel Disease, Rose 1/East,
Beth Israel Deaconess,
Medical Center, 330
Brookline Avenue, Boston,
MA 02215, USA
Tel.: +1 617 667 1088
Fax: +1 617 667 2134
amoss@bidmc.harvard.edu
5-aminosalicylates remain the first-line treatment for patients with ulcerative colitis. A number
of formulations are available for the treatment of active ulcerative colitis, including
encapsulated mesalazine and mesalazine in combination with other molecules. Balsalazide is
an aminosalicylate prodrug that releases mesalazine in the colon, thus exerting its multiple
anti-inflammatory effects in areas of colitis. This review will examine the pharmacological and
therapeutic features of balsalazide as an anti-inflammatory agent in ulcerative colitis. The
introduction of novel aminosalicylate formulations and an appreciation of their molecular
mode of action, has renewed interest in these agents in both maintenance of disease
remission and cancer prevention.
KEYWORDS: 4-ABA • balsalazide • balsalazide disodium • balsalazine • BX661A • Colazal® • Colazide®
Ulcerative colitis is a chronic inflammatory
disease characterized by mucosal inflammation
of the colon. The clinical course involves
recurrent episodes of active disease separated
by periods of remission. The inflammation
typically involves the rectum and can extend
continuously and proximally to involve the
entire large intestine. Symptoms can include
bloody diarrhea, tenesmus, urgency and
abdominal pain [1].
The etiology of ulcerative colitis has not been
completely elucidated. However, recent
advances in the understanding of the pathogenesis of inflammatory bowel disease (IBD)
have revealed epithelial barrier function and
innate and adaptive immunity to be key factors. It appears that the regulation of the
immune response to colonic microflora, both
at the level of innate protective mechanisms,
and mucosal humoral responses, is the pivotal
factor that determines disease initiation. In
patients with genetic susceptibility, the disruption of immune regulation can result in an
enhanced inflammatory response to commensal
bacteria [2].
The severity of the symptoms of ulcerative colitis is determined by the degree of inflammation
and the anatomic extent of disease. Mild disease in
the distal colon usually causes urgency, diarrhea
and rectal bleeding. Moderate disease increases the
diarrhea frequency, and induces abdominal pain
and cramps. Severe disease can manifest in any
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10.1586/17474124.2.2.177
part of the colon and lead to greater than ten stools
a day, fever, anemia requiring blood transfusion
and weight loss [3].
The drug 5-aminosalicylic acid (5-ASA) is a
potent anti-inflammatory agent in the colon,
and is first-line therapy for inducing and maintaining remission in active mild-to-moderate
ulcerative colitis. Its efficacy and safety have
been confirmed in numerous clinical trials.
Overview of the market
Inflammatory bowel disease affects approximately
1 million individuals in the USA, and 4 million
people worldwide, the majority of whom are prescribed medication for induction or maintenance
of remission [4]. At any point in time, over 75%
of patients with IBD are taking prescription medication, which is threefold higher than the nonIBD population [5]. In addition to standard therapies, developments in molecular biology have
identified many novel therapeutic targets that will
add to patients’ future options. Currently, 24 new
drugs are registered in the USA in development
for ulcerative colitis and 36 for Crohn’s disease
[101]. As a consequence, the market for drugs for
IBD patients is valued at US$1–2 billion in the
USA, a number that is expected to rise [4]. The
mesalazine market segment alone for ulcerative
colitis is estimated to be worth approximately
$800 million in the USA, and $1.6 billion worldwide. Asacol® (mesalazine) has traditionally held
© 2008 Future Drugs Ltd
ISSN 1747-4124
177
Drug Profile
Patil & Moss
50–70% of the mesalazine market in the USA and Europe, with
Pentasa (mesalazine) approximately 15–20% and Colazal® (balsalazide) about 5–10%. The newly introduced Lialda™ (Mezavant; mesalazine) has gained approximately 5% of the market
since its introduction in 2007.
Given the multifactorial etiology of ulcerative colitis, medical
management has centered on treating acute inflammation and
preventing flares. Oral aminosalicylates are the mainstay of
treatment of mild-to-moderate presentations of active disease
and maintenance of remission. The currently available preparations are sulfasalazine (Azulfidine), mesalazine (Salofalk, Pentasa, Asacol and Lialda), olsalazine (Dipentum®), and balsalazide (Colazal®, Colazide®). Treatment of disease limited to
the rectum and distal sigmoid colon can also be augmented
with topical aminosalicylates (e.g., enemas, suppositories).
Sulfasalazine is the original compound that led to the development of 5-aminosalicylic acid (5-ASAs). It was initially
developed as a treatment for rheumatoid arthritis but was
found to be effective in IBD [6,7]. This prodrug is reduced in
the colon by bacterial azo-reductase to release mesalazine ASA
and sulfapyridine. The 5-ASA compound is responsible for the
anti-inflammatory effects of sulfasalazine while sulfapyridine
accounts for most of its side effects [8].
Initial oral formulations of mesalazine alone were largely
absorbed in the proximal intestinal tract, significantly reducing the
amount that reached the colon. Delayed-release formulations were
developed by coating 5-ASA with ethylcellulose or acrylic resins
membranes that break down at a specific pH in an effort to improve
delivery [9]. In addition, two prodrugs, balsalazide and olsalazine,
were developed by joining mesalazine to an inert carrier molecule
or another mesalazine molecule, respectively. Similar to sulfasalazine, release of the therapeutic component of both of these drugs
requires cleavage by coliform bacterial enzymes in the colon [10].
molecular weight of 437.32 g/mol [102]. It is a prodrug composed
of mesalazine joined by an azo bond to an inert carrier molecule,
4-aminobenzoyl-β-alanine (ABA). The azo bond is cleaved by
bacterial azo-reductases in the colon to release mesalazine. Each
750-mg capsule leads to the release of 267 mg of mesalazine in
the colon.
Pharmacodynamics
The active moiety of balsalazide is mesalazine. The mechanism by which mesalazine exerts its therapeutic effects is not
completely understood, but is thought to include modification of the mucosal prostaglandin profile in the colon, alteration of intestinal microflora, and inhibition of proinflammatory mediators such as nitric oxide, leukotrienes, and
thromboxanes. The peroxisome proliferator-activated receptor (PPAR)γ has emerged as a key receptor mediating the antiinflammatory effects of aminosalicylates. Recent studies have
shown that aminosalicylates are synthetic ligands for PPARγ
in colonic epithelial cells. 5-ASA is able to induce PPARγ
expression, bind PPARγ and induce translocation and conformational change and recruit vitamin D3 receptor interacting
protein (DRIP), a coactivator molecule [11]. Activation of
PPARγ results in the regulation of inflammatory signaling
pathways and impairs mucosal production of inflammatory
cytokines, proliferation of inflammatory cells, and expression
of adhesion molecules.
Balsalazide has also been demonstrated to be a scavenger of
reactive oxygen metabolites and an inhibitor of histamine
release from mast cells in laboratory studies [12,13]. It has been
shown to increase ileal secretion in an animal model, which is a
common feature of azo-bond drugs [14]. Balsalazide also produces a dose-dependent chemopreventive effect on colonic carcinogenesis in animal models [15]. The clinical significance of
these effects in humans is uncertain.
Introduction to balsalazide disodium
Balsalazide is manufactured by Salix Pharmaceuticals, Inc. (NC,
USA) under the trade name Colazal [102] and, since December
2007, by Laboratorios Almirall SA (Barcelona, Spain) under the
trade name Colazide [103]. Colazal was originally approved by the
US FDA in 2000, and is currently licensed for the treatment of
mild-to-moderately active ulcerative colitis in patients aged 5 years
and older. In Europe, Colazide was first approved by the UK Medicines Control Agency in July 1997 as a treatment for acute ulcerative colitis. Multiple clinical trials have demonstrated at least similar efficacy to other aminosalicylate agents in the treatment of
ulcerative colitis. The pharmacodynamic properties, efficacy data
and safety issues of balsalazide will be further elucidated here.
Chemistry
The chemical name of balsalazide disodium is (E)-5-[[4-[[(2-carboxyethyl)amino]carbonyl]phenyl]azo]-2-hydroxybenzoic
acid,
disodium salt, dihydrate (C17H15N3O6Na2·2H2O), with a
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Pharmacokinetics & metabolism
Colonic bacteria produce azo-reductases that reduce the azo
bond of balsalazide, resulting in release of equimolar amounts of
mesalazine and 4-ABA. Administration of 6.75 g of balsalazide
is equivalent to the release of 2.4 g of mesalazine in humans.
The therapeutic effects of mesalazine are exerted via local exposure to the colonic epithelium. Of the total parent compound
administered, 1% is excreted in the urine,and 12% in the feces,
whereas 30% of the total 5-ASA component is excreted in the
urine and 46% in the feces [10,16]. Given that balsalazide relies
on colonic bacteria for its activity, it has been speculated
whether concomitant antibiotic treatment or an individual’s
colonic flora can affect its efficacy. Although there are reports of
decreased azo-reduction in the setting of profuse diarrhea [17],
and a third reduction in the cleavage of sulfasalazine after a
course of ampicillin antibiotics [18], this does not appear to be a
common clinical issue.
Expert Rev. Gastroenterol. Hepatol. 2(2), (2008)
Balsalazide disodium
The pharmacokinetic properties of balsalazide have been well
described [19]. Values were studied in 54 patients who were taking 3–6 g/day of balsalazide for 1 year, normalized to a statim
dose of 3.43 mmol. The peak plasma concentration (Cmax) was
0.324 µmol/l, trough plasma concentration (Cmin)
0.035 µmol/l, area under the plasma concentration–time curve
over 0–12 h 1.34 µmol/l/h and clearance 4.5 l/h. The Cmax of
balsalazide was achieved within 2 h of the dose. Plasma concentrations decreased to Cmin within 8 h. Following a 2.25 g dose
of balsalazide, Cmax values of mesalazine and 4-ABA were
reached after 9 and 10 h [16].
The majority of orally administered balsalazide is eliminated
in the feces. Approximately 25% of its metabolites (mesalazine,
N-acetyl-mesalazine, 4-ABA and N-acetyl-4-ABA) are systemically absorbed after being inactivated by the colonic mucosa
and the liver. Only 10–15% of total balsalazide metabolite
absorption is 4-ABA. Plasma concentration of 4-ABA is found
to be below the level of detection at all times [16].
The pharmacokinetic properties of balsalazide do not
appear to be affected by age in those greater than 60 years.
Cmax and Cmin values, however, were higher in female than
male patients. Fasting appears to slightly increase systemic
absorption of balsalazide and its metabolites; however, adjustment of dosages are not required. Mild renal impairment (creatinine clearance < 80 ml/min) resulted in higher Cmin values
than with normal renal function (0.06 vs 0.02 µmol/l). Clearance of balsalazide was also slightly lower in patients with
mild renal impairment (4.03 vs 4.88 l/h). The areas under the
plasma concentration–time curves, however, were similar with
mildly impaired and normal renal function (1.17 vs
1.37 µmol/l/h) [16].
Balsalazide may increase plasma concentrations of drugs
that are renally secreted, such as methotrexate. In addition,
mesalazine (and mesalazine-containing products) reversibly
inhibit thiopurine methyltransferase, which converts 6-mercaptopurine (MP) to 6-methylmercaptopurine (MMP).
Coadministration of azathioprine/6-MP with mesalazine 4 g
led to increases in serum 6-TG levels and leucopenia in one
study, but balsalazide 6.75 g (mesalazine 2.4 g) did not cause
similar effects [20].
Drug Profile
Clinical efficacy
Balsalazide was first developed in 1983. Animal studies and
human pharmacokinetic studies showed balsalazide to be an
effective method of delivering 5-ASA to the colon while minimizing systemic absorption [10]. Several trials have been conducted to examine the efficacy of balsalazide in inducing
remission in active ulcerative colitis.
Induction of response in active disease
The data comparing balsalazide with delayed-release mesalazine
have demonstrated at least similar efficacy to mesalazine preparations (TABLE 1). In a study by Green et al., balsalazide
6.75 g/day induced complete remission in a significantly
greater proportion of patients with mild-to-moderate ulcerative
colitis than mesalazine 2.4 g/day at 4, 8 and 12 weeks [21].
Remission was also achieved sooner in this trial (10 vs 25 days;
p = 0.003) when compared with mesalazine. Of interest, given
its mode of action, patients with left-sided disease were less
likely (p = 0.052) to achieve complete remission after 4 weeks
(31% balsalazide, 6% mesalazine) than patients with disease in
the proximal colon in this study. However, this was a post hoc
analysis, and not a primary end point. It was noted that the
preparations of mesalazine used in this study were not standard
US versions, which may account for the weaker performance of
mesalazine [24].
Two other 8-week trials, however, showed no significant difference between balsalazide and mesalazine in remission rates
(primary end point), but some differences in secondary end
points in subgroups of patients. Pruitt et al. reported similar
symptomatic remission rates at 8 weeks for both agents; 46%
(balsalazide) versus 44% (mesalazine) [22]. There was no overall
differences in the median time to symptomatic remission
between balsalazide 6.75 g and mesalazine 2.4 g, except for
those with new diagnosis and less than 40 cm of disease (11 vs
22 days; p = 0.031). Levine et al. found no significant difference between balsalazide 6.75 g and mesalazine 2.4 g in complete remission rates at 8 weeks, but did show significantly
improved sigmoidoscopic scores at 2 weeks with balsalazide
(54.7 vs 29.4%; p = 0.006) [23].
Table 1. Clinical trials comparing balsalazide in active ulcerative colitis.
Study
n
Green et al. (1998)
99
Levine et al. (2002)
Green et al. (2002)
Complete remission
Withdrawal due
to adverse events
6.75 Mesalazine 2.4 g/day
52 vs 37% at 12 weeks; p < 0.001
1 vs 1%; NS
[21]
154
6.75 Mesalazine 2.4 g/day
23 vs 19% at 8 weeks; NS
2 vs 4%; NS
[23]
57
6.75 Sulfasalazine 3 g/day
75 vs 59% at 12 weeks; NS
7 vs 31%; p = 0.04
[26]
Mansfield et al. (2002) 50
6.75 Sulfasalazine 4 g/day
50 vs 38% at 8 weeks; p < 0.001
4 vs 38%; p = 0.004
[25]
Pruitt et al. (2002)
6.75 Mesalazine 2.4 g/day
46 vs 44% at 8 weeks; NS
4 vs 6%; NS
[22]
173
Balsalazide Comparator
(g/day)
Ref.
NS: Not significant.
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Drug Profile
Patil & Moss
Two small trials examining the difference in efficacy between
balsalazide 6.75 g/day and sulfasalazine 3 or 4 g/day found no
significant difference in remission rates at 8 weeks [25] or
12 weeks [26]. Bowel frequency scores, however, were significantly better than baseline in the balsalazide group after 2
(p = 0.011) and 8 (p < 0.001) weeks, whereas improvement in
the sulfasalazine group did not emerge until 4 weeks (p = 0.03),
suggesting faster improvement in symptoms with balsalazide [26].
The efficacy of varying dosages of balsalazide has also been
explored in induction of remission. Balsalazide 6.75 g/day was
found to be significantly more effective than balsalazide
2.25 g/day in improving rectal bleeding, sigmoidoscopic score
and stool frequency [23]. These results are similar to the known
dose–response effects of mesalazine.
Concomitant therapy with a probiotic was found to be superior to balsalazide alone, or mesalazine, in one small study in
patients with mild-to-moderate colitis. Balsalazide (2.25 g) in
combination with VSL#3 probiotic had significantly better
intention-to-treat remission rates (80%) at 8 weeks than either
balsalazide 4.5 g (70% in remission) or mesalazine 2.4 g (53%
in remission; p < 0.02) [27].
Maintenance of remission
Balsalazide has also been established to be effective in maintaining remission in ulcerative colitis, as outlined in five clinical trials (TABLE 2). Balsalazide was again compared with delayedrelease mesalazine and sulfasalazine, as well as to itself at varying doses. The trials were conducted with durations of 6 [28,29]
and 12 months [30–32], with the primary end point designated
as clinical remission at completion of the trial.
Balsalazide demonstrated similar efficacy in comparison with
delayed-release mesalazine. In a 12-month trial by Green et al., the
percentage of patients in remission was identical (58%) in both the
balsalazide 3 g/day and mesalazine 1.2 g/day treatment groups.
Significant differences in favor of balsalazide were seen in some secondary outcomes involving symptoms [32]. Balsalazide at a higher
dose of 6 g/day appeared to be more effective than mesalazine
1.5 g/day in maintaining remission after 6 months (78 vs 57%;
p = 0.045) [29]. In comparison with sulfasalazine 2 g/day, no significant difference was seen with balsalazide 2 g/day in the percentage
of patients with maintained remission after 6 months [28].
The trial by Kruis et al. displayed the higher efficacy of balsalazide 6 g/day compared with 3 g/day in maintaining
remission after 6 months (78 vs 44%; p = 0.001) [29]. A significant difference in clinical relapse rates was evident between
balsalazide 4 and 2 g/day in a 12-month, dose-comparison
trial [30].
Postmarketing surveillance
The prescribing information for balsalazide documents that
hepatic toxicity, including liver necrosis and failure, a Kawasaki-like syndrome, and alopecia have been reported to the
manufacturer since FDA approval [102]. Historical case reports
and case series have uncovered some rare risks of mesalazine
therapy, which can likely be extrapolated to balsalazide given
that it releases mesalazine in the colon.
Interstitial nephritis has been frequently described in case
reports in patients taking mesalazine, with 34 reports since the
first case in 1989 [33]. A large epidemiologic study of 19,000
patients from the UK calculated the incidence of any renal disease in IBD patients taking 5-ASA agents as 0.17 per
100 patients per year, which was similar to the incidence in
IBD patients not taking 5-ASAs (0.25), but higher than controls (0.08) [34]. The absolute risk of renal disease was thought
to correlate with IBD and not aminosalicylate use in this
study. Other events revealed in case reports include pancreatitis, pneumonitis, pericardial and pleural effusions, diarrhea,
allergic reactions, hepatitis, myocarditis, blood dyscrasias and a
lupus-like reaction. The drug histories of over 3500 patients
with acute pancreatitis were compared with controls in a UK
prescription-based study. Mesalazine was associated with a significantly increased risk of acute pancreatitis amongst recent
users (odds ratio [OR]: 9.0; 95% confidence interval [CI]:
1.8–44.6), and continuous users (OR: 2.5; 95% CI: 1.2–5.0) [35].
Individual case reports of oligospermia, pseudotumor cerebri,
pill esophagitis, peripheral neuropathy and otalgia have also
been documented in association with mesalazine use. These
events do not appear to be isolated to either acute or maintenance treatment with mesalazine [36]. There is one specific
case report of a hypersensitivity reaction to balsalazide in the
literature [37].
Table 2. Clinical trials comparing balsalazide in remission in ulcerative colitis.
Study
n
Balsalazide
(g/day)
Comparator
Maintenance of remission
Withdrawal due
to adverse event
Ref.
McIntyre et al. (1988)
79
2
Sulfasalazine 2 g/day
51 vs 63% at 6 months; NS
5 vs 26%; p = 0.017
Giaffer et al. (1992)
133
4
Balsalazide 2 g/day
64 vs 45% at 12 months; p < 0.01 12 vs 19%; NS
[30]
Green et al. (1992)
108
6
Balsalazide 3 g/day
68 vs 77% at 12 months; NS
NS
[31]
Green et al. (1998)
99
3
Mesalazine 1.2 g/day
58 vs 58% at 12 months; NS
7 vs 2%
[32]
Kruis et al. (2001)
133
6
Mesalazine 1.5 g/day
78 vs 56% at 26 weeks; p = 0.006 5 vs 9%; NS
[28]
[29]
NS: Not significant.
180
Expert Rev. Gastroenterol. Hepatol. 2(2), (2008)
Balsalazide disodium
Postmarketing studies have also resulted in discovery of
additional benefits of mesalazine therapy. Therapy with
5-aminosalicylates has demonstrated a protective association
against colorectal cancer from meta-analysis (OR: 0.51; 95%
CI: 0.37–0.69) [38]. One case–control study concluded that
maintenance mesalazine therapy reduces the risk of colorectal
cancer by 81% (OR: 0.19; 95% CI: 0.06–0.61; p = 0.006) [39].
The adjusted OR with mesalazine was only significant at
doses greater than 1.2 g/day in this study. Balsalazide has also
been shown to prevent acute radiation-induced proctosigmoiditis in a randomized, double-blind, placebo-controlled
trial in prostate cancer patients [40].
Safety & tolerability
When administered in therapeutic dosages, balsalazide is generally well-tolerated. The adverse-event profile was found to be
similar to placebo in most studies; the most common side effects
reported being headache (8%), abdominal pain (6%), diarrhea
(5%), nausea (5%), vomiting (4%), respiratory infection (4%)
and arthralgias (4%) [102]. Administration of balsalazide
2–6 g/day over 6–12 months was also generally well-tolerated in
five randomized trials. Comparison of 2 g/day to 4 g/day reveals
no significant difference in occurrence of adverse events [30].
Similar findings were apparent with comparison of 3 g/day to
6 g/day [29]. Adverse events in long-term maintenance trials do
not appear to be dose related. There are generally no appreciable
changes in hematological, biochemical or urine chemistry tests
during both active-disease and maintenance trials [25,26,30].
When compared with sulfasalazine, balsalazide appears to have
a superior adverse event profile. Balsalazide has fewer adverse
events than sulfasalazine in both induction and maintenance
treatment of ulcerative colitis [41]. Sulfasalazine (3 g/day) was
found to have inferior tolerability to balsalazide (6.75 g/day), with
significantly greater number of withdrawals due to adverse events
(38 vs 4%; p = 0.004) [26]. The sulfasalazine group had significantly higher occurrence of headache (54 vs 19%; p = 0.018),
nausea (33 vs 8%; p = 0.035) and vomiting (16 vs 0%; p = 0.03).
Other gastrointestinal events, including dyspepsia and abdominal
pain, occurred with similar frequency in the sulfasalazine and balsalazide groups [25]. During a randomized crossover trial (30 days
for each drug), 70% of sulfasalazine-intolerant patients with
ulcerative colitis or Crohn’s disease tolerated balsalazide (2 g/day)
and olsalazine (1 g/day), and 63% tolerated delayed-release
mesalazine (1.2 g/day). The sulfasalazine-intolerant patients were
also unable to tolerate small dosages (1 g/day) of standard and
enteric-coated sulfasalazine [42]. Two male patients presented
with infertility after 9–60 months of treatment with sulfasalazine 2–3 g/day. Normalization of sperm count and motility, as
well as maintenance of remission, was seen with substitution of
balsalazide 2 g/day for 4 months in these patients [43].
Three trials in patients with active ulcerative colitis show similar tolerability of balsalazide and mesalazine. Balsalazide at
doses of 6.75 and 2.25 g/day was compared with mesalamine
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Drug Profile
2.4 g/day in patients with active ulcerative colitis. One trial
showed superior tolerability of balsalazide over delayedrelease mesalazine, with 48 vs 71% (p = 0.024) of patients
reporting adverse events [23]. Another trial examining longterm administration showed no significant differences in the
incidence of adverse events after 12 months of balsalazide
3 g/day versus mesalazine 1.2 g/day (61 vs 65%) [32]. One
study examining laboratory tests showed a discrepancy in
ALT values between balsalazide and mesalazine [32]. ALT was
found to decrease by 2.29 IU/l in patients receiving balsalazide
3 g/day, compared with an increase of 1.83 IU/l in those receiving mesalazine 1.5 g/day. This difference, however, is thought
to be clinically insignificant.
In pregnancy, balasalazide is a category B drug according to
the FDA, on the basis of studies showing no evidence of
impaired fertility or harm to the fetus in rats and rabbits at up
to 4.7-times the recommended does in humans [104]. As with
most 5-ASA agents, it is considered safe by clinicians if required
in pregnancy.
Regulatory affairs
Balsalazide was approved in the USA in 2000 for treatment of
mild-to-moderately active ulcerative colitis in doses up to
6.75 g/day for 8 weeks [102]. Revisions to the labeling in 2002,
for renal adverse effects, and 2006, for absorption in different
oral intake settings, were approved by the FDA [105]. In 2006,
the approved patient population was expanded to include
children aged over 5 years, and for mixing of the drug with
apple sauce if necessary for administration. Additional labeling alterations in 2007 warned of the potential for worsening
of symptoms in patients with ulcerative colitis. In December
2007, the FDA approved the Abbreviated New Drug Application for generic production of balsalazide 750 mg capsules by
three companies in the USA: Mylan Pharma, Apotex and
Roxane Laboratories. It is also approved in the UK for active
ulcerative colitis, with the maximum duration of therapy
extended to 12 weeks [103]. Balsalazide is approved for administration in the UK for maintenance of remission at a dosage
of 1.5–3 g twice daily.
The efficacy and safety of balsalazide is not established in
pediatric patients below 5 years of age. It is not recommended
for use in children below this age in either the USA or UK
[102,103]. In the UK, balsalazide is contraindicated in pregnant
and breastfeeding women, patients with severe hepatic impairment, and patients with moderate-to-severe renal impairment
[103]. In the USA, caution is recommended when prescribing
balsalazide to these patients [102]. Caution is also recommended
in both the USA and UK when balsalazide is administered to
patients with mild renal impairment, as mesalazine-containing
compounds have been associated with chronic tubulointerstitial
nephritis [31]. Balsalazide is contraindicated for patients with
hypersensitivity to any balsalazide component or metabolites or
salicylates [102,103].
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Drug Profile
Patil & Moss
Conclusion
Balsalazide is an effective method of delivery of mesalazine to
the colon to induce and maintain remission in mild-to-moderate ulcerative colitis. It has been shown to have comparable efficacy to both sulfasalazine and delayed-release mesalazine, with
superior tolerability to sulfasalazine in controlled trials. It has an
excellent safety profile, and is associated with a rare risk of serious side-effects. As with most mesalazine products, compliance
may be an issue in long-term use. The active moiety, mesalazine
has been associated with chemoprevention of colorectal cancer
in patients with ulcerative colitis.
Expert commentary
The clinical trial data on balsalazide have confirmed its equivalent efficacy to mesalazine and sulfasalazine in the induction
and maintenance of remission in patients with active ulcerative
colitis. Its safety appears similar to placebo, and it is better tolerated than sulfasalazine. Some of the studies have reported more
rapid clinical response than mesalazine, which is obviously
important for patients with diarrhea. In addition, greater sigmoidoscopic healing was seen with balsalazide than encapsulated mesalazine, which may be due to more of the active moiety reaching the left colon than pH-dependent or delayedrelease formulations (Asacol, Lialda, Pentasa). This has not been
confirmed in other studies and was a secondary end point. Since
the risk of cancer in the long-term is associated with histological
inflammation, endoscopic healing may have long-term benefits
in the disease process [44]. The lower plasma 5-ASA levels associated with balsalazide administration may lessen the risk of
adverse effects associated with mesalazine, although this is
uncertain. Overall these results position balsalazide as a first-line
agent for active ulcerative colitis.
One drawback to balsalazide is the number of pills required
to obtain a high-dose of active 5-ASA in the colon. Compliance
is a major issue in IBD, and three-times-a-day dosing was an
independent predictor of noncompliance in patients taking
mesalazine in one study [45]. This would put balsalazide at a
potential disadvantage as once-a-day 5-ASA formulations
become available for ulcerative colitis. A 1100-mg tablet of
Colazal has been developed for twice-daily administration,
which, if approved by the FDA, would reduce this pill burden.
Whether once- or twice-a-day dosing improves medication
adherence in IBD is unclear at this timepoint.
Future research in this field for balsalazide should look at
ways of enhancing the therapeutic effect of balsalazide without
increasing the quantity of pills to take. A higher dose balsalazide tablet would need to be assessed in clinical trials to
measure its efficacy, safety and compliance rates. The concept
of combining a probiotic with a lower-dose balsalazide, or combining low-dose balsalazide with another PPARγ ligand should
enhance the beneficial effects of lower-dose drug and provide
concurrent anti-inflammatory effects.
182
There is going to be an increased emphasis on compliance/adherence in the 5-ASA field, and mechanisms to improve the current
low rates. The jury is still out on whether minimal dosing schedules
will improve compliance rates, as one recent study found no relationship between treatment adherence and the number of pill
administrations per day, in contrast to prior data [45,46].
Five-year view
The approval of generic balsalazide 750-mg capsules will probably expand sales of balsalazide in an increasingly competitive
market. Now that the new drug application for a twice-a-day
1100 mg balsalazide tablet has been submitted to the FDA by
Salix, it will probably lead to its approval for active ulcerative colitis in the USA. This would be a welcome addition for patients.
The probable marketing drive associated with this new formulation may enhance balsalazide’s market share as the previously
stagnant 5-ASA arena continues its overhaul. If it becomes apparent from further studies that multiple daily dosing is not an
important factor in medication compliance, then balsalazide’s
position as a first-line agent for active ulcerative colitis will
remain strong. Further research on the interaction between
5-ASA and PPARγ may lead to the development of novel ligands,
which would challenge the dominance of mesalazine in active
ulcerative colitis. Given the excellent safety profile of 5-ASAs
however, they would remain a tough standard to improve upon.
Financial & competing interests disclosure
Alan C Moss has received research support from Proctor & Gamble
(Asacol), educational material from Shire (Pentasa, Colazal, Lialda), and
enjoyed the hospitality of Falk Pharma (Salofalk) and Ferring
Pharmaceuticals (Pentasa). The authors have no other relevant affiliations
or financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or materials
discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
• Aminosalicylates such as mesalazine are PPARγ ligands that
reduce colonic inflammation in ulcerative colitis.
• Balsalazide is a prodrug, composed of mesalazine and
4-aminobenzoyl-β-alanine, which is converted to free
mesalazine and 4-aminobenzoyl-β-alanine by colonic bacteria.
• Several clinical trials have shown that balsalazide has at least
equivalent efficacy and tolerability to delayed-release
mesalazine and sulfasalazine in inducing and maintaining
remission in ulcerative colitis.
• There is evidence of potentially more rapid symptom-response
and endoscopic healing with balsalazide when compared with
mesalazine in some studies.
• The number of pills required for adequate balsalazide dosing
may be reduced with new formulations.
Expert Rev. Gastroenterol. Hepatol. 2(2), (2008)
Balsalazide disodium
systems and inflamed human colorectal
biopsies. Aliment. Pharmacol. Ther. 13(3),
363–372 (1999).
•
Identifies secondary end points where
balsalazide demonstrated benefits
over mesalazine.
13
Peh KH, Wan BC, Assem ES et al. Effect of
sulphasalazine and balsalazide on histamine
release from mast cells. Inflamm. Res.
56(Suppl. 1), S9–S10 (2007).
23
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Kles KA, Vavricka SR, Turner JR et al.
Comparative analysis of the in vitro
secretory effects of balsalazide, sulfasalazine,
olsalazine, and mesalamine in rabbit distal
ileum. Inflamm. Bowel Dis. 11(3), 253–257
(2005).
Levine DS, Riff DS, Pruitt R et al.
A randomized, double-blind dose-response
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balsalazide 2.25 g and mesalamine 2.4 g in
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Farrell RJ, Peppercorn MA. Equimolar
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Affiliations
•
Seema A Patil, MD
Resident, Department of Medicine,
Beth Israel Deaconess Medical Center,
330 Brookline Ave, Boston,
MA 02215, USA
Tel.: +1 617 632 7243
spatil@bidmc.harvard.edu
•
Alan C Moss, MD
Instructor in Medicine, Harvard
Medical School;
and, Director of Translational Research,
Center for Inflammatory Bowel Disease,
Rose 1/East, Beth Israel Deaconess,
Medical Center, 330 Brookline Avenue,
Boston, MA 02215, USA
Tel.: +1 617 667 1088
Fax: +1 617 667 2134
amoss@bidmc.harvard.edu
Expert Rev. Gastroenterol. Hepatol. 2(2), (2008)