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 [email protected] 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 www.future-drugs.com 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 178 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. www.future-drugs.com 179 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 www.future-drugs.com 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]. 181 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 14 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 comparison of balsalazide 6.75 g, balsalazide 2.25 g and mesalamine 2.4 g in the treatment of active, mild to moderate ulcerative colitis. Am. J. Gastroenterol. 97(6), 1398–1407 (2002). 24 Farrell RJ, Peppercorn MA. Equimolar doses of balsalazide and mesalamine: are we comparing apples and oranges? Am. J. Gastroenterol. 97(6), 1283–1285 (2002). 25 Mansfield JC, Giaffer MH, Cann PA et al. 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Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk. Gut 53(12), 1813–1816 (2004). 45 Shale MJ, Riley SA. Studies of compliance with delayed-release mesalazine therapy in patients with inflammatory bowel disease. Aliment. Pharmacol. Ther. 18(2), 191–198 (2003). 46 Ediger JP, Walker JR, Graff L et al. Predictors of medication adherence in inflammatory bowel disease. Am. J. Gastroenterol. 102(7), 1417–1426 (2007). • Questions whether pill burden is a factor in compliance with 5-ASAs. Websites 101 The Pharmaceutical Research and Manufacturers of America (PhRMA). New Medicines Database. http://newmeds.phrma.org/results.php?drug= &indication=332&company=&status=2007 102 Salix Pharmaceuticals. ColazalTM (balsalazide disodium) capsules, US full prescribing information. www.colazal.com 103 Shire Pharmaceuticals Limited. ColazideTM (balsalazide disodium), UK full prescribing information. http://ehc.vhn.net 104 FDA Approval Label for Colazal. www.fda.gov/Cder/foi/label/2000/ 20610lbl.pdf 105 FDA Drug Details. www.accessdata.fda.gov/scripts/cder/ drugsatfda/ 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 [email protected] • 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 [email protected] Expert Rev. Gastroenterol. Hepatol. 2(2), (2008)
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