Editorial
Budesonide multi-matrix system formulation for treating ulcerative colitis Cosimo Prantera† & Maria Lia Scribano
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Kainan University on 03/10/15 For personal use only.
Gastroenterology Unit, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy
Budesonide is a corticosteroid characterized by high topical activity and low systemic effect associated with fewer glucocorticoid-related adverse events than conventional steroids. Differently from Crohn’s disease, no evidence suggests that oral budesonide is effective for the induction of remission of ulcerative colitis (UC). Budesonide multi-matrix (MMX) system is a new oral preparation that, by employing a MMX, provides the release of the drug throughout the entire colon. Its efficacy in inducing UC remission, at a dose of 9 mg, is based on some recent trials. However, in two studies the absolute differences between budesonide MMX and placebo were much lower than the rate of success reported in previous trials with mesalazines. In addition, the therapeutic advantage of budesonide MMX 9 mg over 5-aminosalicylic acid (5-ASA) showed by one study, and the advantage of budesonide MMX over budesonide reported in the other study, was only 5.8 and 4.8%, respectively. The evidence supporting the use of budesonide MMX at a dose of 6 mg for maintenance is weak. Therefore, the effective dosage should be 9 mg also in maintenance, but not for > 4 -- 6 months, because a prolonged treatment has showed to increase the rate of side effects. Keywords: budesonide, local therapy, multi-matrix system, ulcerative colitis Expert Opin. Pharmacother. (2014) 15(6):741-743
Ulcerative colitis (UC) is a chronic inflammatory disease, which mainly affects the colonic mucosa, only rarely passing the superficial intestinal layer [1]. Because of this feature, the main treatment of mild to moderate forms of UC has been addressed to using drugs, such as 5-ASA compounds, that work by local activity. The principal delivery systems that have been employed in order to release the 5-ASA compounds in the inflamed part of the colon entail eudragit L and S, diazo-bond link and, more recently, multi-matrix (MMX) system. Budesonide is a steroid with high affinity for the glucocorticoid receptor. Its affinity is 195-fold greater than hydrocortisone. It is on market as nasal, oral and rectal formulations. The budesonide oral formulation is absorbed by the ileum and ascending colon and undergoes 90% first-pass metabolism. Because of this property, it has been employed as local therapy for treating inflammation in the distal ileum and right colon, limiting patient’s systemic exposure. The formulation of gastro-resistant, controlled release capsule of budesonide (Entocort), at a dose of 9 mg/day, has been demonstrated to be more effective than placebo and seems non-inferior when compared with conventional oral steroids for treating mild to moderately active Crohn’s disease (CD) involving the distal ileum and/or right colon. Vice versa, a Cochrane review investigating the efficacy of oral budesonide was published in 2010 and concluded that there was no evidence
10.1517/14656566.2014.884072 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
741
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Kainan University on 03/10/15 For personal use only.
C. Prantera & M. L. Scribano
to suggest that oral budesonide is effective for the induction of remission in UC [2]. Budesonide rectal enema or foam is also used as treatment of distal UC. In two randomized trials, enema was superior to placebo for inducing remission. In one of the studies, which was extended for 12 months, enema was not effective in maintaining remission [3]. Failure of active UC to respond to 5-ASA therapy is an indication for oral or parenteral steroids treatment. Prednisolone, among the steroids, is the most commonly used. However, steroid therapy is burdened by important side effects especially if the treatment lasts a long period of time. Then, budesonide can be a valid alternative to systemic steroid employment. Oral budesonide in this setting, however, has given unsatisfactory results probably ascribed to a delivery system, which does not permit a good contact of the drug in the left part of the colon. Budesonide MMX is a gastro-resistant prolonged release tablet developed by Cosmo Technologies Ltd, designed to release the drug throughout the entire colon, overcoming the limited use of other budesonide formulation for treating UC, especially in the left-sided location. The MMX system has been already employed for delivering 5-ASA. 5-ASA delivered by MMX system has shown a small advantage over other 5-ASA compounds in the treatment of UC probably because of higher concentration of drug in the left colon [4]. Documentation of efficacy of budesonide MMX in inducing UC remission is based on two pivotal studies and one supporting study [5-7]. The better results were obtained by the 9 mg dose. The two pivotal studies involving 919 patients adopted a very strict criterion of success defined as a combination of clinical and endoscopic remission with a ulcerative colitis disease activity index (UCDAI) score £ 1 point, with subscores of 0 for both rectal bleeding and stool frequency [5,6]. Obtaining this level of remission could have reduced the rates of success in these two trials in all the arms, budesonide MMX 9 and 6 mg, Asacol 2.4 g, Entocort 9 mg and Placebo. Nevertheless, the two trials registered absolute differences of 10 and 13% between budesonide MMX 9 mg and placebo that, although statistically significant, were much lower than the rates of success reported in previous trials with mesalazines. Can we then adopt budesonide MMX at the dose of 9 mg as treatment of UC refractory to mesalazines? Can this therapy substitute the reliable treatment with systemic steroids? Can the probable reduction of side effects counterbalance the increased cost? And finally, can the treatment by budesonide MMX be continued in maintenance? In one of the two pivotal trials, the therapeutic advantage of budesonide MMX 9 mg over Asacol 2.4 g was only 5.8% and there was no therapeutic advantage over 5-ASA concerning clinical improvement [5]. Although Asacol was a non-powered reference arm suggested as active control, we should consider 742
that 65.3% of the patients treated by Asacol had a moderate flare and that, in case of moderate activity, a recent Cochrane review suggests that patients with moderately active disease may benefit from an initial dosage of 4 to 4.8 g of mesalazine [8-11]. Furthermore, the formulation of budesonide MMX is designed to provide a homogeneous distribution of budesonide throughout the entire colon. This delivery system should ensure in UC a superior efficacy over Entocort, which is a budesonide preparation mainly delivered in the terminal ileum and right colon. However, in the second pivotal study, the advantage of budesonide MMX over Entocort at 8 weeks was only 4.8% [6]. Moreover, the delivery system MMX seems to influence the different efficacy of treatment following the disease location: the better results of budesonide MMX in the two studies were obtained in the left colon, while, when the inflammation was extended over the splenic flexure, the advantage over placebo was not more statistically significant. For this reason, the comparison with Asacol, which has a different delivery system, could have been misleading, given that two different drugs and two different delivery systems were compared. The tolerability of budesonide is well established: compared with conventional steroids it is associated with fewer steroid-related adverse events. The most common side effects associated with budesonide oral capsules are gastrointestinal and endocrine system-related events, with only rare occurrences of the clinically severe adverse events associated with traditional systemic steroids [12]. It’s probable that with short-term treatment of budesonide MMX the steroid side effects are still further reduced. However, it has been shown that maintenance treatment with oral budesonide may be associated with lumbar spine and femoral neck bone loss [13]. It is also well known that the number of steroidrelated side effects increases when the treatment is prolonged. In all the studies on 9 mg budesonide MMX at 8 weeks a decline of cortisol levels has been registered, even if this decrease did not appear to be translated into an increase in clinical glucocorticoid effect. This datum makes the use of 9 mg in maintenance inadvisable [14]. One abstract reports that budesonide MMX employed for 12 months at the dose of 6 mg reduced the relapse rate of UC but the difference from placebo was not statistically significant [15]. However, the prolonged treatment did not modify the bone mineral density but 30% of patients had an abnormal adrenal function. From these data, one can suggest that the effective dose of budesonide MMX should be 9 mg also in maintenance, given that the evidence supporting 6 mg for maintenance is weak. A strategy could be to prolong budesonide MMX 9 mg for not > 4 -- 6 months, probably increasing the rate of remission and, similarly to the strategy employed in CD, using it as a bridge therapy to thiopurine. More studies however, are warranted to clarify such an approach.
Expert Opin. Pharmacother. (2014) 15(6)
Budesonide multi-matrix system formulation for treating ulcerative colitis
Finally, before adopting this new drug in the therapeutic armamentarium of UC resistant to mesalazines, more data must be explored:
- Is budesonide MMX as a stepping stone to thiopurine comparable to a short course of oral steroid regarding efficacy and number of side effects?
- Does budesonide MMX work better than a mesalazine with the same delivery system at the dose of 4.8 g? - Is budesonide MMX a good stepping stone for permitting thiopurine to be effective?
Declaration of interest
Bibliography
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Kainan University on 03/10/15 For personal use only.
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1. .
Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med 2011;365:1713-25 This is a recent and exhaustive review on ulcerative colitis.
2.
Sherlock ME, Seow CH, Steinhart AH, et al. Oral budesonide for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2010;(10):CD007698
3.
Lindgren S, L€ofberg R, Bergholm L, et al. Effect of budesonide enema on remission and relapse rate in distal ulceratice colitis and proctitis. Scand J Gastroenterol 2002;37:705-10
4.
Prantera C, Viscido A, Biancone L, et al. A new oral delivery system for 5-ASA: preliminary clinical findings for MMx: inflamm Bowel Dis. 2005;11:421-7 The article describes for the first time the delivery system MMX.
.
5.
.
6.
Sandborn WJ, Travis S, Moro L, 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;143:1218-26 The results of the trial with the new budesonide formulation compared with mesalamine and placebo are reported in this article. Travis SPL, Danese S, Kupcinskas L, et al. Once-daily budesonide MMX in
.
7.
C Prantera is a Consultant for Giuliani. ML Scribano has no conflict of interest to declare.
active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study. Gut 2013. [Epub ahead of print] In this European study, budesonide MMX is compared with Entocort (budesonide controlled ileal-release formulation) and placebo. D’ Haens GR, Kova´cs A´, Vergauwe P, et al. Clinical trial: preliminary efficacy and safety study of a new budesonideMMX 9 mg extended-release tablets in patients with active left-sided ulcerative colitis. J Crohns Colitis 2010;4:153-60
8.
Hanauer SB, Sandborn WJ, Kornbluth A, 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;100:2478-85
9.
Hanauer SB, Sandborn WJ, Dallaire C, 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;21:827-34
10.
Sandborn WJ, Regula J, Feagan BG, et al. Delayed-release oral mesalamine 4.8 g/day (800-mg tablet) is effective for patients with moderately active ulcerative colitis. Gastroenterology 2009;137:1934-43
11.
Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.
Expert Opin. Pharmacother. (2014) 15(6)
Cochrane Database Syst Rev 2012;10:CD000544 12.
Lichtenstein GR, Bengtsson B, Hapten-White L, et al. Oral budesonide for maintenance of remission of Crohn’s disease: a pooled safey analysis. Aliment Pharmacol Ther 2009;29:643-53
13.
Cino M, Greenberg GR. Bone mineral density in Crohn’s disease: a longitudinal study of budesonide, prednisone, and nonsteroid therapy. Am J Gastroenterol 2002;97:915-21
14.
Benchimol EI, Seow CH, Otley AR, Steinhart AH. Budesonide for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev 2009;(1):CD002913
15.
Sandborn WJ, Danese S, Ballard ED, et al. Efficacy of budesonide MMx 6 mg QD for the maintenance of remission in patients with ulcerative colitis: results from a phase III, 12 month safety and extended use study. Gastroenterology 2012;142(5):S-564
Affiliation
Cosimo Prantera† MD & Maria Lia Scribano † Author for correspondence Gastroenterology Unit, Azienda Ospedaliera San Camillo-Forlanini, Circonvallazione Gianicolense, 87 -- 00152 Rome, Italy Tel: +39 6 3202643; Fax: +39 6 3202643; E-mail: [email protected]
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Budesonide multi-matrix system formulation for treating ulcerative colitis Cosimo Prantera† & Maria Lia Scribano
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Kainan University on 03/10/15 For personal use only.
Gastroenterology Unit, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy
Budesonide is a corticosteroid characterized by high topical activity and low systemic effect associated with fewer glucocorticoid-related adverse events than conventional steroids. Differently from Crohn’s disease, no evidence suggests that oral budesonide is effective for the induction of remission of ulcerative colitis (UC). Budesonide multi-matrix (MMX) system is a new oral preparation that, by employing a MMX, provides the release of the drug throughout the entire colon. Its efficacy in inducing UC remission, at a dose of 9 mg, is based on some recent trials. However, in two studies the absolute differences between budesonide MMX and placebo were much lower than the rate of success reported in previous trials with mesalazines. In addition, the therapeutic advantage of budesonide MMX 9 mg over 5-aminosalicylic acid (5-ASA) showed by one study, and the advantage of budesonide MMX over budesonide reported in the other study, was only 5.8 and 4.8%, respectively. The evidence supporting the use of budesonide MMX at a dose of 6 mg for maintenance is weak. Therefore, the effective dosage should be 9 mg also in maintenance, but not for > 4 -- 6 months, because a prolonged treatment has showed to increase the rate of side effects. Keywords: budesonide, local therapy, multi-matrix system, ulcerative colitis Expert Opin. Pharmacother. (2014) 15(6):741-743
Ulcerative colitis (UC) is a chronic inflammatory disease, which mainly affects the colonic mucosa, only rarely passing the superficial intestinal layer [1]. Because of this feature, the main treatment of mild to moderate forms of UC has been addressed to using drugs, such as 5-ASA compounds, that work by local activity. The principal delivery systems that have been employed in order to release the 5-ASA compounds in the inflamed part of the colon entail eudragit L and S, diazo-bond link and, more recently, multi-matrix (MMX) system. Budesonide is a steroid with high affinity for the glucocorticoid receptor. Its affinity is 195-fold greater than hydrocortisone. It is on market as nasal, oral and rectal formulations. The budesonide oral formulation is absorbed by the ileum and ascending colon and undergoes 90% first-pass metabolism. Because of this property, it has been employed as local therapy for treating inflammation in the distal ileum and right colon, limiting patient’s systemic exposure. The formulation of gastro-resistant, controlled release capsule of budesonide (Entocort), at a dose of 9 mg/day, has been demonstrated to be more effective than placebo and seems non-inferior when compared with conventional oral steroids for treating mild to moderately active Crohn’s disease (CD) involving the distal ileum and/or right colon. Vice versa, a Cochrane review investigating the efficacy of oral budesonide was published in 2010 and concluded that there was no evidence
10.1517/14656566.2014.884072 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
741
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Kainan University on 03/10/15 For personal use only.
C. Prantera & M. L. Scribano
to suggest that oral budesonide is effective for the induction of remission in UC [2]. Budesonide rectal enema or foam is also used as treatment of distal UC. In two randomized trials, enema was superior to placebo for inducing remission. In one of the studies, which was extended for 12 months, enema was not effective in maintaining remission [3]. Failure of active UC to respond to 5-ASA therapy is an indication for oral or parenteral steroids treatment. Prednisolone, among the steroids, is the most commonly used. However, steroid therapy is burdened by important side effects especially if the treatment lasts a long period of time. Then, budesonide can be a valid alternative to systemic steroid employment. Oral budesonide in this setting, however, has given unsatisfactory results probably ascribed to a delivery system, which does not permit a good contact of the drug in the left part of the colon. Budesonide MMX is a gastro-resistant prolonged release tablet developed by Cosmo Technologies Ltd, designed to release the drug throughout the entire colon, overcoming the limited use of other budesonide formulation for treating UC, especially in the left-sided location. The MMX system has been already employed for delivering 5-ASA. 5-ASA delivered by MMX system has shown a small advantage over other 5-ASA compounds in the treatment of UC probably because of higher concentration of drug in the left colon [4]. Documentation of efficacy of budesonide MMX in inducing UC remission is based on two pivotal studies and one supporting study [5-7]. The better results were obtained by the 9 mg dose. The two pivotal studies involving 919 patients adopted a very strict criterion of success defined as a combination of clinical and endoscopic remission with a ulcerative colitis disease activity index (UCDAI) score £ 1 point, with subscores of 0 for both rectal bleeding and stool frequency [5,6]. Obtaining this level of remission could have reduced the rates of success in these two trials in all the arms, budesonide MMX 9 and 6 mg, Asacol 2.4 g, Entocort 9 mg and Placebo. Nevertheless, the two trials registered absolute differences of 10 and 13% between budesonide MMX 9 mg and placebo that, although statistically significant, were much lower than the rates of success reported in previous trials with mesalazines. Can we then adopt budesonide MMX at the dose of 9 mg as treatment of UC refractory to mesalazines? Can this therapy substitute the reliable treatment with systemic steroids? Can the probable reduction of side effects counterbalance the increased cost? And finally, can the treatment by budesonide MMX be continued in maintenance? In one of the two pivotal trials, the therapeutic advantage of budesonide MMX 9 mg over Asacol 2.4 g was only 5.8% and there was no therapeutic advantage over 5-ASA concerning clinical improvement [5]. Although Asacol was a non-powered reference arm suggested as active control, we should consider 742
that 65.3% of the patients treated by Asacol had a moderate flare and that, in case of moderate activity, a recent Cochrane review suggests that patients with moderately active disease may benefit from an initial dosage of 4 to 4.8 g of mesalazine [8-11]. Furthermore, the formulation of budesonide MMX is designed to provide a homogeneous distribution of budesonide throughout the entire colon. This delivery system should ensure in UC a superior efficacy over Entocort, which is a budesonide preparation mainly delivered in the terminal ileum and right colon. However, in the second pivotal study, the advantage of budesonide MMX over Entocort at 8 weeks was only 4.8% [6]. Moreover, the delivery system MMX seems to influence the different efficacy of treatment following the disease location: the better results of budesonide MMX in the two studies were obtained in the left colon, while, when the inflammation was extended over the splenic flexure, the advantage over placebo was not more statistically significant. For this reason, the comparison with Asacol, which has a different delivery system, could have been misleading, given that two different drugs and two different delivery systems were compared. The tolerability of budesonide is well established: compared with conventional steroids it is associated with fewer steroid-related adverse events. The most common side effects associated with budesonide oral capsules are gastrointestinal and endocrine system-related events, with only rare occurrences of the clinically severe adverse events associated with traditional systemic steroids [12]. It’s probable that with short-term treatment of budesonide MMX the steroid side effects are still further reduced. However, it has been shown that maintenance treatment with oral budesonide may be associated with lumbar spine and femoral neck bone loss [13]. It is also well known that the number of steroidrelated side effects increases when the treatment is prolonged. In all the studies on 9 mg budesonide MMX at 8 weeks a decline of cortisol levels has been registered, even if this decrease did not appear to be translated into an increase in clinical glucocorticoid effect. This datum makes the use of 9 mg in maintenance inadvisable [14]. One abstract reports that budesonide MMX employed for 12 months at the dose of 6 mg reduced the relapse rate of UC but the difference from placebo was not statistically significant [15]. However, the prolonged treatment did not modify the bone mineral density but 30% of patients had an abnormal adrenal function. From these data, one can suggest that the effective dose of budesonide MMX should be 9 mg also in maintenance, given that the evidence supporting 6 mg for maintenance is weak. A strategy could be to prolong budesonide MMX 9 mg for not > 4 -- 6 months, probably increasing the rate of remission and, similarly to the strategy employed in CD, using it as a bridge therapy to thiopurine. More studies however, are warranted to clarify such an approach.
Expert Opin. Pharmacother. (2014) 15(6)
Budesonide multi-matrix system formulation for treating ulcerative colitis
Finally, before adopting this new drug in the therapeutic armamentarium of UC resistant to mesalazines, more data must be explored:
- Is budesonide MMX as a stepping stone to thiopurine comparable to a short course of oral steroid regarding efficacy and number of side effects?
- Does budesonide MMX work better than a mesalazine with the same delivery system at the dose of 4.8 g? - Is budesonide MMX a good stepping stone for permitting thiopurine to be effective?
Declaration of interest
Bibliography
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Kainan University on 03/10/15 For personal use only.
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1. .
Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med 2011;365:1713-25 This is a recent and exhaustive review on ulcerative colitis.
2.
Sherlock ME, Seow CH, Steinhart AH, et al. Oral budesonide for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2010;(10):CD007698
3.
Lindgren S, L€ofberg R, Bergholm L, et al. Effect of budesonide enema on remission and relapse rate in distal ulceratice colitis and proctitis. Scand J Gastroenterol 2002;37:705-10
4.
Prantera C, Viscido A, Biancone L, et al. A new oral delivery system for 5-ASA: preliminary clinical findings for MMx: inflamm Bowel Dis. 2005;11:421-7 The article describes for the first time the delivery system MMX.
.
5.
.
6.
Sandborn WJ, Travis S, Moro L, 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;143:1218-26 The results of the trial with the new budesonide formulation compared with mesalamine and placebo are reported in this article. Travis SPL, Danese S, Kupcinskas L, et al. Once-daily budesonide MMX in
.
7.
C Prantera is a Consultant for Giuliani. ML Scribano has no conflict of interest to declare.
active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study. Gut 2013. [Epub ahead of print] In this European study, budesonide MMX is compared with Entocort (budesonide controlled ileal-release formulation) and placebo. D’ Haens GR, Kova´cs A´, Vergauwe P, et al. Clinical trial: preliminary efficacy and safety study of a new budesonideMMX 9 mg extended-release tablets in patients with active left-sided ulcerative colitis. J Crohns Colitis 2010;4:153-60
8.
Hanauer SB, Sandborn WJ, Kornbluth A, 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;100:2478-85
9.
Hanauer SB, Sandborn WJ, Dallaire C, 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;21:827-34
10.
Sandborn WJ, Regula J, Feagan BG, et al. Delayed-release oral mesalamine 4.8 g/day (800-mg tablet) is effective for patients with moderately active ulcerative colitis. Gastroenterology 2009;137:1934-43
11.
Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.
Expert Opin. Pharmacother. (2014) 15(6)
Cochrane Database Syst Rev 2012;10:CD000544 12.
Lichtenstein GR, Bengtsson B, Hapten-White L, et al. Oral budesonide for maintenance of remission of Crohn’s disease: a pooled safey analysis. Aliment Pharmacol Ther 2009;29:643-53
13.
Cino M, Greenberg GR. Bone mineral density in Crohn’s disease: a longitudinal study of budesonide, prednisone, and nonsteroid therapy. Am J Gastroenterol 2002;97:915-21
14.
Benchimol EI, Seow CH, Otley AR, Steinhart AH. Budesonide for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev 2009;(1):CD002913
15.
Sandborn WJ, Danese S, Ballard ED, et al. Efficacy of budesonide MMx 6 mg QD for the maintenance of remission in patients with ulcerative colitis: results from a phase III, 12 month safety and extended use study. Gastroenterology 2012;142(5):S-564
Affiliation
Cosimo Prantera† MD & Maria Lia Scribano † Author for correspondence Gastroenterology Unit, Azienda Ospedaliera San Camillo-Forlanini, Circonvallazione Gianicolense, 87 -- 00152 Rome, Italy Tel: +39 6 3202643; Fax: +39 6 3202643; E-mail: [email protected]
743
