Mesalamine Formulations Research Articles

Drug development in inflammatory bowel disease: The role of the FDA

All medicinal compounds sold in the United States for inflammatory bowel disease (IBD) are regulated by the Food and Drug Administration (FDA) via a number of regulations dating back to 1906. The primary contemporary role of the FDA is in the assessment of safety and efficacy, and subsequent marketing, of medications based on preclinical and clinical trial data provided by sponsors. This includes pharmacokinetic, toxicology and clinical studies, and postapproval safety monitoring. Mesalamine formulations, budesonide, and biologic therapies have all been assessed for efficacy and safety in IBD by the FDA via large randomized controlled trials (RCTs). There has been considerable evolution in the endpoints used by the FDA to approve medications for IBD, and the mechanisms through which newer agents have been approved. This review examines the methods of drug approval by the FDA, the bench-marks used to approve drugs for IBD, and recent controversies in the FDA's role in drug approval in general.

Ulcerative proctitis patients' preference for topical formulations of mesalamine.

Ulcerative proctitis patients' preference for topical formulations of mesalamine.

Ulcerative Proctitis Patientsʼ Preferences for Topical Formulations of Mesalamine

Purpose: Ulcerative proctitis (UP) is a common inflammatory bowel disease associated with significant morbidity. Topical mesalamine (5-aminosalicylic acid; 5-ASA) reduces symptoms, disease flares, improves outcomes, and is considered first-line therapy. Dosing oral 5-ASA encumbers a large pill burden and carries increased risk of adverse events, but 5-ASA suppositories have low systemic absorption and fast onset of action (within days). Social factors have prevented patients from using rectal formulations. This study assessed patient perceptions and preferences for 5-ASA suppositories vs. enemas in the management of UP and potential effects of their use on compliance. Methods: Two phases of research were utilized. Phase 1, a qualitative study, used semi-structured, individual-depth methodology to explore UP treatment issues and validated questions asked in phase 2, an online survey of patients with UP on maintenance therapy. Results: Fourteen patients with UP and 21 gastroenterologists were interviewed in phase 1; 250 patients completed phase 2. Of these patients, 60% were female, 74% were Caucasian, 83% were 25-54 years old, and 57% perceived their UP as at least moderate severity. Symptoms (Table) were completely controlled in only 4% of patients despite oral 5-ASA maintenance therapy. Medication convenience was important; 84% of patients reported traveling during the past year, with 33% traveling >3 weeks/year. Patients experienced ˜6 UP flares over the past year. Forty percent of patients perceived their UP had not improved and 12% reported their UP had worsened since diagnosis. Of patients prescribed topical mesalamine, 62% would use a suppository without hesitation, while 38% would use an enema. Among patients who perceived their UP was worsening, >90% were willing to take a suppository compared with ˜50% willing to take an enema. Suppositories were rated by 90% of patients as clean or cleaner than enemas and 87% rated suppositories as being as discrete as or more discrete than enemas. Most patients (82%) reported that suppositories take the same or less time to administer than enemas and 86% rated suppositories as equal or superior to enemas in terms of portability. Conclusion: Mesalamine suppositories are a safe and well-accepted therapeutic option for patients with UP and may improve compliance compared with oral and enema formulations. This research was funded in part by Axcan Pharma Inc, QC, Canada. Disclosure: Dr Barrett and Herbert Swanson are employees of Axcan Pharma Inc. Dr Sanderson does not have a relevant financial relationship. This research was supported by an industry grant from Axcan Pharma.Table

Long-term Compliance with Mesalamine Therapy in Patients with Quiescent Ulcerative Colitis: Results from a Long-term Phase IV Study of MMX® Mesalamine

Purpose: Patients with quiescent ulcerative colitis (UC) are often required to remain on long-term maintenance therapy to prevent recurrence of active disease. However, patients frequently report forgetting to take their medication, particularly in the absence of symptoms. This may be made worse by the requirement for multiple tablets, with multiple times daily administration. MMX® mesalamine (Shire Pharmaceuticals Inc., USA; MMX, Cosmo Technologies Ltd., Ireland) features a low pill burden and once-daily (QD) dosing. In this analysis of a long-term phase IV maintenance study using MMX mesalamine, we examine compliance over time with a once-daily mesalamine formulation. Methods: The Strategies in Maintenance for Patients Receiving Long-term Therapy (SIMPLE) study was a phase IV, multicenter, open-label trial conducted in 51 centers across the USA. Patients with quiescent UC (defined as no rectal bleeding and 0-1 more bowel movements than normal per day, either at enrollment or following 8 weeks' treatment with MMX mesalamine [2.4-4.8g/day; acute phase]) received MMX mesalamine 2.4g/day QD for 12 months (maintenance phase). We examined compliance at 6 months, and 12 months after entry to the maintenance phase. Compliance was assessed via prescription refill data using the formula: [sum of days' supply dispensed]/[sum of days in all refill intervals] x 100. Patients who took ≥80% of study medication were considered to be compliant. Results: In total, 208 patients were enrolled to the 12-month maintenance phase, and 207 were included in the maintenance phase efficacy population. During the maintenance phase, 79.2 and 77.3% of patients remained compliant with their prescribed treatment at 6 and 12 months, respectively. Considering all patients, average compliance with MMX mesalamine in was 86.7% by month 12. Compliance was similar in patients who entered the maintenance phase directly (87.3%) and those who first required acute treatment with MMX mesalamine to achieve disease quiescence (84.8%). Examination of patient outcomes according to some predefined patient and disease characteristics did not identify any significant differences. Conclusion: In this study, the majority of patients were compliant with MMX mesalamine after 6 months treatment, and a similar proportion were also complaint after 12 months. Additionally, compliance was maintained regardless of previous treatment and was equally high in patients who entered the maintenance phase directly, and those who required additional acute phase treatment with MMX mesalamine to achieve disease quiescence. This research was funded by Shire Pharmaceuticals Inc. Disclosure: Sunanda Kane - Research Funding from Shire Pharmaceuticals Inc. Dory Solomon - Employee, Shire Pharmaceuticals Inc. Mary Palmen - Employee, Shire Pharmaceuticals Inc. Karen Barrett - - Employee, Shire Pharmaceuticals Inc. This study was funded by Shire Pharmaceuticals Inc.

Once-Daily vs. Twice-Daily Mesalamine for Ulcerative Colitis

Two recently marketed formulations of oral mesalamine (Lialda and Apriso) have been approved for once-daily dosing to maintain remission of ulcerative

S1043 A Direct Comparative Study of Two Different Mesalamine Formulations Revealed Appropriate use of Mesalamine for Patients With Active Ulcerative Colitis Depending on the Characteristics of Disease

S1043 A Direct Comparative Study of Two Different Mesalamine Formulations Revealed Appropriate use of Mesalamine for Patients With Active Ulcerative Colitis Depending on the Characteristics of Disease

Direct comparison of two different mesalamine formulations for the maintenance of remission in patients with ulcerative colitis: A double-blind, randomized study

Background:Mesalamine has been used as the first-line medication for the treatment of ulcerative colitis (UC). We directly compared the efficacy and safety of two different mesalamine formulations in the maintenance of remission in patients with UC.Methods:In a multicenter, double-blind, randomized study, 131 patients with quiescent UC were assigned to two groups: 65 to receive a pH-dependent release formulation of mesalamine at 2.4 g/day (pH-2.4 g) and 66 to receive a time-dependent release formulation of mesalamine at 2.25 g/day (Time-2.25 g). Both formulations were administered three times daily for 48 weeks. The primary endpoint was the proportion of patients without bloody stools.Results:In the full analysis set (n = 130), the proportion of patients without bloody stools was 76.9% in the pH-2.4 g and 69.2% in the Time-2.25 g, demonstrating the noninferiority of pH-2.4 g to Time-2.25 g. No statistically significant difference in time to bloody stools was found between the two formulations (P = 0.27, log-rank test), but the time to bloody stools tended to be longer in pH-2.4 g compared to Time-2.25 g, and a similar trend was observed with regard to the time to relapse. No differences were observed between the safety profiles of the two formulations.Conclusions:The pH- and time-dependent release of mesalamine formulations were similarly safe and effective. Interestingly, the remission phase tended to be longer in the group that received the pH-dependent formulation compared to the group that received the time-dependent formulation (UMIN Clinical Trials Registry, no. C000000289). (Inflamm Bowel Dis 2010)

Direct comparison of two different mesalamine formulations for the induction of remission in patients with ulcerative colitis: A double-blind, randomized study

Background:Mesalamine is the first-line drug for the treatment of ulcerative colitis (UC). We directly compared the efficacy and safety of two mesalamine formulations for the induction of remission in patients with UC.Methods:In a multicenter, double-blind, randomized study, 229 patients with mild-to-moderate active UC were assigned to 4 groups: 66 and 65 received a pH-dependent release formulation of 2.4 g/day (pH-2.4 g) or 3.6 g/day (pH-3.6 g), respectively; 65 received a time-dependent release formulation of 2.25 g/day (Time-2.25 g), and 33 received placebo (Placebo). The drugs were administered three times daily for eight weeks. The primary endpoint was a decrease in the UC disease activity index (UC-DAI).Results:In the full analysis set (n = 225) the decrease in UC-DAI in each group was 1.5 in pH-2.4 g, 2.9 in pH-3.6 g, 1.3 in Time-2.25 g and 0.3 in Placebo, respectively. These results demonstrate the superiority of pH-3.6 g over Time-2.25 g (P = 0.003) and the noninferiority of pH-2.4 g to Time-2.25 g. Among the patients with proctitis-type UC, a significant decrease in UC-DAI was observed in pH-2.4 g and pH-3.6 g as compared to Placebo, but not in Time-2.25 g. No differences were observed in the safety profiles.Conclusions:Higher dose of the pH-dependent release formulation was more effective for induction of remission in patients with mild-to-moderate active UC. Additionally, the pH-dependent release formulation was preferable to the time-dependent release formulation for patients with proctitis-type UC (UMIN Clinical Trials Registry, no. C000000288). (Inflamm Bowel Dis 2010)

Update on the role of modified release mesalamine in the management of ulcerative colitis and Crohn’s disease

5-aminosalicyclates (5-ASA) remain a key first-line therapy for patients with ulcerative colitis (UC). A range of 5-ASA preparations is available and Eudragit-S(®) coated modified release formulations of mesalamine, such as Asacol(®), remain among the most popular choices. We here review the current understanding of the mechanism of action of 5-ASA in inflammatory bowel disease. We evaluate evidence supporting the efficacy and safety of modified release mesalamine for both induction and remission maintenance in UC, including a review of the data from the recent ASCEND studies. We also examine the controversial issue of the role of mesalamine in treatment of Crohn's disease (CD) and highlight data supporting its use following surgically induced remission of CD. Evidence supporting the use of mesalamine as prophylaxis for colorectal cancer and dysplasia will be considered. Finally, recent developments in our understanding of how to use modified release mesalamine in a safe and cost-effective manner are evaluated, including discussion of the importance of studying patient non-adherence as a key component of future studies in this area.

Preliminary outcomes from the MMX mesalamine patient experience program in patients with ulcerative colitis

The MMX mesalamine patient experience program was designed to evaluate the efficacy of MMX mesalamine treatment in patients who were beginning a new course of therapy for ulcerative colitis (UC). This program was launched in October 2007. Patients who were beginning a new course of treatment on or after this date were invited to participate. Surveys were completed via the internet or an automated telephone system, and questions examined perceived symptom severity, self-assessed disruption to daily activities, prior UC medication and treatment satisfaction, at baseline and at approximately 30 and 60 days post-baseline. Additional disease education and related questions was included in the survey and further questions included examined patients' understanding of their disease and its management. Reponses from patients who completed the baseline and 60-day surveys are included in this analysis. In total, 319 patients were enrolled into the program, of whom 110 had completed the 60-day post baseline questionnaire at the time of reporting. Almost 75% of patients had previously received UC medication (most had received a mesalamine formulation [other than MMX mesalamine]). Patients' self-reported adherence to MMX mesalamine was 88%, and higher satisfaction was reported for MMX mesalamine than with other formulations, giving an average satisfaction score of over 7 out of 9. Indeed, after 60 days' treatment, patients reported a 36-57% reduction in symptom severity, with an approximately 46% reduction in the disruption to their daily activities. Overall, 81% of patients indicated that they would continue taking MMX mesalamine, with 78% stating that they would recommend it. The majority of patients (67%) felt that the patient experience program enhanced communication with their physician, with 80% stating that they would participate in similar programs in the future. The results of this patient experience program indicate that treatment of UC with MMX mesalamine could reduce symptom severity and disruption to daily activities. In general, patients preferred this formulation over previous treatments that they had received, and most would continue using MMX mesalamine. Positive perception of their medication regimen may benefit patient adherence with MMX mesalamine therapy. This research was funded by Shire Pharmaceuticals Inc., Wayne, Pennsylvania, USA.

MMX® Mesalamine Treatment for Ulcerative Colitis: Preliminary Outcomes from a Patient Experience Program

Purpose: In this program, we evaluated the impact of MMX mesalamine (LIALDA®; Shire Pharmaceuticals Inc., USA; MMX; Cosmo Technologies Limited, Wicklow, Ireland) treatment in patients who were commencing a new course of therapy for ulcerative colitis (UC). Methods: Patients initiating MMX mesalamine therapy were invited to participate in the LIALDA patient experience program (launched in October 2007). Patients were surveyed using a secure website or automated telephone system, where they completed a questionnaire on perceived symptom severity, self-assessed disruption to daily activities, prior UC medication and treatment satisfaction, at baseline and at approximately 30 and 60 days post-baseline. Patients were also questioned on their understanding of UC and its management, and received further UC education. Reponses from those patients who completed the baseline and 60-day surveys are included in this analysis. Results: Overall, 319 patients were enrolled and 110 had completed the 60-day post-baseline questionnaire at the time of reporting. After 60 days' treatment, patients reported a reduction in UC symptom severity of 36-57%, and a reduction of approximately 46% in disruption to daily activities. Almost 75% of patients had previously received UC medication (the majority of whom received another mesalamine formulation). Patient-reported adherence to MMX mesalamine was 88%, and patients were more satisfied with MMX mesalamine than with other formulations, giving an average satisfaction score of >7 out of 9. Indeed, 81% of patients stated that they would continue taking MMX mesalamine, and 78% would recommend it. Overall, most patients (67%) believed that communication with their physicians was enhanced by this program, and the majority (80%) indicated that they would volunteer for similar patient experience programs. Conclusion: Patients reported that MMX mesalamine treatment reduced UC symptom severity and disruption to daily activities. This formulation was generally preferred compared with patients' previous treatments, and most patients would continue using MMX mesalamine. Positive patient perception of their medication regimen may enhance treatment adherence with MMX mesalamine therapy. This research was funded by Shire Pharmaceuticals Inc., Wayne, Pennsylvania, USA. Disclosure: Dr T Hamilton - Employee, Shire Pharmaceuticals Inc Dr M Sumner - Employee, Shire Pharmaceuticals Inc Dr D Solomon - Employee, Shire Pharmaceuticals Inc Dr D Kerney - Employee, InfoMedics Inc. Funded by Shire Pharmaceuticals Inc.

Encapsulated Mesalamine Granules (Apriso) for Ulcerative Colitis

Apriso (Salix) is a new formulation of mesalamine (5-aminosalicylic acid; 5-ASA) approved by the FDA for maintenance of remission in mild to moderate ulcerative colitis (UC). Mesalamine is a locally acting antiinflammatory agent that is widely used both to maintain and induce remission in inflammatory bowel disease. Various mesalamine formulations have been developed to target drug delivery to areas of the small intestine and colon. Most of these agents require frequent dosing and have a high pill burden. The newest products--Lialda, introduced in 2007, and now Apriso--can be dosed once daily.

Patient considerations in the management of ulcerative colitis: role of once-daily MMX mesalamine.

Mesalamine and its derivatives are effective and well-tolerated therapies for ulcerative colitis. However, patient adherence to traditional mesalamine-based therapy is poor, and is often limited by heavy pill burdens and frequent dosing intervals. This can lead to ineffective disease control, impaired quality of life, and preventable morbidity and mortality. Previous studies have suggested that a once-daily mesalamine regimen would be strongly adhered to in the outpatient setting, but at that time no such formulation of mesalamine existed. In 2007, clinical trial data showed a novel, once-daily, multi-matrix (MMX) formulation of mesalamine to be effective in both remission induction and remission maintenance. This breakthrough in drug delivery allowed the unification of an effective therapeutic with a formulation that enables outpatients to be increasingly adherent to their medication. In theory, this might result in improved outpatient disease control and a decreased number of flares. As the use of MMX mesalamine increases, studies examining the outpatient community adherence rate need to be performed.

New approaches to adherence issues when dosing oral aminosalicylates in ulcerative colitis

Adherence issues with the use of available aminosalicylates for the treatment of ulcerative colitis (UC) are discussed. In the clinical setting, adherence to aminosalicylate therapy has been less than optimal. Topical formulations are associated with poor retention, abdominal bloating, and discomfort during administration. Although oral formulations are more convenient than topical formulations, many require multiple-daily-dosing regimens and have a high pill burden, which make patient adherence poor. A number of oral aminosalicylate formulations use colonic bacteria to release the active drug. Although these oral formulations are effective for the treatment of active UC, therapy is not optimal with regard to clinical outcome. Because of the short half-life, the vast majority of current therapies require multiple daily dosing. In addition, the dose strength of these formulations ranges from 250 to 500 mg, which requires patients to take several tablets at a time. Some patients may also require additional topical aminosalicylate to maintain treatment efficacy. However, many patients dislike topical formulations, and refill rates have been shown to be much lower than with oral formulations. New aminosalicylate formulations are now being designed to improve dosing schedules and increase patient adherence, potentially improving clinical and economic outcomes. High-dose, oral mesalamine formulations have been designed to reduce pill burden. While aminosalicylates are recommended as first-line treatment for the reduction of symptoms and the prevention of relapse in patients with mild-to-moderate UC, many available formulations require patients to take multiple tablets or capsules two to four times daily, which may affect adherence. New dosage regimens and delivery systems have been developed or are under development to improve convenience of dosing and potentially improve adherence.

Sustained Delivery of Intact Drug to the Colon: Mesalamine Formulation and Temporal Gastrointestinal Transit Analysis

The goal was to use temporal gastrointestinal transit simulations and formulation to predict and provide sustained input of target-site directed oral drug delivery exclusively into the colon. Using mesalamine as the model drug for formulation coupled with stomach emptying rates (fed and unfed) plus intestinal transit times demonstrates concepts and provides a specific example for treatment in ulcerative colitis. Formulation involved extrusion and spheronization into beads which were then coated with aqueous Eudragit® S. Drug is released only at colonic pH and gastrointestinal transit predicts sustained drug input into the colon, especially when food effects are included.

Combining pharmacokinetic, scintigraphic and tablet dissolution analyses to investigate the drug release profiles of delayed-release mesalamine formulations

Combining pharmacokinetic, scintigraphic and tablet dissolution analyses to investigate the drug release profiles of delayed-release mesalamine formulations

Combining pharmacokinetic, scintigraphic and tablet dissolution analyses to investigate the drug release profiles of delayed-release mesalamine formulations

Combining pharmacokinetic, scintigraphic and tablet dissolution analyses to investigate the drug release profiles of delayed-release mesalamine formulations

Consistency of coating thickness of delayed-release mesalamine formulations

Consistency of coating thickness of delayed-release mesalamine formulations

Consistency of coating thickness of delayed-release mesalamine formulations: drug release characteristics across the pH range found in the GI tract of patients with ulcerative colitis

Consistency of coating thickness of delayed-release mesalamine formulations: drug release characteristics across the pH range found in the GI tract of patients with ulcerative colitis

Combined pharmacokinetic and scintigraphic analyses for the comparison of 5-ASA release profiles from MMX™ mesalamine and another delayed-release mesalamine formulation

Combined pharmacokinetic and scintigraphic analyses for the comparison of 5-ASA release profiles from MMX™ mesalamine and another delayed-release mesalamine formulation