Oral Budesonide for Maintenance of Remission of Crohn's Disease
Oral Budesonide for Maintenance of Remission of Crohn's Disease
Background: Budesonide exhibits similar efficacy to systemic glucocorticosteroids (GCSs) in Crohn's disease (CD), but with fewer adverse events (AEs).
Aim: To evaluate budesonide's safety profile in CD patients, in particular, incidences of clinically important AEs known to be associated with systemic GCSs.
Methods: Five 1-year, double-blind, placebo-controlled trials evaluating budesonide for mild-to-moderate CD were pooled for analysis.
Results: The highest incidence rates of AEs were gastrointestinal- and endocrine systems-related in both groups (budesonide 6 mg/day, n = 208; placebo, n = 209). Incidence rates were similar, except for higher incidence of endocrine disorders in budesonide versus placebo patients (P = 0.0042) caused by a higher overall occurrence of cutaneous GCS symptoms (P = 0.0036) in the budesonide group; differences in individual symptoms were nonsignificant. Percentage of patients with normal adrenal function was significantly lower at 13 weeks (three of five studies), but not at 52 weeks (two studies) in the budesonide versus placebo groups. Occurrence of clinically important or serious AEs associated with systemic GCSs, including sepsis, cataracts, adrenal insufficiency was rare and similar between groups.
Conclusions: Budesonide treatment for up to 1 year is well-tolerated in CD patients, with an AE profile similar to placebo and only rare occurrences of clinically important AEs associated with systemic GCSs.
Crohn's disease (CD) is a chronic inflammatory disease characterized by episodes of active flares and remission. As a consequence of the relapsing nature of this disease, the goal of therapy is to induce remission and then maintain remission. Systemic glucocorticosteroids (GCSs), such as prednisone or prednisolone, are an effective treatment for CD; however, they are associated with clinically important adverse events (AEs), such as adrenal suppression, hypertension, impaired glucose tolerance, cataracts, osteoporosis, osteonecrosis, psychiatric disorders and other cushingoid symptoms. Thus, although systemic GCSs are efficacious for the treatment of active CD, they are not recommended for long-term treatment of CD.
Budesonide is a targeted synthetic corticosteroid that was developed to provide efficacy similar to that of other GCSs, but with fewer AEs. Budesonide has a very high affinity for the GCS receptor and following oral administration, it undergoes extensive first-pass metabolism, whereby the liver metabolizes 80-90% of the parent compound, resulting in much less systemic exposure of the drug than is seen with systemic GCSs. In addition, the oral capsule formulation of budesonide provides a time-dependent, targeted release of the drug into the ileum and ascending colon. Thus, the combination of localized delivery, high topical GCS activity and considerable first-pass metabolism in the liver of oral budesonide results in a lower potential for the systemic AEs that are commonly associated with the use of systemic GCSs.
The efficacy, safety and tolerability of short-term oral budesonide capsules have been well-established in patients with CD. Furthermore, it has been suggested that budesonide should be used as first-line therapy to induce remission in mild-to-moderate CD because of its efficacy superior to placebo and mesalazine (mesalamine) and its efficacy and improved safety compared with systemic corticosteroids.
Budesonide capsules have been investigated in long-term clinical studies of CD patients. A recent combined analysis that had a primary focus of evaluating medication efficacy of four 1-year clinical trials revealed that budesonide capsules significantly prolong the median time to clinical relapse compared with placebo treatment (114 day longer) while demonstrating a safety profile similar to placebo. Budesonide 6 mg/day was significantly more effective than placebo in maintaining remission for up to 6 months. Furthermore, a 2-year maintenance therapy trial by Schoon et al., which stratified patients according to previous steroid use, demonstrated that budesonide capsules, when used to maintain symptomatic remission in patients with CD, were associated with a significantly lower incidence of GCS-related AEs than prednisolone. In addition, budesonide provided a significant advantage in terms of preservation of bone mass in the lumbar spine compared with prednisolone in steroid-naive CD patients.
Despite these findings, physicians may still have lingering concerns about using budesonide capsules for the treatment of mild-to-moderate CD because budesonide belongs to the same class of compounds as the systemic GCSs. Safety data from five double-blind placebo-controlled clinical trials of patients with mild-to-moderate CD were evaluated to assess the incidence of clinically important AEs, particularly, categories of AEs that are associated with systemic exposure of GCSs, following 1-year treatment with budesonide or placebo. Although guidelines do not suggest 1 year of continuous budesonide use, patients may be exposed to budesonide treatment for longer than 6 months. The US Food and Drug Administration has approved and American Gastroenterology Association guidelines recommend budesonide for 8 weeks for induction of remission (clinically, patients may actually receive treatment for up to 10 week) and for an additional 3 months of maintenance. In clinical practice, some patients may receive two cycles of induction and maintenance treatment in a single year. In addition, patients switched from conventional corticosteroids to budesonide may be exposed to budesonide for longer than 6 months. Thus, the data from this study provide important safety information for patients who may be exposed to budesonide for longer than 6 months.
Abstract and Introduction
Abstract
Background: Budesonide exhibits similar efficacy to systemic glucocorticosteroids (GCSs) in Crohn's disease (CD), but with fewer adverse events (AEs).
Aim: To evaluate budesonide's safety profile in CD patients, in particular, incidences of clinically important AEs known to be associated with systemic GCSs.
Methods: Five 1-year, double-blind, placebo-controlled trials evaluating budesonide for mild-to-moderate CD were pooled for analysis.
Results: The highest incidence rates of AEs were gastrointestinal- and endocrine systems-related in both groups (budesonide 6 mg/day, n = 208; placebo, n = 209). Incidence rates were similar, except for higher incidence of endocrine disorders in budesonide versus placebo patients (P = 0.0042) caused by a higher overall occurrence of cutaneous GCS symptoms (P = 0.0036) in the budesonide group; differences in individual symptoms were nonsignificant. Percentage of patients with normal adrenal function was significantly lower at 13 weeks (three of five studies), but not at 52 weeks (two studies) in the budesonide versus placebo groups. Occurrence of clinically important or serious AEs associated with systemic GCSs, including sepsis, cataracts, adrenal insufficiency was rare and similar between groups.
Conclusions: Budesonide treatment for up to 1 year is well-tolerated in CD patients, with an AE profile similar to placebo and only rare occurrences of clinically important AEs associated with systemic GCSs.
Introduction
Crohn's disease (CD) is a chronic inflammatory disease characterized by episodes of active flares and remission. As a consequence of the relapsing nature of this disease, the goal of therapy is to induce remission and then maintain remission. Systemic glucocorticosteroids (GCSs), such as prednisone or prednisolone, are an effective treatment for CD; however, they are associated with clinically important adverse events (AEs), such as adrenal suppression, hypertension, impaired glucose tolerance, cataracts, osteoporosis, osteonecrosis, psychiatric disorders and other cushingoid symptoms. Thus, although systemic GCSs are efficacious for the treatment of active CD, they are not recommended for long-term treatment of CD.
Budesonide is a targeted synthetic corticosteroid that was developed to provide efficacy similar to that of other GCSs, but with fewer AEs. Budesonide has a very high affinity for the GCS receptor and following oral administration, it undergoes extensive first-pass metabolism, whereby the liver metabolizes 80-90% of the parent compound, resulting in much less systemic exposure of the drug than is seen with systemic GCSs. In addition, the oral capsule formulation of budesonide provides a time-dependent, targeted release of the drug into the ileum and ascending colon. Thus, the combination of localized delivery, high topical GCS activity and considerable first-pass metabolism in the liver of oral budesonide results in a lower potential for the systemic AEs that are commonly associated with the use of systemic GCSs.
The efficacy, safety and tolerability of short-term oral budesonide capsules have been well-established in patients with CD. Furthermore, it has been suggested that budesonide should be used as first-line therapy to induce remission in mild-to-moderate CD because of its efficacy superior to placebo and mesalazine (mesalamine) and its efficacy and improved safety compared with systemic corticosteroids.
Budesonide capsules have been investigated in long-term clinical studies of CD patients. A recent combined analysis that had a primary focus of evaluating medication efficacy of four 1-year clinical trials revealed that budesonide capsules significantly prolong the median time to clinical relapse compared with placebo treatment (114 day longer) while demonstrating a safety profile similar to placebo. Budesonide 6 mg/day was significantly more effective than placebo in maintaining remission for up to 6 months. Furthermore, a 2-year maintenance therapy trial by Schoon et al., which stratified patients according to previous steroid use, demonstrated that budesonide capsules, when used to maintain symptomatic remission in patients with CD, were associated with a significantly lower incidence of GCS-related AEs than prednisolone. In addition, budesonide provided a significant advantage in terms of preservation of bone mass in the lumbar spine compared with prednisolone in steroid-naive CD patients.
Despite these findings, physicians may still have lingering concerns about using budesonide capsules for the treatment of mild-to-moderate CD because budesonide belongs to the same class of compounds as the systemic GCSs. Safety data from five double-blind placebo-controlled clinical trials of patients with mild-to-moderate CD were evaluated to assess the incidence of clinically important AEs, particularly, categories of AEs that are associated with systemic exposure of GCSs, following 1-year treatment with budesonide or placebo. Although guidelines do not suggest 1 year of continuous budesonide use, patients may be exposed to budesonide treatment for longer than 6 months. The US Food and Drug Administration has approved and American Gastroenterology Association guidelines recommend budesonide for 8 weeks for induction of remission (clinically, patients may actually receive treatment for up to 10 week) and for an additional 3 months of maintenance. In clinical practice, some patients may receive two cycles of induction and maintenance treatment in a single year. In addition, patients switched from conventional corticosteroids to budesonide may be exposed to budesonide for longer than 6 months. Thus, the data from this study provide important safety information for patients who may be exposed to budesonide for longer than 6 months.