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Overview of budesonide therapy for adults with inflammatory bowel disease

Overview of budesonide therapy for adults with inflammatory bowel disease
Authors:
Mark A Peppercorn, MD
Adam S Cheifetz, MD
Section Editor:
J Thomas Lamont, MD
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Literature review current through: Feb 2022. | This topic last updated: Jan 15, 2021.

INTRODUCTION — Budesonide is a glucocorticoid with high first-pass metabolism; thus, the systemic bioavailability of the drug is decreased. This topic will review the pharmacology, indications, dosing, and safety of budesonide in the management of chronic, inflammatory bowel disease (IBD). The efficacy of budesonide for treating adult patients with Crohn disease, ulcerative colitis, pouchitis, or microscopic colitis, and the approach to medical management for these conditions are discussed in detail separately.

(See "Overview of the medical management of mild (low risk) Crohn disease in adults".)

(See "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease".)

(See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis".)

(See "Management of the hospitalized adult patient with severe ulcerative colitis".)

(See "Management of acute and chronic pouchitis".)

(See "Microscopic (lymphocytic and collagenous) colitis: Clinical manifestations, diagnosis, and management".)

PHARMACOLOGY

Metabolism — Budesonide is a glucocorticoid that is metabolized in the liver via cytochrome P450 isoenzyme CYP3A4 into two metabolites: 16 alpha-hydroxyprednisolone and 6 beta-hydroxybudesonide [1].

Approximately 90 percent of orally administered budesonide undergoes first-pass metabolism resulting in low systemic bioavailability of 10 to 15 percent [1-6]. The low systemic effect of budesonide results in less effect on adrenal function and bone mass compared with conventional glucocorticoids (eg, prednisone) [7]. (See 'Adverse effects' below.)

Factors that interfere with drug metabolism and may lead to increases in systemic bioavailability by two- to eight-fold include:

Concurrent use of moderate and strong inhibitors of CYP3A4 such as ketoconazole or grapefruit juice (table 1) [8,9].

Cirrhosis of the liver [3].

To assess specific drug interactions, the Lexicomp drug interactions program included with UpToDate can be used.

Mechanism of action — Budesonide has high topical anti-inflammatory activity and may work by depressing the activity of endogenous chemical mediators of inflammation (eg, kinins, prostaglandins). Glucocorticoids such as budesonide inhibit protein synthesis and transcription and downregulate the production of inflammatory cytokines [1].

Formulation characteristics

Oral formulations — In its native form without an encapsulation system, budesonide is absorbed in the proximal small bowel. Oral budesonide formulations are engineered to be resistant to gastric acid and allow for targeted, pH-dependent budesonide release, and they include (table 2) [1,7]:

Ileal release formulations:

Controlled ileal release formulation (CIR, pH- and time-dependent release) – The controlled ileal release formulation is a gelatin capsule filled with enteric coated granules that dissolve at a pH ≥5.5. This facilitates drug delivery to the ileum and ascending colon.

pH-dependent release formulation – This pH-dependent release formulation (not available in the United States or Canada) is a gelatin capsule containing budesonide pellets coated with methacrylic polymers. This formulation delivers the drug at pH >6.4 in the ileum and ascending colon.

Either controlled ileal release or pH-dependent release formulations may be used for treating patients with Crohn disease, and the choice between the two formulations is based on availability [10]. (See "Overview of the medical management of mild (low risk) Crohn disease in adults", section on 'Budesonide'.)

Colonic release formulation – This formulation of multimatrix budesonide extends its delivery to the entire colon and is used for treating patients with mild to moderate ulcerative colitis. (See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis", section on 'Subsequent therapy'.)

Colonic release budesonide is covered in a coating that resists gastric acid and dissolves at a pH ≥7. When the tablet reaches an alkaline environment, the coating dissolves and intestinal fluid comes into contact with the hydrophilic matrix. The matrix then swells and gradually dissolves, thereby releasing budesonide throughout the colon.

Rectal formulations — Rectal formulations include budesonide liquid enema and budesonide foam. Liquid enemas reach the proximal sigmoid colon and splenic flexure in patients who are able to retain them. In contrast, foam preparations generally reach the mid-sigmoid colon. Foam preparations are easier to retain compared with liquid enemas, especially in patients with rectal inflammation resulting in decreased rectal compliance.

Timing of response — Budesonide is generally a fast-acting drug. A clinical response is typically observed after 7 to 10 days of therapy with either the oral formulation or the topical preparations.

CONTRAINDICATIONS AND CAUTIONS

Patients who require special consideration include:

Patients with cirrhosis – We avoid using budesonide for patients with cirrhosis because of a greater than two-fold increase in systemic bioavailability in these patients (compared with patients without liver disease) and possible increased risk of adverse effects related to systemic glucocorticoids [3]. (See 'Adverse effects' below.)

Patients on CYP3A inhibitors – The combination of budesonide and a CYP3A inhibitor (eg, ketoconazole or grapefruit juice) is avoided because drugs (or substances) that inhibit CYP3A enzymes may increase the serum concentration of budesonide. (See 'Metabolism' above.)

For specific drug interactions, refer to the Lexicomp drug interactions program included in UpToDate.

DOSING

Oral formulations

Starting dose and subsequent taper — The starting dose and subsequent tapering schedule of the oral budesonide formulations (eg, controlled ileal release form, budesonide multimatrix [MMX]) generally begins with budesonide 9 mg taken daily. For example, in patients with ulcerative colitis, we give budesonide MMX 9 mg daily for six to 10 weeks. If symptoms of active IBD such as diarrhea and rectal bleeding improve with treatment, the budesonide dose is reduced to 9 mg every other day for two weeks, followed by discontinuation, for a total of eight to 12 weeks of therapy. (See 'Oral formulations' above.)

If the patient does not respond after four weeks of budesonide 9 mg daily, a change in drug therapy is usually required. Subsequent drug selection depends on a number of factors including the severity and location of disease. The management of patients who do not respond to budesonide MMX, in addition to the approach to induction and maintenance therapy for ulcerative colitis, are discussed separately. (See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis".)

For patients with Crohn disease, the initial dosing regimen typically begins with oral budesonide 9 mg taken daily for four to eight weeks, followed by a taper, for a total of 8 to 12 weeks of therapy. (See "Overview of the medical management of mild (low risk) Crohn disease in adults".)

Disease activity is assessed clinically by observing a change in symptoms. Serum and stool markers of inflammation (eg, C-reactive protein, fecal calprotectin) can also be obtained to assess clinical response. (See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults".)

We usually limit budesonide to a single course. Therapeutic options for patients whose symptoms improve initially but then flare when budesonide is tapered or discontinued are discussed separately. (See "Management of moderate to severe ulcerative colitis in adults", section on 'Induction of remission'.)

The goal of tapering is to use a rate of change in dosing that will permit observation of the early signs of a disease flare.

Other instructions — Budesonide capsules should be swallowed whole and cannot be chewed or crushed [11].

Rectal formulations — Rectal budesonide formulations are used for treating symptoms of diarrhea and rectal bleeding in patients with ulcerative proctosigmoiditis or left-sided ulcerative colitis [12,13]. Dosing depends on whether the budesonide is given as a rectal foam or an enema, and neither preparation requires tapering [1]:

Rectal foam (2 mg per application) – Initial therapy with budesonide foam is given twice daily for two weeks followed by once daily maintenance therapy for four weeks. Response to treatment is assessed clinically by observing a change in symptoms.

Enema (2 mg per 100 mL application, available in Canada only) – Initial therapy is given once daily at bedtime for four weeks. If symptoms do not improve, daily enema therapy at bedtime may continue for an additional four weeks.

The management of patients with ulcerative colitis who do not respond to topical therapy is discussed separately. (See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis".)

MONITORING — We do not routinely monitor patients on budesonide for glucocorticoid-related adverse (eg, hyperglycemia or osteoporosis) because of the low systemic bioavailability of budesonide and its use only as induction therapy (maximum treatment duration of three months).

ADVERSE EFFECTS

Frequency of adverse effects — Budesonide has an overall excellent safety profile and is associated with fewer adverse effects compared with conventional glucocorticoids [14,15]. In a pooled analysis of three studies including over 900 patients with ulcerative colitis, the risk of having at least one adverse event was not significantly different for patients receiving budesonide multimatrix formulation compared with placebo (RR 1.09, 95% CI 0.95-1.26) [14].

Systemic adverse effects (eg, adrenal suppression, decreased bone mass) occur less often in patients treated with budesonide compared with conventional glucocorticoids (eg, prednisone) due to location-specific delivery and a high first-pass metabolism resulting in limited systemic bioavailability (10 to 15 percent) [7,15-18]. (See 'Pharmacology' above.)

Effect on bone mineral density — While systemic glucocorticoid therapy is associated with an appreciable risk of bone loss, the available data suggest that budesonide has limited effect on bone mineral density because of its low systemic bioavailability [17,19,20]. (See 'Metabolism' above.)

In particular, budesonide therapy is associated with better preservation of bone mineral density in patients who are glucocorticoid-naïve prior to receiving budesonide. In a trial including 272 patients with Crohn disease involving the ileum and/or ascending colon, no significant differences were observed in bone mineral density at two-year follow-up between budesonide-treated patients compared with patients on prednisolone [17]. However, the reduction in bone mineral density was significantly less in patients who had never before received glucocorticoids and were subsequently treated with budesonide compared with those receiving prednisolone.

Despite this potential benefit of budesonide, patients with IBD may have other risk factors for osteoporosis including disease-related inflammatory activity, nutritional deficiency, hypogonadism, and prior use of systemic glucocorticoids. The risk factors for and treatment of metabolic bone disease in patients with IBD are discussed separately (see "Metabolic bone disease in inflammatory bowel disease").

The clinical features and evaluation of glucocorticoid-induced bone loss are discussed separately. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)

Hypothalamic-pituitary-adrenal (HPA) axis suppression — Budesonide can reduce the response of the HPA axis to stress, but to a lesser extent compared with conventional glucocorticoids [15,21]. In addition, supplementation with a systemic glucocorticoid may be required in patients taking budesonide who undergo surgery or other stressful situations (eg, bacterial sepsis). (See "The management of the surgical patient taking glucocorticoids" and "Glucocorticoid withdrawal".)

The approach to withdrawal of glucocorticoids, HPA suppression, and the clinical manifestations of adrenal insufficiency are presented separately. (See "Glucocorticoid withdrawal" and "Pharmacologic use of glucocorticoids", section on 'HPA axis suppression' and "Clinical manifestations of adrenal insufficiency in adults".)

PREGNANCY — Budesonide is considered low risk in pregnancy and is used for the same indications as a nonpregnant patient with IBD. While we use budesonide for women with IBD throughout pregnancy, we counsel patients that there is a possible, rare risk of cleft palate described with conventional glucocorticoids given during the first trimester [22,23]. Palatal closure is usually complete by the 12th week of pregnancy, thus, the risk is limited to administration during the first trimester. (See "Etiology, prenatal diagnosis, obstetric management, and recurrence of cleft lip and/or palate".)

Throughout pregnancy, the lowest possible dose of budesonide necessary for symptom control is given. (See "Overview of the medical management of mild (low risk) Crohn disease in adults", section on 'Maintenance of remission' and "Medical management of low-risk adult patients with mild to moderate ulcerative colitis".)

Limited data suggest that budesonide is well tolerated in pregnant women with IBD and is not associated with increased risk of adverse outcomes. In a small study of eight pregnant women with Crohn disease who were treated with budesonide, there were no cases of maternal adrenal suppression, glucose intolerance, ocular side effects, hypertension, or fetal congenital abnormalities [24].

Budesonide is compatible with breastfeeding. The side effects of glucocorticoids and the safety of glucocorticoids in pregnancy and lactation are discussed in detail, separately. (See "Fertility, pregnancy, and nursing in inflammatory bowel disease", section on 'Glucocorticoids'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ulcerative colitis in adults" and "Society guideline links: Crohn disease in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Crohn disease in adults (The Basics)")

Beyond the Basics topics (see "Patient education: Crohn disease (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Budesonide is a glucocorticoid that is metabolized in the liver via cytochrome P450 isoenzyme CYP3A4 into two metabolites: 16 alpha-hydroxyprednisolone and 6 beta-hydroxybudesonide [1]. Approximately 90 percent of orally administered budesonide undergoes first-pass metabolism resulting in low systemic bioavailability of 10 to 15 percent. (See 'Metabolism' above.)

Without an encapsulation system, budesonide is absorbed in the proximal small bowel and cannot be delivered to the site of inflammation. Oral budesonide formulations are engineered to be resistant to gastric acid and allow for targeted, pH dependent drug release. Available formulations include (table 2) (see 'Oral formulations' above):

Controlled ileal release formulation (pH- and time-dependent release)

pH-dependent release formulation (not available in the United States or Canada)

Colonic release formulation (multimatrix formulation)

Rectal formulations include budesonide liquid enema and budesonide foam. Liquid enemas reach the proximal sigmoid colon and splenic flexure in patients who are able to retain them. In contrast, foam preparations generally reach the mid-sigmoid colon. (See 'Rectal formulations' above.)

Contraindications to budesonide include severe, systemic bacterial or fungal infection. We avoid using budesonide for patients with cirrhosis because of a greater than two-fold increase in systemic bioavailability in these patients. (See 'Contraindications and cautions' above.)

The initial dosing regimen for patients with Crohn disease typically begins with oral budesonide 9 mg taken daily for four to eight weeks, followed by a taper, for an 8 to 12-week course of therapy. (See 'Dosing' above and "Overview of the medical management of mild (low risk) Crohn disease in adults".)

Budesonide has an overall excellent safety profile. Systemic adverse effects (eg, bone loss, adrenal suppression) occur less often in patients treated with budesonide compared with conventional glucocorticoids due to location-specific delivery and a high first-pass metabolism resulting in limited systemic bioavailability. (See 'Adverse effects' above.)

Budesonide is considered low risk in pregnancy and is used for the same indications as a nonpregnant patient IBD. The lowest possible dose of budesonide necessary to control symptoms is given. (See 'Pregnancy' above and "Fertility, pregnancy, and nursing in inflammatory bowel disease".)

ACKNOWLEDGMENT — We are saddened by the death of Paul Rutgeerts, MD, who passed away in September 2020. UpToDate gratefully acknowledges Dr. Rutgeerts' work as our Section Editor for Gastroenterology.

REFERENCES

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  3. Edsbäcker S, Andersson T. Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn's disease. Clin Pharmacokinet 2004; 43:803.
  4. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021324s016lbl.pdf (Accessed on August 27, 2018).
  5. https://www.medicines.org.uk/emc/product/138/smpc (Accessed on August 27, 2018).
  6. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203634s004lbl.pdf (Accessed on August 27, 2018).
  7. Iborra M, Alvarez-Sotomayor D, Nos P. Long-term safety and efficacy of budesonide in the treatment of ulcerative colitis. Clin Exp Gastroenterol 2014; 7:39.
  8. Seidegård J. Reduction of the inhibitory effect of ketoconazole on budesonide pharmacokinetics by separation of their time of administration. Clin Pharmacol Ther 2000; 68:13.
  9. Seidegård J, Randvall G, Nyberg L, Borgå O. Grapefruit juice interaction with oral budesonide: equal effect on immediate-release and delayed-release formulations. Pharmazie 2009; 64:461.
  10. Hanauer S, Sandborn WJ, Persson A, Persson T. Budesonide as maintenance treatment in Crohn's disease: a placebo-controlled trial. Aliment Pharmacol Ther 2005; 21:363.
  11. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021324s016lbl.pdf (Accessed on August 23, 2018).
  12. Sandborn WJ, Bosworth B, Zakko S, et al. Budesonide foam induces remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis. Gastroenterology 2015; 148:740.
  13. Lindgren S, Löfberg R, Bergholm L, et al. Effect of budesonide enema on remission and relapse rate in distal ulcerative colitis and proctitis. Scand J Gastroenterol 2002; 37:705.
  14. Sherlock ME, MacDonald JK, Griffiths AM, et al. Oral budesonide for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2015; :CD007698.
  15. Rutgeerts P, Löfberg R, Malchow H, et al. A comparison of budesonide with prednisolone for active Crohn's disease. N Engl J Med 1994; 331:842.
  16. Bar-Meir S, Chowers Y, Lavy A, et al. Budesonide versus prednisone in the treatment of active Crohn's disease. The Israeli Budesonide Study Group. Gastroenterology 1998; 115:835.
  17. Schoon EJ, Bollani S, Mills PR, et al. Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn's disease. Clin Gastroenterol Hepatol 2005; 3:113.
  18. Lichtenstein GR, Loftus EV, Isaacs KL, et al. ACG Clinical Guideline: Management of Crohn's Disease in Adults. Am J Gastroenterol 2018; 113:481.
  19. D'Haens G, Verstraete A, Cheyns K, et al. Bone turnover during short-term therapy with methylprednisolone or budesonide in Crohn's disease. Aliment Pharmacol Ther 1998; 12:419.
  20. 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. Greenberg GR, Feagan BG, Martin F, et al. Oral budesonide for active Crohn's disease. Canadian Inflammatory Bowel Disease Study Group. N Engl J Med 1994; 331:836.
  22. Hviid A, Mølgaard-Nielsen D. Corticosteroid use during pregnancy and risk of orofacial clefts. CMAJ 2011; 183:796.
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  24. Beaulieu DB, Ananthakrishnan AN, Issa M, et al. Budesonide induction and maintenance therapy for Crohn's disease during pregnancy. Inflamm Bowel Dis 2009; 15:25.
Topic 4061 Version 24.0

References

1 : Budesonide for the treatment of ulcerative colitis.

2 : Oral locally active steroids in inflammatory bowel disease.

3 : Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn's disease.

4 : Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn's disease.

5 : Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn's disease.

6 : Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn's disease.

7 : Long-term safety and efficacy of budesonide in the treatment of ulcerative colitis.

8 : Reduction of the inhibitory effect of ketoconazole on budesonide pharmacokinetics by separation of their time of administration.

9 : Grapefruit juice interaction with oral budesonide: equal effect on immediate-release and delayed-release formulations.

10 : Budesonide as maintenance treatment in Crohn's disease: a placebo-controlled trial.

11 : Budesonide as maintenance treatment in Crohn's disease: a placebo-controlled trial.

12 : Budesonide foam induces remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis.

13 : Effect of budesonide enema on remission and relapse rate in distal ulcerative colitis and proctitis.

14 : Oral budesonide for induction of remission in ulcerative colitis.

15 : A comparison of budesonide with prednisolone for active Crohn's disease.

16 : Budesonide versus prednisone in the treatment of active Crohn's disease. The Israeli Budesonide Study Group.

17 : Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn's disease.

18 : ACG Clinical Guideline: Management of Crohn's Disease in Adults.

19 : Bone turnover during short-term therapy with methylprednisolone or budesonide in Crohn's disease.

20 : Bone mineral density in Crohn's disease: a longitudinal study of budesonide, prednisone, and nonsteroid therapy.

21 : Oral budesonide for active Crohn's disease. Canadian Inflammatory Bowel Disease Study Group.

22 : Corticosteroid use during pregnancy and risk of orofacial clefts.

23 : Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies.

24 : Budesonide induction and maintenance therapy for Crohn's disease during pregnancy.