Budesonide

What it is

Budesonide is a synthetic glucocorticoid (a corticosteroid) that is deliberately designed to act where it is placed and then be destroyed quickly by the liver. The US label for the oral capsule describes it as having “a high topical glucocorticosteroid (GCS) activity and a substantial first pass elimination”, and states that its affinity for glucocorticoid receptors is about 200-fold that of cortisol. It is sold in many physically different products – pressurised and dry-powder inhalers, nasal sprays, enteric-coated capsules that dissolve in the small bowel, multi-matrix tablets that release along the colon, rectal foam, a targeted-release capsule aimed at gut lymphoid tissue, and fixed combinations with the long-acting bronchodilator formoterol. Each formulation has its own evidence base, so “does budesonide work” has a different answer depending on which product and which disease is meant.

What the research says

The evidence is strong for several specific uses and weak or negative for others, and the formulation matters more than the molecule. A Cochrane systematic review found oral controlled-ileal-release budesonide better than placebo for inducing remission in mild-to-moderate Crohn's disease of the ileum but less effective than conventional steroids, and no better than placebo for keeping people in remission. Multi-matrix tablets roughly double the chance of combined clinical and endoscopic remission in mild-to-moderate ulcerative colitis, and rectal foam helps distal disease. Inhaled budesonide reduced severe asthma exacerbations by about half over three years in a 7,241-person trial, and a targeted-release oral capsule slowed kidney function loss in IgA nephropathy. Against that: inhaled corticosteroids as a class increase pneumonia in COPD and slow children's growth by roughly half a centimetre in the first year, and even the “local” oral forms measurably suppress the adrenal axis.

Evidence grade: Well established.

How it works

Drug class: Synthetic non-halogenated glucocorticoid (corticosteroid), formulated for local delivery with high first-pass hepatic metabolism

Budesonide switches off inflammatory gene programmes by binding glucocorticoid receptors in the tissue where it is delivered. Because most of what is absorbed is destroyed on its first pass through the liver, the aim is a strong local anti-inflammatory effect with less of the whole-body steroid effect. The oral capsule achieves this with granules that stay intact in the stomach and dissolve only once they reach the duodenum, then release drug slowly along the small bowel. (Source 1)

What it is used for

• In a Cochrane systematic review of 13 induction trials, budesonide 9 mg/day put more people into remission than placebo (47% vs 22%) but fewer than conventional steroids such as prednisolone. Evidence: established. (Source 2)
• The FDA label records approval for up to three months on the basis of a longer time to relapse. The Cochrane meta-analysis of the same literature found no difference from placebo in the proportion still in remission at one year. Evidence: disputed. (Source 2)
• Two identically designed trials and a Cochrane pooled analysis of 900 patients found budesonide MMX 9 mg about twice as likely as placebo to achieve combined clinical and endoscopic remission at 8 weeks, with most of the benefit in left-sided disease. Evidence: established. (Source 3)
• A systematic review of three placebo-controlled trials in 711 patients found rectal budesonide foam superior to placebo for inducing clinical remission and endoscopic improvement; it performed similarly to rectal mesalazine. Evidence: limited. (Source 4)
• In the 7,241-patient START trial, three years of once-daily low-dose inhaled budesonide roughly halved the risk of a first severe asthma-related event, with small lung-function gains and a measurable loss of height in children. Evidence: established. (Source 5)
• A meta-analysis of four trials found as-needed budesonide-formoterol reduced severe exacerbations compared with as-needed short-acting beta-agonist alone (RR 0.46) while delivering a lower daily steroid dose than maintenance budesonide. Evidence: established. (Source 6)
• Cochrane reviewers describe fewer exacerbations, better lung function and better quality of life as the known benefits of inhaled steroids in COPD, but found that budesonide also increases pneumonias serious enough to need hospital admission. Evidence: limited. (Source 7)
• In the 364-patient NefIgArd phase 3 trial, nine months of a gut-targeted budesonide capsule preserved eGFR over two years by about 5 mL/min/1.73 m2 compared with placebo, at the cost of more oedema, hypertension and acne. Evidence: limited. (Source 8)
• Off-label in the United States. A clinical-practice cohort reports that controlled studies show high short-term remission rates with budesonide in collagenous colitis, but that relapse after stopping is common and about a fifth of patients need a higher maintenance dose. Evidence: limited. (Source 9)

Interactions

• Ketoconazole and other strong CYP3A4 inhibitors (itraconazole, ritonavir, erythromycin and similar) (pharmacokinetic study): Blocking the enzyme that destroys budesonide on its first pass through the liver pushes blood levels up several-fold, which converts a “local” steroid into a systemic one and can cause Cushing-like effects. (Source 10)
• Grapefruit and grapefruit juice (pharmacokinetic study): Grapefruit inhibits CYP3A in the gut wall, roughly doubling how much oral budesonide reaches the bloodstream. The label advises avoiding it while on treatment. Orange and apple juice do not have this effect. (Source 10)
• St John's wort and other CYP3A4 inducers (theoretical): St John's wort is a known CYP3A4 inducer. The budesonide label does not name it, but states that inducing CYP3A4 lowers budesonide blood levels, which would be expected to reduce its effect. This is reasoning from the enzyme pathway rather than a study of St John's wort with budesonide. (Source 10)
• Omeprazole (and other acid-suppressing drugs) (pharmacokinetic study): The enteric coating on the oral capsule dissolves above pH 5.5, so in theory acid suppression could change where the drug is released. Tested directly, omeprazole 20 mg daily made no difference. (Source 10)
• Cimetidine (pharmacokinetic study): With an uncoated budesonide formulation, cimetidine raised peak levels slightly and this was enough to suppress cortisol measurably. (Source 10)
• Combined oral contraceptives containing ethinyl estradiol (pharmacokinetic study): No interaction in either direction was found, despite both drugs using CYP3A4. (Source 10)
• A high-fat meal (pharmacokinetic study): Food delays how quickly the oral capsule is absorbed without changing total exposure, which is why the label tells patients to take the capsule consistently and swallow it whole. (Source 10)

Stopping it

• The label itself treats budesonide as a drug to be tapered rather than stopped abruptly after maintenance treatment, and says continuing beyond three months adds no substantial benefit. (Source 11)
• Because budesonide blunts the adrenal stress response, the label advises adding a systemic steroid around surgery or other physiological stress – the practical consequence of the ACTH-test suppression seen in the Cochrane review. (Source 12)
• In collagenous colitis, relapse after stopping budesonide is the usual pattern, and about one in five people in a practice cohort needed a higher maintenance dose to stay well. (Source 9)
• For inhaled steroids in COPD the best withdrawal evidence is the WISDOM trial, which stepped the inhaled steroid down over 12 weeks in people already on two long-acting bronchodilators. It used fluticasone, not budesonide, so it speaks to the class rather than to budesonide specifically: exacerbation risk did not rise, but lung function fell slightly. (Source 13)
• In that same trial the price of withdrawal was measured in lung function rather than flare-ups: trough FEV1 fell by about 38 mL more in the withdrawal group by week 18 and 43 mL more by week 52, while breathlessness did not change and health status changed only slightly. (Source 13)
• The trial authors' own summary of what withdrawal does and does not cost, for inhaled corticosteroids as a class rather than budesonide specifically. (Source 14)

What goes wrong

Maintenance budesonide 6 mg/day nearly tripled the chance of an abnormal ACTH stimulation test compared with placebo, showing measurable suppression of the adrenal axis. (Source 15)

• Systematic review, Low certainty.
• Size: 297 participants across four trials.
• Who: Adults with Crohn's disease in remission on maintenance budesonide.
• How long: up to 12 months.
• Result: Pooled RR 2.72 (95% CI 1.62–4.58), P = 0.0002, I2 = 0%; the 3 mg/day dose was not significantly different from placebo (RR 1.89, 95% CI 0.76–4.69)
• Funding: not stated.

Limit of this finding: Two things in this review need care. The authors graded their own evidence on this outcome as low quality, because the data are sparse and not every trial reported the test. And elsewhere in the same paper they describe budesonide as producing 'significantly fewer' abnormal ACTH tests than conventional steroids on a result of RR 0.60 with a confidence interval of 0.36 to 1.00 – an interval that reaches 1.00, meaning 'no difference' is not excluded. Treat the comparison with conventional steroids as suggestive rather than settled.

Maintenance doses of budesonide 6 mg/day also increased the likelihood of an abnormal ACTH test relative to placebo (pooled RR 2.72; 95% CI, 1.62–4.58; P = 0.0002; I 2 = 0%; four studies; 297 participants

Budesonide 9 mg/day suppressed plasma cortisol in healthy volunteers, though less than prednisolone 20 mg/day. (Source 16)

• Blood level study, Low certainty.
• Size: not stated in the passage read (crossover study in healthy volunteers)
• Who: Healthy volunteers.
• How long: 5 days.
• Result: Mean decrease in integrated 0–24 hour plasma cortisol 45% with budesonide 9 mg/day versus 78% with prednisolone 20 mg/day.
• Funding: industry-funded (manufacturer's label)

The mean decrease in the integrated 0-24 hour plasma cortisol concentration was greater (78%) with prednisolone 20 mg/day compared to 45% with ENTOCORT EC 9 mg/day.

In the same asthma trial, children under 11 taking inhaled budesonide grew 1.34 cm less over three years than those on placebo, with most of the loss in year one. (Source 5)

• Randomized trial, High certainty.
• Size: Children younger than 11 within the 7,241-patient trial.
• Who: Children under 11 with mild persistent asthma on budesonide 200 µg/day.
• How long: 3 years.
• Result: 3-year growth reduced by 1.34 cm; 0.58 cm in year 1, then 0.43 cm and 0.33 cm in years 2 and 3.
• Funding: industry-funded.

In children younger than 11 years, 3-year growth was reduced in the budesonide group by 1.34 cm.

Across inhaled corticosteroids as a class, regular low-to-medium doses slowed children's growth by about half a centimetre in the first year of treatment. (Source 17)

• Systematic review, High certainty.
• Size: 14 trials with 5,717 participants for growth velocity; 15 trials with 3,275 for change in height.
• Who: Children up to 18 with mild to moderate persistent asthma, six different inhaled corticosteroid molecules including budesonide.
• How long: 1 year (trials ran 3 months to 4–6 years)
• Result: Mean difference −0.48 cm/year in linear growth velocity and −0.61 cm in change from baseline height during one year of treatment.
• Funding: not stated.

Evidence derived from this meta-analysis of randomized trials shows that regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm per year in linear growth velocity and 0.61 cm in change from baseline in height during a one-year treatment in children with mild to moderate persistent asthma.

One trial followed children into adulthood and found a small permanent height deficit after prepubertal budesonide at 400 micrograms a day. (Source 18)

• Systematic review, Moderate certainty.
• Size: One trial with follow-up into adulthood, within a Cochrane review of 25 trials and 8,471 children.
• Who: Children given inhaled budesonide 400 micrograms/day in prepubertal years.
• How long: mean 4.3 years of treatment, followed into adulthood.
• Result: Mean reduction in adult height of 1.20 cm (95% CI -1.90 to -0.50) versus placebo. Three of four trials reporting growth after treatment stopped did not describe statistically significant catch-up growth two to four months later.
• Funding: not stated.

One trial with follow-up into adulthood showed that participants of prepubertal age treated with budesonide 400 μg/d for a mean duration of 4.3 years had a mean reduction of 1.20 cm (95% CI -1.90 to -0.50) in adult height compared with those treated with placebo.

Inhaled corticosteroids increase pneumonia in people with COPD, with a dose-response gradient. (Source 19)

• Meta-analysis, Moderate certainty.
• Size: 59 randomised controlled trials, 103,477 patients.
• Who: Adults with COPD randomised to inhaled corticosteroid versus non-inhaled-corticosteroid treatment.
• How long: varied; subgroup analyses by treatment duration were consistent.
• Result: Peto OR 1.43 (95% CI 1.34–1.53) overall; low dose 1.33 (1.22–1.45), medium 1.50 (1.28–1.76), high 1.64 (1.45–1.85)
• Funding: not stated.

All types of ICSs significantly increased the pneumonia risk (Peto OR, 1.43; 95% CI, 1.34–1.53).

A Cochrane review dedicated to pneumonia found budesonide did increase pneumonias classed as serious, at roughly six extra hospital admissions per 1,000 people treated over nine months. (Source 7)

• Systematic review, Moderate certainty.
• Size: 43 studies, more than 30,000 people with COPD; 17 budesonide studies with 10,150 people.
• Who: Mostly men (around 70%) with generally severe COPD.
• How long: nine months for the budesonide estimate; 18 months for fluticasone.
• Result: Six more hospital admissions for pneumonia per 1,000 people treated with budesonide over nine months; 18 more per 1,000 over 18 months with fluticasone. A lower budesonide dose (320 mcg) was associated with fewer serious pneumonias than 640 mcg.
• Funding: not stated.

Over nine months, six more hospital admissions were reported for every 1000 individuals treated with budesonide.

In that IgA nephropathy trial the gut-targeted budesonide caused clearly more oedema, hypertension, muscle spasms and acne than placebo. (Source 8)

• Randomized trial, Moderate certainty.
• Size: 364 patients.
• Who: Adults with primary IgA nephropathy.
• How long: 9 months of treatment.
• Result: Peripheral oedema 31 (17%) vs 7 (4%); hypertension 22 (12%) vs 6 (3%); muscle spasms 22 (12%) vs 7 (4%); acne 20 (11%) vs 2 (1%); headache 19 (10%) vs 14 (8%); no treatment-related deaths.
• Funding: industry-funded (Calliditas Therapeutics)

The most commonly reported treatment-emergent adverse events during treatment with Nefecon were peripheral oedema (31 [17%] patients, vs placebo, seven [4%] patients), hypertension (22 [12%] vs six [3%]), muscle spasms (22 [12%] vs seven [4%]), acne (20 [11%] vs two [1%]), and headache (19 [10%] vs 14 [8%]).

In two-year rodent studies oral budesonide increased gliomas and liver tumours in male rats, as did the reference corticosteroids tested alongside it. (Source 20)

• Animal study, Very low certainty.
• Size: Two-year studies in Sprague-Dawley rats and a 91-week mouse study.
• Who: Rats and mice.
• How long: 91 weeks to 2 years.
• Result: Statistically significant increase in gliomas in male rats at 50 mcg/kg (about 0.05 times the maximum human dose by body surface area) and in hepatocellular tumours from 25 mcg/kg; no tumorigenicity in female rats or in mice up to 200 mcg/kg; prednisolone and triamcinolone acetonide showed similar findings.
• Funding: industry-funded (manufacturer's label)

In a two-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg

What the evidence supports

Oral controlled-ileal-release budesonide 9 mg/day induced remission in Crohn's disease more often than placebo but less often than conventional corticosteroids. (Source 2)

• Systematic review, Moderate certainty.
• Size: 13 induction trials; 379 participants in the 9 mg/day versus placebo comparison and 750 in the comparison with conventional steroids.
• Who: Adults (and in some trials children) with mild-to-moderate active Crohn's disease, mostly ileal or right-sided ileocolonic.
• How long: 8 weeks.
• Result: Remission 47% (115/246) on budesonide 9 mg/day vs 22% (29/133) on placebo, pooled RR 1.93 (95% CI 1.37–2.73); versus conventional steroids 52% (211/406) vs 61% (210/344), pooled RR 0.85 (95% CI 0.75–0.97)
• Funding: not stated.

Budesonide 9 mg/day was more effective than placebo (RR 1.93; 95% CI, 1.37–2.73; GRADE: moderate) but less effective than conventional steroids (RR 0.85; 95% CI, 0.75–0.97; GRADE: moderate) to induce remission.

The absolute remission rates behind that relative risk were 47% on budesonide 9 mg/day and 22% on placebo at eight weeks. (Source 21)

• Systematic review, Moderate certainty.
• Size: 379 participants across three trials.
• Who: Adults with mild-to-moderate active Crohn's disease; all three trials excluded people with distal colonic disease.
• How long: 8 weeks.
• Result: 47% (115 of 246) vs 22% (29/133); absolute difference about 25 percentage points, pooled RR 1.93 (95% CI 1.37–2.73), P = 0.00018, I2 = 0%.
• Funding: not stated.

At eight weeks, 47% (115 of 246) of those receiving a daily dose of budesonide 9 mg/day entered remission compared with 22% (29/133) of those receiving placebo

Budesonide caused fewer corticosteroid-type side effects than conventional steroids when used to induce remission in Crohn's disease, and no more than placebo. (Source 2)

• Systematic review, Moderate certainty.
• Size: Induction trials comparing budesonide with conventional steroids; 384 participants across three trials for the 9 mg/day versus placebo comparison.
• Who: Adults and children with active Crohn's disease.
• How long: 8 weeks.
• Result: Versus conventional steroids pooled RR 0.64 (95% CI 0.54–0.76); versus placebo RR 0.97 (95% CI 0.76–1.23)
• Funding: not stated.

Corticosteroid-related AEs occurred less often with induction doses of budesonide than steroids (RR 0.64; 95% CI, 0.54–0.76; GRADE: moderate); budesonide did not increase AEs relative to placebo (RR 0.97; 95% CI, 0.76–1.23; GRADE: moderate).

Budesonide multi-matrix 9 mg was about twice as effective as placebo for combined clinical and endoscopic remission in mild-to-moderate ulcerative colitis. (Source 22)

• Systematic review, Certainty not rated.
• Size: 900 patients pooled from three randomised trials.
• Who: Adults with mild-to-moderate ulcerative colitis, including people already on mesalamine.
• How long: 8 weeks.
• Result: RR 2.25 (95% CI 1.50 to 3.39); left-sided colitis RR 2.98 (95% CI 1.56 to 5.67) versus pancolitis RR 2.42 (95% CI 0.61 to 9.56)
• Funding: not stated.

showed that budesonide MMX 9 mg daily was twice as effective as the placebo for induction of combined clinical and endoscopic remission at 8 weeks (RR 2.25; 95% CI 1.50 to 3.39)

In the two pivotal CORE trials the absolute remission rates with budesonide MMX were about 18% versus 4–7% on placebo – a real but modest difference. (Source 3)

• Expert review, not systematic, Moderate certainty.
• Size: Two identically designed randomised trials (CORE I and CORE II)
• Who: Adults with active mild-to-moderate ulcerative colitis.
• How long: 8 weeks.
• Result: CORE I 17.9% vs 7.4% (p = 0.0143); CORE II 17.4% vs 4.5% (p = 0.005)
• Funding: not stated.

In both studies clinical and endoscopic remission was achieved in a significantly greater percentage of patients receiving budesonide MMX compared with placebo (17.9% vs 7.4%, p = 0.0143 in CORE I, 17.4% vs 4.5%, p = 0.005 in CORE II)

Rectal budesonide foam was better than placebo for inducing clinical remission in distal ulcerative colitis. (Source 4)

• Expert review, not systematic, Certainty not rated.
• Size: 3 randomised placebo-controlled trials, 711 patients.
• Who: Adults with mild-to-moderate distal ulcerative colitis.
• How long: 2–6 weeks.
• Result: The review reports only confidence intervals and no point estimates: 1.41 to 2.37 for clinical remission and 1.23 to 1.68 for endoscopic improvement, both excluding 1.
• Funding: not stated.

Limit of this finding: The review prints confidence intervals without the risk ratios they belong to, so the figures 1.41 to 2.37 and 1.23 to 1.68 show that the benefit was statistically significant but not how large it was. The size of the effect cannot be read from this paper; it would have to come from the meta-analysis it is citing.

showed that budesonide foam was significantly superior to placebo for the induction of clinical remission (95% CI: 1.41, 2.37) and endoscopic improvement (95% CI: 1.23, 1.68)

Three years of low-dose inhaled budesonide roughly halved the risk of a first severe asthma-related event in recent-onset mild persistent asthma. (Source 5)

• Randomized trial, High certainty.
• Size: 7,241 patients in 32 countries.
• Who: People aged 5–66 with mild persistent asthma for less than 2 years, not previously on regular glucocorticosteroids.
• How long: 3 years.
• Result: 198 of 3,568 on placebo versus 117 of 3,597 on budesonide had at least one severe exacerbation (5.5% vs 3.3%); hazard ratio 0.56 (95% CI 0.45–0.71, p<0.0001). Post-bronchodilator FEV1 gain versus placebo was 1.48% of predicted at 1 year and 0.88% at 3 years.
• Funding: industry-funded (budesonide manufacturer-sponsored multinational trial)

198 of 3568 patients on placebo and 117 of 3597 on budesonide had at least one severe asthma exacerbation; hazard ratio 0.56 (95% CI 0.45-0.71, p<0.0001).

As-needed budesonide-formoterol reduced severe asthma exacerbations compared with an as-needed short-acting bronchodilator alone, using less inhaled steroid than daily maintenance budesonide. (Source 6)

• Meta-analysis, Moderate certainty.
• Size: 4 trials; 4,023 as-needed budesonide-formoterol, 4,042 budesonide maintenance, 1,500 as-needed SABA.
• Who: Adolescents and adults with mild persistent asthma.
• How long: up to 52 weeks in the included trials.
• Result: RR 0.46 (95% CI 0.36-0.59, p < 0.001) for severe exacerbations versus as-needed SABA, and HR 0.43 (95% CI 0.33-0.56, p < 0.001) for time to first severe exacerbation; versus maintenance budesonide the difference did not reach significance (RR 0.86, 95% CI 0.62-1.04, p = 0.093; HR 0.77, 95% CI 0.57-1.03, p = 0.079); no difference in adverse events between the three groups.
• Funding: not stated.

The results showed that the incidence of severe exacerbations and the time to first severe exacerbation in the budesonide-formoterol group were significantly different from those for the SABA group (RR = 0.46, 95% CI = 0.36-0.59, p < 0.001; HR = 0.43, 95% CI = 0.33-0.56, p < 0.001; respectively), but there was no difference between the budesonide-formoterol group and budesonide group (RR = 0.86, 95% CI = 0.62-1.04, p = 0.093; HR = 0.77, 95% CI = 0.57-1.03, p = 0.079; respectively).

A gut-targeted oral budesonide capsule slowed kidney function decline over two years in primary IgA nephropathy. (Source 8)

• Randomized trial, Moderate certainty.
• Size: 364 patients (182 per group) at 132 sites in 20 countries.
• Who: Adults with primary IgA nephropathy, eGFR 35–90 mL/min/1.73 m2 and persistent proteinuria despite optimised renin-angiotensin blockade.
• How long: 9 months of treatment, 2-year follow-up.
• Result: Time-weighted average eGFR over 2 years was 5.05 mL/min/1.73 m2 better on Nefecon than on placebo (95% CI 3.24 to 7.38, p<0.0001). Within groups the time-weighted average change was -2.47 mL/min/1.73 m2 (95% CI -3.88 to -1.02) on Nefecon and -7.52 mL/min/1.73 m2 (-8.83 to -6.18) on placebo.
• Funding: industry-funded (Calliditas Therapeutics)

The time-weighted average of eGFR over 2 years showed a statistically significant treatment benefit with Nefecon versus placebo (difference 5·05 mL/min per 1·73 m2 [95% CI 3·24 to 7·38], p<0·0001), with a time-weighted average change of -2·47 mL/min per 1·73 m2 (95% CI -3·88 to -1·02) reported with Nefecon and -7·52 mL/min per 1·73 m2 (-8·83 to -6·18) reported with placebo.

In collagenous colitis, budesonide induces short-term remission in most patients but relapse after withdrawal is common. (Source 9)

• Cohort study, Low certainty.
• Size: 75 patients in a multicentre retrospective cohort.
• Who: Adults with collagenous colitis treated in routine practice between 2013 and 2015 (85% women, mean age 62)
• How long: not stated; clinical-practice follow-up.
• Result: Clinical remission induced in 92% of patients; 14 of 68 (21%, 95% CI 13–32%) needed budesonide ≥6 mg/day to stay in remission; NSAID intake at diagnosis predicted that need (OR 8.6, 95% CI 1.6–44)
• Funding: not stated.

Controlled studies show high efficacy of budesonide in inducing short-term clinical remission in collagenous colitis (CC), but relapses are common after its withdrawal.

What the evidence does not support

Budesonide did not keep people with Crohn's disease in remission any better than placebo at one year. (Source 2)

• Systematic review, Moderate certainty.
• Size: 420 participants across five trials (6 mg/day) and 442 across five trials (3 mg/day)
• Who: Adults with Crohn's disease in remission, including two postoperative-recurrence trials.
• How long: 12 months.
• Result: 6 mg/day: 55% (114/208) still in remission vs 48% (101/212) on placebo, pooled RR 1.13 (95% CI 0.94–1.35), P = 0.19; 3 mg/day: 42% vs 40%, RR 1.08 (95% CI 0.87–1.34)
• Funding: not stated.

Budesonide 6 mg/day was not different from placebo for maintaining remission (RR 1.13; 95% CI, 0.94–1.35; GRADE: moderate).

The review's own absolute figures for maintenance were 55% versus 48% at twelve months, a difference that was not statistically significant. (Source 23)

• Systematic review, Moderate certainty.
• Size: 420 participants across five trials.
• Who: Adults with Crohn's disease in remission.
• How long: 12 months.
• Result: 114 of 208 (55%) on budesonide 6 mg/day vs 101 of 212 (48%) on placebo, pooled RR 1.13 (95% CI 0.94–1.35), P = 0.19, I2 = 0%.
• Funding: not stated.

Limit of this finding: The review is inconsistent about how good this evidence is: this part of the paper grades both the 3 mg and 6 mg maintenance comparisons as moderate quality, while its own abstract grades the 3 mg comparison very low and the 6 mg comparison low in the related adrenal-function analysis. The result itself – no significant difference from placebo at twelve months – is not in doubt; the confidence to place in it is.

Fifty-five percent (114 of 208) of those receiving budesonide 6 mg/day remained in remission compared with 48% (101 of 212) of those receiving placebo (pooled RR 1.13; 95% CI, 0.94–1.35; P = 0.19; I 2 = 0%; five studies; 420 participants).

In mild-to-moderate ulcerative colitis trials, serious adverse events with budesonide MMX were no more frequent than with placebo, and the commonest event in both arms was a colitis relapse. (Source 24)

• Expert review, not systematic, Low certainty.
• Size: CORE I and CORE II plus a 510-patient add-on trial.
• Who: Adults with mild-to-moderate ulcerative colitis.
• How long: 8 weeks.
• Result: UC relapse 11.8% and 14.6% with budesonide MMX versus 9.6% on placebo; headache 4.5% and 4.7% versus 4.1%; severe adverse events highest in the placebo arm of CORE I (12.4% vs 6.3%)
• Funding: not stated.

The most common treatment-emergent adverse events (AE) in CORE I 6 and CORE II 7 were, in frequency order, UC relapse (11.8% and 14.6% vs 9.6% in placebo groups), headache (4.5% and 4.7% vs 4.1% in placebo group) and nausea.

In that same meta-analysis, fluticasone raised the risk of serious pneumonia specifically whereas budesonide and beclomethasone did not. (Source 19)

• Meta-analysis, Low certainty.
• Size: Subgroup analysis within 59 trials and 103,477 patients.
• Who: Adults with COPD.
• How long: varied.
• Result: Fluticasone Peto OR 1.75 (95% CI 1.44–2.14) for serious pneumonia; budesonide and beclomethasone did not reach significance for this outcome.
• Funding: not stated.

Subgroup analysis based on severity of pneumonia showed that fluticasone (Peto OR, 1.75; 95% CI, 1.44–2.14) increased the risk of serious pneumonia, while budesonide and beclomethasone did not.

Where the evidence is mixed

Neither budesonide nor fluticasone has been shown to change the chance of dying in COPD, and the pneumonia risk has to be weighed against real benefits. (Source 25)

• Systematic review, Moderate certainty.
• Size: 43 studies, more than 30,000 people.
• Who: Adults with COPD.
• How long: up to 18 months.
• Result: No excess deaths in the inhaled corticosteroid groups; deaths related to pneumonia too rare to judge; no difference between the two drugs for serious pneumonia or death.
• Funding: not stated.

Neither has been shown to affect the chance of dying compared with not taking ICS. Comparison of the two drugs revealed no difference in serious pneumonias or risk of death.

Where the research disagrees

Whether oral budesonide works for maintaining remission in Crohn's disease

• Cochrane systematic review authors (Kuenzig, Rezaie and colleagues, 2018), Systematic review and meta-analysis of 10 maintenance trials; GRADE moderate certainty: “Budesonide was not effective for the maintenance of remission.” (Source 26)
• FDA-approved ENTOCORT EC label (DailyMed, label updated February 7, 2012), Four 12-month double-blind placebo-controlled trials in 380 patients, reported as time to relapse rather than proportion in remission: “ENTOCORT EC 6 mg/day prolonged the time to relapse, defined as an increase in CDAI of at least 60 units to a total score >150 or withdrawal due to disease deterioration.” (Source 27)

Whether budesonide specifically raises the risk of serious pneumonia in COPD

• Cochrane reviewers (Kew and Seniukovich, 2014), Systematic review of 43 trials in more than 30,000 people: “Budesonide also increased pneumonias that were classed as 'serious'. Over nine months, six more hospital admissions were reported for every 1000 individuals treated with budesonide.” (Source 7)
• Chen and colleagues, meta-analysis of 59 randomised trials (2021), Meta-analysis of 59 randomised controlled trials, 103,477 patients: “Subgroup analysis based on severity of pneumonia showed that fluticasone (Peto OR, 1.75; 95% CI, 1.44–2.14) increased the risk of serious pneumonia, while budesonide and beclomethasone did not.” (Source 19)

How much

• Reference intake: There is no dietary reference intake for budesonide; it is a prescription medicine and the dose is set by the prescriber for the formulation and condition. As a position, the US label for ENTOCORT EC (DailyMed, label updated February 7, 2012) states the adult dose for active ileal/right-colonic Crohn's disease is 9 mg once daily in the morning for up to 8 weeks. (Source 11)
• Upper limit: No upper limit is set by a nutrition body. As a position, the ENTOCORT EC label (DailyMed, 2012) caps the active-disease course at 9 mg once daily for up to 8 weeks and the maintenance dose at 6 mg once daily for up to 3 months, stating that continuing 6 mg beyond 3 months has not been shown to give substantial benefit. (Source 11)
• Studied: Crohn's disease induction trials gave oral controlled-ileal-release budesonide 3, 9 or 15 mg/day for 8 weeks; maintenance trials gave 3 or 6 mg/day for 12 months. (Source 2)
• Studied: Ulcerative colitis trials gave budesonide MMX 9 mg or 6 mg once daily for 8 weeks, compared with mesalamine 2.4 g, budesonide CIR 9 mg or placebo. (Source 3)
• Studied: The START asthma trial gave inhaled budesonide 400 µg once daily, or 200 µg for children younger than 11, for 3 years. (Source 5)
• Studied: The NefIgArd IgA nephropathy trial gave 16 mg/day of the targeted-release oral capsule for 9 months. (Source 8)

A common belief, and what the research shows

The belief: Budesonide is a “local” or “non-systemic” steroid, so it has none of the side effects of prednisone.

What the research shows: It is designed to act locally and it does cause fewer steroid side effects than prednisolone – the Cochrane review found “Corticosteroid-related AEs occurred less often with induction doses of budesonide than steroids (RR 0.64; 95% CI, 0.54–0.76; GRADE: moderate)”. But “fewer” is not “none”. The same review found that maintenance budesonide 6 mg/day “increased the likelihood of an abnormal ACTH test relative to placebo (pooled RR 2.72; 95% CI, 1.62–4.58”, and the manufacturer's own crossover study found a 45% fall in 24-hour plasma cortisol on 9 mg/day. Inhaled budesonide measurably slows children's growth, and the Cochrane authors state plainly that “the long-term effects on the adrenal axis and bone health remain unknown.”

Questions and answers

What is it?

Budesonide is a laboratory-made corticosteroid – a close relative of the cortisol your adrenal glands produce, but far more potent at the receptor. Its defining feature is that most of what gets absorbed is destroyed by the liver before it circulates, so it is used in forms that deliver it straight to the inflamed tissue: inhalers, nasal sprays, enteric-coated capsules, colon-release tablets and rectal foam. The oral capsule works by granules that survive the stomach and only dissolve once they reach the small bowel. (Source 1)

What does it do in the body?

Inside cells it binds the glucocorticoid receptor and shuts down the genes that drive inflammation – the same machinery prednisone uses, but with a much stronger grip on the receptor. The manufacturer's label puts its receptor affinity at roughly 200 times that of cortisol and 15 times that of prednisolone, with little mineralocorticoid (salt-retaining) activity. In the airway that means less swelling and mucus; in the bowel, less mucosal inflammation. (Source 16)

Is it good or bad for you?

Both, and which one depends on the formulation, the condition and how long it is used. For inducing remission in ileal Crohn's disease or mild-to-moderate ulcerative colitis, and for preventing asthma attacks, trials show real benefit with fewer steroid side effects than prednisolone. For maintaining Crohn's remission the meta-analysis found no benefit at all. Longer use carries measurable costs: adrenal suppression, slowed growth in children, and more pneumonia when inhaled in COPD. The Cochrane authors are explicit that the long-term picture is not settled. (Source 26)

How do you get more of it?

Budesonide is not in food and is not available over the counter except as a nasal spray in some countries; the prescription forms are prescribed and dosed by a clinician for a specific condition and formulation. As a record of what the regulator approved, the capsule label sets 9 mg once daily in the morning for up to eight weeks for active ileal Crohn's disease, then 6 mg daily for up to three months. Nothing here is a dose for a reader to act on. (Source 11)

If it is harmful, what reduces it?

If budesonide is causing problems, the route out is a planned reduction rather than an abrupt stop, because the drug suppresses the body's own cortisol production and stopping suddenly can leave the adrenal glands unable to respond. The label's own instruction after maintenance treatment is to attempt a taper to complete cessation. Avoiding grapefruit and strong CYP3A4 inhibitors lowers blood levels of the oral forms. (Source 11)

Why might someone be low in it or missing it?

Budesonide is not something a body can be “low in” – it is only present if someone is taking it. Levels in the blood can end up lower than expected if another drug or supplement induces the CYP3A4 enzyme that breaks budesonide down, if the capsule is chewed or broken rather than swallowed whole, or if doses are missed. The label notes that inducing CYP3A4 lowers budesonide plasma levels. (Source 10)

Which whole foods contain it or feed it?

No whole food contains budesonide. The food that matters is grapefruit, which works in the opposite direction: it blocks the gut enzyme that normally destroys budesonide and roughly doubles how much enters the bloodstream, so the label tells patients to avoid it. Other juices such as orange and apple do not do this, and a high-fat meal only delays absorption without changing the total amount absorbed. (Source 10)

What happens if you do not have it?

Nothing happens from never having taken it – it is a medicine, not a nutrient. What the evidence does show is what happens when it is withdrawn from someone whose disease was being held in check: in collagenous colitis relapse after withdrawal is common, and in asthma the trial benefit depended on continuing daily treatment. In Crohn's maintenance, by contrast, the meta-analysis found stopping made no measurable difference to relapse rates. (Source 9)

How can you test for it?

There is no routine blood test for budesonide levels in ordinary care. What trials measured instead was the drug's effect on the adrenal axis, using an ACTH (adrenocorticotropic hormone) stimulation test, and plasma cortisol. Those tests pick up suppression reliably enough to show a near-tripling of abnormal results on maintenance budesonide 6 mg/day, but the Cochrane authors rated this evidence low quality because of sparse data and selective reporting. (Source 15)

References

1. DailyMed (US National Library of Medicine) / AstraZeneca. ENTOCORT EC (budesonide) capsule — US prescribing information on DailyMed, label updated February 7, 2012 [ent_clinpharm section]. 2012. Read the source
2. Journal of the Canadian Association of Gastroenterology. Budesonide for the Induction and Maintenance of Remission in Crohn’s Disease: Systematic Review and Meta-Analysis for the Cochrane Collaboration. 2018. PMID 30656288, DOI 10.1093/jcag/gwy018. Read the source
3. Therapeutics and Clinical Risk Management. Budesonide MMX in the Treatment of Ulcerative Colitis: Current Perspectives on Efficacy and Safety (CORE I and CORE II). 2021. PMID 33854320, DOI 10.2147/TCRM.S263835. Read the source
4. Therapeutics and Clinical Risk Management. Budesonide MMX in the Treatment of Ulcerative Colitis: Current Perspectives on Efficacy and Safety (rectal budesonide foam). 2021. PMID 33854320, DOI 10.2147/TCRM.S263835. Read the source
5. Lancet. Early intervention with budesonide in mild persistent asthma: A randomised, double-blind trial (START). 2003. PMID 12672309, DOI 10.1016/S0140-6736(03)12891-7. Read the source
6. Frontiers in pharmacology. Is It Really Feasible to Use Budesonide-Formoterol as Needed for Mild Persistent Asthma? A Systematic Review and Meta-Analysis.. 2021. PMID 34149408, DOI 10.3389/fphar.2021.644629. Read the source
7. Cochrane Database of Systematic Reviews. Do inhaled steroids increase the risk of pneumonia in people with chronic obstructive pulmonary disease (COPD)? (Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease, Cochrane Database of Systematic Reviews, CD010115) — what we found. 2014. DOI 10.1002/14651858.CD010115.pub2. Read the source
8. Lancet (London, England). Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial.. 2023. PMID 37591292, DOI 10.1016/s0140-6736(23)01554-4. Read the source
9. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. Collagenous colitis: Requirement for high-dose budesonide as maintenance treatment.. 2017. PMID 28457904, DOI 10.1016/j.dld.2017.03.026. Read the source
10. DailyMed (US National Library of Medicine) / AstraZeneca. ENTOCORT EC (budesonide) capsule — US prescribing information on DailyMed, label updated February 7, 2012 [ent_interactions section]. 2012. Read the source
11. DailyMed (US National Library of Medicine) / AstraZeneca. ENTOCORT EC (budesonide) capsule — US prescribing information on DailyMed, label updated February 7, 2012 [ent_dosage section]. 2012. Read the source
12. DailyMed (US National Library of Medicine) / AstraZeneca. ENTOCORT EC (budesonide) capsule — US prescribing information on DailyMed, label updated February 7, 2012 [ent_warnings section]. 2012. Read the source
13. The New England journal of medicine. Withdrawal of inhaled glucocorticoids and exacerbations of COPD.. 2014. PMID 25196117, DOI 10.1056/nejmoa1407154. Read the source
14. The New England journal of medicine. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. [Conclusions section]. 2014. PMID 25196117, DOI 10.1056/nejmoa1407154. Read the source
15. Journal of the Canadian Association of Gastroenterology. Budesonide for the Induction and Maintenance of Remission in Crohn’s Disease: Systematic Review and Meta-Analysis for the Cochrane Collaboration (Results, abnormal ACTH stimulation tests after maintenance treatment). 2018. PMID 30656288, DOI 10.1093/jcag/gwy018. Read the source
16. DailyMed (US National Library of Medicine) / AstraZeneca. ENTOCORT EC (budesonide) capsule — US prescribing information on DailyMed, label updated February 7, 2012 [ent_potency section]. 2012. Read the source
17. Paediatric Respiratory Reviews. Effect of inhaled corticosteroids on linear growth in children with persistent asthma (Cochrane Corner summary of Cochrane review CD009471) — discussion. 2014. DOI 10.1016/j.prrv.2014.07.001. Read the source
18. Cochrane Database of Systematic Reviews. Inhaled corticosteroids in children with persistent asthma: effects on growth.. 2014. PMID 25030198, DOI 10.1002/14651858.CD009471.pub2. Read the source
19. Frontiers in Pharmacology. Inhaled Corticosteroids and the Pneumonia Risk in Patients With Chronic Obstructive Pulmonary Disease: A Meta-analysis of Randomized Controlled Trials. 2021. PMID 34267661, DOI 10.3389/fphar.2021.691621. Read the source
20. DailyMed (US National Library of Medicine) / AstraZeneca. ENTOCORT EC (budesonide) capsule — US prescribing information on DailyMed, label updated February 7, 2012 [ent_carcino section]. 2012. Read the source
21. Journal of the Canadian Association of Gastroenterology. Budesonide for the Induction and Maintenance of Remission in Crohn’s Disease: Systematic Review and Meta-Analysis for the Cochrane Collaboration (Results, induction of clinical remission). 2018. PMID 30656288, DOI 10.1093/jcag/gwy018. Read the source
22. Therapeutics and Clinical Risk Management. Budesonide MMX in the Treatment of Ulcerative Colitis: Current Perspectives on Efficacy and Safety (pooled Cochrane data). 2021. PMID 33854320, DOI 10.2147/TCRM.S263835. Read the source
23. Journal of the Canadian Association of Gastroenterology. Budesonide for the Induction and Maintenance of Remission in Crohn’s Disease: Systematic Review and Meta-Analysis for the Cochrane Collaboration (Results, maintenance of clinical remission). 2018. PMID 30656288, DOI 10.1093/jcag/gwy018. Read the source
24. Therapeutics and Clinical Risk Management. Budesonide MMX in the Treatment of Ulcerative Colitis: Current Perspectives on Efficacy and Safety (safety). 2021. PMID 33854320, DOI 10.2147/TCRM.S263835. Read the source
25. Cochrane Database of Systematic Reviews. Do inhaled steroids increase the risk of pneumonia in people with chronic obstructive pulmonary disease (COPD)? (Cochrane review CD010115) — conclusion. 2014. DOI 10.1002/14651858.CD010115.pub2. Read the source
26. Journal of the Canadian Association of Gastroenterology. Budesonide for the Induction and Maintenance of Remission in Crohn’s Disease: Systematic Review and Meta-Analysis for the Cochrane Collaboration (Abstract, Conclusion). 2018. PMID 30656288, DOI 10.1093/jcag/gwy018. Read the source
27. DailyMed (US National Library of Medicine) / AstraZeneca. ENTOCORT EC (budesonide) capsule — US prescribing information on DailyMed, label updated February 7, 2012 [ent_maint_trial section]. 2012. Read the source