Mechanism Of Action
Budesonide is an
anti-inflammatory corticosteroid and has a high glucocorticoid effect and a
weak mineralocorticoid effect, and the affinity of budesonide to glucocorticoid
receptors, which reflects the intrinsic potency of the drug, is about 200-fold
that of cortisol and 15-fold that of prednisolone.
Treatment with glucocorticoids,
including ORTIKOS is associated with a suppression of endogenous cortisol
concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA)
axis function. There was a positive correlation between the percent (%)
reduction of AUC0-24 of plasma cortisol and systemic exposure to budesonide
both in pediatric and adult patients.
Plasma cortisol suppression was
compared following five days' administration of oral budesonide and
prednisolone in a crossover study in healthy volunteers. The mean decrease in
the area under the plasma cortisol concentration-time curve over 24 hour (AUC0-24)
was greater (78%) with prednisolone 20 mg per day compared to 45% with
budesonide 9 mg per day.
The effect of budesonide on
endogenous cortisol concentrations was compared between pediatric patients
(n=8, aged 9 to 14 years) and adults (n=6) with active Crohn's disease
following administration of oral budesonide 9 mg once daily for 7 days. Compared
to baseline values before treatment, the mean decrease in the AUC0-24 of
cortisol was 64% (±18%) in pediatric patients and 50% (±27%) in adults after
budesonide treatment [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS
Â and Use In Specific Populations].
The responses to
adrenocorticotropin challenge (i.e., ACTH stimulation test) was studied in
pediatric patients aged 8 to 17 years, with mild to moderate active Crohn's
disease in randomized, double-blind, active control study [see Clinical
Studies]. After 8 weeks of treatment with oral budesonide 9 mg once daily
or with prednisolone, administered at tapering doses starting from 1 mg/kg, the
proportion of patients with normal response to the ACTH challenge was 6% in the
budesonide group compared to none in the prednisolone group; the proportion of
patients with morning p-cortisol of greater than 5 mcg/dL was 50% in the
budesonide group compared to 22% in the prednisolone group. The mean morning
p-cortisol was 6.3 mcg/dL in the budesonide group and 2.6 mcg/dL in the
prednisolone group (Table 4).
Table 4: Proportion of
Pediatric Patients 8 to 17 years old with Peak Endogenous Cortisol Levels
(above 18 mcg/dL) after ACTH Stimulation and Normal Response* to ACTH Challenge
Following Administration of Oral Budesonide or Prednisolone for 8 weeks
|Peak plasma cortisol above 18 mcg/dL
|At week 8
|Normal response* to ACTH challenge
|At week 8
|*The normal response to ACTH challenge included 3
criteria, as defined in the cosyntropin label: 1) morning cortisol level above
5 mcg/dL; 2) increase in cortisol level by at least 7 mcg/dL above the morning
(prechallenge) level following ACTH challenge; and cortisol level of above 18
mcg/dL following ACTH challenge. Cortisol concentration was measured at 30 min
after intravenous or intramuscular injection of 0.25
mg cosyntropin at baseline and at week 8 after treatment.
Following administration of
oral budesonide, the time to peak concentration varied in individual patients
between 2.5 to 8 hours. Mean oral bioavailability of budesonide ranged from 9%
to 21% both in patients and in healthy subjects, demonstrating a high first-pass
elimination of the drug.
were dose-proportional following repeated administration in the dose range of 3
mg to 15 mg. No accumulation of budesonide was observed following repeated
Following administration of oral
budesonide 9 mg for five days in healthy subjects, the mean peak plasma
concentration and the steady state area under the plasma concentration time
curve for budesonide were 5.3 ± 1.8 nmol/L and 37.0 ±14.6 nmol•hr/L,
Following administration of
oral budesonide 9 mg once daily in patients with active Crohn's disease, the
mean peak plasma concentration and AUC were 4.0 ±2.1 nmol/L and 35.0 ±19.8
Concomitant administration of a
high-fat meal delayed the time to peak concentration of budesonide by 1 hour
and overall exposure was increased by about 25%.
The mean volume of distribution
(Vss) of budesonide varied between 2.2 L/kg and 3.9 L/kg in healthy subjects
and in patients. Plasma protein binding was estimated to be 85% to 90% in the
concentration range 1 nmol/L to 230 nmol/L, independent of gender. The
erythrocyte/plasma partition ratio at clinically relevant concentrations was
Budesonide had a plasma
clearance, 0.9 L/min to 1.8 L/min in healthy adults. Mean plasma clearance
after intravenous administration of budesonide in patients with Crohn's disease
was 1.0 L/min. These plasma clearance values approached the estimated liver
blood flow, and, accordingly, suggest that budesonide is a high hepatic
clearance drug. The plasma elimination half-life, after administration of
intravenous doses ranged between 2 and 3.6 hours, and did not differ between
healthy adults and patients with Crohn's disease.
budesonide is subject to high first pass metabolism (80% to 90%). In vitro experiments
in human liver microsomes demonstrated that budesonide is rapidly and
extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites,
6β-hydroxy budesonide and 16α-hydroxy prednisolone. The
corticosteroid activity of these metabolites was negligible (less than 1/100)
in relation to that of the parent compound. In vivo investigations with
intravenous doses in healthy subjects were in agreement with the in vitro findings.
Budesonide was excreted in urine and feces in the form of
metabolites. After oral as well as intravenous administration of micronized [3H]-budesonide,
approximately 60% of the recovered radioactivity was found
in urine. The major metabolites, including 6β-hydroxy budesonide and
16α-hydroxy prednisolone, are mainly renally excreted, intact or in
conjugated forms. No unchanged budesonide was detected in urine.
Age: Pediatric Population (8 Years
The pharmacokinetics of
budesonide were investigated in pediatric patients aged 9 to 14 years (n=8)
after oral administration of budesonide and intravenous administration of
budesonide. Following administration of 9 mg oral budesonide once daily for 7
days, the median time to peak plasma concentration of budesonide was 5 hours
and the mean peak plasma concentration was 6.0 ± 3.5 nmol/L. The mean AUC was
41.3 ±12.2 nmol•h/L and 17% higher than that in adult patients with Crohn's
disease in the same study. The mean absolute oral availability was 9.2% (3 to
17%; n=4) in pediatric patients.
After single dose
administration of intravenous budesonide (n=4), the mean volume of distribution
(Vss) was 2.2 ± 0.4 L/kg and mean clearance was 0.81 ± 0.2 L/min. The mean
elimination half-life was 1.9 hours in pediatric patients. The body-weight
normalized clearance in pediatric patients was 20.5 mL/min/kg in comparison to
15.9 mL/min/kg in adult patients after intravenous administration [see WARNINGS
AND PRECAUTIONS, Use In Specific Population].
Patients With Hepatic
In patients with mild
(Child-Pugh Class A, n=4) or moderate (Child-Pugh Class B, n=4) hepatic
impairment, budesonide 4 mg was administered orally as a single dose. The
patients with moderate hepatic impairment had a 3.5-fold higher AUC compared to
the healthy subjects with normal hepatic function while the patients with mild
hepatic impairment had an approximately 1.4-fold higher AUC. The Cmax values
demonstrated similar increases [see WARNINGS AND PRECAUTIONS]. The
increased systemic exposure in patients with mild hepatic impairment was not
considered to be clinically relevant. Patients with severe liver impairment
(Child-Pugh Class C) were not studied [see Use In Specific Populations].
Drug Interaction Studies
Budesonide is metabolized via
CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma concentrations of
budesonide several-fold. Conversely, induction of CYP3A4 potentially could
result in the lowering of budesonide plasma concentrations.
Effects Of Other Drugs On Budesonide
In an open, non-randomized,
cross-over study, 6 healthy subjects were given budesonide 10 mg as a single
dose, either alone or concomitantly with the last ketoconazole dose of 3 days
treatment with ketoconazole 100 mg twice daily. Coadministration of
ketoconazole resulted in an eight-fold increase in AUC of budesonide, compared
to budesonide alone [see DRUG INTERACTIONS].
In an open, randomized,
cross-over study, 8 healthy subjects were given oral budesonide 3 mg, either alone,
or concomitantly with 600 mL concentrated grapefruit juice (which inhibits
CYP3A4 activity predominantly in the intestinal mucosa), on the last of 4 daily
administrations. Concomitant administration of grapefruit juice resulted in a
2-fold increase of the bioavailability of budesonide compared to budesonide
alone [see DRUG INTERACTIONS].
Oral Contraceptives (CYP3A4
In a parallel study, the
pharmacokinetics of budesonide were not significantly different between healthy
female subjects who received oral contraceptives containing desogestrel 0.15 mg
and ethinyl estradiol 30 mcg and healthy female subjects who did not receive
oral contraceptives. Budesonide 4.5 mg once daily (one-half the recommended
dose) for one week did not affect the plasma concentrations of ethinyl
estradiol, a CYP3A4 substrate. The effect of budesonide 9 mg once daily on the
plasma concentrations of ethinyl estradiol was not studied.
In a study in 11 healthy
subjects, performed in a double-blind, randomized, placebo controlled manner,
the effect of 5 to 6 days treatment with omeprazole 20 mg once daily on the
pharmacokinetics of budesonide administered as oral budesonide 9 mg as a single
dose was investigated. Omeprazole 20 mg once daily did not affect the
absorption or pharmacokinetics of budesonide.
In an open, non-randomized,
cross-over study, the potential effect of cimetidine on the pharmacokinetics of
budesonide was studied. Six healthy subjects received cimetidine 1 gram daily
(200 mg with meals and 400 mg at night) for 2 separate 3-day periods.
Budesonide 4 mg was administered either alone or on the last day of one of the
cimetidine treatment periods. Coadministration of cimetidine resulted in a 52%
and 31% increase in the budesonide peak plasma concentration and the AUC of
The safety and efficacy of
ORTIKOS have been established based on adequate and well-controlled adult
studies of another oral budesonide product in patients with Crohn's Disease.
Below is a display of the results of these adequate and well-controlled studies
of budesonide in these conditions.
Treatment Of Mild To Moderate
Active Crohn’s Disease
The efficacy of oral budesonide
were evaluated in 994 patients with mild to moderate active Crohn's disease of
the ileum and/or ascending colon in 5 randomized and double-blind studies of 8
weeks duration. The study patients ranged in age from 17 to 85 (mean 35), 40%
were male and 97% were white. The Crohn's Disease Activity Index (CDAI) was the
main clinical assessment used for determining efficacy in these 5 studies.1
The CDAI is a validated index based on subjective aspects rated by the
patient (frequency of liquid or very soft stools, abdominal pain rating and
general well-being) and objective observations (number of extraintestinal
symptoms, need for antidiarrheal drugs, presence of abdominal mass, body weight
and hematocrit). Clinical improvement, defined as a CDAI score of less than or
equal to 150 assessed after 8 weeks of treatment, was the primary efficacy
variable in these 5 comparative efficacy studies of oral budesonide. Safety
assessments in these studies included monitoring of adverse reactions. A
checklist of potential symptoms of hypercorticism was used.
One study (Study 1) compared
the efficacy of budesonide 9 mg daily in the morning to a comparator. At
baseline, the median CDAI was 272. Budesonide 9 mg daily resulted in a
significantly higher clinical improvement rate at Week 8 than the comparator.
See Table 5.
Table 5: Clinical Improvement
Rates (CDAI less than or equal to 150) After 8 weeks of Treatment
|9 mg Daily
||4.5 mg Twice Daily
|1 p=0.0004 compared to comparator.
2 p=0.001 compared to placebo.
3 This drug is not approved for the treatment of Crohn’s disease in
the United States.
Two placebo-controlled clinical
trials (Studies 2 and 3) were conducted. Study 2 involved 258 patients and
tested the effects of graded doses of budesonide (1.5 mg twice daily, 4.5 mg
twice daily, or 7.5 mg twice daily) versus placebo. At baseline, the median
CDAI was 290. The 1.5 mg twice daily arm (data not shown) could not be
differentiated from placebo. The 4.5 mg twice daily arm was statistically
different from placebo (Table 5), while no additional benefit was seen when the
daily budesonide dose was increased to 15 mg per day (data not shown). Study 3
was a 3-armed parallel group study. The groups were treated with budesonide 9
mg once daily, budesonide 4.5 mg twice daily and placebo for 8 weeks, followed
by a 2-week double-blind taper phase. The median CDAI at baseline was 263.
Neither 9 mg daily nor 4.5 mg twice daily budesonide dose levels were
statistically different from placebo (Table 5). The recommended dosage of
budesonide for the treatment of mild to moderate active Crohn’s disease
involving the ileum and/or the ascending colon in adults is 9 mg once daily in
the morning for up to 8 weeks [see DOSAGE AND ADMINISTRATION].
Two clinical trials (Studies 4
and 5) compared oral budesonide with oral prednisolone (initial dose 40 mg per
day). Study 4 was a 3-armed parallel group study. The groups were treated with
budesonide 9 mg once daily, budesonide 4.5 mg twice daily and prednisolone 40
mg (tapered dose) for 8 weeks, followed by a 4week double blind taper phase. At
baseline, the median CDAI was 277. Equal clinical improvement rates (60%) were
seen in the budesonide 9 mg daily and the prednisolone groups in Study 4. In
Study 5, 13% fewer patients in the budesonide group experienced clinical improvement
than in the prednisolone group (no statistical difference) (Table 5).
The proportion of patients with
normal plasma cortisol values (greater than 150 nmol/L) was significantly
higher in the budesonide groups in both trials (60% to 66%) than in the
prednisolone groups (26% to 28%) at Week 8.
Pediatric Patients (8 to 17
Years of Age)
The effectiveness of oral
budesonide, in pediatric patients aged 8 to 17 years, who weigh more than 25 kg
with mild to moderate active Crohn's disease (defined as Crohn's Disease
Activity Index (CDAI) ≥ 200) involving the ileum and/or the ascending
colon, was assessed in one randomized, double-blind, active control study. This
study compared budesonide 9 mg once daily, with prednisolone, administered at
tapering doses starting from 1 mg/kg. Twenty-two (22) patients were treated
with budesonide and 24 patients were treated with prednisolone. After 8 weeks
of treatment, 55% (95% CI: 32%, 77%) of patients treated with budesonide
reached the endpoint (CDAI ≤150), as compared to 68% (95% CI: 47%, 89%)
of patients treated with prednisolone. The average number of liquid or very
soft stools per day (assessed over 7 days) decreased from 1.49 at baseline to
0.96 after treatment with budesonide and 2.00 at baseline to 0.52 after
treatment with prednisolone. The average daily abdominal pain rating (where
0=none, 1=mild, 2=moderate, and 3=severe) decreased from 1.49 at baseline to
0.54 after treatment with budesonide and 1.64 at baseline to 0.38 after 8 weeks
of treatment with prednisolone.
Use of budesonide in this age
group is supported by evidence from adequate and well-controlled studies of
budesonide in adults, and by safety and pharmacokinetic studies performed in
Maintenance Of Clinical
Remission Of Mild To Moderate Crohn’s Disease
The efficacy of oral budesonide
for maintenance of clinical remission were evaluated in four double-blind,
placebo-controlled, 12-month trials in which 380 patients were randomized and
treated once daily with 3 mg or 6 mg budesonide or placebo. Patients ranged in
age from 18 to 73 (mean 37) years. Sixty percent of the patients were female
and 99% were Caucasian. The mean CDAI at entry was 96. Among the four clinical
trials, approximately 75% of the patients enrolled had exclusively ileal
disease. Colonoscopy was not performed following treatment. Budesonide 6 mg per
day prolonged the time to relapse, defined as an increase in CDAI of at least
60 units to a total score greater than 150 or withdrawal due to disease
deterioration. The median time to relapse in the pooled population of the 4
studies was 154 days for patients taking placebo, and 268 days for patients
taking budesonide 6 mg per day. Budesonide 6 mg per day reduced the proportion
of patients with loss of symptom control relative to placebo in the pooled
population for the 4 studies at 3 months (28% versus 45% for placebo).
1. Best WR, Becktel JM,
Singleton JW, Kern F: Development of a Crohn's Disease Activity Index, National
Cooperative Crohn's Disease Study. Gastroenterology 1976; 70(3): 439-444.