BUDESONIDE (ENTERIC COATED) (Page 2 of 8)

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adults

The data described below reflect exposure to budesonide capsules (enteric coated) in 520 patients with Crohn’s disease, including 520 exposed to 9 mg per day (total daily dose) for 8 weeks and 145 exposed to 6 mg per day for one year in placebo controlled clinical trials. Of the 520 patients, 38% were males and the age range was 17 to 74 years.

Treatment of Mild to Moderate Active Crohn’s Disease

The safety of budesonide capsules (enteric coated) was evaluated in 651 adult patients in five clinical trials of 8 weeks duration in patients with active mild to moderate Crohn’s disease. The most common adverse reactions, occurring in greater than or equal to 5% of the patients, are listed in Table 1.

Table 1: Common Adverse Reactions * in 8-Week Treatment Clinical Trials

	Budesonide capsules (enteric coated)		Prednisolone †
Adverse Reaction	9 mg n=520 Number (%)	Placebo n=107 Number (%)	40 mg n=145 Number (%)	Comparator ‡ n=88 Number (%)
* Occurring in greater than or equal to 5% of the patients in any treated group. † Prednisolone tapering scheme: either 40 mg in week 1 to 2, thereafter tapering with 5 mg per week; or 40 mg in week 1 to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mg per week. ‡ This drug is not approved for the treatment of Crohn’s disease in the United States.
Headache	107 (21)	19 (18)	31 (21)	11 (13)
Respiratory Infection	55 (11)	7 (7)	20 (14)	5 (6)
Nausea	57 (11)	10 (9)	18 (12)	7 (8)
Back Pain	36 (7)	10 (9)	17 (12)	5 (6)
Dyspepsia	31 (6)	4 (4)	17 (12)	3 (3)
Dizziness	38 (7)	5 (5)	18 (12)	5 (6)
Abdominal Pain	32 (6)	18 (17)	6 (4)	10 (11)
Flatulence	30 (6)	6 (6)	12 (8)	5 (6)
Vomiting	29 (6)	6 (6)	6 (4)	6 (7)
Fatigue	25 (5)	8 (7)	11 (8)	0 (0)
Pain	24 (5)	8 (7)	17 (12)	2 (2)

The incidence of signs and symptoms of hypercorticism reported by active questioning of patients in 4 of the 5 short-term clinical trials are displayed in Table 2.

Table 2: Summary and Incidence of Signs/Symptoms of Hypercorticism in 8-Week Treatment Clinical Trials

	Budesonide capsules (enteric coated)		Prednisolone *
Signs/Symptom	9 mg n=427 Number (%)	Placebo n=107 Number (%)	40 mg n=145 Number (%)
* Prednisolone tapering scheme: either 40 mg in week 1-2, thereafter tapering with 5 mg/week; or 40 mg in week 1 to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mg/week. † Statistically significantly different from budesonide capsules (enteric coated) 9 mg. ‡ including hair growth increased, local and hair growth increased, general.
Total	145 (34%)	29 (27%)	69 (48%)
Acne	63 (15)	14 (13)	33 (23) †
Bruising Easily	63 (15)	12 (11)	13 (9)
Moon Face	46 (11)	4 (4)	53 (37) †
Swollen Ankles	32 (7)	6 (6)	13 (9)
Hirsutism ‡	22 (5)	2 (2)	5 (3)
Buffalo Hump	6 (1)	2 (2)	5 (3)
Skin Striae	4 (1)	2 (2)	0 (0)

Maintenance of Clinical Remission of Mild to Moderate Crohn’s Disease

The safety of budesonide capsules (enteric coated) was evaluated in 233 adult patients in four long-term clinical trials (52 weeks) of maintenance of clinical remission in patients with mild to moderate Crohn’s disease. A total of 145 patients were treated with budesonide capsules (enteric coated) 6 mg once daily.

The adverse reaction profile of budesonide capsules (enteric coated) 6 mg once daily in maintenance of Crohn’s disease was similar to that of short-term treatment with budesonide capsules (enteric coated) 9 mg once daily in active Crohn’s disease. In the long-term clinical trials, the following adverse reactions occurred in greater than or equal to 5% and are not listed in Table 1: diarrhea (10%); sinusitis (8%); infection viral (6%); and arthralgia (5%).

Signs/symptoms of hypercorticism reported by active questioning of patients in the long-term maintenance clinical trials are displayed in Table 3.

Table 3: Summary and Incidence of Signs/Symptoms of Hypercorticism in Long-Term Clinical Trials

	Budesonide capsules (enteric coated)	Budesonide capsules (enteric coated)
Signs/Symptom	3 mg n=88 Number (%)	6 mg n=145 Number (%)	Placebo n=143 Number (%)
Bruising Easily	4 (5)	15 (10)	5 (4)
Acne	4 (5)	14 (10)	3 (2)
Moon Face	3 (3)	6 (4)	0
Hirsutism	2 (2)	5 (3)	1 (1)
Swollen Ankles	2 (2)	3 (2)	3 (2)
Buffalo Hump	1 (1)	1 (1)	0
Skin Striae	2 (2)	0	0

The incidence of signs/symptoms of hypercorticism as described above in long-term maintenance clinical trials was similar to that seen in the short-term treatment clinical trials.

Less Common Adverse Reactions in Treatment and Maintenance Clinical Trials

Less common adverse reactions (less than 5%), occurring in adult patients treated with budesonide capsules (enteric coated) 9 mg (total daily dose) in short-term treatment clinical studies and/or budesonide capsules (enteric coated) 6 mg (total daily dose) in long-term maintenance clinical trials, with an incidence are listed below by system organ class:

Cardiac disorders: palpitation, tachycardia

Eye disorders: eye abnormality, vision abnormal

General disorders and administration site conditions: asthenia, chest pain, dependent edema, face edema, flu-like disorder, malaise, fever

Gastrointestinal disorders: anus disorder, enteritis, epigastric pain, gastrointestinal fistula, glossitis, hemorrhoids, intestinal obstruction, tongue edema, tooth disorder

Infections and infestations: Ear infection-not otherwise specified, bronchitis, abscess, rhinitis, urinary tract infection, thrush

Investigations: weight increased

Metabolism and nutrition disorders: appetite increased

Musculoskeletal and connective tissue disorders: arthritis, cramps, myalgia

Nervous system disorders: hyperkinesia, paresthesia, tremor, vertigo, dizziness, somnolence, amnesia

Psychiatric disorders: agitation, confusion, insomnia, nervousness, sleep disorder

Renal and urinary disorders: dysuria, micturition frequency, nocturia

Reproductive system and breast disorders: intermenstrual bleeding, menstrual disorder

Respiratory, thoracic and mediastinal disorders: dyspnea, pharynx disorder

Skin and subcutaneous tissue disorders: alopecia, dermatitis, eczema, skin disorder, sweating increased, purpura

Vascular disorders: flushing, hypertension

Bone Mineral Density

A randomized, open, parallel-group multicenter safety clinical trial specifically compared the effect of budesonide capsules (enteric coated) (less than 9 mg per day) and prednisolone (less than 40 mg per day) on bone mineral density over 2 years when used at doses adjusted to disease severity. Bone mineral density decreased significantly less with budesonide capsules (enteric coated) than with prednisolone in steroid-naïve patients, whereas no difference could be detected between treatment groups for steroid-dependent patients and previous steroid users. The incidence of symptoms associated with hypercorticism was significantly higher with prednisolone treatment.

Clinical Laboratory Test Findings

The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to budesonide capsules (enteric coated), were reported in greater than or equal to 1% of patients: hypokalemia, leukocytosis, anemia, hematuria, pyuria, erythrocyte sedimentation rate increased, alkaline phosphatase increased, atypical neutrophils, c-reactive protein increased and adrenal insufficiency.

Pediatrics – Treatment of Mild to Moderate Active Crohn’s Disease

Adverse reactions reported in pediatric patients 8 to 17 years of age, who weigh more than 25 kg, were similar to those reactions described above in adult patients.